Dopamine Reviews: 2003
(230 References)
(2003). "Alzheimer's disease: emerging noncholinergic
treatments." Geriatrics 58 Suppl: 3-14, inside back cover.
With population trends skewing toward a larger percentage of elderly,
Alzheimer's disease is projected to afflict many millions in the United States
and around the world in the next 50 years. In terms of cost and psychological
burden, the anticipated burden of this disease on caregivers and society at
large is staggering. It is hoped that, with the development of new insights into
the processes of this devastating illness and the development of new medications
that may interrupt those processes, the projected incidence and impact of AD may
be modified in the near future.
Adir, Y. and J. I. Sznajder (2003). "Regulation of lung edema clearance by
dopamine." Isr Med Assoc J 5(1): 47-50.
In the kidney, dopamine inhibits Na,K-ATPase, which results in natriuresis
because less Na+ is reabsorbed by the proximal and distal tubules. In contrast,
dopamine stimulates Na,K-ATPase activity in the alveolar epithelium, leading to
increased alveolar fluid reabsorption. Importantly, dopamine increases alveolar
fluid reabsorption not only in normal alveolar epithelium but also in models of
lung injury. Dopamine short-term regulation of alveolar epithelial Na,K-ATPase
occurs via D1 receptor activation, protein kinase C and protein phosphatase 2A
pathways, leading to increased Na,K-ATPase activity by recruiting sodium pumps
from the intracellular compartment to the basolateral membranes. Conversely, D2
receptor activation by long-term dopamine regulates (approximately 24 hours)
alveolar epithelial Na,K-ATPase via the MAPK pathway, [figure: see text] which
results in de novo synthesis of Na,K-ATPase proteins. Conceivably, by increasing
Na,K-ATPase activity and promoting alveolar fluid reabsorption, dopamine can be
of clinical relevance for the treatment of patients with acute hypoxemic
respiratory failure due to pulmonary edema.
Agid, Y., I. Arnulf, et al. (2003). "Parkinson's disease is a neuropsychiatric
disorder." Adv Neurol 91: 365-70.
Ahlskog, J. E. (2003). "Slowing Parkinson's disease progression: recent dopamine
agonist trials." Neurology 60(3): 381-9.
In recent clinical trials, chronic treatment of patients with PD with
pramipexole or ropinirole was associated with a slower decline of imaged
striatal dopaminergic signal, compared to levodopa monotherapy. Although this
could reflect slowed progression of PD, equally plausible is a pharmacologic
effect on proteins that interact with the imaging radioligands. To date, there
is no compelling evidence favoring dopamine agonists over levodopa; either is an
appropriate choice for initial treatment of PD.
Albin, R. L. and K. A. Frey (2003). "Initial agonist treatment of Parkinson
disease: a critique." Neurology 60(3): 390-4.
The evidence supporting initial dopamine agonist treatment of PD is reviewed.
The two rationales for initial agonist treatment are reduced frequency of motor
complications and possible relative neuroprotection by dopamine agonists. The
basic science supporting these rationales is equivocal. The clinical evidence
for advantages of initial agonist treatment is incomplete. More data are
required to determine the optimal initial treatment for PD.
Areosa, S. A. and F. Sherriff (2003). "Memantine for dementia." Cochrane
Database Syst Rev(1): CD003154.
BACKGROUND: Alzheimer's disease, vascular and mixed dementia are the commonest
forms of dementia in older people. There is evidence that the excitatory
activity of L-glutamate plays a role in the pathogenesis of Alzheimer's disease
and in the damage from an ischaemic stroke. A low affinity antagonist to
N-Methyl-D-aspartate (NMDA) type receptors, such as memantine, may prevent
excitatory amino acid neurotoxicity without interfering with the physiological
actions of glutamate required for memory and learning. OBJECTIVES: To determine
the clinical efficacy and safety of memantine for people with Alzheimer's
disease, vascular, or mixed dementia. SEARCH STRATEGY: Trials were identified
from a search of the Trial-based Specialized Register of the Cochrane Dementia
and Cognitive Improvement Group on 9 October 2002 using the terms: memantin*,
D-145, DMAA, DRG-0267. All major health care databases and trial databases
within the scope of the group are searched regularly to keep this Register up to
date. SELECTION CRITERIA: Double-blind, parallel group, placebo-controlled,
randomized and unconfounded trials in which memantine was administered to people
with dementia. DATA COLLECTION AND ANALYSIS: Data were extracted, pooled where
possible, and weighted mean differences, standardized mean differences or odds
ratios were estimated. Intention-to-treat (ITT) and observed cases (OC) analyses
are reported, where data were available. MAIN RESULTS: There were a total of
seven trials that met inclusion criteria, of which five had sufficient data for
analysis. The analysis of change from baseline for cognition gave statistically
significant results in favour of memantine (20 mg/day) (MD: -2,83 95% CI -4.37
to -1.29, P=0.0003) at 28 weeks and for memantine (30mg/day) at 6 weeks (MD:
-3.04. 95% CI -5.68 to -0.40, P=0.02). Effects on Activities of Daily living (ADL)
were difficult to interpret. One study provided data using a non-validated scale
for measuring five simple instrumental tasks under the guidance of an
investigator. When pooled with another study the analysis gave statistically
significant results in favour of memantine for 30 mg/day at 6 weeks (SMD: -1.36
95% CI -1.77 to -0.96, P=0.0003). Mood and behaviour: One trial provided data on
memantine 30 mg/day at 6 weeks using the NOSIE scale. The OC analysis found
statistically significant differences in favour of treatment (MD: 23.30 95% CI
17.83 to 28.77, P<0.00001). Global scales: The analysis revealed a statistically
significant difference in favour of memantine (20mg/day ) at 6 weeks (MD: -12.30
95% CI -16.90 to -7.70, P<0.00001). Similar results were found for larger doses
(memantine 30 mg/day) at 6 weeks in a pooled meta-analysis of two other studies
(WMD: -10.77 95% CI -13.46 to -8.09, P<0.00001). With regard to the Global
Impression of Change three studies found statistically significant results in
favour of 10, 20 and 30 mg/day of memantine compared with placebo at 6 or 12
weeks. There was a benefit in favour of memantine (20 mg/day) compared with
placebo at 6 weeks, for the numbers improved ( 24/41 compared with 11/41)(OR,
3.85, 95% CI 1.52 to 9.75, P=0.004), in favour of memantine (30 mg/day) compared
with placebo at 6 weeks, for the numbers improved ( 20/30 compared with
8/29)(OR, 5.25, 95% CI 1.72 to 15.98, P=0.004) and in favour of memantine (10
mg/day) compared with placebo at 12 weeks, for the numbers improved ( 60/82
compared with 38/84)(OR, 3.30, 95% CI 1.72 to 6.33, P=0.0003). In general
memantine seemed to be well tolerated. There was no statistically significant
difference between memantine and placebo for the three studies that reported
adverse events.There were some data on specific adverse events. In one study the
incidence of restlessness by the end of the treatment at 6 weeks was
statistically significantly lower in the placebo group than in the group taking
memantine 30 mg/day (15/30 compared with 2/29) (OR 13.50, 95% CI 2.71 to 67.19,
P=0.001). The number of dropouts was similar in treatment and placebo groups at
6 or 28 weeks time for memantine 20 mg/day and at 6 weeks for memantine 30
mg/day. REVIEWER'S CONCLUSIONS: Memantine is a safe drug and may be useful for
treating Alzheimer's, vascular,and mixed dementia of all severities. Most of the
trials so far reported have been small and not long enough to detect clinically
important benefits. However there is a possible benefit on cognition and global
measures, and an early improvement in behaviour in people with dementia. More
studies are needed.
Asif, A., R. A. Preston, et al. (2003). "Radiocontrast-induced nephropathy."
Am J Ther 10(2): 137-47.
Radiocontrast administration remains the third leading cause of
hospital-acquired acute renal failure. Clinically, radiocontrast-induced
nephropathy (RIN) is defined as a sudden decline in renal function after
radiocontrast administration. Typically, the serum creatinine level begins to
increase at 24 to 72 hours after the administration of contrast, peaks at 3 to 5
days, and requires another 3 to 5 days to return to baseline. RIN increases the
incidence of life-threatening complications such as sepsis, bleeding, and
respiratory failure and increases the cost of medical care by extending the
hospital stay. The increased mortality associated with acute renal failure
encountered in this scenario calls for a heightened awareness of the diagnosis
and prevention of RIN. Whereas individuals with healthy renal function are not
generally considered to be at particular risk for RIN, patients with preexisting
renal insufficiency and diabetes mellitus are much more likely to experience
acute renal failure after contrast administration. In the past, a variety of
therapeutic interventions have been used to prevent or attenuate RIN, including
saline hydration, diuretics, mannitol, calcium channel antagonists, theophylline,
endothelin receptor antagonists, hemodialysis, and dopamine. More recently,
studies demonstrate a positive impact of fenoldopam (dopamine-1 receptor,
dopamine-1 agonist) and the antioxidant N-acetylcysteine in ameliorating RIN.
This article discusses the pathophysiology, risk factors, and prevention of RIN.
Azorin, J. M. (2003). "[Criteria defining antimanic drugs (psychopharmacological
specificity and/or nonspecificity?)]." Encephale 29(Pt 1): 59-67.
The question as to whether specific antimanic drugs differ in their action
profile from nonspecific drugs is addressed in regard to symptomatic,
nosographic, regulatory and physiopathological issues. Results from clinical
studies have shown that mood stabilizers and typical neuroleptics differ as
regards improvement of manic symptoms: the former appear to act more evenly on
all symptoms of mania, showing a more total normalization of affect, ideation
and behaviour whereas the latter tend to sedate patients or to cause a
psychomotor retardation, leaving the core manic symptoms unaffected. This has
been many times underlined, in particular for lithium, notwithstanding the fact
that rating scales employed in clinical trials have often been charged to fall
far short of being sensitive enough to pick up the qualitative changes in manic
psychopathology. Antimanic drugs may also be more or less specific in their
capacities to treat all facets of the manic episode (psychotic, depressive,
irritable) whatever the bipolar subtype (bipolar I, II, rapid and non-rapid
cycling, secondary bipolar disorder) or the disease stage (early and late
episodes). In this respect divalproate seems to have a broader spectrum of
efficacy than other available agents. Newer antipsychotics such as olanzapine
are promising too. From a regulatory point of view, the current European
requirements for a specific antimanic drug are more stringent than the US
requirements of the Food and Drug Administration (FDA). Efficacy must be
demonstrated in short-term studies showing an effect in acute mania; moreover it
has to be shown that efficacy is to be maintained during the episode. So far,
three armed randomized controlled trials are required, in which the test product
is compared both with placebo and with a standard treatment. A possible design
is a comparison of test product, placebo and active control for 3 weeks followed
by a two-arm phase for the remaining 9 weeks, comparing only test product and
active control. In addition, a specific antimanic has to demonstrate that it
does not cause switching to depression. As regards physiopathology, integrative
models of bipolar disorder, ie kindling and behavioural sensitization, offer an
exciting perspective on the specificity issue; agents active in these models
initialize a cascade of intracellular signaling that leads to changes in the
expression of immediate early genes as well as late effector genes in
corticolimbic structures: the former may contribute to acute symptomatology
whereas the latter give rise to neuroanatomical reorganization which could
underlie more stable changes in mood and cognition. Due to their action on
intracellular messaging systems, dopamine D(1) receptors, serotonin 5HT(1a) or
5HT(2a) receptors, especially in orbitofrontal circuit, antimanic agents may
exhibit a more specific activity than other drugs. This specificity could
concern a whole spectrum of bipolarity which might be characterized by
impulsivity.
Babel, B. T., A. Nemeth, et al. (2003). "[Multidisciplinary therapy of Tourette
syndrome]." Orv Hetil 144(5): 211-6.
The marked fluctuation in symptoms with a spectrum of behavioral problems
contribute to misdiagnosis of Tourette syndrome. The authors review the recent
progress in diagnosis and management with an emphasis on multidisciplinary
approach. Possible associations with various genes have been found in etiology
of Tourette syndrome. Development of the disease comes of dopaminerg
neurotransmission disorder resulting in cortico-striato-thalamic system
dysfunction. Tics are brief movements or sounds that occur intermittently and
unpredictably mimicking fragments of normal behavior. Diagnostic criteria are
based on the motor and vocal phenomena and their dynamics. The key concept in
management are the tic severity scaling correlating with quality of life
measurements. Therapeutic interventions indicated at severe alteration in
patient's quality of life. Treatment plan combines various drug protocols,
psychotherapy and behavioral therapy which should be optimalized for most
disabling symptom. Social isolation and self injurious behavior complicates the
treatment resistant, severe cases. In these subgroup of patient, an adequate
selection of stereotactic intervention could provide an effective control of tic
severity or behavioral disorder. Tourette syndrome, as a typical
neuropsychiatric disorder, is a striking example for improved efficacy of
multidisciplinary approach.
Bailer, U. F. and W. H. Kaye (2003). "A review of neuropeptide and
neuroendocrine dysregulation in anorexia and bulimia nervosa." Curr Drug
Target CNS Neurol Disord 2(1): 53-9.
Neuropeptides play an important role in the regulation of feeding behavior and
obesity. The mechanisms for controlling food intake involve a complicated
interplay between peripheral systems (including gustatory stimulation,
gastrointestinal peptide secretion, and vagal afferent nerve responses) and
central nervous system (CNS) neuropeptides and/or monoamines. These neuronal
systems include neuropeptides (CRH, opioids, neuropeptide-Y (NPY) and peptide YY
(PYY), vasopressin and oxytocin, CCK, and leptin) and monamines (serotonin,
dopamine, norepinephrine). In addition to regulating eating behavior, a number
of CNS neuropeptides participate in the regulation of neuroendocrine pathways.
Thus, clinical studies have evaluated the possibility that CNS neuropeptide
alterations may contribute to dysregulated secretion of the gonadal hormones,
cortisol, thyroid hormones and growth hormone in the eating disorders. Most of
the neuroendocrine and neuropeptide alterations apparent during symptomatic
episodes of AN and BN tend to normalize after recovery. This observation
suggests that most of the disturbances are consequences rather than causes of
malnutrition, weight loss and/or altered meal patterns. Still, an understanding
of these neuropeptide disturbances may shed light on why many people with AN or
BN cannot easily "reverse" their illness and even after weight gain and
normalized eating patterns, many individuals who have recovered from AN or BN
have physiological, behavioral and psychological symptoms that persist for
extended periods of time.
Bailey, R. K. (2003). "Atypical psychotropic medications and their adverse
effects: a review for the African-American primary care physician." J Natl
Med Assoc 95(2): 137-44.
There are now five new-generation atypical psychiatric medications currently
available. As these new treatments have become more common, they have grown to
account for a significant percentage of all psychiatric medications prescribed.
This is because of their efficacy in the treatment of several psychiatric
disorders, ease of administration, and absence of the well-known extrapyramidal
adverse effects long-attributed to the standard dopamine blocking anti-psychotic
medications. As these medications have become treatments of choice, we have
discovered additional information about their respective side effects. Issues
such as bone marrow suppression, endocrine abnormalities, and most recently
cardiac arrhythmia have produced concern. This paper will address all in an
attempt to inform the primary care physician of the most prominent and
clinically relevant adverse effects of these agents. A particular focus will
address the increasing concern that these new medications can produce
hyperglycemia and diabetes mellitus.
Barbarich, N. C., W. H. Kaye, et al. (2003). "Neurotransmitter and imaging
studies in anorexia nervosa: new targets for treatment." Curr Drug Target CNS
Neurol Disord 2(1): 61-72.
Anorexia and Bulimia Nervosa are disorders of unknown etiology that invariably
begin during adolescence and near in time to puberty in young women. These
disorders are associated with aberrant eating behaviors, body image distortions,
impulse and mood disturbances, as well as characteristic temperament and
personality traits. It is well known that malnutrition produces changes in
neuroendocrine function. More recently, disturbances in neuronal systems have
been found to play a role in the modulation of feeding, mood, and impulse
control. These neuronal systems include neuropeptides (CRH, opioids,
neuropeptide-Y (NPY) and peptide YY (PYY), vasopressin and oxytocin, CCK, and
leptin) and monoamines (serotonin, dopamine, norepinephrine). Disturbances of
most of these neuronal systems have been found when people are ill with an
eating disorder, but it was not certain whether they were a cause or consequence
of symptoms. In order to address these questions, a growing number of studies
have investigated whether neuromodulatory disturbances persist after recovery.
Studies from several centers tend to show altered serotonin activity persists
after prolonged normalization of weight, nutrition, and menstrual function, as
do anxiety, obsessionality, and perfectionism. While there are fewer data, there
may be persistent alterations of dopamine or some neuropeptides in some subjects
in a recovered state. The inaccessibility of the central nervous system has made
it difficult to understand brain and behavior. In the past decade, new tools,
such as brain imaging, have offered the possibility of better characterization
of complex neuronal function and behavior. Such studies have tended to
consistently find that alterations of brain regions, such as the temporal lobe,
occur in people who are ill with anorexia nervosa and appear to persist after
some degree of weight gain and recovery. New imaging technology, that marries
Positron Emission Tomography (PET) imaging with selective neurotransmitter
radioligands, confirms that altered serotonin neuronal pathway activity persists
after recovery from an eating disorder and supports the possibility that these
psychobiological alterations might contribute to traits, such as increased
anxiety or extremes of impulse control, that, in turn, may contribute to a
vulnerability to the development of an eating disorder. In summary, studies of
pathophysiology are starting to nominate new candidates for treatment leading to
the possibility of finding effective treatments for this often chronic or fatal
disorder.
Barros, D. M., L. A. Izquierdo, et al. (2003). "Pharmacological findings
contribute to the understanding of the main physiological mechanisms of memory
retrieval." Curr Drug Target CNS Neurol Disord 2(2): 81-94.
Recent pharmacological findings have shown that retrieval of one-trial avoidance
learning requires glutamate receptors, cAMP-dependent protein kinase and mitogen-activated
protein kinases in the hippocampus, entorhinal, posterior parietal and anterior
cingulate cortex. It requires AMPA but not other type of glutamate receptors or
the protein kinases in the amygdala. Retrieval is modulated by dopamine D1,
beta-noradrenergic, serotonin 1A and cholinergic receptors in the four cortical
structures mentioned, and by beta-noradrenergic receptors in the basolateral
amygdala. Further, retrieval is also modulated by peripheral ACTH,
glucocorticoids, vasopressin, beta-endorphin and catecholamines; these hormones
probably act through beta-noradrenergic receptor systems in the basolateral
amygdala. Exposure to novelty or the systemic administration of antidepressant
drugs prior to retention tests enhances retrieval, even for very remote
memories. The effect of novelty is mediated by molecular mechanisms similar to
those of retrieval itself.
Barzilai, A., D. Daily, et al. (2003). "The molecular mechanisms of dopamine
toxicity." Adv Neurol 91: 73-82.
Bastia, E. and M. A. Schwarzschild (2003). "DARPP chocolate: a caffeinated
morsel of striatal signaling." Sci STKE 2003(165): PE2.
The psychomotor stimulant effects of caffeine, the most widely consumed
psychoactive substance, are mediated through its antagonism of extracellular
adenosine receptors in the basal ganglia. In the absence of caffeine, adenosine
stimulates inhibitory striatopallidal neurons that suppress motor activity by
binding to A2A receptors, thereby activating a cyclic adenosine
3',5'-monophosphate (cAMP) and protein kinase A signaling pathway. Bastia and
Schwarzschild discuss recent research implicating DARRP-32 (dopamine- and cAMP-regulated
phosphoprotein of 32 kilodaltons) as an attractive mediator of the sustained
psychomotor stimulant effect seen with low doses of caffeine. They highlight the
role of postsynaptic A2A receptor blockade, but leave open the possibility that
antagonism of presynaptic or postsynaptic A1 receptors also contributes to
DARPP-32-dependent psychomotor stimulation by caffeine.
Batra, V., A. A. Patkar, et al. (2003). "The genetic determinants of smoking."
Chest 123(5): 1730-9.
Dependence on tobacco, like many other drug dependencies, is a complex behavior
with both genetic and environmental factors contributing to the variance. The
heritability estimates for smoking in twin studies have ranged from 46 to 84%,
indicating a substantial genetic component to smoking. Candidate gene studies
have detected functional polymorphisms in genes coding for the cytochrome P450
enzymes, and variations in these genes that lead to more rapid nicotine
metabolism have been implicated in smoking. Similarly, smoking has been
associated with polymorphisms in dopaminergic genes that may influence the
dopamine receptor number and/or function. Animal experiments have localized
specific subunits of the nicotinic receptors that may mediate the reinforcing
properties of nicotine and have investigated their role in nicotine dependence.
However, environmental factors have also been found to contribute to the risk of
initiation and persistence of smoking. We review the scientific evidence that
supports a role for genetic influences on smoking, discuss the specific genetic
and neurobiological mechanisms that may mediate susceptibility to nicotine
dependence, identify possible gene/environmental interactions that may be
important in understanding smoking behavior, and suggest directions for future
research. Insights into the genetic contributions to smoking can potentially
lead to more effective strategies to reduce smoking.
Beard, J. (2003). "Iron deficiency alters brain development and functioning."
J Nutr 133(5 Suppl 1): 1468S-72S.
Iron deficiency anemia in early life is related to altered behavioral and neural
development. Studies in human infants suggest that this is an irreversible
effect that may be related to changes in chemistry of neurotransmitters,
organization and morphology of neuronal networks, and neurobiology of
myelination. The acquisition of iron by the brain is an age-related and
brain-region-dependent process with tightly controlled rates of movement of iron
across the blood-brain barrier. Dopamine receptors and transporters are altered
as are behaviors related to this neurotransmitter. The growing body of evidence
suggests that brain iron deficiency in early life has multiple consequences in
neurochemistry and neurobiology.
Beinfeld, M. C. (2003). "What we know and what we need to know about the role of
endogenous CCK in psychostimulant sensitization." Life Sci 73(6):
643-54.
The unique distribution of CCK and its receptors and its co-localization with
dopamine makes it ideally situated to pay a role in dopamine-mediated reward and
psychostimulant sensitization. A number of studies support the hypothesis that
CCK acting through the CCK 1 and CCK 2 receptors is an endogenous modulator of
dopamine neurotransmission. Behavioral studies with CCK antagonists and CCK 1
receptor mutant rats support a role for endogenous CCK in behavioral
sensitization to psychostimulants. CCK microdialysis studies in the nucleus
accumbens (NAC) have demonstrated that extracellular CCK is increased in the NAC
by psychostimulants, providing neurochemical evidence that CCK could be involved
in the behavioral response to psychostimulants. A model for how CCK may be
acting in multiple brain regions to foster sensitization is presented and the
gaps in our knowledge about the role of CCK in psychostimulant sensitization are
described.
Berridge, C. W. and B. D. Waterhouse (2003). "The locus coeruleus-noradrenergic
system: modulation of behavioral state and state-dependent cognitive processes."
Brain Res Brain Res Rev 42(1): 33-84.
Through a widespread efferent projection system, the locus coeruleus-noradrenergic
system supplies norepinephrine throughout the central nervous system. Initial
studies provided critical insight into the basic organization and properties of
this system. More recent work identifies a complicated array of behavioral and
electrophysiological actions that have in common the facilitation of processing
of relevant, or salient, information. This involves two basic levels of action.
First, the system contributes to the initiation and maintenance of behavioral
and forebrain neuronal activity states appropriate for the collection of sensory
information (e.g. waking). Second, within the waking state, this system
modulates the collection and processing of salient sensory information through a
diversity of concentration-dependent actions within cortical and subcortical
sensory, attention, and memory circuits. Norepinephrine-dependent modulation of
long-term alterations in synaptic strength, gene transcription and other
processes suggest a potentially critical role of this neurotransmitter system in
experience-dependent alterations in neural function and behavior. The ability of
a given stimulus to increase locus coeruleus discharge activity appears
independent of affective valence (appetitive vs. aversive). Combined, these
observations suggest that the locus coeruleus-noradrenergic system is a critical
component of the neural architecture supporting interaction with, and navigation
through, a complex world. These observations further suggest that dysregulation
of locus coeruleus-noradrenergic neurotransmission may contribute to cognitive
and/or arousal dysfunction associated with a variety of psychiatric disorders,
including attention-deficit hyperactivity disorder, sleep and arousal disorders,
as well as certain affective disorders, including post-traumatic stress
disorder. Independent of an etiological role in these disorders, the locus
coeruleus-noradrenergic system represents an appropriate target for
pharmacological treatment of specific attention, memory and/or arousal
dysfunction associated with a variety of behavioral/cognitive disorders.
Bertoldi, M. and C. Borri Voltattorni (2003). "Reaction and substrate
specificity of recombinant pig kidney Dopa decarboxylase under aerobic and
anaerobic conditions." Biochim Biophys Acta 1647(1-2): 42-7.
Dopa decarboxylase (DDC) catalyzes as main reaction the stereospecific CO(2)
abstraction from L-Dopa and L-5-hydroxytryptophan (5-HTP), generating the
corresponding aromatic amines, dopamine and serotonin, respectively. Side
reactions with turnover time of minutes are also catalyzed by the enzyme. In
particular, DDC exhibits half-transaminase activity toward D-aromatic amino
acids and oxidative deaminase activity toward aromatic amines. The latter
reaction could represent a new activity for this class of enzymes. Studies on
the effect exerted by O(2) on reaction specificity of DDC revealed that under
anaerobic conditions decarboxylation of L-aromatic amino acids takes place with
a k(cat) approximately half of that measured in the presence of O(2), and is
accompanied by a decarboxylation-dependent transamination, whereas oxidative
deamination of aromatic amines is replaced by half-transamination. Half-transamination
of D-aromatic amino acids is unaffected by the presence or absence of O(2). Some
structural elements relevant for the control of reaction and substrate
specificity of DDC have been identified by means of limited tryptic digestion
and site-directed mutagenesis studies. All together, the data indicate that the
chemical nature of the substrate, the presence of O(2), the integrity of a
mobile loop, the absence of perturbation in the coenzyme-binding cleft and pH
are important requirements for the achievement of a closed conformational state
where the highest level of reaction specificity is reached.
Bezard, E., C. E. Gross, et al. (2003). "Presymptomatic compensation in
Parkinson's disease is not dopamine-mediated." Trends Neurosci 26(4):
215-21.
The symptoms of Parkinson's disease (PD) appear only after substantial
degeneration of the dopaminergic neuron system (e.g. an 80% depletion of
striatal dopamine)--that is, there is a substantive presymptomatic period of the
disease. It is widely believed that dopamine-related compensatory mechanisms are
responsible for delaying the appearance of symptoms. Recent advances in
understanding the presymptomatic phase of PD have increased our understanding of
these dopamine-related compensatory mechanisms and have highlighted the role of
non-dopamine-mediated mechanisms both within and outside the basal ganglia. This
increased knowledge of plasticity within cortical-basal-ganglia-thalamocortical
circuitry as dopaminergic neuron degeneration progresses has implications for
understanding plasticity in neural circuits generally and, more specifically,
for developing novel therapeutics or presymptomatic diagnostics for PD.
Bigal, M. E. and S. J. Tepper (2003). "Ergotamine and dihydroergotamine: a
review." Curr Pain Headache Rep 7(1): 55-62.
The ergot alkaloids were the first specific antimigraine therapy available.
However, with the advent of the triptans, their use in the treatment of migraine
has declined and their role has become less clear. This review discusses the
pharmacology, efficacy, and safety of the ergots. In randomized clinical trials,
oral ergotamine was found to be superior to placebo, but inferior to 100 mg of
oral sumatriptan. In contrast, rectal ergotamine was found to have higher
efficacy (73% headache relief) than rectal sumatriptan (63% headache relief).
Intranasal dihydroergotamine was found to be superior to placebo, but less
effective than subcutaneous and intranasal sumatriptan. Ergotamine is still
widely used in some countries for the treatment of severe migraine attacks. It
is generally regarded as a safe and useful drug if prescribed for infrequent
use, in the correct dose, and in the absence of contraindications; however,
safer and more effective options do exist in the triptans. In patients with
status migrainous and patients with frequent headache recurrence, ergotamine is
still probably useful.
Black, D. L. and P. J. Grabowski (2003). "Alternative pre-mRNA splicing and
neuronal function." Prog Mol Subcell Biol 31: 187-216.
Blanchet, P. J. (2003). "Antipsychotic drug-induced movement disorders." Can
J Neurol Sci 30 Suppl 1: S101-7.
Very early in the process of diagnosing abnormal involuntary movement (AIM)
disorders, one can be rewarded by keeping a high index of suspicion for possible
drug-induced causes, not only through a complete list of current medications,
but also identification of the drugs the patient used to take and other possible
offending medications that might be available from family members and other
sources. Among drug-induced movement disorders, antipsychotic drugs and other
dopamine receptor blocking agents occupy a central place. Their various acute
and tardive motor complications provide the template of this short review.
Movement disorders caused by antidepressants, lithium, antiemetics,
antiparkinsonian agents, anticonvulsants, calcium channel blockers,
sympathomimetics and others are only briefly covered in table form.
Blanchet, P. J. (2003). "The fluctuating Parkinsonian patient--clinical and
pathophysiological aspects." Can J Neurol Sci 30 Suppl 1: S19-26.
Although levodopa-related motor response complications remain challenging from a
pathophysiological and therapeutic standpoint, major advances have been made in
the last decade, supporting the development of several promising drugs.
Eventually, these drugs may help us to prevent, alleviate, or even "deprime"
these frequent and disabling complications. Knowledge of the basic mechanisms
and hypotheses underlying this fascinating conversion in the parkinsonian brain
allows neurologists to understand the rationale behind emerging treatment
strategies.
Blanchet, P. J., L. V. Metman, et al. (2003). "Renaissance of amantadine in the
treatment of Parkinson's disease." Adv Neurol 91: 251-7.
Bodack, M. I. (2003). "Blurred vision during airline flight reveals prolactinoma."
Optometry 74(3): 159-72.
BACKGROUND: Pituitary adenomas can manifest with a variety of endocrinologic
signs and symptoms, including amenorrhea, galactorrhea, infertility, and
acromegaly. Because of the anatomic location of the pituitary gland, and its
proximity to the optic chiasm and cavernous sinuses, pituitary adenomas can also
result in decreased visual acuity, diplopia, ophthalmoplegia, visual-field loss,
and optic atrophy. In general, these tumors are slow-growing. However, there are
reports in the medical literature of patients with previously undiagnosed brain
tumors in whom neurological signs suddenly developed when in higher altitudes.
CASE REPORT: A 47-year-old woman came in for an evaluation of a one-month
history of blurry peripheral vision that occurred during-then persisted
following--an international flight. Examination and automated visual-field
testing revealed a decrease in her best-corrected visual acuity and a
bi-temporal hemianopsia. Subsequent examinations by a neurologist and
endocrinologist revealed a significant pituitary adenoma-specifically, a
prolactinoma. The patient was treated with bromocriptine and has shown a rapid
improvement in her visual field and a regression of the tumor, as evidenced by a
repeat MRI. CONCLUSION: In this case, the sudden development of the patients
symptoms during an airline flight, and the persistence of the symptoms after
landing, resulted in the discovery of a prolactinoma.
Boksa, P. and B. F. El-Khodor (2003). "Birth insult interacts with stress at
adulthood to alter dopaminergic function in animal models: possible implications
for schizophrenia and other disorders." Neurosci Biobehav Rev 27(1-2):
91-101.
Altered subcortical dopaminergic activity is thought to be involved in the
pathophysiology of several disorders including schizophrenia, substance abuse
and attention deficit hyperactivity disorder. Epidemiological studies have
implicated perinatal insults, particularly obstetric complications involving
fetal or neonatal hypoxia, as etiological risk factors for schizophrenia. This
suggests the possibility that perinatal hypoxia might have lasting effects on
dopaminergic function. In animal models, dopaminergic systems appears to be
particularly vulnerable to a wide range of perinatal insults, resulting in
persistent alterations in function of mesolimbic and mesostriatal pathways. This
review summarizes recent work characterizing long-term changes in dopaminergic
function and biochemistry in models of Caesarean section (C-section) birth and
of C-section birth with added global anoxia in the rat and guinea pig. C-section
birth and C-section with anoxia appear to be two distinct hypoxic birth insults,
with somewhat differing patterns of lasting effects on dopamine systems. In
addition, birth insult alters the manner in which dopaminergic function is
regulated by stress at adulthood. The possible relevance of these finding to
effects of human birth procedures is discussed.
Bolos, J. (2003). "Current strategies for the development of novel antipsychotic
drugs." Mini Rev Med Chem 3(3): 239-51.
While classical neuroleptics are characterized by dopamine D(2) antagonism, this
is also considered to be the cause of their neurological side effects. In recent
years, novel antipsychotic drugs with improved efficacy, devoid of
extrapyramidal effects are being developed. The mechanisms of action of these
new atypical antipsychotics can be classified into three general groups: a)
binding to D(2) together with non-dopaminergic receptors, b) interaction with
dopamine receptor subtypes other than D(2) and c) selective binding to non-dopaminergic
systems, such as glutamatergic, sigma, neurotensin, and cannabinoid.
Bonci, A., G. Bernardi, et al. (2003). "The dopamine-containing neuron: maestro
or simple musician in the orchestra of addiction?" Trends Pharmacol Sci
24(4): 172-7.
Dopamine-containing neurons originating in the ventral tegmental area project
primarily to the nucleus accumbens and the prefrontal cortex, forming the
mesolimbic and mesocortical systems, respectively. Virtually every drug of abuse
influences dopamine-mediated neurotransmission by affecting directly or
indirectly the activity of these cells. Amphetamine and cocaine, in addition to
opioids and nicotine, induce short- and long-term modifications of firing in the
dopamine-containing neurons of the ventral mesencephalon. Although exposure to
psychostimulants mainly depresses neuronal activity, nicotine and morphine
enhance neuronal activity. However, under particular conditions, these drugs
could cause different changes of firing. In this article, we propose that
changes in the activity of dopamine-containing neurons are related to the
processes of addiction. Therefore, we suggest that both the modulation of
dopamine release in the extracellular space and transient or enduring changes in
the firing of dopamine-containing neurons could be associated with important
features of drugs of abuse.
Bowles, T. M. and G. M. Levin (2003). "Aripiprazole: a new atypical
antipsychotic drug." Ann Pharmacother 37(5): 687-94.
OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical efficacy, and
safety profile of aripiprazole for the treatment of schizophrenia. DATA SOURCES:
Information was selected from MEDLINE (1995-August 2002). Abstracts, scientific
posters, and presentations were also used. STUDY SELECTION/DATA EXTRACTION: All
published information regarding the pharmacokinetic, pharmacodynamic, and
clinical characteristics of aripiprazole was considered. Studies providing a
comprehensive description of aripiprazole were selected. DATA SYNTHESIS:
Aripiprazole is a dopamine partial agonist and a serotonin-2A antagonist; it is
dosed 10-30 mg/d, with no initial titration necessary. Short-term clinical
trials demonstrated efficacy in acute exacerbations, and long-term studies
showed that aripiprazole can maintain remission of schizophrenia. Most adverse
events were mild. The incidence of extrapyramidal symptoms was low, with
akathisia being the most common. CONCLUSIONS: Aripiprazole currently
demonstrates comparable efficacy and safety for use in schizophrenia.
Brandstadter, D. and W. H. Oertel (2003). "Depression in Parkinson's disease."
Adv Neurol 91: 371-81.
Briguori, C., D. Tavano, et al. (2003). "Contrast agent--associated
nephrotoxicity." Prog Cardiovasc Dis 45(6): 493-503.
Radiocontrast media can lead to a reversible form of acute renal failure that
begins soon after the contrast dye administration and generally is benign.
Contrast media accounts for 10% of all causes of hospital-acquired acute renal
failure and represents the third leading cause of in-hospital renal function
deterioration after decreased renal perfusion and postoperative renal
insufficiency. The in-hospital mortality rate in patients developing renal
insufficiency is related directly to the magnitude increase of serum creatinine
concentration. The mortality rate ranges from 3.8% with an increase in serum
creatinine level of 0.5 to 0.9 mg/dL to 64% with an increase of greater than 3.0
mg/dL. The mechanism by which contrast-induced renal failure occurs is not well
understood. Contrast agent-associated nephrotoxicity appears to be a result of
direct contrast-induced renal tubular epithelial cell toxicity and renal
medullary ischemia. Furthermore, a key mechanism seems to be alteration in renal
dynamics, probably caused by imbalances between vasodilator and vasoconstrictor
factors, including the activities of nitric oxide, prostaglandins, endothelin,
and reactive oxygen species. The optimal strategy to prevent contrast-associated
nephrotoxicity remains uncertain. At present, recommendations are as follows:
(1) periprocedural hydration, (2) use of a low-osmolality contrast, and (3)
limiting the amount of contrast agent. Recently, considerable interest has
resulted from the preliminary positive data on the effectiveness of prophylactic
administration of acetylcysteine and fenoldopam. The former may prevent the
direct oxidative tissue damage, whereas the latter is a selective intrarenal
vasodilator.
Brooks, D. J. (2003). "Imaging end points for monitoring neuroprotection in
Parkinson's disease." Ann Neurol 53 Suppl 3: S110-8; discussion
S118-9.
In this review, the potential role of positron emission tomography and
single-photon emission computed tomography as biological markers for following
the progression of Parkinson's disease (PD) is discussed, and their value for
assessing the efficacy of putative neuroprotective agents in PD is considered.
It is concluded that functional imaging provides a valuable adjunct to clinical
assessment when judging the efficacy of neuroprotective approaches to PD.
Bruno, A. (2003). "Cerebrovascular complications of alcohol and sympathomimetic
drug abuse." Curr Neurol Neurosci Rep 3(1): 40-5.
Alcohol abuse has been linked to intracranial hemorrhage, both intracerebral and
subarachnoid. Some studies have found a dose-response relationship, so that
increasing levels of abuse are associated with greater risk of hemorrhage.
However, alcohol abuse has not been clearly linked to cerebral infarction, and
some studies find that mild-to-moderate drinking appears to be associated with a
decreased risk of cerebral infarction. Intravenous administration of drugs of
abuse predisposes to endocarditis, which may lead to embolic stroke.
Associations have been reported between various sympathomimetic drugs and
cerebral infarction. A possible mechanism for cerebral infarction is focal
arterial vasoconstriction and occasionally cerebral vasculitis. Associations
have also been reported between various sympathomimetic drugs and intracranial
hemorrhage. A likely mechanism for intracranial hemorrhage is acute arterial
hypertension. With the exception of endocarditis, management of stroke related
to drug abuse is largely supportive, with emphasis on supportive care to prevent
stroke complications, physical and occupational therapy, and aggressive
addiction rehabilitation.
Burke, W. J. (2003). "3,4-dihydroxyphenylacetaldehyde: a potential target for
neuroprotective therapy in Parkinson's disease." Curr Drug Target CNS Neurol
Disord 2(2): 143-8.
The simplest explanation for the selective loss of substantia nigra (SN)
dopamine (DA) neurons in Parkinson's disease (PD) is that DA or a metabolite is
neurotoxic. Recently, a series of investigations implicate the MAO metabolite of
DA, 3,4-dihydroxyphenylacetaldehyde (DOPAL), as the critical endogenous toxin
which triggers DA neuron loss in PD: 1. Hereditary PD contains mutations in the
gene for alpha-synuclein (alpha-syn). Investigations implicate a DA metabolite
as mediator of alpha-syn neurotoxicity, and DOPAL is 1000-fold more toxic than
DA in vivo. 2. A deficit in mitochondrial complex I is found in PD SN.
Inhibition of complex I causes increases in DOPAL levels and death of DA neurons
in vitro and in vivo. 3. L-DOPA, the precursor of DA, which is used to treat PD,
is toxic and contributes to the progression of PD. L-DOPA-treated rats have an
18-fold increase in striatal DOPAL. 4. Free hydroxyl radicals (.OH) trigger
aggregation of alpha-syn to its toxic form. DOPAL with H(2)O(2) generates.OH
radicals. These investigations provide several therapeutic strategies to limit
DOPAL toxicity and progression of PD: 1. Delaying the start of L-DOPA therapy by
early use of DA receptor agonists, which may also be free radical scavengers,
limits the amount of DOPAL formed from L-DOPA. 2. Nonspecific MAO inhibitors may
more effectively decrease production of DOPAL from DA than MAO-B inhibitors. 3.
Newer more potent and targeted free radical scavengers could block DOPAL
toxicity. 4. Coenzyme Q(10) increases complex I activity and nicotine adenine
dinucleotide (NAD) synthesis, and thereby could enhance DOPAL catabolism by
aldehyde dehydrogenase, which uses NAD as a cofactor. 5. DA uptake blockers
could be used to limit intraneuronal DOPAL production. 6. Tauroursodeoxycholic
acid, an inhibitor of apoptosis shown to be effective in models of Huntington's
disease, may also prove effective in blocking DOPAL toxicity in PD. 7. Agents
which block aggregation of alpha-syn should limit DOPAL toxicity.
Bymaster, F. P., D. L. McKinzie, et al. (2003). "Use of M1-M5 muscarinic
receptor knockout mice as novel tools to delineate the physiological roles of
the muscarinic cholinergic system." Neurochem Res 28(3-4): 437-42.
In this review we report recent findings on the physiological role of the five
known muscarinic acetylcholine receptors (mAChRs) as shown by gene targeting
technology. Using knockout mice for each mAChRs subtype, the role of mAChRs
subtypes in a number of physiological functions was confirmed and new activities
were discovered. The M1 mAChRs modulate neurotransmitter signaling in cortex and
hippocampus. The M3 mAChRs are involved in exocrine gland secretion, smooth
muscle contractility, pupil dilation, food intake, and weight gain. The role of
the M5 mAChRs involves modulation of central dopamine function and the tone of
cerebral blood vessels. mAChRs of the M2 subtype mediate muscarinic
agonist-induced bradycardia, tremor, hypothermia, and autoinhibition of release
in several brain regions. M4 mAChRs modulate dopamine activity in motor tracts
and act as inhibitory autoreceptors in striatum. Thus, as elucidated by gene
targeting technology, mAChRs have widespread and manifold functions in the
periphery and brain.
Bymaster, F. P., R. K. McNamara, et al. (2003). "New approaches to developing
antidepressants by enhancing monoaminergic neurotransmission." Expert Opin
Investig Drugs 12(4): 531-43.
Major depressive disorder (MDD) is a serious illness with far reaching societal
and economic ramifications. The monoamine-deficiency hypothesis that depressive
symptoms are associated with reductions in monoamine neurotransmission,
particularly serotonin and noradrenaline, is supported by both neurochemical
findings and the successful treatment of MDD with compounds that enhance
monoaminergic neurotransmission. This review focuses on novel compounds in
different stages of development for the treatment of MDD that enhance
monoaminergic neurotransmission via a number of different mechanisms, including
re-uptake inhibition of one or more monoamines, monoamine oxidase inhibitors,
the combination of monoamine antagonists with re-uptake inhibitors and monoamine
receptor subtype agonists. Compounds that enhance individual monoamines have
antidepressant properties and compounds that enhance multiple monoamines appear
to have a synergistic antidepressant effect and potentially faster onset of
action. The differing mechanisms of action possessed by these novel
monoamine-enhancing compounds will offer greater treatment flexibility in the
therapeutic management of MDD.
Cacciari, B., G. Pastorin, et al. (2003). "Medicinal chemistry of A2A adenosine
receptor antagonists." Curr Top Med Chem 3(4): 403-11.
Due to the clearly demonstrated receptor-receptor interaction between adenosine
A(2A) and dopamine D(2) receptors in the basal ganglia, the discovery and
development of potent and selective A(2A)adenosine receptor antagonists became,
in the last ten years, an attractive field of research to discovery new drugs
for the treatment of neurodegenerative disorders, such as Parkinsons disease.
Different compounds have been deeply investigated as A(2A) adenosine receptor
antagonists, which could be classified in two great families: xanthine
derivatives and nitrogen poliheterocyclic systems. These studies led to the
discovery of some highly potent and selective A(2A) adenosine receptor
antagonists such as ZM241385, SCH58261 and some xanthine derivatives (KW6002),
which have been used as pharmacological tools for studying this receptor
subtype. However, those compounds showed some problems that do not permit their
use in clinical studies, such as poor water solubility (SCH58261, and xanthine
derivatives) or good affinity for A(2B) adenosine receptor subtype (ZM241385).
In the last few years great efforts have been made to overcome these problems,
trying to optimize not only the pharmacological profile but also the
pharmacokinetic character of this class of compounds. The aim of this report is
to briefly summarize the recent progress made in this attractive field of
research.
Caceda, R., B. Kinkead, et al. (2003). "Do neurotensin receptor agonists
represent a novel class of antipsychotic drugs?" Semin Clin Neuropsychiatry
8(2): 94-108.
Schizophrenia is one of the major psychiatric disorders for which effective
pharmacotherapy has been available for approximately 50 years. Study of the
mechanism of action of these antipsychotic drugs (APDs) has largely focused on
the mesolimbic dopamine system and in the neurotransmitter systems that regulate
it. Modulation of the neurotensin (NT) circuit in the mesolimbic system can
underlie the mechanism of action of APDs. Several lines of evidence support this
hypothesis, including: (1) association of NT with neural circuits relevant to
the pathophysiology of schizophrenia and the therapeutic effects of APDs; (2)
prediction of antipsychotic efficacy and side effect liability based on APD
effects on the NT system; (3) low concentrations of NT in the cerebrospinal
fluid of a subset of patients with schizophrenia and its normalization after
associated clinical improvement with APDs; and (4) remarkable behavioral
similarities between peripherally administered APDs and central NT
administration. For these reasons, drugs that directly modify the activity of NT
systems, particularly NT receptor agonists, could plausibly represent a novel
class of APDs.
Carroll, F. I. (2003). "2002 Medicinal Chemistry Division Award address:
monoamine transporters and opioid receptors. Targets for addiction therapy."
J Med Chem 46(10): 1775-94.
Ceballos-Baumann, A. O. (2003). "Functional imaging in Parkinson's disease:
activation studies with PET, fMRI and SPECT." J Neurol 250 Suppl 1:
I15-23.
Activation studies with positron emission tomography (PET) and functional
magnetic resonance imaging (fMRI) represent a powerful tool to study the
functional anatomy of Parkinson's disease (PD). Activation studies offer the
opportunity to study regional cerebral function in man in vivo under different
conditions with the analysis of task specific changes in regional cerebral blood
flow (rCBF) with PET or in the blood oxygenation level dependent (BOLD) effect
with fMRI. The combination of PET and deep brain stimulation is particularly
attractive to study the effects of discrete perturbations at different target
structures throughout the basal ganglia-thalamocortical circuitries. The use of
rCBF PET and fMRI to study the pathophysiology of PD in the motor and sensory
system and mechanisms of dopaminergic therapy as well as surgical interventions
will be reviewed.
Clarke, C. E. (2003). "Dopamine agonist monotherapy in early Parkinson's
disease." Hosp Med 64(1): 8-11.
While levodopa therapy for Parkinson's disease is still considered the gold
standard, motor complications are significant disadvantages of treatment.
Monotherapy with dopamine agonists may present an alternative approach with a
reduced likelihood of developing dyskinesias. Further studies are required
before a definitive judgment can be made.
Couldwell, W. T., R. L. Rovit, et al. (2003). "Role of surgery in the treatment
of microprolactinomas." Neurosurg Clin N Am 14(1): 89-92, vii.
Prolactinomas are a common cause of reproductive and sexual dysfunction and
account for a large proportion of pituitary adenomas. The objectives for
treatment of hyperprolactinemia due to microprolactinomas are to suppress
excessive hormone secretion, preserve residual pituitary function, and prevent
disease recurrence. These objectives may be achieved in most patients harboring
microprolactinomas by medical treatment with effective dopamine agonists or
microsurgical or endoscopic adenomectomy by an experienced surgeon. The choice
of pituitary surgery should be made in consideration of the volume and location
of the adenoma, age of the patient, the desire for restoration of fertility, and
the efficacy and tolerability of dopamine agonists. The presence of a
symptomatic microprolactinoma, especially in a young patient, should remain an
indication for micro- or endoscopic tumor removal. This article reviews the
emergence of radiosurgery as a treatment for microprolactinomas.
Cox, B., M. E. Durieux, et al. (2003). "Toxicity of local anaesthetics." Best
Pract Res Clin Anaesthesiol 17(1): 111-36.
The complications of failure, neural injury and local anaesthetic toxicity are
common to all regional anaesthetic techniques, and individual techniques are
associated with specific complications. All potential candidates for regional
anaesthesia should be thoroughly evaluated and informed of potential
complications. Central neural blockades still account for more than 70% of
regional anaesthesia procedures. Permanent neurological injury is 0.02-0.07%.
Pain on injection and paraesthesias while performing regional anaesthesia are
danger signals of potential injury and must not be ignored. The incidence of
systemic toxicity to local anaesthetics has significantly decreased in the past
30 years, from 0.2 to 0.01%. Peripheral nerve blocks are associated with the
highest incidence of systemic toxicity (7.5 per 10,000) and the lowest incidence
of serious neural injury (1.9 per 10,000).
Crosby, N., K. H. Deane, et al. (2003). "Amantadine in Parkinson's disease."
Cochrane Database Syst Rev(1): CD003468.
BACKGROUND: Although levodopa is the most common drug prescribed to relieve the
symptoms of Parkinson's disease it is associated with motor and psychiatric
side-effects. Consequently, interest has turned to alternative drugs with
improved side-effect profiles to replace or augment levodopa. Amantadine,
originally used as an antiviral drug, has been shown to improve the symptoms of
Parkinson's disease. OBJECTIVES: To compare the efficacy and safety of
amantadine therapy (monotherapy or adjuvant therapy) versus placebo in treating
people with Parkinson's disease. SEARCH STRATEGY: Electronic searches of The
Cochrane Controlled Trials Register (The Cochrane Library Issue 3, 2001),
MEDLINE (1966-2001), EMBASE (1974-2001), SCISEARCH (1974-2001), BIOSIS
(1993-2001), GEROLIT (1979-2001), OLDMEDLINE (1957-1965), LILACS (1982-2001),
MedCarib (17th Century - 2001), PASCAL (1973-2001), JICST-EPLUS (1985-2001),
RUSSMED (1973-2001), DISSERTATION ABSTRACTS (2000-2001), SIGLE (1980-2001),
ISI-ISTP (1990-2001), Aslib Index to Theses (2001), Clinicaltrials.gov (2001),
metaRegister of Controlled Trials (2001), NIDRR (2001) and NRR (2001) were
conducted. Grey literature was hand searched and the reference lists of
identified studies and reviews examined. The manufacturers of amantadine were
contacted. SELECTION CRITERIA: Randomised controlled trials comparing amantadine
with placebo in the treatment of patients with a clinical diagnosis of
idiopathic Parkinson's disease. DATA COLLECTION AND ANALYSIS: Data was
abstracted independently by NC and KD onto standardised forms and disagreements
were resolved by discussion. MAIN RESULTS: Six randomised controlled trials were
found comparing amantadine monotherapy or adjuvant therapy with placebo in the
treatment of idiopathic Parkinson's disease. Five examined amantadine as
adjuvant therapy with optimal levels of levodopa or anticholinergics and one
examined amantadine as an adjuvant therapy with minimum tolerated levels of
anticholinergics or as a monotherapy. Five were double-blind cross-over studies
and one was a double-blind parallel group study. In total they examined 215
patients. The parallel group study allowed the randomisation codes to be broken
and allowed patients in the placebo group to then receive amantadine. This could
have led to bias. One study did not present the results of the placebo arm of
the trial, hence we could not determine the difference between the two treatment
groups. Two cross-over studies presented the results of the combined data from
both treatment and placebo arms. The risk of carry-over effect into the second
arm meant that these results could not be analysed. The final two studies
presented at least some of their data from the end of the first arm of the
trials. However only means were given, without standard deviations, so we could
not determine the statistical significance of any difference between the
amantadine and placebo groups. Although the authors did report on the
side-effects from amantadine (such as livido recticularis, dry mouth and blurred
vision), they state that none of them were severe. REVIEWER'S CONCLUSIONS: A
considerable amount of evidence on the effectiveness of amantadine has accrued
from non-controlled trials, often in patients with Parkinsonian conditions other
than idiopathic Parkinson's disease. However, rigorous analysis of the six
randomised controlled trials of amantadine reveals insufficient evidence of its
efficacy and safety in the treatment of idiopathic Parkinson's disease.
Dada, L. A. and J. I. Sznajder (2003). "Mechanisms of pulmonary edema clearance
during acute hypoxemic respiratory failure: role of the Na,K-ATPase." Crit
Care Med 31(4 Suppl): S248-52.
Pulmonary edema is the hallmark of acute respiratory distress syndrome. It
occurs when the permeability of the alveolar-capillary barrier is increased,
causing alveolar flooding and impaired gas exchange. The mechanisms of alveolar
fluid resorption are different from those of alveolar edema formation. Alveolar
fluid resorption into the vessels is brought about mainly by active transport of
sodium ions (Na+) out of the alveolar spaces with water following the osmotic
gradient. Na+ transport across the alveolar epithelium, and thus alveolar fluid
resorption, is regulated by apical Na+ channels, the basolateral sodium
potassium-adenosine triphosphatase (Na,K-ATPase), and possibly chloride
channels. The Na,K-ATPase has been localized to the alveolar epithelium and the
importance of its role in contributing to lung edema clearance has been
demonstrated. In models of lung injury, several reports have shown that
catecholamines such as isoproterenol and dopamine up-regulate Na+ channels and
the Na,K-ATPase giving rise to increased alveolar fluid resorption. Although
recombinant gene technology is not yet a therapeutic option for the treatment of
pulmonary edema, several experimental studies have reported that overexpression
of Na,K-ATPase genes causes increased fluid resorption during hyperoxic lung
injury. There is significant evidence that fluid clearance is impaired in
patients with lung injury. Therapeutic strategies aimed at increasing the
ability of alveolar epithelium to resorb the edema should lead to benefits for
patients with acute respiratory distress syndrome.
Dantzler, T. E. and E. J. Lawitz (2003). "Treatment of chronic hepatitis C in
nonresponders to previous therapy." Curr Gastroenterol Rep 5(1):
78-85.
About 55% to 60% of treatment-naive patients fail to achieve a sustained
virologic response after therapy with standard interferon and ribavirin. The use
of polyethylene glycol-enhanced interferon (PEG-IFN) plus ribavirin for
retreatment of this challenging group is currently being evaluated by several
investigators. Although no sustained virologic response rates have been reported
yet from these trials, reported on-treatment response rates for previous
nonresponders range from 25% to 30%, and an early estimate of the sustained
virologic response rate is about 11%. Outcomes for treatment of relapsers and
interferon monotherapy nonresponders have been significantly better than those
for combination nonresponders. On-treatment responses of 40% to 43% in previous
combination therapy nonresponders are now being seen with the addition of
amantadine (triple therapy), and sustained response rates with this regimen are
awaited. Large trials are underway to evaluate the role of maintenance therapy
for virologic nonresponders with advanced liver disease.
Das, D. and B. Ali (2003). "Towards evidence based emergency medicine: best BETs
from the Manchester Royal Infirmary. Conservative management [correction of
mangement] of asymptomatic cocaine body packers." Emerg Med J 20(2):
172-4.
A short cut review was carried out to establish whether asymptomatic cocaine
body packers can be managed conservatively. Altogether 171 papers were found
using the reported search, of which four presented the best evidence to answer
the clinical question. The author, date and country of publication, patient
group studied, study type, relevant outcomes, results and study weaknesses of
these best papers are tabulated. A clinical bottom line is stated.
Davids, E., K. Zhang, et al. (2003). "Animal models of attention-deficit
hyperactivity disorder." Brain Res Brain Res Rev 42(1): 1-21.
Attention-deficit hyperactivity disorder (ADHD) involves clinically
heterogeneous dysfunctions of sustained attention, with behavioral overactivity
and impulsivity, of juvenile onset. Experimental models, in addition to
mimicking syndromal features, should resemble the clinical condition in
pathophysiology, and predict potential new treatments. One of the most
extensively evaluated animal models of ADHD is the spontaneously hypertensive
rat. Other models include additional genetic variants (dopamine transporter gene
knock-out mouse, coloboma mouse, Naples hyperexcitable rat, acallosal mouse,
hyposexual rat, and population-extreme rodents), neonatal lesioning of dopamine
neurons with 6-hydroxydopamine, and exposure to other neurotoxins or hippocampal
irradiation. None is fully comparable to clinical ADHD. The pathophysiology
involved varies, including both deficient and excessive dopaminergic
functioning, and probable involvement of other monoamine neurotransmitters.
Improved models as well as further testing of their ability to predict treatment
responses are required.
de Erausquin, G. A. (2003). "[Mechanism of molecular action of neuroleptics]."
Vertex 14(51): 36-44.
The discovery of the neurotransmitter function of dopamine in the central
nervous system opened the most successful chapter in the pharmacological
treatment of psychosis. It is a generally accepted fact that the antipyschotic
action of neuroleptics depends upon blockade of D2 receptors, in part because
all of currently used neuroleptics share that action, and in part because for
all typical neuroleptics there is a tight correlation between D2 receptor
affinity and clinical potency. The differencial effect of atypical neuroleptics
has been correlated with the ratio of affinities of for the D2 and the 5HT2A
receptors. Alternatively, it has been proposed that the lack of motor side
effects is due to fast dissociation of the ligand from the D2 receptor.
Regardless of the receptor interaction involved, it is evident that ligand-receptor
interactions, occuring over miliseconds, cannot fully account for clinical
effects observed over weeks or months. Chronic neuroleptic treatment causes
structural and morpholog ical changes in striatum, accumbens and prefrontal and
limbic cortex that distinguish between typical and atypical drugs, and thar are
correlated with sustained changes in the expression of transcription factors,
immediate early genes, second messengers and neuropeptides.
De Lima, M. S. and M. Hotopf (2003). "Benefits and risks of pharmacotherapy for
dysthymia: a systematic appraisal of the evidence." Drug Saf 26(1):
55-64.
BACKGROUND: Dysthymia is a prevalent form of subthreshold depressive disorder,
associated with considerable disability and high co-morbidity. This paper
systematically appraises the evidence for the efficacy and acceptability of the
pharmacological treatment for this condition. METHODS: Randomised, controlled
trials evaluating the efficacy of drug therapies for dysthymia were included. A
comprehensive search of the literature was performed, aiming to avoid
publication bias. Pooled relative risks (RR) and 95% CIs were calculated with
the Random Effect Model method. The number needed to treat (NNT) and number
needed to harm (NNH) were estimated for statistically significant results.
RESULTS: Twenty-five trials were included for the main comparisons. Regarding
placebo-controlled trials (n = 16), similar results were obtained in terms of
efficacy for different groups of drugs, such as tricyclic antidepressants
(TCAs), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase
inhibitors (MAOIs) and other drugs (sulpiride, amineptine, and ritanserin). The
pooled RR for treatment response was 0.68 (95% CI 0.57-0.81) for TCA and the NNT
was 4.3 (95% CI 3.2-6.5); 0.68 (95% CI 0.56-0.82) for SSRIs (NNT 5.1; 95% CI
3.9-7.7); 0.59 (95% CI 0.48-0.71) for MAOIs (NNT 2.9; 95% CI 2.2-4.3). Other
drugs (amisulpride, amineptine and ritanserin) showed similar results. The
equivalent efficacy between antidepressants as found in trials where active
medications were compared confirmed the efficacy findings from placebo trials.
In general, patients treated with a TCA were more likely to report adverse
events, compared with placebo and SSRIs. CONCLUSIONS: Pharmacotherapy for
dysthymia appears to be an effective short-term treatment for dysthymic
disorder. Newer antidepressants are equally effective and have better
acceptability than TCAs, although their higher cost must be balanced against
this assumed advantage.
Del Arco, A., G. Segovia, et al. (2003). "Changes in dialysate concentrations of
glutamate and GABA in the brain: an index of volume transmission mediated
actions?" J Neurochem 85(1): 23-33.
Brain microdialysis has become a frequently used method to study the
extracellular concentrations of neurotransmitters in specific areas of the
brain. For years, and this is still the case today, dialysate concentrations and
hence extracellular concentrations of neurotransmitters have been interpreted as
a direct index of the neuronal release of these specific neurotransmitter
systems. Although this seems to be the case for neurotransmitters such as
dopamine, serotonin and acetylcholine, the extracellular concentrations of
glutamate and GABA do not provide a reliable index of their synaptic exocytotic
release. However, many microdialysis studies show changes in extracellular
concentrations of glutamate and GABA under specific pharmacological and
behavioural stimuli that could be interpreted as a consequence of the activation
of specific neurochemical circuits. Despite this, we still do not know the
origin and physiological significance of these changes of glutamate and GABA in
the extracellular space. Here we propose that the changes in dialysate
concentrations of these two neurotransmitters found under specific treatments
could be an expression of the activity of the neurone-astrocyte unit in specific
circuits of the brain. It is further proposed that dialysate changes of
glutamate and GABA could be used as an index of volume transmission mediated
actions of these two neurotransmitters in the brain. This hypothesis is based
firstly on the assumption that the activity of neurones is functionally linked
to the activity of astrocytes, which can release glutamate and GABA to the
extracellular space; secondly, on the existence of extrasynaptic glutamate and
GABA receptors with functional properties different from those of GABA receptors
located at the synapse; and thirdly, on the experimental evidence reporting
specific electrophysiological and neurochemical effects of glutamate and GABA
when their levels are increased in the extracellular space. According to this
concept, glutamate and GABA, once released into the extracellular compartment,
could diffuse and have long-lasting effects modulating glutamatergic and/or
GABAergic neurone-astrocytic networks and their interactions with other
neurotransmitter neurone networks in the same areas of the brain.
Delmas, C. (2003). "[Hyperactivity in children]." Soins Psychiatr(224):
42-4.
DiMaio, S., N. Grizenko, et al. (2003). "Dopamine genes and attention-deficit
hyperactivity disorder: a review." J Psychiatry Neurosci 28(1):
27-38.
OBJECTIVE: To review the results of genetic studies investigating
dopamine-related genes in attention-deficit hyperactivity disorder (ADHD). DATA
SOURCES: Papers (association/linkage, meta-analyses and animal model studies)
were identified through searches of the PubMed database and systematically
reviewed. DATA SYNTHESIS: Consistent results from molecular genetic studies are
pointing strongly to the possible link between 2 specific genes, the dopamine
transporter (SLC3A6) and the dopamine receptor 4 (DRD4), and ADHD. CONCLUSIONS:
The implication of SLC6A3 and DRD4 genes in ADHD appears to be one of the most
replicated in psychiatric genetics and strongly suggests the involvement of the
brain dopamine systems in the pathogenesis of ADHD. However, more work is
required to further these findings by genotype-to-phenotype correlations and
identify the functional allelic variants/mutations that are responsible for
these associations. The role of other dopamine genes, which may have smaller
effects than SLC6A3 and DRD4, needs also to be determined.
Dobner, P. R., A. Y. Deutch, et al. (2003). "Neurotensin: dual roles in
psychostimulant and antipsychotic drug responses." Life Sci 73(6):
801-11.
Central administration of neurotensin (NT) results in a variety of
neurobehavioral effects which, depending upon the administration site, resemble
the effects of antipsychotic drugs (APDs) and psychostimulants. All clinically
effective APDs exhibit significant affinities for dopamine D(2) receptors,
supporting the hypothesis that an increase in dopaminergic tone contributes to
schizophrenic symptoms. Psychostimulants increase extracellular dopamine (DA)
levels and chronics administration can produce psychotic symptoms over time.
APDs and psychostimulants induce Fos and NT expression in distinct striatal
subregions, suggesting that changes in gene expression underlie some of their
effects. To gain insight into the functions of NT, we analyzed APD and
psychostimulant induction of Fos in NT knockout mice and rats pretreated with
the NT antagonist SR 48692. In both NT knockout mice and rats pretreated with SR
48692, haloperidol-induced Fos expression was markedly attenuated in the
dorsolateral striatum; amphetamine-induced Fos expression was reduced in the
medial striatum. These results indicate that NT is required for the activation
of specific subpopulations of striatal neurons in distinct striatal subregions
in response to both APDs and psychostimulants. This review integrates these new
findings with previous evidence implicating NT in both APD and psychostimulant
responses.
Doi, N. (2003). "[Anti-tuberculosis drugs]." Nippon Rinsho 61 Suppl 2:
762-7.
Donnelly, C. L. (2003). "Pharmacologic treatment approaches for children and
adolescents with posttraumatic stress disorder." Child Adolesc Psychiatr Clin
N Am 12(2): 251-69.
Posttraumatic stress disorder is a common cause of morbidity in children and
adolescents. The disorder in youth is similar to that in adults, with high rates
of psychiatric comorbidity. Children seem to be more sensitive to the effects of
trauma, and early life trauma exposure may induce a complex sequence of events
that leads to the development of multiple psychiatric disorders in adulthood.
The state of knowledge regarding medication treatments for children and
adolescents is in the earliest stages of development. There are no
well-conducted, randomized clinical trials to guide practitioners. Medication
may play an important role in reducing debilitating symptoms of PTSD and
providing a buffer for children while they confront difficult material in
therapy and may help to improve their general functioning in day-to-day life.
Given the various medications with potential usefulness in PTSD, it is helpful
to use a stepwise approach to treatment. As a general principal, broad-spectrum
agents, such as the SSRIs, are a good first choice. The SSRIs have efficacy in
treating the core symptoms of PTSD and conditions such as the anxiety disorders
and depression that commonly co-occur with PTSD. These agents also improve
social and occupational functioning and an individual's perception of improved
quality of life [41, 45, 46]. Although the SSRIs are generally effective for a
broad spectrum of problems, clinicians should systematically monitor for the
persistence of symptoms that do not respond to these agents. For example,
despite significant improvements in core PTSD symptoms in one study that used
sertraline, little improvement was seen in patients' comorbid anxiety and
depressive symptoms [41]. This finding demonstrates the value of continuous
symptom monitoring and shows that residual or comorbid symptoms may require a
different medication to augment effective SSRI treatment for PTSD. A reasonable
approach is to begin with a broad-spectrum agent, such as an SSRI, which should
target anxiety, mood, and reexperiencing symptoms. Adrenergic agents, such as
clonidine, used either alone or in combination with an SSRI may be useful when
symptoms of hyperarousal and impulsivity are problematic. Supplementing with a
mood stabilizer may be necessary in severe affective dyscontrol. Similarly,
introduction of an atypical neuroleptic agent may be necessary in cases of
severe self-injurious behavior, dissociation, psychosis, or aggression. Comorbid
conditions such as ADHD should be targeted with pharmacotherapy known to be
effective, such as psychostimulants or newer agents such as atomoxetine.
Pharmacologic treatment of PTSD in childhood is one approach to alleviating the
acute and chronic symptoms of the disorder. Despite the lack of well-designed,
randomized, controlled trials that support efficacy, medication can be used in a
rational and safe manner. Reduction in even one disabling symptom, such as
insomnia or hyperarousal, may have a positive ripple effect on a child's overall
functioning. Pharmacotherapy is typically used as one component of a more
comprehensive multiple modality treatment package, including psychoeducation of
the parent and child, focused exposure-based psychotherapy with adjunctive
family therapy when indicated, and long-term booster interventions that use an
admixture of psychodynamic, cognitive-behavioral, and pharmacologic
interventions.
Douglass, A. B. (2003). "Narcolepsy: differential diagnosis or etiology in some
cases of bipolar disorder and schizophrenia?" CNS Spectr 8(2):
120-6.
Does narcolepsy, a neurological disease, need to be considered when diagnosing
major mental illness? Clinicians have reported cases of narcolepsy with
prominent hypnagogic hallucinations that were mistakenly diagnosed as
schizophrenia. In some bipolar disorder patients with narcolepsy, the HH
resulted in their receiving a more severe diagnosis (ie, bipolar disorder with
psychotic features or schizoaffective disorder). The role of narcolepsy in
psychiatric patients has remained obscure and problematic, and it may be more
prevalent than commonly believed. Classical narcolepsy patients display the
clinical "tetrad"--cataplexy, hypnagogic hallucinations, daytime sleep attacks,
and sleep paralysis. Over 85% also display the human leukocyte antigen marker
DQB1*0602 (subset of DQ6). Since 1998, discoveries in neuroanatomy and
neurophysiology have greatly advanced the understanding of narcolepsy, which
involves a nearly total loss of the recently discovered orexin/hypocretin
(hypocretin) neurons of the hypothalamus, likely by an autoimmune mechanism.
Hypocretin neurons normally supply excitatory signals to brainstem nuclei
producing norepinephrine, serotonin, histamine, and dopamine, with resultant
suppression of sleep. They also project to basal forebrain areas and cortex. A
literature review regarding the differential diagnosis of narcolepsy, affective
disorder, and schizophrenia is presented. Furthermore, it is now possible to
rule out classical narcolepsy in difficult psychiatric cases. Surprisingly,
psychotic patients with narcolepsy will likely require stimulants to fully
recover. Many conventional antipsychotic drugs would worsen their symptoms and
make them appear to become a "chronic psychotic," while in fact they can now be
properly diagnosed and treated.
Earley, C. J. (2003). "Clinical practice. Restless legs syndrome." N Engl J
Med 348(21): 2103-9.
Ebbert, J. O., L. C. Rowland, et al. (2003). "Treatments for spit tobacco use: a
quantitative systematic review." Addiction 98(5): 569-83.
AIMS: Spit tobacco use is prevalent in the United States and is associated with
adverse health consequences. Health-care providers have neither evidence
summaries nor evidence-based guidelines to assist them in treating patients who
use spit tobacco. DESIGN: We completed a systematic review of the literature to
determine the efficacy and safety of pharmacological and behavioral
interventions for the treatment of spit tobacco use. FINDINGS: We found six
randomized controlled trials testing pharmacological interventions and eight
testing behavioral interventions. Using random-effects meta-analyses,bupropion
sustained-release (SR) increased point prevalence tobacco abstinence at 12 weeks
[odds ratio (OR) 2.1; 95% confidence interval (CI), 1.0-4.2]. Nicotine
replacement therapy with patch or gum increased point prevalence tobacco
abstinence at 6 months (OR 1.3; 95% CI, 1.0-1.6).Behavioral interventions
increased long-term (6 month)point prevalence tobacco abstinence (OR 1.7; 95%
CI, 1.1-2.9).Studies including an oral examination followed by feedback to the
patient had the highest treatment effect. CONCLUSIONS: Behavioral interventions
for ST users are effective for increasing ST abstinence rates. Bupropion SR is
probably effective and nicotine replacement therapy may be effective. This
evidence from randomized controlled trials provides health-care professionals
with information necessary to effectively treat spit tobacco use.
Eberhardt, O. and J. B. Schulz (2003). "Apoptotic mechanisms and antiapoptotic
therapy in the MPTP model of Parkinson's disease." Toxicol Lett 139(2-3):
135-51.
The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model constitutes the
best-characterized toxin paradigm for Parkinson's disease, faithfully
replicating most of its clinical and pathological hallmarks. Many lines of
evidence point to a significant contribution of apoptosis to cell death after
application of 1-methyl-4-phenylpyridinium (MPP(+)) in cell culture or MPTP in
vivo. This holds true for apoptotic DNA strand breaks, activation of the JNK
pathway and caspases, induction of Par-4 protein and the protection conferred by
interference with p53, Apaf-1 or Bax signalling. In MPTP models, intervention in
upstream events of apoptosis, e.g. by inhibition of the JNK pathway, provides
morphological and functional rescue. In contrast, inhibition of the propagation
and execution phase of apoptosis, e.g. by inhibition of caspases, blocks or
delays cell death but may not recover neuronal function. At this stage, the
combination of an anti-apoptotic together with a neurorestorative therapy may be
promising.
Ellenbroek, B. A. and J. F. Liegeois (2003). "JL 13, an atypical antipsychotic:
a preclinical review." CNS Drug Rev 9(1): 41-56.
The extensive pharmacological evaluation of JL 13 as an atypical antipsychotic
drug has revealed a close similarity to clozapine, however with some major
advantages. JL 13 was characterized as a weak D(2) antagonist, both in vitro and
in vivo, with a strong affinity for the D(4) and the 5-HT(2A) receptors. It has
no affinity for the 5-HT(2C) receptor. In vivo microdialysis experiments in rat
showed that JL 13, like clozapine, preferentially increased extracellular
dopamine concentrations in the prefrontal cortex compared to nucleus accumbens
or striatum. Behavioral studies showed that JL 13, like clozapine, has the
profile of an atypical antipsychotic. Thus, JL 13 did not antagonize
apomorphine-induced stereotypy nor did it produce catalepsy, but it antagonized
apomorphine-induced climbing in rodents. It was inactive against
d-amphetamine-induced stereotypy but antagonized d-amphetamine-induced
hyperactivity in the mouse. Likewise, in the paw test, it was more effective in
prolonging hindlimb retraction time than prolonging forelimb retraction time.
Like other antipsychotic drugs, JL 13 reversed the apomorphine- and
amphetamine-induced disruption of prepulse inhibition. In a complex temporal
regulation schedule in the dog, JL 13 showed a high resemblance with clozapine
without inducing sialorrhea, palpebral ptosis or any significant motor side
effects. In rats and squirrel monkeys JL 13 induced a high degree of
generalization (70%) to clozapine. Regarding behavioral toxicology, JL 13 did
not produce dystonia or Parkinsonian symptoms in haloperidol-sensitized monkeys.
After acute administration, again like clozapine, JL 13 induced only a transient
increase in circulating prolactin. Last but not the least, regarding a possible
hematological toxicity, unlike clozapine, JL 13 did not present sensitivity to
peroxidase-induced oxidation. Moreover, its electrooxidation potential was close
to that of loxapine and far from that of clozapine. Taking all these preclinical
data into account, it appears that JL 13 is a promising atypical antipsychotic
drug.
Escalante, C. P. (2003). "Treatment of cancer-related fatigue: an update."
Support Care Cancer 11(2): 79-83.
Fatigue, a common complaint of cancer patients, requires a multidisciplinary
evaluation and treatment approach because of the multiple etiologies and
contributing factors. Current treatments for fatigue include educating patients
and caregivers about fatigue, applying etiology-specific treatments, utilizing
nonpharmacologic interventions, and prescribing pharmacologic therapies. Often,
an individualized treatment plan that includes several modalities may be
developed. Presently, there is a lack of well-designed clinical trials to
evaluate pharmacologic agents for the treatment of cancer-related fatigue.
Esler, M., G. Lambert, et al. (2003). "Sympathetic nerve activity and
neurotransmitter release in humans: translation from pathophysiology into
clinical practice." Acta Physiol Scand 177(3): 275-84.
AIM: There has been a revolution in cardiovascular neuroscience in recent years
with, in some cases, translation into clinical practice of the knowledge of
pathophysiology gained through application of sympathetic nerve recording and
catecholamine isotope dilution methodology. OBESITY-RELATED HYPERTENSION: An
earlier hypothesis, based on findings in most models, was that weight gain in
obesity is due in part to sympathetic nervous underactivity reducing
thermogenesis. Microneurography and regional noradrenaline spillover
measurements in human obesity have disproven this hypothesis, weakening the case
for the use of beta3-adrenergic agonists to stimulate thermogenesis. Sympathetic
nerve firing rates in post-ganglionic fibres directed to the skeletal muscle
vasculature are increased, as is renal sympathetic tone, with a doubling of the
spillover rate of noradrenaline from the kidneys. Given these findings,
antiadrenergic antihypertensive drugs may be the preferred agents for
obesity-related hypertension, but this has not been adequately tested. ESSENTIAL
HYPERTENSION: Whether stress causes high blood pressure, previously hotly
debated, has been under recent review by an Australian Government body, the
Specialist Medical Review Council. Despite medicolegal implications, the ruling
was that stress is one proven cause of hypertension. The judgment was reached
after consideration of the epidemiological evidence, but in particular the
described neural pathophysiology of essential hypertension: (a) persistent
sympathetic nervous stimulation is commonly present, (b) suprabulbar projections
of noradrenergic brainstem neurones are activated and (c) adrenaline is released
as a cotransmitter in sympathetic nerves. These were taken to be biological
markers of stress. CARDIAC FAILURE: At one time, the failing heart was thought
to be sympathetically denervated. Longterm administration of inotropic
adrenergic agonists, to provide the cardiac catecholamine stimulation thought to
be lacking, increased mortality. Noradrenaline isotope dilution methodology
subsequently demonstrated that the sympathetic outflow to the heart was
preferentially activated, cardiac noradrenaline spillover being increased as
much as 50-fold. The level of stimulation of the cardiac sympathetic nerves was
the most powerful predictor of death. These observations provide the theoretical
foundation for the very successful introduction of beta-adrenergic blockers for
treatment of heart failure.
Ferguson, S. S. (2003). "Receptor tyrosine kinase transactivation: fine-tuning
synaptic transmission." Trends Neurosci 26(3): 119-22.
G-protein-coupled receptors generate signals that promote gene transcription
through the 'transactivation' of receptor tyrosine kinases (RTKs) and activation
of the mitogen-activated protein kinase (MAPK) cascade -- a process that
involves RTK autophosphorylation and endocytosis. Pioneering work now suggests
that D4-dopamine-receptor-mediated transactivation of the platelet-derived
growth factor beta receptor has immediate effects on synaptic neurotransmission
via Ca(2+)-dependent inactivation of NMDA receptors. The demonstration of a
physiological role for RTK transactivation in the CNS provides novel
opportunities for understanding how aberrant dopamine signalling might
contribute to cognitive and attention deficits associated with schizophrenia and
attention-deficit hyperactivity disorder.
Ferry, L. and J. A. Johnston (2003). "Efficacy and safety of bupropion SR for
smoking cessation: data from clinical trials and five years of postmarketing
experience." Int J Clin Pract 57(3): 224-30.
Bupropion SR was introduced for smoking cessation in the US in 1997. This review
assesses the efficacy and safety of bupropion SR for treatment of tobacco
dependence based on data from clinical trials and five years of postmarketing
experience. Through June 2001, there were approximately 32 million patient
exposures to bupropion (9 million for smoking cessation) in clinical practice,
and more than 8000 patients have been studied in clinical trials for tobacco
dependence. In clinical trials, bupropion SR was more effective than placebo at
improving initial and long-term abstinence rates and preventing relapse.
Bupropion SR is generally well tolerated. The most common adverse event in
clinical trials or clinical practice is insomnia, which can also be a symptom of
nicotine withdrawal. The two main risks of treatment with bupropion SR are major
motor seizure and hypersensitivity reaction. Clinical trials data suggest that
the incidence of seizure is approximately 0.1%, and that of serious cases of
hypersensitivity approximately 0.12%. Benefit-risk assessment, assuming a 30%
one-year quit rate demonstrates that for every 10,000 smokers treated with
bupropion SR, 19 lives are saved and 86 cases of smoking-attributed morbidity
are averted in a five-year period while the risk of experiencing one of the two
potentially serious adverse events during treatment is 0.22%. These data further
establish both the efficacy and safety of bupropion SR and its use in preventing
the adverse health effects of chronic tobacco use.
Fleminger, S., R. J. Greenwood, et al. (2003). "Pharmacological management for
agitation and aggression in people with acquired brain injury." Cochrane
Database Syst Rev(1): CD003299.
BACKGROUND: Of the many psychiatric symptoms that may result from brain injury,
agitation and/or aggression are often the most troublesome. It is therefore
important to evaluate the efficacy of psychotropic medication used in its
management. OBJECTIVES: To evaluate the effects of drugs for agitation and/or
aggression following acquired brain injury (ABI). SEARCH STRATEGY: We searched
MEDLINE (1966-2002), EMBASE (1980-2002) and the Cochrane Controlled Trials
Register (1996-2002), Web of Science Citation Index, reference lists of papers
meeting the inclusion criteria and recent reviews. We handsearched Brain Injury
and the Journal of Head Trauma Rehabilitation. There were no language
restrictions. SELECTION CRITERIA: Randomised controlled trials (RCTs) that
evaluated the efficacy of drugs acting on the central nervous system for
agitation and/or aggression, secondary to ABI, in participants over 10 years of
age. Studies using lower levels of evidence (i.e. case series studies, single
case studies and controlled group comparison studies), were collated in an
appendix. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted
data and assessed trial quality. Authors were contacted where necessary for
additional information. Studies of patients within six months after brain injury
and/or in a confusional state, were distinguished from those of patients more
than six months post-injury, or who were not confused. MAIN RESULTS: Six
randomised controlled trials were identified. Four RCTs evaluated the
beta-blockers, propranolol and pindolol, one RCT evaluated the central nervous
system stimulant, methylphenidate and one RCT evaluated amantadine, a drug
normally used in parkinsonism and related disorders. The best evidence of
effectiveness in the management of agitation and/or aggression following ABI was
for beta-blockers. Two RCTs found propranolol to be effective (one study early
and one late after injury). However, these studies used relatively small
numbers, have not been replicated, used large doses, and did not use a global
outcome measure or long-term follow-up. Comparing early agitation to late
aggression, there was no evidence for a differential drug response. Firm
evidence that carbamazepine or valproate is effective in the management of
agitation and/or aggression following ABI is lacking. REVIEWER'S CONCLUSIONS:
Numerous drugs have been tried in the management of aggression in ABI but
without firm evidence of their efficacy. It is therefore important to choose
drugs with few side effects and to monitor their effect. Beta-blockers have the
best evidence for efficacy and deserve more attention. The lack of evidence
highlights the need for better evaluations of drugs for this important problem.
Fraser, M. O. and M. B. Chancellor (2003). "Neural control of the urethra and
development of pharmacotherapy for stress urinary incontinence." BJU Int
91(8): 743-8.
This review discusses the control of the urethra by the central nervous system,
emphasizing the importance of nervous system control and the role of serotonin
and noradrenaline in storage, micturition and sphincter reflexes. The concept of
pharmacological neuromodulation and the use of pharmacological therapy as
first-line therapy for stress urinary incontinence (SUI) is presented.
Coordination between the urinary bladder and urethra is mediated by many reflex
pathways organized in the brain and spinal cord. During bladder filling,
activation of mechanoreceptor afferent nerves in the bladder wall triggers
firing in the cholinergic efferent pathways to the external urethral sphincter
and in sympathetic adrenergic pathways to the urethral smooth muscle. These
storage reflexes depend on interneuronal circuitry in the spinal cord and are
modulated by descending pathways. It would therefore seem that neurotransmission
in the central nervous system and periphery may be important in SUI, and
moreover that pharmacological agents affecting these neurotransmitter pathways
may be used to treat SUI. The central and peripheral mechanisms of action of
duloxetine affect serotonin and noradrenaline neurotransmission in ways that may
ameliorate the symptoms of SUI.
Friedman, H., C. Newton, et al. (2003). "Microbial infections, immunomodulation,
and drugs of abuse." Clin Microbiol Rev 16(2): 209-19.
The use of recreational drugs of abuse has generated serious health concerns.
There is a long-recognized relationship between addictive drugs and increased
levels of infections. Studies of the mechanisms of actions of these drugs became
more urgent with the advent of AIDS and its correlation with abused substances.
The nature and mechanisms of immunomodulation by marijuana, opiates, cocaine,
nicotine, and alcohol are described in this review. Recent studies of the
effects of opiates or marijuana on the immune system have demonstrated that they
are receptor mediated, occurring both directly via specific receptors on immune
cells and indirectly through similar receptors on cells of the nervous system.
Findings are also discussed that demonstrate that cocaine and nicotine have
similar immunomodulatory effects, which are also apparently receptor mediated.
Finally, the nature and mechanisms of immunomodulation by alcohol are described.
Although no specific alcohol receptors have been identified, it is widely
recognized that alcohol enhances susceptibility to opportunistic microbes. The
review covers recent studies of the effects of these drugs on immunity and on
increased susceptibility to infectious diseases, including AIDS.
Garcia-Borreguero, D., O. Larrosa, et al. (2003). "Parkinson's disease and
sleep." Sleep Med Rev 7(2): 115-29.
Sleep disorders are common in Parkinson's disease (PD), as almost two thirds of
PD patients report them. From a clinical point of view, they can be classified
into disorders of initiation and maintenance of sleep (DIMS), parasomnias, and
excessive daytime sleepiness (EDS). Among the causes of DIMS are degenerative
changes in the CNS affecting centers for sleep regulation, persistence into the
night of daytime PD-related symptoms, concomitant medical or psychiatric
disease, disruption of circadian rhythms, and effects of dopaminergic (and
other) medication on sleep regulation. Parasomnias might further contribute to
sleep disturbance, as they can be accompanied by motor desinhibition during REM
sleep. Parasomnias can precede by several years the presence of daytime PD
symptoms. EDS has been over the last years the focus of attention for both sleep
and movement disorders specialists, due to the fact that it might predispose to
traffic accidents. However, the so-called "sleep attacks" never occur without
preexisting somnolence. Thus, a careful sleep history can be helpful to
determine which patients are exposed to suffer them. Although EDS was initially
attributed to the effects of dopaminergic medication, it seems likely that
several disease-related factors might also play an important role. An adequate
education of the PD patients in sleep hygiene measures and a skilled use of the
medication seem necessary to prevent sleep disturbance.
Gerdeman, G. L., J. G. Partridge, et al. (2003). "It could be habit forming:
drugs of abuse and striatal synaptic plasticity." Trends Neurosci 26(4):
184-92.
Drug addiction can take control of the brain and behavior, activating behavioral
patterns that are directed excessively and compulsively toward drug usage. Such
patterns often involve the development of repetitive and nearly automatic
behaviors that we call habits. The striatum, a subcortical brain region
important for proper motor function as well as for the formation of behavioral
habits, is a major target for drugs of abuse. Here, we review recent studies of
long-term synaptic plasticity in the striatum, emphasizing that drugs of abuse
can exert pronounced influences on these processes, both in the striatum and in
the dopaminergic midbrain. Synaptic plasticity in the ventral striatum appears
to play a prominent role in early stages of drug use, whereas dopamine- and
endocannabinoid-dependent synaptic plasticity in the dorsal striatum could
contribute to the formation of persistent drug-related habits when casual drug
use progresses towards compulsive drug use and addiction.
Gerlach, M., P. Foley, et al. (2003). "The relevance of preclinical studies for
the treatment of Parkinson's disease." J Neurol 250 Suppl 1:
I31-4.
An essential element of pharmaceutical development, defined as the period
between the discovery of a new agent and its market release, is provided by the
"preclinical studies". They consist of the in vitro and in vivo studies
performed before examination of the agent in human subjects. Regulatory
authorities prescribe specific requirements regarding the nature and number of
preclinical studies. In the present paper, we discuss the relevance of these
studies for the treatment of Parkinson's disease (PD) on the basis of three
examples: the L-DOPA ( L-3,4-dihydroxyphenylalanine, levodopa) story; the
development of selegiline as a palliative and neuroprotective drug; and the
safety concerns regarding tolcapone, an inhibitor of central and peripheral
catechol-O-methyltransferase (COMT).
Gleason, O. C. (2003). "Delirium." Am Fam Physician 67(5):
1027-34.
Delirium is characterized by an acute change in cognition and a disturbance of
consciousness, usually resulting from an underlying medical condition or from
medication or drug withdrawal. Delirium affects 10 to 30 percent of hospitalized
patients with medical illness; more than 50 percent of persons in certain
high-risk populations are affected. The associated morbidity and mortality make
diagnosis of this condition extremely important. Patients with delirium can
present with agitation, somnolence, withdrawal, and psychosis. This variation in
presentation can lead to diagnostic confusion and, in some cases, incorrect
attribution of symptoms to a primary psychiatric disorder. To make the
distinction, it is important to obtain the history of the onset and course of
the condition from family members or caregivers. Primary care physicians must be
able to recognize delirium so that the underlying etiology can be ascertained
and addressed. The management of delirium involves identifying and correcting
the underlying problem, and symptomatically managing any behavioral or
psychiatric symptoms. Low doses of antipsychotic drugs can help to control
agitation. The use of benzodiazepines should be avoided except in cases of
alcohol or sedative-hypnotic withdrawal. Environmental interventions, including
frequent reorientation of patients by nursing staff and education of patients
and families, should be employed in all cases.
Goldstein, L. B. (2003). "Pharmacotherapy in stroke rehabilitation." Adv
Neurol 92: 447-50.
Goldstein, D. S., G. Eisenhofer, et al. (2003). "Sources and significance of
plasma levels of catechols and their metabolites in humans." J Pharmacol Exp
Ther 305(3): 800-11.
Human plasma contains several catechols, including the catecholamines
norepinephrine, epinephrine, and dopamine, their precursor,
L-3,4-dihydroxyphenylalanine (L-DOPA), and their deaminated metabolites,
dihydroxyphenylglycol, the main neuronal metabolite of norepinephrine, and
dihydroxyphenylacetic acid, a deaminated metabolite of dopamine. Products of
metabolism of catechols include 3-methoxytyrosine (from L-DOPA), homovanillic
acid and dopamine sulfate (from dopamine), normetanephrine, vanillylmandelic
acid, and methoxyhydroxyphenylglycol (from norepinephrine), and metanephrine
(from epinephrine). Plasma levels of catechols and their metabolites have
related but distinct sources and therefore reflect different functions of
catecholamine systems. This article provides an update about plasma levels of
catechols and their metabolites and the relevance of those levels to some issues
in human health and disease.
Goldstein, L. B. (2003). "Amphetamines and related drugs in motor recovery after
stroke." Phys Med Rehabil Clin N Am 14(1 Suppl): S125-34, x.
Studies in laboratory animals indicate that the rate and extent of functional
recovery after focal brain injury can be modulated by drugs affecting specific
central neurotransmitters. Preliminary clinical studies suggest that similar
drug effects may occur in humans recovering from stroke. Combined with
principles derived from the laboratory, these clinical studies provide important
insights to guide the rational design of trials aimed at determining the
clinical use of this approach to improving poststroke recovery.
Gordin, A., S. Kaakkola, et al. (2003). "Position of COMT inhibition in the
treatment of Parkinson's disease." Adv Neurol 91: 237-50.
Goth, M. I., E. Hubina, et al. (2003). "Physiological and pathological
angiogenesis in the endocrine system." Microsc Res Tech 60(1):
98-106.
Formation of new blood vessels occurs in many physiological states (during
development of the embryo, cycling changes of the female reproductive tract), as
well as in pathological processes (such as diabetic retinopathy and wound
healing). Angiogenesis has been shown to be related to tumor formation,
prognosis, and response to treatment in many tumor types. Intratumoral
microvessels can be related to tumor behavior or hormone secretion in different
endocrine tumors. For example, invasive prolactinomas are more vascular than
noninvasive adenomas; a surgical approach is more successful in
macroprolactinomas with lower microvessel density. A higher number of
microvessels have been found in papillary thyroid carcinomas during recurrences.
A correlation between microvessel count and prognosis in papillary and medullary
thyroid carcinomas has been suggested. Several stimulating and inhibiting
factors involved in the regulation of angiogenesis have been identified. Among
them, vascular endothelial growth factor (VEGF) has been shown to be critically
involved in angiogenesis and also in the neovascularization of solid tumors.
Dopamine agonists (already in clinical use for prolactinomas) have potent
inhibitory actions on VEGF signaling, and thus may be a new tool in
antiangiogenic therapy. Secretion of VEGF in the great majority of human
pituitary adenomas is inhibited by dexamethasone. This suggests that
glucocorticoids can be considered in the treatment of certain pituitary tumors.
The cyclic nature of angiogenesis in the female reproductive tract indicates
that stimulation or inhibition of paracrine angiogenic factors may lead to new
approaches for being able to influence reproductive endocrine disorders.
Experimental and clinical aspects of interactions between angiogenic factors and
tumor growth of the endocrine system are also discussed.
Grunblatt, E., R. Schlosser, et al. (2003). "Preclinical versus clinical
neuroprotection." Adv Neurol 91: 309-28.
Gudelsky, G. A. and B. K. Yamamoto (2003). "Neuropharmacology and neurotoxicity
of 3,4-methylenedioxymethamphetamine." Methods Mol Med 79: 55-73.
The existing data indicate that MDMA produces long-term deficits in markers of
5-HT axon terminals in the rodent brain. Increased cleavage of the cytoskeletal
protein tau, impairment of axonal transport, and functional consequences
associated with a 5-HT depleting regimen of MDMA support the view that MDMA
induces structural brain damage, that is, axonal degeneration. A confluence of
oxidative stress and bioenergetic stress induced by MDMA is hypothesized to
underlie the process of MDMA neurotoxicity (Fig. 3). The actions of MDMA on the
5-HT transporter to promote free radical formation and/or intracellular calcium
may synergize with MDMA-induced disturbances in cellular energetics and
hyperthermia to effect selective toxicity to 5-HT axon terminals.
Gupta, S. (2003). "Safety in treating bipolar disorder." J Fam Pract
Suppl: S26-9.
Guttman, M., S. J. Kish, et al. (2003). "Current concepts in the diagnosis and
management of Parkinson's disease." Cmaj 168(3): 293-301.
Parkinson's disease is a progressive neurological disorder characterized by rest
tremor, bradykinesia, rigidity and postural instability. The cause is unknown,
but growing evidence suggests that it may be due to a combination of
environmental and genetic factors. Treatment during the early stage of
Parkinson's disease has evolved, and evidence suggests that dopamine agonist
monotherapy may prevent the response fluctuations that are associated with
disease progression. L-dopa therapy, however, remains the most efficacious
treatment. Treatment during the advanced stage focuses on improving control of a
number of specific clinical problems. Successful management of motor response
fluctuations (e.g., "wearing off," on-off fluctuations, nighttime deterioration,
early morning deterioration and dyskinesias) and of psychiatric problems is
often possible with specific treatment strategies. Surgical treatment is an
option for a defined patient population.
Hadj Tahar, A., R. Grondin, et al. (2003). "New insights in Parkinson's disease
therapy: can levodopa-induced dyskinesia ever be manageable." Adv Neurol
91: 51-64.
Hain, T. C. and M. Uddin (2003). "Pharmacological treatment of vertigo." CNS
Drugs 17(2): 85-100.
This review discusses the physiology and pharmacological treatment of vertigo
and related disorders. Classes of medications useful in the treatment of vertigo
include anticholinergics, antihistamines, benzodiazepines, calcium channel
antagonists and dopamine receptor antagonists. These medications often have
multiple actions. They may modify the intensity of symptoms (e.g. vestibular
suppressants) or they may affect the underlying disease process (e.g. calcium
channel antagonists in the case of vestibular migraine). Most of these agents,
particularly those that are sedating, also have a potential to modulate the rate
of compensation for vestibular damage. This consideration has become more
relevant in recent years, as vestibular rehabilitation physical therapy is now
often recommended in an attempt to promote compensation. Accordingly, therapy of
vertigo is optimised when the prescriber has detailed knowledge of the
pharmacology of medications being administered as well as the precise actions
being sought. There are four broad causes of vertigo, for which specific
regimens of drug therapy can be tailored. Otological vertigo includes disorders
of the inner ear such as Meniere's disease, vestibular neuritis, benign
paroxysmal positional vertigo (BPPV) and bilateral vestibular paresis. In both
Meniere's disease and vestibular neuritis, vestibular suppressants such as
anticholinergics and benzodiazepines are used. In Meniere's disease, salt
restriction and diuretics are used in an attempt to prevent flare-ups. In
vestibular neuritis, only brief use of vestibular suppressants is now
recommended. Drug treatments are not presently recommended for BPPV and
bilateral vestibular paresis, but physical therapy treatment can be very useful
in both. Central vertigo includes entities such as vertigo associated with
migraine and certain strokes. Prophylactic agents (L-channel calcium channel
antagonists, tricyclic antidepressants, beta-blockers) are the mainstay of
treatment for migraine-associated vertigo. In individuals with stroke or other
structural lesions of the brainstem or cerebellum, an eclectic approach
incorporating trials of vestibular suppressants and physical therapy is
recommended. Psychogenic vertigo occurs in association with disorders such as
panic disorder, anxiety disorder and agoraphobia. Benzodiazepines are the most
useful agents here. Undetermined and ill-defined causes of vertigo make up a
large remainder of diagnoses. An empirical approach to these patients
incorporating trials of medications of general utility, such as benzodiazepines,
as well as trials of medication withdrawal when appropriate, physical therapy
and psychiatric consultation is suggested.
Halaris, A. (2003). "Neurochemical aspects of the sexual response cycle." CNS
Spectr 8(3): 211-6.
What drives the human sexual response cycle? The human sexual response cycle is
a highly complex phenomenon that encompasses many transmitters and transmitter
systems centrally and peripherally. The endocrine system is also intricately
involved in the brain and in the periphery organs. Integration of these systems
is a function of the nervous system that ultimately produces a vast array of
cognitive, emotional, physiological, and behavioral responses. Therefore, it is
not surprising that a disturbance in even a single system will lead to
dysfunction in one or more phases of the sexual response cycle. This article
highlights the complex roles the aminergic system plays along with key hormones
that are equally involved. The article also points out how rudimentary and
fragmented our knowledge is in this field and how few controlled studies are
available. The potential for development of specific agents that target
selective sexual dysfunctions is exemplified in sildenafil, the first such agent
ever to be brought to market.
Hamada, T., I. Hisatome, et al. (2003). "[Drug-induced hyperuricemia]."
Nippon Rinsho 61 Suppl 1: 333-7.
Hassaballa, H. A. and R. A. Balk (2003). "Torsade de pointes associated with the
administration of intravenous haloperidol." Am J Ther 10(1):
58-60.
Torsade de pointes is a malignant dysrhythmia that has been reported in a
variety of clinical settings and associated with several pharmacologic agents.
Patients with a prolonged QTc for heart rate are at higher risk for the
development of this arrhythmia. We review the literature supporting the
relationship of haloperidol to the development of this malignant dysrhythmia.
Clinicians in the critical care setting should be aware of potentially lethal
drug-induced ventricular tachydysrhythmias such as torsade de pointes.
Haustein, K. O. (2003). "Bupropion: pharmacological and clinical profile in
smoking cessation." Int J Clin Pharmacol Ther 41(2): 56-66.
Chemistry, pharmacokinetics, pharmacology, clinical efficacy, adverse effects
and dosage of bupropion hydrochloride (BP), an aminoketone antidepressant used
in smoking cessation, are reviewed. The nicotinergic acetylcholine receptors are
inhibited at clinically relevant concentrations of BP. BP does not inhibit
monoamine oxidase, and it has minimal inhibitory effects on presynaptic
noradrenaline and dopamine uptake. BP is rapidly absorbed after oral
administration and demonstrates biphasic elimination with an elimination
half-life of 11 - 14 hours. BP is extensively metabolized by oxidation and
reduction to at least 6 metabolites, 2 of which may be active. The plasma levels
of the erythro-amino alcohol of BP correlate with several side effects such as
insomnia and dry mouth. Efficacy of BP(SR) in smoking cessation has been
examined in several double-blind, randomized trials in which daily doses of 150
or 300 mg have been administered for 7 or 9 weeks. In addition, 1 study examined
the combination of BP(SR) plus nicotine patch. The point prevalences of stopping
smoking reached values between 21.2 and 38%, but they did not exceed those after
nicotine replacement therapy alone. Long-term administration (52 weeks) of BP
did not improve abstinence compared with placebo after a 2-year follow-up
period. Thus, the efficacy of BP in smoking cessation is comparable to that of
nicotine replacement therapy. However, BP possesses a broad spectrum of
infrequent adverse effects and interferes with the degradation of several drugs
such as tricyclic antidepressants, beta-recpetor blocking agents, class
Ic-antiarrhythmics etc. As the risk-benefit ratio of BP is smaller than that of
nicotine replacement, BP should be considered as a second-line treatment in
smoking cessation.
Hays, J. T. and J. O. Ebbert (2003). "Bupropion for the treatment of tobacco
dependence: guidelines for balancing risks and benefits." CNS Drugs 17(2):
71-83.
Tobacco use, particularly cigarette smoking, is now a global pandemic. The
expected morbidity and mortality from smoking-attributable diseases will
continue to rise for the next 30 years. In order to reduce this negative impact
on worldwide health, effective therapy to aid smoking cessation must be provided
to current smokers. Treatment for tobacco dependence involves the combination of
behavioural therapies and pharmacological treatment. The most common
pharmacological treatments include nicotine replacement therapy and non-nicotine
medications, including antidepressants. The antidepressant with the greatest
weight of evidence for efficacy in the treatment of tobacco dependence is
bupropion. Sustained-release bupropion is approved for the treatment of tobacco
dependence in over 50 countries worldwide. The efficacy of bupropion for the
treatment of tobacco dependence is attributed to the blockage of dopamine
reuptake in the mesolimbic dopaminergic system. This area of the brain is
believed to mediate reward for nicotine use and for other drugs of dependence.
Randomised, controlled clinical trials have shown that bupropion approximately
doubles abstinence rates compared with placebo. In addition, long-term treatment
with bupropion may reduce or delay smoking relapse. Bupropion also appears to be
effective in the treatment of smokers who have recently relapsed and smokers
with other comorbid psychiatric conditions. Bupropion has a good adverse events
profile, but the risk exists for serious adverse effects such as seizures.
Recent postmarketing surveillance reports have raised safety concerns about
bupropion, although no causal relationship between bupropion and the reported
serious adverse events or death has been established.
Henderson, A. (2003). "Domperidone. Discovering new choices for lactating
mothers." AWHONN Lifelines 7(1): 54-60.
Hirsch, E. C., G. Orieux, et al. (2003). "Nondopaminergic neurons in Parkinson's
disease." Adv Neurol 91: 29-37.
Homann, C. N., K. Wenzel, et al. (2003). "Sleep attacks--facts and fiction: a
critical review." Adv Neurol 91: 335-41.
Horstink, M. W., E. Strijks, et al. (2003). "Estrogen and Parkinson's disease."
Adv Neurol 91: 107-14.
Hudson, T. J., G. Sullivan, et al. (2003). "Economic evaluations of novel
antipsychotic medications: a literature review." Schizophr Res 60(2-3):
199-218.
OBJECTIVE: To evaluate the evidence that novel antipsychotic medications offer a
cost advantage compared to traditional antipsychotic medications. METHODS:
Literature for this review was identified through a computerized search of
Medline, Healthstar and Psyc-INFO databases inclusive from January 1989 to
January 2002. Articles included in the review were required to include cost
evaluation and to be published in peer-reviewed journals. RESULTS: Twenty-two
studies met inclusion criteria. All five studies that used experimental designs
found that second-generation antipsychotic medications were associated with a
cost advantage or were cost-neutral, and, in some cases, improved quality of
life. Of the ten studies using a pre-post design, four found an increase in
total costs, six reported a decrease in total costs, and four reported increased
effectiveness with use of a second-generation antipsychotic. All seven of the
simulation studies reported a cost advantage for novel antipsychotics for
specific patient populations under certain conditions. CONCLUSIONS: The majority
of studies found that novel antipsychotics are at least cost-neutral and may
offer cost advantages compared to traditional agents. Some studies also reported
greater improvement in effectiveness and quality of life when novel
antipsychotics were compared to traditional antipsychotic medications. However,
it is difficult to draw firm conclusions given the small sample sizes and
limited study designs available in this literature.
Hunot, S. and E. C. Hirsch (2003). "Neuroinflammatory processes in Parkinson's
disease." Ann Neurol 53 Suppl 3: S49-58; discussion S58-60.
Parkinson's disease (PD) is a movement disorder characterized by the progressive
degeneration of dopaminergic neurons in the midbrain. To date, its cause remains
unknown and the mechanism of nerve cell death uncertain. Apart from the massive
loss of dopaminergic neurons, PD brains also show a conspicuous glial reaction
together with signs of a neuroinflammatory reaction manifested by elevated
cytokine levels and upregulation of inflammatory-associated factors such as
cyclooxygenase-2 and inducible nitric oxide synthase. Mounting evidence also
suggests a possible deleterious effect of these neuroinflammatory processes in
experimental models of the disease. We propose that, in PD, neuroinflammation
plays a role in the cascade of events leading to nerve cell death, thus
propagating the neurodegenerative process. In this review, we summarize and
discuss the latest findings regarding neuroinflammatory aspects in PD.
Hussain, T. and M. F. Lokhandwala (2003). "Renal dopamine receptors and
hypertension." Exp Biol Med (Maywood) 228(2): 134-42.
Dopamine has been recognized as an important modulator of central as well as
peripheral physiologic functions in both humans and animals. Dopamine receptors
have been identified in a number of organs and tissues, which include several
regions within the central nervous system, sympathetic ganglia and
postganglionic nerve terminals, various vascular beds, the heart, the
gastrointestinal tract, and the kidney. The peripheral dopamine receptors
influence cardiovascular and renal function by decreasing afterload and vascular
resistance and promoting sodium excretion. Within the kidney, dopamine receptors
are present along the nephron, with highest density on proximal tubule
epithelial cells. It has been reported that there is a defective dopamine
receptor, especially D(1) receptor function, in the proximal tubule of various
animal models of hypertension as well as in humans with essential hypertension.
Recent reports have revealed the site of and the molecular mechanisms
responsible for the defect in D(1) receptors in hypertension. Moreover, recent
studies have also demonstrated that the disruption of various dopamine receptor
subtypes and their function produces hypertension in rodents. In this review, we
present evidence that dopamine and dopamine receptors play an important role in
regulating renal sodium excretion and that defective renal dopamine production
and/or dopamine receptor function may contribute to the development of various
forms of hypertension.
Ibanez, A., C. Blanco, et al. (2003). "Genetics of pathological gambling." J
Gambl Stud 19(1): 11-22.
Pathological gambling (PG) is an impulse control disorder and a model
'behavioral' addiction. Familial factors have been observed in clinical studies
of pathological gamblers, and twin studies have demonstrated a genetic influence
contributing to the development of PG. Serotonergic, noradrenergic, and
dopaminergic dysfunction have been reported as biological factors contributing
to the pathophysiology of PG. Molecular genetic techniques have been used to
investigate the role of genetic factors in PG. Molecular genetic research has
identified specific allele variants of candidate genes corresponding to these
neurotransmitter systems to be associated with PG. Associations have been
reported between pathological gamblers and allele variants of polymorphisms at
dopamine receptor genes, the serotonin transporter gene, and the
monoamine-oxidase A gene. Although preliminary data suggest that some of these
differences are gender-specific, more research needs to be performed to
substantiate gender-specific genetic contributions to the development of
pathological gambling. The review of the current findings on genetics of PG
suggests that liability to PG is in part mediated by genetic factors. Additional
studies are needed to replicate and extend these findings, as well as to better
understand the influence of specific allelic variants to differences in
biological and behavioral functioning.
Inoue, T., Y. Kitaichi, et al. (2003). "[Treatment strategy of refractory
depression and its presynaptic mechanism of action]." Nihon Shinkei Seishin
Yakurigaku Zasshi 23(1): 11-20.
Most antidepressants used in Japan are reuptake inhibitors of monoamine, such as
noradrenaline and serotonin. Incidence of refractory depression, which is
resistant to at least two monoamine reuptake inhibitors, is 10-20%. ECT and the
addition of lithium, thyroid hormones or dopamine agonists is used for the
treatment of refractory depression. Bupropion and MAO inhibitors are also
effective for refractory depression but not approved in Japan. The presynaptic
mechanism of action of these antidepressants has been studied by in vivo
microdialysis studies. Serotonin reuptake inhibitors increase extracellular
serotonin concentrations in the brain. Noradrenaline reuptake inhibitors
increase extracellular noradrenaline concentrations in the brain, and increase
extracellular dopamine concentrations in the frontal cortex, but not in the
nucleus accumbens or striatum. ECT and MAO inhibitors increase extracellular
serotonin concentrations in the brain, and ECT, bupropion and MAO inhibitors
increase extracellular noradrenaline concentrations in the brain. In contrast to
monoamine reuptake inhibitors, ECT, bupropion and MAO inhibitors increase
extracellular dopamine concentrations not only in the frontal cortex but also in
the nucleus accumbens and striatum. The facilitation of mesolimbic or
nigrostriatal dopamine neurotransmission may be the mechanism of action behind
these treatments' efficacies for refractory depression. Although there are only
a few studies concerning the mechanism of action of augmentation therapy, recent
studies demonstrated that subchronic lithium treatment increases basal
concentrations of extracellular serotonin in the frontal cortex and hippocampus.
Subchronic lithium further increases SSRI-induced increases in extracellular
serotonin concentrations, and this effect is suggested to be the mechanism of
action for lithium augmentation of antidepressants.
Isacson, O., L. M. Bjorklund, et al. (2003). "Toward full restoration of
synaptic and terminal function of the dopaminergic system in Parkinson's disease
by stem cells." Ann Neurol 53 Suppl 3: S135-46; discussion S146-8.
New therapeutic nonpharmacological methodology in Parkinson's disease (PD)
involves cell and synaptic renewal or replacement to restore function of
neuronal systems, including the dopaminergic (DA) system. Using fetal DA cell
therapy in PD patients and laboratory models, it has been demonstrated that
functional motor deficits associated with parkinsonism can be reduced. Similar
results have been observed in animal models with stem cell-derived DA neurons.
Evidence obtained from transplanted PD patients further shows that the
underlying disease process does not destroy transplanted fetal DA cells,
although degeneration of the host nigrostriatal system continues. The optimal DA
cell regeneration system would reconstitute a normal neuronal network capable of
restoring feedback-controlled release of DA in the nigrostriatal system. The
success of cell therapy for PD is limited by access to preparation and
development of highly specialized dopaminergic neurons found in the A9 and A10
region of the substantia nigra pars compacta as well as the technical and
surgical steps associated with the transplantation procedure. Recent laboratory
work has focused on using stem cells as a starting point for deriving the
optimal DA cells to restore the nigrostriatal system. Ultimately, understanding
the cell biological principles necessary for generating functional DA neurons
can provide many new avenues for better treatment of patients with PD.
Jaworski, J. N., A. Vicentic, et al. (2003). "CART peptides are modulators of
mesolimbic dopamine and psychostimulants." Life Sci 73(6): 741-7.
CART peptide produces behavioral effects when injected into the VTA or nucleus
accumbens. In the VTA, the peptide behaves like an endogenous psychostimulant
and produces increased locomotor activity and conditioned place preference.
Since this is blocked by dopamine receptor blockers, it presumably involves
release of dopamine. But in the nucleus accumbens, CART peptide reduces the
locomotor-increasing effects of cocaine. This suggests that the peptide is an
interesting target for medications development.
Jenner, P. (2003). "Oxidative stress in Parkinson's disease." Ann Neurol
53 Suppl 3: S26-36; discussion S36-8.
Oxidative stress contributes to the cascade leading to dopamine cell
degeneration in Parkinson's disease (PD). However, oxidative stress is
intimately linked to other components of the degenerative process, such as
mitochondrial dysfunction, excitotoxicity, nitric oxide toxicity and
inflammation. It is therefore difficult to determine whether oxidative stress
leads to, or is a consequence of, these events. Oxidative damage to lipids,
proteins, and DNA occurs in PD, and toxic products of oxidative damage, such as
4-hydroxynonenal (HNE), can react with proteins to impair cell viability. There
is convincing evidence for the involvement of nitric oxide that reacts with
superoxide to produce peroxynitrite and ultimately hydroxyl radical production.
Recently, altered ubiquitination and degradation of proteins have been
implicated as key to dopaminergic cell death in PD. Oxidative stress can impair
these processes directly, and products of oxidative damage, such as HNE, can
damage the 26S proteasome. Furthermore, impairment of proteasomal function leads
to free radical generation and oxidative stress. Oxidative stress occurs in
idiopathic PD and products of oxidative damage interfere with cellular function,
but these form only part of a cascade, and it is not possible to separate them
from other events involved in dopaminergic cell death.
Jenner, P. (2003). "The contribution of the MPTP-treated primate model to the
development of new treatment strategies for Parkinson's disease."
Parkinsonism Relat Disord 9(3): 131-7.
Current research into Parkinson's disease (PD) is directed at developing novel
agents and strategies for improved symptomatic management. The aim of this
research is to provide effective and maintained symptom control throughout the
course of the disease without loss of efficacy and without priming the basal
ganglia for the onset of dyskinesia. To achieve these objectives, it is
important to have relevant animal models of PD in which new pharmacological
agents and treatment strategies can be assessed prior to clinical assessment. At
present, the most effective experimental model of PD is the methyl phenyl
tetrahydropyridine (MPTP)-treated primate. Primates treated with MPTP develop
motor disturbances resembling those seen in idiopathic PD, including
bradykinesia, rigidity and postural abnormalities. In addition, MPTP-treated
primates are responsive to all commonly used antiparkinsonian agents and display
treatment-associated motor complications such as dyskinesia, wearing-off and
on-off, which occur during the long-term treatment of the illness.This review
examines how studies conducted in MPTP-treated primates have contributed to the
development of dopaminergic therapies. There is now accumulating evidence that
the pulsatile manner in which short-acting agents stimulate striatal dopamine
receptors is a key contributing factor to the priming of the basal ganglia for
dyskinesia induction. It has been suggested that providing more continuous
stimulation of dopamine receptors will avoid the development of motor
complications, particularly dyskinesia. So far, the actions of all commonly used
antiparkinsonian drugs assessed in MPTP-treated primates have proved to be
highly predictive of drug action in PD. These primate studies have demonstrated
that long-acting dopamine agonists and levodopa given in combination with a
catechol-O-methyl transferase (COMT) inhibitor (to increase its relatively short
half-life), induce significantly less dyskinesia than occurs with standard
levodopa therapy.
Joseph, A. M. and S. S. Fu (2003). "Safety issues in pharmacotherapy for smoking
in patients with cardiovascular disease." Prog Cardiovasc Dis 45(6):
429-41.
Twenty percent of patients with cardiovascular disease smoke, and smoking
cessation results in a dramatic decline in the relative risk of future
cardiovascular events. Questions regarding the safety of nicotine-replacement
therapy and bupropion SR for smoking cessation in patients with cardiovascular
disease have arisen, in particular because of potential hemodynamic effects of
these agents. There have been several randomized, controlled, clinical trials
testing the safety of transdermal nicotine in patients with cardiovascular
disease that failed to show an increased risk for cardiac events in active
treatment conditions compared with placebo. Efficacy trials conducted in other
patient populations also support the safety of nicotine-replacement use in
cardiac disease patients. To date there is one randomized controlled trial to
test bupropion for smoking cessation conducted in this population. Studies to
test the efficacy of bupropion for smoking cessation and depression suggest it
is safe to use in cardiac disease patients despite recent case reports of
adverse events associated with bupropion use. Nicotine-replacement therapy and
bupropion significantly increase long-term smoking cessation rates, and the
benefits of cessation exceed the risks for pharmacotherapy in patients with
cardiovascular disease.
Kalivas, P. W., S. Toda, et al. (2003). "The temporal sequence of changes in
gene expression by drugs of abuse." Methods Mol Med 79: 3-11.
Kalsi, J. S., S. Minhas, et al. (2003). "Oral agents for erectile dysfunction."
Hosp Med 64(5): 292-5.
Erectile dysfunction is a common disease affecting the lives of millions of men
worldwide. Sildenafil was the first oral treatment licensed for male erectile
dysfunction. However, there are now a number of other options available. In this
article the currently available oral treatments are reviewed.
Kamitani, W., K. Tomonaga, et al. (2003). "[Borna disease virus infection]."
Nippon Rinsho 61 Suppl 2: 128-34.
Kantak, K. M. (2003). "Anti-cocaine vaccines: antibody protection against
relapse." Expert Opin Pharmacother 4(2): 213-8.
The past decade has seen the development of several vaccines against
illicit-drugs. These include vaccines for producing antibodies against cocaine,
heroin, methamphetamine and nicotine. The present focus is on anti-cocaine
vaccines, as more research has been conducted with these vaccines than other
vaccines targeted against a drug of abuse. Attention needs to be given to the
structure of the hapten being conjugated, the characteristics of the carrier
protein for conjugation with the hapten and the immunisation regimen for
antibody production. These issues have an impact on the level of and variability
in the anti-cocaine antibodies actively induced and, consequently, on the
pharmacokinetic and pharmacodynamic properties of the vaccine. These issues also
have an impact on the preclinical and clinical success of the vaccine in
protecting against drug use and relapse. If an anti-cocaine vaccine is to be
clinically useful, it must induce a sufficient level of antibody in the blood to
prevent easy surmountability of protection by continued cocaine use and should
be compatible with other treatment medications that may be simultaneously
administered.
Kao, L. W., M. A. Kirk, et al. (2003). "Droperidol, QT prolongation, and sudden
death: what is the evidence?" Ann Emerg Med 41(4): 546-58.
STUDY OBJECTIVE: Droperidol is a butyrophenone commonly used as an antiemetic
and antipsychotic in the United States since US Food and Drug Administration
(FDA) approval in 1970. Its labeling has recently been revised, with a black box
warning for cases of QT prolongation leading to torsades de pointes and death. A
black box warning is applied when serious adverse drug reactions are uncovered
for medications. We sought to examine the evidence of a causal association
suggested by the black box warning to aid clinicians in their risk-benefit
analyses regarding further use of droperidol. METHODS: A literature search was
undertaken to determine the evidence regarding the association between
droperidol and QT prolongation or torsades de pointes. The evidence was then
evaluated by using evidence-based medicine principles. In addition, a review of
the FDA regulatory process is presented. RESULTS: Three clinical studies, 1
published abstract, and 7 case reports were reviewed. Available postmarketing
surveillance data (MedWatch reports) were also reviewed. Applying the criteria
of evidence-based medicine and Hill's criteria, the evidence is not convincing
for a causal relationship between therapeutic droperidol administration and
life-threatening cardiac events. CONCLUSION: The recent black box warning
appears to have originated from postmarketing surveillance data rather than data
reported in the peer-reviewed medical literature. Ongoing monitoring of drug
safety and more definitive study appear appropriate.
Kapur, S. (2003). "Psychosis as a state of aberrant salience: a framework
linking biology, phenomenology, and pharmacology in schizophrenia." Am J
Psychiatry 160(1): 13-23.
OBJECTIVE: The clinical hallmark of schizophrenia is psychosis. The objective of
this overview is to link the neurobiology (brain), the phenomenological
experience (mind), and pharmacological aspects of psychosis-in-schizophrenia
into a unitary framework. METHOD: Current ideas regarding the neurobiology and
phenomenology of psychosis and schizophrenia, the role of dopamine, and the
mechanism of action of antipsychotic medication were integrated to develop this
framework. RESULTS: A central role of dopamine is to mediate the "salience" of
environmental events and internal representations. It is proposed that a
dysregulated, hyperdopaminergic state, at a "brain" level of description and
analysis, leads to an aberrant assignment of salience to the elements of one's
experience, at a "mind" level. Delusions are a cognitive effort by the patient
to make sense of these aberrantly salient experiences, whereas hallucinations
reflect a direct experience of the aberrant salience of internal
representations. Antipsychotics "dampen the salience" of these abnormal
experiences and by doing so permit the resolution of symptoms. The
antipsychotics do not erase the symptoms but provide the platform for a process
of psychological resolution. However, if antipsychotic treatment is stopped, the
dysregulated neurochemistry returns, the dormant ideas and experiences become
reinvested with aberrant salience, and a relapse occurs. CONCLUSIONS: The
article provides a heuristic framework for linking the psychological and
biological in psychosis. Predictions of this hypothesis, particularly regarding
the possibility of synergy between psychological and pharmacological therapies,
are presented. The author describes how the hypothesis is complementary to other
ideas about psychosis and also discusses its limitations.
Keck, P. E., Jr. and S. L. McElroy (2003). "Aripiprazole: a partial dopamine D2
receptor agonist antipsychotic." Expert Opin Investig Drugs 12(4):
655-62.
This paper reviews the clinical pharmacology, efficacy and safety of the novel
antipsychotic drug aripiprazole. All published citations regarding aripiprazole
were reviewed using a Medline((R)) search (completed for citations through
mid-year, 2002). In addition, abstracts from recent scientific meetings
presenting data not yet published (nor peer-reviewed) were reviewed.
Aripiprazole has a unique mechanism of action as a dopamine D2 partial agonist,
serotonin 5-HT(1A) partial agonist and serotonin 5-HT(2A) antagonist. Like other
new antipsychotics, aripiprazole has the profile of an atypical agent, with
efficacy in the treatment of positive and negative symptoms of psychosis as well
as mood symptoms, a low rate of neurological side effects and no significant
adverse effect on serum prolactin concentrations. In addition, aripiprazole was
not associated with significant weight gain or QTc prolongation in both acute
and long-term treatment trials.
Khurana, S., V. Batra, et al. (2003). "Twenty-first century tobacco use: it is
not just a risk factor anymore." Respir Med 97(4): 295-301.
Despite availability of effective treatments for nicotine addiction, smoking
remains prevalent with serious health consequences. Most smokers recognize the
ill effects of smoking but are unable to quit. Nicotine addiction may be viewed
as any other chronic illness that results from exposure to a recognizable agent
(tobacco) and manifests with a well-documented set of signs and symptoms. Much
like any chronic disease, both environmental and genetic factors determine the
occurrence and severity of this affliction. There has been recent focus on
uncovering the genetic basis of nicotine addiction. In this article, we have
attempted to briefly review the current evidence for the role of genetics in
smoking as well as comment on available pharmacotherapeutic options for treating
nicotine dependence.
Klinman, J. P. (2003). "The multi-functional topa-quinone copper amine
oxidases." Biochim Biophys Acta 1647(1-2): 131-7.
The mature copper amine oxidases (CAOs) contain a tyrosine-derived
2,4,5-trihydroxyphenylalanyl quinone (topa quinone or TPQ) and a cupric ion in
close proximity. Through a combination of structural, spectroscopic and kinetic
analyses, a chemical mechanism for the self-processing of an active site
tyrosine to TPQ has been proposed. Once formed, TPQ acts as a switch between the
heterolytic transformation of amine substrates to aldehydes, via a pyridoxal
phosphate-like Schiff base complex, and one electron chemistry involving
reduction of molecular oxygen. The relationship between the biogenetic and
catalytic processes is discussed.
Knegtering, H., A. E. van der Moolen, et al. (2003). "What are the effects of
antipsychotics on sexual dysfunctions and endocrine functioning?"
Psychoneuroendocrinology 28 Suppl 2: 109-23.
The literature is reviewed and preliminary results of new studies are presented
showing that treatment with classical antipsychotics, as well as risperidone,
induces sexual dysfunctions in 30-60% of the patients. These antipsychotics also
frequently induce amenorrhoea and galactorrhoea.Although comparative studies are
rare, it is likely that prolactin-sparing antipsychotics, as recently shown in a
randomized trial of olanzapine versus risperidone, induce less sexual side
effects.From these studies, it becomes apparent that prolactin elevation induced
by classical antipsychotics and risperidone is probably a factor in inducing
sexual dysfunctions, amenorrhoea and galactorrhoea. The role of other factors
inducing sexual dysfunctions like sedation, proportional, variant -blockade,
testosterone, dopamine, and serotonin is discussed. Finally, it is concluded
that sexual and hormonal effects of antipsychotics, although clearly important,
are often neglected in research as in clinical practice. Lowering the dosage or
switching to a prolactin-sparing antipsychotic often reduces sexual side
effects, amenorrhoea, and galactorrhoea.
Korczyn, A. D. (2003). "Dopaminergic drugs in development for Parkinson's
disease." Adv Neurol 91: 267-71.
Kumar, A., Z. Huang, et al. (2003). "Mechanisms of motor complications in
treatment of Parkinson's disease." Adv Neurol 91: 193-201.
Lambert, T. J. and D. J. Castle (2003). "Pharmacological approaches to the
management of schizophrenia." Med J Aust 178 Suppl: S57-61.
Pharmacological treatment remains the mainstay of the management of
schizophrenia. Older, "typical" antipsychotics carry a significant burden of
side effects, notably extrapyramidal and neurocognitive side effects. Newer,
"atypical" agents carry a lower risk of extrapyramidal side effects. They appear
to have added benefit for treating negative and cognitive symptoms of
schizophrenia, and hence can enhance the quality of life of some patients. The
choice of particular agents for individual patients requires a balancing of
efficacy and side effects. Medication is only one element of what should be an
individualised comprehensive treatment plan for people with schizophrenia.
Langfelder, K., M. Streibel, et al. (2003). "Biosynthesis of fungal melanins and
their importance for human pathogenic fungi." Fungal Genet Biol 38(2):
143-58.
For more than 40 years fungi have been known to produce pigments known as
melanins. Predominantly these have been dihydroxyphenylalanine (DOPA)-melanin
and dihydroxynaphthalene (DHN)-melanin. The biochemical and genetical analysis
of the biosynthesis pathways have led to the identification of the genes and
corresponding enzymes of the pathways. Only recently have both these types of
melanin been linked to virulence in some human pathogenic and phytopathogenic
fungi. The absence of melanin in human pathogenic and phytopathogenic fungi
often leads to a decrease in virulence. In phytopathogenic fungi such as
Magnaporthe grisea and Colletotrichum lagenarium, besides other possible
functions in pathogenicity, DHN-melanin plays an essential role in generating
turgor for plant appressoria to penetrate plant leaves. While the function of
melanin in human pathogenic fungi such as Cryptococcus neoformans, Wangiella
dermatitidis, Sporothrix schenckii, and Aspergillus fumigatus is less well
defined, its role in protecting fungal cells has clearly been shown.
Specifically, the ability of both DOPA- and DHN-melanins to quench free radicals
is thought to be an important factor in virulence. In addition, in several fungi
the production of fungal virulence factors, such as melanin, has been linked to
a cAMP-dependent signaling pathway. Many of the components involved in the
signaling pathway have been identified.
Langlois, M., F. Richer, et al. (2003). "New perspectives on dystonia." Can J
Neurol Sci 30 Suppl 1: S34-44.
Dystonia is a syndrome of sustained muscular contractions with numerous
underlying etiologies. This review examines the varied phenomenology of
dystonias, its evolving classification including recent genetic data as well as
its clinical investigation and treatment. Although age of onset, anatomical
distribution and family history are key elements of the investigation of
dystonia, classification increasingly relies on etiologic and genetic criteria.
Physiological abnormalities in striato-cortical circuits are common in dystonia
but the pathophysiology is still unclear. In recent years, a great deal has been
learned on the more common primary dystonias such as primary torsion dystonia
and on dystonia-plus syndromes such as dopamine responsive dystonia. Treatment
of dystonia has also evolved and there are now a number of therapeutic agents
with clear beneficial effects including anticholinergics, benzodiazepines, and
botulinum toxin and there is growing interest in neurofunctional surgery
including deep brain stimulation.
Larsen, J. P. (2003). "Sleep disorders in Parkinson's disease." Adv Neurol
91: 329-34.
Lata, P. F. and D. L. Pigarelli (2003). "Chronic metoclopramide therapy for
diabetic gastroparesis." Ann Pharmacother 37(1): 122-6.
OBJECTIVE: To review the safety and efficacy of chronic metoclopramide for
diabetic gastroparesis. DATA SOURCES: Medical literature was accessed through
MEDLINE (1965 to October 2002) and PubMed (1965 to October 2002). Key search
terms included metoclopramide; diabetic gastroparesis; and dyskinesia, drug
induced. DATA SYNTHESIS: Metoclopramide is often used for diabetic
gastroparesis, despite the risk of tardive dyskinesia. Published information is
limited regarding long-term efficacy and toxicity of metoclopramide. The
literature was assessed concerning these topics. CONCLUSIONS: Limited data do
not provide sufficient evidence to conclude whether metoclopramide is
efficacious for chronic use. Routine monitoring may mitigate the risk associated
with metoclopramide therapy.
Lau, Y. S. and G. E. Meredith (2003). "From drugs of abuse to parkinsonism. The
MPTP mouse model of Parkinson's disease." Methods Mol Med 79:
103-16.
Lavenstein, B. L. (2003). "Treatment approaches for children with Tourette's
syndrome." Curr Neurol Neurosci Rep 3(2): 143-8.
Tourette's syndrome has been of neurologic and psychiatric interest since the
original description of this condition by Gilles de la Tourette in 1885, and it
has been associated with a wide variety of treatments over the years. With the
advent of advances in neurochemistry and neuropharmacology, a neurobiologic
approach has emerged with the application of many drugs from the fields of
neurology and psychiatry. In addition, many of the comorbid conditions that
coexist, such as attention deficit disorder and obsessive compulsive disorder
(OCD), are amenable to both pharmacologic and behavioral approaches. Drug
treatment has included dopamine receptor blockers for tics, dopamine agonists,
dopamine depletors, and stimulants for attention deficit hyperactivity disorder
(ADHD), noradrenergic drugs for tics and ADHD, serotonergic drugs for OCD, and
chemical denervation for involuntary movements with the use of botulinum toxin
and stereotactic surgery. It is the purpose of this review to outline the
various approaches that are currently available as treatments, realizing that as
new drugs are introduced in neurology and psychiatry, they too will find their
way into treatment options.
Lavigne, G. J., T. Kato, et al. (2003). "Neurobiological mechanisms involved in
sleep bruxism." Crit Rev Oral Biol Med 14(1): 30-46.
Sleep bruxism (SB) is reported by 8% of the adult population and is mainly
associated with rhythmic masticatory muscle activity (RMMA) characterized by
repetitive jaw muscle contractions (3 bursts or more at a frequency of 1 Hz).
The consequences of SB may include tooth destruction, jaw pain, headaches, or
the limitation of mandibular movement, as well as tooth-grinding sounds that
disrupt the sleep of bed partners. SB is probably an extreme manifestation of a
masticatory muscle activity occurring during the sleep of most normal subjects,
since RMMA is observed in 60% of normal sleepers in the absence of grinding
sounds. The pathophysiology of SB is becoming clearer, and there is an abundance
of evidence outlining the neurophysiology and neurochemistry of rhythmic jaw
movements (RJM) in relation to chewing, swallowing, and breathing. The sleep
literature provides much evidence describing the mechanisms involved in the
reduction of muscle tone, from sleep onset to the atonia that characterizes
rapid eye movement (REM) sleep. Several brainstem structures (e.g., reticular
pontis oralis, pontis caudalis, parvocellularis) and neurochemicals (e.g.,
serotonin, dopamine, gamma aminobutyric acid [GABA], noradrenaline) are involved
in both the genesis of RJM and the modulation of muscle tone during sleep. It
remains unknown why a high percentage of normal subjects present RMMA during
sleep and why this activity is three times more frequent and higher in amplitude
in SB patients. It is also unclear why RMMA during sleep is characterized by
co-activation of both jaw-opening and jaw-closing muscles instead of the
alternating jaw-opening and jaw-closing muscle activity pattern typical of
chewing. The final section of this review proposes that RMMA during sleep has a
role in lubricating the upper alimentary tract and increasing airway patency.
The review concludes with an outline of questions for future research.
Le Crom, S., M. Kapsimali, et al. (2003). "Dopamine receptors for every species:
gene duplications and functional diversification in Craniates." J Struct
Funct Genomics 3(1-4): 161-76.
The neuromodulatory effects of dopamine on the central nervous system of
craniates are mediated by two classes of G protein-coupled receptors (D1 and
D2), each comprising several subtypes. A systematic isolation and
characterization of the D1 and D2-like receptors was carried out in most of the
Craniate groups. It revealed that two events of gene duplications took place
during vertebrate evolution, before or simultaneously to the emergence of
Gnathostomes. It led to the conservation of two-to-four paralogous receptors
(subtypes), depending on the species. Additional duplication of dopamine
receptor gene occurred independently in the teleost fish lineage. Duplicated
genes were maintained in most of the vertebrate groups, certainly by the
acquisition of a few functional characters, specific of each subtypes, as well
as by discrete changes in their expression territories in the brain. The
evolutionary scenario elaborated from these data suggests that receptor gene
duplications were the necessary conditions for the expansion of vertebrate
forebrain to occur, allowing dopamine systems to exert their fundamental role as
modulator of the adaptive capabilities acquired by vertebrate species.
Lepor, N. E. (2003). "A review of contemporary prevention strategies for
radiocontrast nephropathy: a focus on fenoldopam and N-acetylcysteine." Rev
Cardiovasc Med 4 Suppl 1: S15-20.
The mechanism most likely responsible for the development of radiocontrast
nephropathy (RCN) is contrast-induced renal tubular ischemia. At this time,
intravenous hydration remains the mainstay for preventing RCN. The
antihypertensive agent fenoldopam has been shown in a canine model, as well as
in small, retrospective, prospective, and randomized human evaluations, to be
effective for preventing RCN. In addition, studies have reported the ability of
the free radical scavenger N-acetylcysteine (NAC) to prevent RCN. The clinical
trial data for NAC, however, are not consistent regarding this effect, which, if
present, appears to be modest and perhaps restricted to lower-risk clinical
scenarios.
Leri, F., J. Bruneau, et al. (2003). "Understanding polydrug use: review of
heroin and cocaine co-use." Addiction 98(1): 7-22.
The use of cocaine by heroin-dependent individuals, or by patients in methadone
or buprenorphine maintenance treatment, is substantial and has negative
consequences on health, social adjustment and outcome of opioid-addiction
treatment. The pharmacological reasons for cocaine use in opioid-dependent
individuals, however, are poorly understood and little is known about the
patterns of heroin and cocaine co-use. We reviewed anecdotal evidence suggesting
that cocaine is co-used with opioid drugs in a variety of different patterns, to
achieve different goals. Clinical and preclinical experimental evidence
indicates that the simultaneous administration of cocaine and heroin (i.e.
'speedball') does not induce a novel set of subjective effects, nor is it more
reinforcing than either drug alone, especially when the doses of heroin and
cocaine are high. There is mixed evidence that the subjective effects of cocaine
are enhanced in individuals dependent on opioids, although it is clear that
cocaine can alleviate the severity of symptoms of withdrawal from opioids. We
also reviewed preclinical studies investigating possible neurobiological
interactions between opioids and cocaine, but the results of these studies have
been difficult to interpret mainly because the neurochemical mechanisms
mediating the motivational effects of cocaine are modified by dependence on, and
withdrawal from, opioid drugs. Our analysis encourages further systematic
investigation of cocaine use patterns among opioid-dependent individuals and in
laboratory animals. Once clearly identified, pharmacological and neuroanatomical
methods can be employed in self-administering laboratory animals to uncover the
neurobiological correlates of specific patterns of co-use.
Licata, S. C. and R. C. Pierce (2003). "The roles of
calcium/calmodulin-dependent and Ras/mitogen-activated protein kinases in the
development of psychostimulant-induced behavioral sensitization." J Neurochem
85(1): 14-22.
Although the development of behavioral sensitization to psychostimulants such as
cocaine and amphetamine is confined mainly to one nucleus in the brain, the
ventral tegmental area (VTA), this process is nonetheless complex, involving a
complicated interplay between neurotransmitters, neuropeptides and trophic
factors. In the present review we present the hypothesis that calcium-stimulated
second messengers, including the calcium/calmodulin-dependent protein kinases
and the Ras/mitogen-activated protein kinases, represent the major biochemical
pathways whereby converging extracellular signals are integrated and amplified,
resulting in the biochemical and molecular changes in dopaminergic neurons in
the VTA that represent the critical neuronal correlates of the development of
behavioral sensitization to psychostimulants. Moreover, given the important role
of calcium-stimulated second messengers in the expression of behavioral
sensitization, these signal transduction systems may represent the biochemical
substrate through which the transient neurochemical changes associated with the
development of behavioral sensitization are translated into the persistent
neurochemical, biochemical and molecular alterations in neuronal function that
underlie the long-term expression of psychostimulant-induced behavioral
sensitization.
Lima, M. S., A. A. Reisser, et al. (2003). "Antidepressants for cocaine
dependence." Cochrane Database Syst Rev(2): CD002950.
BACKGROUND: Cocaine dependence is a common and serious condition, which has
become a substantial public health problem. The past decade has witnessed a
sustained search for an effective pharmacotherapeutic agent for the treatment of
cocaine dependence. While administration of cocaine acutely increases
intercellular dopamine, serotonin, and norepinephrine levels by blocking their
presynaptic reuptake, chronic cocaine abuse leads to down-regulation of
monoamine systems. Post-cocaine use depression and cocaine craving may be linked
to this down-regulation. Antidepressant pharmacotherapy, by augmenting monoamine
levels, may alleviate cocaine abstinence symptomatology, as well as relieving
dysphoria and associated craving by general antidepressant action. OBJECTIVES:
To conduct a systematic review of all RCTs on the use of antidepressants for
treating cocaine dependence. SEARCH STRATEGY: We searched the Cochrane
Controlled Trials Register (Cochrane Library, issue 4, 2000), MEDLINE (from 1966
- 2000), EMBASE (from 1980 - 2000), LILACS (from 1982 - 2000), PsycLIT (from
1974 - 2000), Biological Abstracts (1982 to 2000). Other searches:reference
searching; personal communication; conference abstracts; unpublished trials from
pharmaceutical industry; book chapters on treatment of cocaine dependence.
SELECTION CRITERIA: The inclusion criteria for all randomised controlled trials
were that they should focus on the use of antidepressants on the treatment of
cocaine dependence. Trials including patients with additional diagnosis such as
opiate dependence were also eligible. DATA COLLECTION AND ANALYSIS: The
reviewers extracted the data independently and Relative Risks, weighted mean
difference and number needed to treat were estimated. The reviewers assumed that
people who died or dropped out had no improvement and tested the sensitivity of
the final results to this assumption. MAIN RESULTS: 18 studies were included in
the review, with 1177 people randomised. Positive urine sample for cocaine
metabolites was the main efficacy outcome, with no significant results obtained
regardless of the type of antidepressant. Compared to other drugs, desipramine
performed better but showing just a non significant trend with heterogeneity
present as revealed by the chi-square test (8.6, df=3; p=0.04). One single trial
showed imipramine performed better than placebo in terms of clinical response
according to patient's self-report. A similar rate of patients remaining in
treatment was found for both patients taking desipramine or placebo. Results
from one single trial suggest fluoxetine patients on SSRIs are less likely to
dropout. Similar results were obtained for trials where patients had additional
diagnosis of opioid dependence and/or were in methadone maintenance treatment.
REVIEWER'S CONCLUSIONS: There is no current evidence supporting the clinical use
of antidepressants in the treatment of cocaine dependence. Given the high rate
of dropouts in this population, clinicians may consider adding psychotherapeutic
supportive measures aiming to keep patients in treatment.
Lingford-Hughes, A. R., S. J. Davies, et al. (2003). "Addiction." Br Med Bull
65: 209-22.
Alcohol and psycho-active substance misuse has far-reaching social,
psychological and physical consequences. Advances in neuroimaging technology
have allowed neurobiological theories of addiction to become better
characterized. We describe the neurobiology of dependence, withdrawal,
abstinence and craving states in alcohol, stimulant and opiate misuse.
Structural neuroimaging techniques such as CT and MRI with new analytical
approaches such as voxel-based morphometry have shown wide-spread changes in
stimulant and opiate abuse and atrophy, particularly in the frontal lobes, in
alcoholism. Functional neuroimaging techniques such as PET, SPECT and fMRI
reveal altered regional cerebral activity by all drugs of abuse. The
neurochemistry of addiction, particularly involving dopamine, serotonin, opiate
and GABA, has been studied with PET and SPECT and similarities between all drugs
of abuse have been found such as reduced dopaminergic markers. The evidence
derived from these advances in neuroimaging is likely to herald the emergence of
new biological treatments in this important field.
Lingford-Hughes, A. and D. Nutt (2003). "Neurobiology of addiction and
implications for treatment." Br J Psychiatry 182: 97-100.
Liu, B. and J. S. Hong (2003). "Neuroprotective effect of naloxone in
inflammation-mediated dopaminergic neurodegeneration. Dissociation from the
involvement of opioid receptors." Methods Mol Med 79: 43-54.
Liu, B. and J. S. Hong (2003). "Role of microglia in inflammation-mediated
neurodegenerative diseases: mechanisms and strategies for therapeutic
intervention." J Pharmacol Exp Ther 304(1): 1-7.
Evidence from postmortem analysis implicates the involvement of microglia in the
neurodegenerative process of several degenerative neurological diseases,
including Alzheimer's disease and Parkinson's disease. It remains to be
determined, however, whether microglial activation plays a role in the
initiation stage of disease progression or occurs merely as a response to
neuronal death. Activated microglia secrete a variety of proinflammatory and
neurotoxic factors that are believed to induce and/or exacerbate
neurodegeneration. In this article, we summarize recent advances on the study of
the role of microglia based on findings from animal and cell culture models in
the pathogenesis of neurodegenerative diseases, with particular emphasis on
Parkinson's disease. In addition, we also discuss novel approaches to potential
therapeutic strategies.
Loonam, T. M., P. A. Noailles, et al. (2003). "Substance P and cholecystokinin
regulate neurochemical responses to cocaine and methamphetamine in the
striatum." Life Sci 73(6): 727-39.
The mechanism of action of drugs of abuse like cocaine and amphetamines has been
studied extensively in the dopamine terminal field areas of the caudate-putamen
(CPu) and the nucleus accumbens (NAc) of the rodent brain. These brain regions
contain several neuropeptides that must play important roles in the normal
physiological functions of these brain regions. The study of neuropeptide
physiology in the context of the neurobiological responses to drugs of abuse may
shed some light on the intrinsic mechanism of action of neuropeptides of the CPu
and the NAc. The neuropeptides substance P (SP) and cholecystokinin (CCK) are
present in the striatum where they could play an important role regulating the
effects of psychostimulants like cocaine and amphetamines (methamphetamine
[METH] is a long acting derivative of d-amphetamine). These highly addictive
agents induce the release of dopamine (DA) (and other catecholamines) from
dopaminergic terminals of the striatum. The excessive release of DA in the
striatum and the NAc has been implicated in the habit-forming properties of
these drugs. In order to study the contribution of SP and CCK in the striatum
during psychostimulant treatment, we employed selective non-peptide neurokinin-1
(NK-1) and cholecystokinin-2 (CCK-2) receptor antagonists that readily cross the
blood brain barrier. We infused the neurokinin-1 receptor (NK-1R) antagonist,
L-733,060, into the striatum of freely moving rats via a microdialysis probe in
order to assess the effects of SP on cocaine-induced DA overflow in the
striatum. Infusion of the NK-1R antagonist prior to a systemic injection of
cocaine (10 mg/kg i.p.) significantly attenuated DA overflow in the striatum.
Conversely, infusion of a CCK-2 receptor (CCK-2R) antagonist, L-369,293, through
the microdialysis probe evoked DA overflow in the striatum in the absence of
cocaine and potentiated DA overflow after a single injection of cocaine (10
mg/kg i.p.). Exposure to METH (10 mg/kg 4x at two-hour intervals) produced
deficits of dopamine transporters (DAT) in mice striatum that are detectable
three days after the treatment and are long lasting. Pre-treatment (i.p.
injections) with the NK-1R antagonist, WIN-51,708 30 minutes before the 1st and
4th injections of METH prevented the loss of DAT in the striatum. Moreover,
pre-treatment with the NK-1R antagonist prevents METH-induced cell death. Taken
together, these results demonstrate that the NK-1R and the CCK-2R are important
modulators of the actions of the psychostimulants cocaine and METH. Neuropeptide
receptors represent an important control point mediating the effects of the
neurotransmitter DA in the striatum of the rodent brain.
Mandel, S., O. Weinreb, et al. (2003). "Using cDNA microarray to assess
Parkinson's disease models and the effects of neuroprotective drugs." Trends
Pharmacol Sci 24(4): 184-91.
The remarkable progress made by molecular biology and molecular genetics during
the past decade, and the advent of the novel tools of genomics and proteomics,
are expected to reveal differential expression profiles of thousands of genes
and proteins involved in the degeneration of dopamine-containing cells in
Parkinson's disease and allow more focused treatments according to individual
genotypes. Of particular interest is the application of microarrays in drug
discovery and design to identify 'fingerprints' as potential candidate targets
for drug intervention. The major microarray findings relevant to Parkinson's
disease and its neurotoxin-induced animal and cell models will be discussed,
with particular reference to the neuroprotective therapeutic potential that
could arise from the development of drugs 'a la carte'.
Mandel, S., E. Grunblatt, et al. (2003). "Genes and oxidative stress in
parkinsonism: cDNA microarray studies." Adv Neurol 91: 123-32.
Mangiavacchi, M. and E. Gronda (2003). "[Inotropic agents in advanced and
refractory heart failure]." Ital Heart J 4(1 Suppl): 3-7.
Marek, K., D. Jennings, et al. (2003). "Dopamine agonists and Parkinson's
disease progression: what can we learn from neuroimaging studies." Ann Neurol
53 Suppl 3: S160-6; discussion S166-9.
Marek, K., D. Jennings, et al. (2003). "Single-photon emission tomography and
dopamine transporter imaging in Parkinson's disease." Adv Neurol 91:
183-91.
Markley, H. G. (2003). "Topical agents in the treatment of cluster headache."
Curr Pain Headache Rep 7(2): 139-43.
This article discusses topical intranasal medications in the treatment of
cluster headache.
Marles, S. L., M. Reed, et al. (2003). "Humeroradial synostosis, ulnar aplasia
and oligodactyly, with contralateral amelia, in a child with prenatal cocaine
exposure." Am J Med Genet 116A(1): 85-9.
Humeral "bifurcation" due to humeroradial synostosis, and amelia are both very
rare limb anomalies. We report on a Canadian. Aboriginal boy with both these
limb deficiencies. The family history was unremarkable, but he was exposed
prenatally to cocaine at the time of limb development. Humeroradial synostosis
with ulnar aplasia has been reported by several authors. The majority of cases
are unilateral. When both upper limbs arms are involved, cases with oligodactyly
often have asymmetrical limb deficiencies and have all been sporadic to date.
Some appear to represent cases of the femur-fibula-ulna or FFU complex. Affected
individuals with normal hands usually have symmetrical defects and show an
autosomal recessive pattern of inheritance. Limb deficiencies have been reported
in several infants exposed prenatally to cocaine and have been inducible in
animal models. Most are terminal transverse defects or deficiencies of middle
digits. When more than one limb is involved, the defects are usually asymmetric.
Our case appears to be one of the most severely affected children reported to
date.
Marras, C. and A. E. Lang (2003). "Measuring motor complications in clinical
trials for early Parkinson's disease." J Neurol Neurosurg Psychiatry
74(2): 143-6.
Martin, W. R. and M. Wieler (2003). "Treatment of Parkinson's disease." Can J
Neurol Sci 30 Suppl 1: S27-33.
Parkinson's disease is a progressive neurodegenerative disorder that demands a
holistic approach to treatment. Both pharmacologic and nonpharmacologic
interventions play an important role in the comprehensive management of this
disorder. While levodopa remains the single most effective medication for
symptomatic treatment, dopamine agonists are playing an increasingly important
role. Motor complications of dopaminergic therapy are a significant issue,
particularly in patients with more advanced disease who have been on levodopa
for several years. All therapeutic interventions must be tailored to the
individual and modified as the disease progresses, with the goal of minimizing
significant functional disability as much as possible.
Marwick, T. H. (2003). "Stress echocardiography." Heart 89(1):
113-8.
Mathur, V. S. (2003). "The role of the DA1 receptor agonist fenoldopam in the
management of critically ill, transplant, and hypertensive patients." Rev
Cardiovasc Med 4 Suppl 1: S35-40.
Fenoldopam, a selective agonist of dopamine-1 receptors, is a regional and
systemic vasodilator. In randomized, controlled clinical trials, fenoldopam has
been found to preserve renal function in situations of potential renal ischemia,
such as during radiocontrast administration, cardiac and peripheral vascular
surgery, liver transplantation, and treatment of severe hypertension. Fenoldopam
lowers blood pressure in patients with hypertension, but has little or no effect
on blood pressure in those who are normotensive. The role of fenoldopam in
managing critically ill, transplant, and hypertensive patients is reviewed in
this article.
McKeith, I. G., D. J. Burn, et al. (2003). "Dementia with Lewy bodies." Semin
Clin Neuropsychiatry 8(1): 46-57.
The objective was to summarize recent findings about the clinical features,
diagnosis and investigation of dementia with Lewy (DLB) bodies, together with
its neuropathology, neurochemistry and genetics. Dementia with Lewy bodies (DLB)
is a primary, neurodegenerative dementia sharing clinical and pathological
characteristics with both Parkinson's disease (PD) and Alzheimer's disease (AD).
Antiubiquitin immunocytochemical staining, developed in the early 1990s, allowed
the frequency and distribution of cortical LBs to be defined. More recently,
alpha-synuclein antibodies have revealed extensive neuritic pathology in DLB
demonstrating a neurobiological link with other "synucleinopathies" including PD
and multiple system atrophy (MSA). The most significant correlates of cognitive
failure in DLB appear to be with cortical LB and Lewy neurites (LNs) rather than
Alzheimer type pathology. Clinical diagnostic criteria for DLB, published in
1996, have been subjected to several validation studies against autopsy
findings. These conclude that although diagnostic specificity is high (range 79-
100%, mean 92%), sensitivity is lower (range 0- 83 %, mean, 49%). Improved
methods of case detection are therefore required. Fluctuating impairments in
attention, visual recognition and construction are more indicative of DLB than
AD. Relative preservation of medial temporal lobe volume on structural MRI and
the use of SPECT tracers for regional blood flow and the dopamine transporter
are the most reliable current biomarkers for DLB. There are no genetic or CSF
tests recommended for the diagnosis of DLB at present. Between 15 and 20% of all
elderly demented cases reaching autopsy have DLB, making it the most common
cause of degenerative dementia after AD. Exquisite, not infrequently fatal,
sensitivity to neuroleptic drugs and encouraging reports of the effects of
cholinesterase inhibitors on cognitive, psychiatric and neurological features,
mean that an accurate diagnosis of DLB is more than merely of academic interest.
Dementia developing late in the course of PD shares many of the same clinical
and pathological characteristics.
Melis, M. R. and A. Argiolas (2003). "Central oxytocinergic neurotransmission: a
drug target for the therapy of psychogenic erectile dysfunction." Curr Drug
Targets 4(1): 55-66.
A group of oxytocinergic neurons originating in the paraventricular nucleus of
the hypothalamus and projecting to extrahypothalamic brain areas (e.g.
hippocampus, medulla oblongata and spinal cord) control penile erection.
Activation of these neurons by dopamine and dopamine agonists, excitatory amino
acids (N-methyl-D-aspartic acid) or oxytocin itself, or by electrical
stimulation leads to penile erection, while their inhibition by GABA and GABA
agonists or by opioid peptides and opiate-like drugs inhibits this sexual
response. The activation of oxytocinergic neurons in the paraventricular nucleus
by dopamine, oxytocin and excitatory amino acids is apparently secondary to the
activation of nitric oxide (NO) synthase. NO in turn activates, by a mechanism
that is as yet unidentified, the release of oxytocin from oxytocinergic neurons
in extrahypothalamic brain areas. Several peptide analogues of hexarelin, a
growth hormone releasing peptide, also induce penile erection when injected into
the paraventricular nucleus and, to a lesser extent, systemically, apparently by
acting on a specific receptor to activate oxytocinergic neurons as shown for the
above drugs and oxytocin. Paraventricular oxytocinergic neurons and mechanisms
similar to those reported above are also involved in the expression of penile
erection in physiological contexts, namely when penile erection is induced in
the male by the presence of an inaccessible receptive female, which is
considered a model for psychogenic impotence in man, as well as during
copulation. These findings show that paraventricular oxytocinergic neurons
projecting to extra-hypothalamic brain areas and to the spinal cord are a likely
target for the treatment of erectile dysfunction of central origin.
Merza, Z. (2003). "Modern treatment of acromegaly." Postgrad Med J 79(930):
189-93; quiz 192-4.
Acromegaly is an endocrine disorder characterised by increased morbidity and
mortality. It is usually caused by a growth hormone secreting pituitary adenoma
and is manifested by a variety of clinical features. Surgery is usually the
treatment of choice, however over the last few years, several new methods of
treatment have been developed. A recent consensus on the targets for treatment
has led to multiple studies being conducted to assess the efficacy of the
currently available options. This review examines the evidence for and against
these treatments.
Misu, Y., K. Kitahama, et al. (2003). "L-3,4-Dihydroxyphenylalanine as a
neurotransmitter candidate in the central nervous system." Pharmacol Ther
97(2): 117-37.
Historically, 3,4-dihydroxyphenylalanine (DOPA) has been believed to be an inert
amino acid that alleviates the symptoms of Parkinson's disease by its conversion
to dopamine via the enzyme aromatic L-amino acid decarboxylase. In contrast to
this generally accepted idea, we propose that DOPA itself is a neurotransmitter
and/or neuromodulator, in addition to being a precursor of dopamine. Several
criteria, such as synthesis, metabolism, active transport, existence,
physiological release, competitive antagonism, and physiological or
pharmacological responses, must be satisfied before a compound is accepted as a
neurotransmitter. Recent evidence suggests that DOPA fulfills these criteria in
its involvement mainly in baroreflex neurotransmission in the lower brainstem
and in delayed neuronal death by transient ischemia in the striatum and the
hippocampal CA1 region of rats.
Mitamura, K. (2003). "[Antiviral agents for influenza]." Nippon Rinsho
61 Suppl 2: 798-803.
Moldrich, R. X. and P. M. Beart (2003). "Emerging signalling and protein
interactions mediated via metabotropic glutamate receptors." Curr Drug Target
CNS Neurol Disord 2(2): 109-22.
Metabotropic glutamate receptors (mGlu) are GTP-binding (G) protein-coupled
receptors (GPCRs) that are involved in learning and memory, cardiovascular
control and motor function. Their structure and pharmacology has been reviewed
recently in Current Drug Targets: CNS and Neurological Disorders (Vol. 1, Issue
3) where their roles in a variety of neurological disorders were highlighted.
The present review focuses on the emerging evidence for interactions of mGlu
receptors with other GPCRs in the CNS at the membrane interface and amongst
signaling cascades in the cytosol (e.g. intracellular Ca(2+), cAMP and
scaffolding proteins). While initially non-selective activity was thought to be
responsible for many atypical responses, increasing evidence points to GPCR
interactions in neurons and glia, with adrenoceptors, adenosine receptors,
dopamine receptors and muscarinic receptors. For example, group II mGlu
receptors were found to be required for group I mGlu receptor induction of
long-term potentiation at the postsynaptic terminal. Increasing evidence
demonstrates the intimate interaction of adenosine receptors and mGlu receptors,
particularly in the regulation of neurotransmitter release. While adenosine
itself can be released from astrocytes by co-activation of group II mGlu and
beta-adrenergic receptors. Given the complexity of neurological disorders such
as ischemic stroke, Alzheimer's disease and epilepsy, exploitation mGlu
receptor-associated GPCR interactions may prove efficacious in the treatment of
such disorders.
Montastruc, J. L., L. Schmitt, et al. (2003). "[Pathological gambling behavior
in a patient with Parkinson's disease treated with levodopa and bromocriptine]."
Rev Neurol (Paris) 159(4): 441-3.
The occurrence of a pathological gambling behavior in a 61-year-old patient with
idiopathic Parkinson's disease treated with dopaminergic drugs is reported. This
is the first case reported with bromocriptine. The main characteristics and the
mechanism of this recently described and a unexpected, adverse drug reaction are
discussed.
Montgomery, J. H. and J. L. Tekell (2003). "Adjunctive quetiapine treatment of
the polydipsia, intermittent hyponatremia, and psychosis syndrome: a case
report." J Clin Psychiatry 64(3): 339-41.
Montorsi, F., A. Salonia, et al. (2003). "Pharmacological management of erectile
dysfunction." BJU Int 91(5): 446-54.
Erectile dysfunction (ED) is a common medical condition that affects the sexual
life of millions of men worldwide. Many drugs are now available for treating ED;
oral pharmacotherapy represents the first-line option for most patients with ED.
Sildenafil, an inhibitor of the enzyme phosphodiesterase type 5, is currently
the most widely prescribed oral agent and has a very satisfactory
efficacy-safety profile in all patient categories. Apomorphine SL is a dopamine
D1- and D2-receptor agonist which has recently been approved for marketing in
Europe. It is best selected for treating patients with mild to moderate ED.
Vardenafil and tadalafil are new phosphodiesterase type 5 inhibitors which are
expected to be approved this year. Both of them have significant positive
efficacy-safety profiles. Patients who do not respond to oral pharmacotherapy or
who cannot use it are good candidates for intracavernosal and intraurethral
therapy. Alprostadil is the most widely used drug, both for injection therapy
and for the intraurethral route. The efficacy of second-line treatment is high
but the attrition rate remains significant.
Moret, C., B. Grimaldi, et al. (2003). "The role and therapeutic potential of
5-HT-moduline in psychiatry." Semin Clin Neuropsychiatry 8(2):
137-46.
The endogenous neuropeptide, 5-HT-moduline, selectively and allosterically
interacts with 5-HT(1B) receptors. By binding at a site distinct from that bound
by 5-HT, 5-HT-moduline induces structural changes in 5-HT(1B) receptors or
stabilizes a particular conformation of these receptors. These conformational
changes ultimately lead to the prevention of 5-HT binding resulting in
desensitization of these receptors and reduction of the serotonergic function.
The efficacy of 5-HT(1B) receptor agonists, for example, has been shown to be
reduced by this peptide in vitro and behaviorally. In addition, 5-HT-moduline
increases 5-HT release, which is regulated by presynaptic 5-HT(1B)
autoreceptors. The release of 5-HT-moduline itself is increased after acute
restraint stress in rats, whereas deactivation of 5-HT-moduline by specific
antibodies in mice prevents the development of anxiety in a classic behavioral
model, suggesting a potential role of the peptide in the control of anxiety. It
is thus hypothesized that agents inhibiting the effect of 5-HT-moduline could
have anxiolytic activity. Because the serotonergic activity is known to play a
key role in psychiatric disorders such as depression and anxiety, compounds
capable of mimicking or inhibiting the activity of 5-HT-moduline can represent
novel antidepressants or anxiolytics.
Muntener, M., S. Suter, et al. (2003). "[Erectile dysfunction: reasonable
diagnostics and treatment in general practice]." Schweiz Rundsch Med Prax
92(5): 179-86.
The availability of efficacious oral drugs has radically changed the diagnostic
and therapeutic approach to erectile dysfunction. Complicated examinations as
well as invasive treatment options have been widely abandoned. Instead the
management of impotent men has become much more pragmatic and focused on the
symptom. Consequently only a minority of impotent men needs to be referred to an
urologist, which makes the therapy of erectile dysfunction increasingly
attractive for general practitioners. However, successful treatment first of all
still needs time and a genuine interest in the field of erectile dysfunction. In
this article a reasonable diagnostic evaluation of impotent patients in general
practice is described. Furthermore indication and use of little or non-invasive
therapies are discussed.
Myhrer, T. (2003). "Neurotransmitter systems involved in learning and memory in
the rat: a meta-analysis based on studies of four behavioral tasks." Brain
Res Brain Res Rev 41(2-3): 268-87.
From previous literature, it appears that most classical neurotransmitter
systems can in some way influence learning and memory in the rat. A matter of
crucial interest is, however, whether the chemical systems contribute in a
similar manner or whether they have different abilities to support cognitive
processes. The purpose of the present study was to investigate this issue. The
investigation was carried out by reviewing relevant studies of neurochemistry
and cognition. Inclusion criteria were set for selection of behavioral tasks to
be elucidated and for studies employing acceptable tasks. Morris water maze,
radial maze, passive avoidance, and spontaneous alternation met the criteria for
inclusion, and a table for each of these tests summarizes the neurochemical
results of the studies accepted for inclusion. In this way, a reliable
comparability of results from relevant studies was obtained. The comparisons
revealed that for both systemic and targeted infusions of agents the
neurochemical systems possess different abilities to influence learning and
memory. Calculation of impact factors (percentage of significant effects of
chemical agents like agonists, antagonists, neurotoxins) showed that glutamate
was ranking highest (93), followed by GABA (81), dopamine (81), acetylcholine
(81), serotonin (55), and norepinephrine (48). No task specific roles were
observed for the transmitter systems. The highest sensitivity (percentage of
significant effects) to interference with neurochemical systems was found for
the spontaneous alternation task (86), followed by water maze (76), passive
avoidance (72), and radial maze (58). The multiple memory systems in the rat
brain can hardly be related to specific transmitter systems, because of the
great extent of interactions between the systems.
Noble, E. P. (2003). "D2 dopamine receptor gene in psychiatric and neurologic
disorders and its phenotypes." Am J Med Genet 116B(1): 103-25.
The D2 dopamine receptor (DRD2) has been one of the most extensively
investigated gene in neuropsychiatric disorders. After the first association of
the TaqI A DRD2 minor (A1) allele with severe alcoholism in 1990, a large number
of international studies have followed. A meta-analysis of these studies of
Caucasians showed a significantly higher DRD2 A1 allelic frequency and
prevalence in alcoholics when compared to controls. Variants of the DRD2 gene
have also been associated with other addictive disorders including cocaine,
nicotine and opioid dependence and obesity. It is hypothesized that the DRD2 is
a reinforcement or reward gene. The DRD2 gene has also been implicated in
schizophrenia, posttraumatic stress disorder, movement disorders and migraine.
Phenotypic differences have been associated with DRD2 variants. These include
reduced D2 dopamine receptor numbers and diminished glucose metabolism in brains
of subjects who carry the DRD2 A1 allele. In addition, pleiotropic effects of
DRD2 variants have been observed in neurophysiologic, neuropsychologic, stress
response, personality and treatment outcome characteristics. The involvement of
the DRD2 gene in certain neuropsychiatric disorders opens up the potential of a
targeted pharmacogenomic approach to the treatment of these disorders.
Norbury, R., W. J. Cutter, et al. (2003). "The neuroprotective effects of
estrogen on the aging brain." Exp Gerontol 38(1-2): 109-17.
The population of the western world is ageing. This increase in the elderly
population will inevitably mean a rise in the prevalence of age-related
cognitive decline and late-onset neuropsychiatric disorder, such as Alzheimer's
disease (AD). There are sex differences in the incidence and age of onset of
these disorders. Sex steroids and sex chromosomes are therefore implicated in
their pathophysiology. We have identified relevant past and current literature
using a Medline search and from the references of relevant papers. These were
then reviewed and relevant articles have been summarized and included in the
review. Evidence is presented for the wide-ranging actions of estrogen in the
brain at the cellular, metabolic and neurotransmitter levels as well as from the
cognitive, AD, depression and cerebrovascular perspectives. The authors conclude
that it is unlikely that estrogen will become a stand-alone treatment for any of
these disorders, although there may still be a role as an adjunctive treatment
and as a prophylactic measure.
Nussmeier, N. A. (2003). "Improving perioperative outcomes in patients with
end-stage heart failure." Rev Cardiovasc Med 4 Suppl 1: S29-34.
In the United States alone, more than 4.5 million people are affected by heart
failure, with more than 500,000 new cases diagnosed each year. Although cardiac
transplantation remains the "gold-standard" surgical treatment for heart failure
unresponsive to maximal medical therapy, the chronic shortage of donor hearts
has necessitated clinical trials of other surgical options. Over the past two
decades, research, technological progress, and extensive clinical experience
have resulted in the application of ventricular assist device (VAD) technology
to a broader population of heart-failure patients, as these devices have proven
to be viable therapeutic alternatives for therapy of end-stage heart failure.
All patients undergoing cardiac transplantation or VAD insertion have multiorgan
dysfunction as a result of irreversible, severe ventricular dysfunction
resulting in low cardiac output. Recently, fenoldopam has been described as a
vasodilator that might be useful in patients with decompensated heart failure,
particularly in the perioperative setting. As a selective dopamine-1 receptor
agonist, fenoldopam causes vasodilation in the systemic, renal, mesenteric,
coronary, and pulmonary vasculature. Potentially, the pharmacologic properties
of fenoldopam could be successfully exploited in patients undergoing medical or
surgical treatment of end-stage heart failure. Controlled randomized trials are
needed to demonstrate improvement in cardiopulmonary or renal outcomes in such
patients.
O'Donnell, P. (2003). "Dopamine gating of forebrain neural ensembles." Eur J
Neurosci 17(3): 429-35.
Dopamine may exert different actions depending on a number of factors. A common
view is that D1 receptors may be responsible for excitatory actions whereas D2
receptors are involved in inhibitory actions. However, this position cannot be
reconciled with several findings indicating otherwise. The role of dopamine on
forebrain neural ensembles may be better understood in the light of functional
states of the system. Pyramidal cortical neurons and striatal medium spiny
neurons alternate between two membrane potential states ('up' and 'down') that
could shape dopamine actions. It is proposed that D1 receptors can act as
state-stabilizers by sustaining up states and thereby facilitating plasticity
mechanisms by providing postsynaptic depolarization and increasing NMDA
function. In this way, dopamine can sustain activity in depolarized units. This
action is accompanied by a decrease in cell firing (perhaps mediated by D2
receptors), which renders the cells responsive only to strong stimuli. The
result would be a net increase in signal-to-noise ratio in a selected assembly
of neurons.
Oxford, J. S., S. Bossuyt, et al. (2003). "Treatment of epidemic and pandemic
influenza with neuraminidase and M2 proton channel inhibitors." Clin
Microbiol Infect 9(1): 1-14.
A small armentarium of anti-influenza drugs now exists, and includes the M2
blockers (amantadine and rimantadine) and the neuraminidase inhibitors (Relenza
and Tamiflu). The neuraminidase inhibitors have certain advantages, including a
broader spectrum of antiviral activity, including influenza A and B viruses. On
the other hand, there is now much clinical experience with the M2 blockers, and
these drugs are inexpensive. It is clear that influenza in different community
groups needs to be managed in specific and targeted ways. For example, in the
over-65-years and at-risk groups, vaccination will remain a mainstay of disease
prevention. However, up to 40% of those in these groups may fail to receive
vaccine, and therefore the antivirals can be used therapeutically, or, in
defined circumstances, as prophylactics. At present, influenza is hardly managed
in the community. The infrequent global outbreaks, pandemics, present further
problems. The more extensive use of the two classes of antivirals, and also
vaccines, in the important interpandemic years will provide a very significant
investment in health benefits in the face of a new pandemic virus in an
otherwise completely vulnerable population.
Padberg, F. and H. J. Moller (2003). "Repetitive transcranial magnetic
stimulation : does it have potential in the treatment of depression?" CNS
Drugs 17(6): 383-403.
Transcranial magnetic stimulation (TMS) has become a major research tool in
experimental clinical neurophysiology as a result of its potential to
noninvasively and focally stimulate cortical brain regions. Currently, studies
are being conducted to investigate whether repetitive TMS (rTMS)-mediated
modulation of cortical function may also provide a therapeutic approach in
neurological and psychiatric disorders. Preclinical findings have shown that
prefrontal rTMS can modulate the function of fronto-limbic circuits, which is
reversibly altered in major depression. rTMS has also been found to exert
effects on neurotransmitter systems involved in the pathophysiology of major
depression (e.g. stimulates subcortical dopamine release and acts on the
hypothalamic pituitary adrenal axis, which is dysregulated in depression).To
date, numerous open and controlled clinical trials with widely differing
stimulation parameters have explored the antidepressant potential of rTMS.
Though conducted with small sample sizes, the majority of the controlled trials
demonstrated significant antidepressant effects of active rTMS compared with a
sham condition. Effect sizes, however, varied from modest to substantial, and
the patient selection focused on therapy-resistant cases. Moreover, the average
treatment duration was approximately 2 weeks, which is short compared with other
antidepressant interventions. Larger multicentre trials, which would be
mandatory to demonstrate the antidepressant effectiveness of rTMS, have not been
conducted to date.A putative future application of rTMS may be the treatment of
patients who did not tolerate or did not respond to antidepressant
pharmacotherapy before trying more invasive strategies such as electroconvulsive
therapy and vagus nerve stimulation. Theoretically, rTMS may be also applied
early in the course of disease in order to speed up and increase the effects of
antidepressant pharmacotherapy. However, this application has not been a focus
of clinical trials to date. Research efforts should be intensified to further
investigate the effectiveness of rTMS as an antidepressant intervention and to
test specific applications of the technique in the treatment of depressive
episodes.
Pagel, J. F. and P. Helfter (2003). "Drug induced nightmares--an etiology based
review." Hum Psychopharmacol 18(1): 59-67.
OBJECTIVE: Recent clinical trials have included patient complaints of nightmares
as a category of reportable medication side effects. This study integrates that
data into current experimental and theoretical research of drug effects that may
alter dreaming and nightmares. The objective is to provide a clinical and
theoretical framework useful in categorizing the potential and reported drug
effects on nightmares. METHODOLOGY: This study reviews case reports and clinical
trials that have reported nightmares or alterations in dreaming occurring
secondary to medication usage. These data are analysed as to the probability of
the drug/nightmare association, and integrated into current electrophysiological
and neurochemical theories of dreaming and nightmares. RESULTS: Pharmacological
agents affecting the neurotransmitters norepinephrine, serotonin and dopamine
are clearly associated with patient reports of nightmares. Agents affecting
immunological response to infectious disease are likely to induce nightmares in
some patients. A possible association exists between reports of nightmares and
agents affecting the neurotransmitters acetylcholine, GABA and histamine, as
well as for some anesthetics, antipsychotics and antiepileptic agents.
CONCLUSION: By utilizing our current experimental and theoretical knowledge
base, the potential etiology of a majority of reported drug effects on
nightmares can be classified. These data support current neurochemical theories
of dreaming, as well as suggesting that the biochemical basis for dreaming and
nightmare induction may be more complex than generally suggested.
Pietrangeli, P., S. Nocera, et al. (2003). "Is the catalytic mechanism of
bacteria, plant, and mammal copper-TPQ amine oxidases identical?" Biochim
Biophys Acta 1647(1-2): 152-6.
This short review is mostly concerned with the work carried out in Rome on the
copper amine oxidase from bovine serum (BSAO). The first target was the copper
oxidation state and its relationship with the organic cofactor. It was found
that copper is not reduced on reaction with amines under anaerobic conditions or
along the catalytic cycle and that it is not within bonding distance of the
quinone cofactor. The copper stability in the oxidised state was supported by
BSAO ability to oxidise benzylhydrazine, a slow substrate, in the presence of
N,N-diethyldithiocarbamate (DDC) and by the substantial catalytic activity of
Co(2+)-substituted BSAO. Parallel work established that only one subunit of the
dimeric enzyme readily binds reagents of the carbonyl group. Flexible hydrazides
with a long aromatic tail were found to be highly specific inhibitors,
suggesting the presence of an extended hydrophobic region at the catalytic site.
A study by stopped-flow transient spectroscopy and steady state kinetics led to
the formulation of a simplified, yet complete and consistent, catalytic
mechanism for BSAO that was compared with that available for lentil seedling
amine oxidase (LSAO). As in other copper amine oxidases, BSAO is inactivated by
H(2)O(2) produced in the catalytic reaction, while the cofactor is stabilised in
its reduced state. A conserved tyrosine hydrogen-bonded to the cofactor might be
oxidised.
Pliszka, S. R. (2003). "Non-stimulant treatment of
attention-deficit/hyperactivity disorder." CNS Spectr 8(4): 253-8.
Stimulants are a highly efficacious and safe treatment for
attention-deficit/hyperactivity disorder (ADHD), with 75% to 90% of patients
responding well if two different stimulants (amphetamine and methylphenidate)
are used. Nonetheless, a subset of ADHD patients will either fail to respond to
stimulants or have side effects that preclude their use (tics, severe loss of
appetite, marked insomnia). For such patients, there are a number of
non-stimulant agents that serve as second-line treatments. Tricyclic
antidepressants (TCAs) are the most studied of these drugs. They are superior to
placebo in the treatment of ADHD and may reduce abnormal movements in patients
with ADHD/tic disorder. TCAs often produce side effects of sedation, dry mouth,
and constipation. Bupropion is superior to placebo in the treatment of ADHD and
has a more favorable side-effect profile than the TCAs. A new selective
norepinephrine reuptake inhibitor, atomoxetine, has been shown to be efficacious
in the treatment of ADHD and has recently received an approvable letter from the
Food and Drug Administration. The a-agonists clonidine and guanfacine have also
been used as alternative agents in ADHD, though the controlled data are more
limited. A recent controlled clinical trial suggests a combination of
methylphenidate and clonidine has advantages in the treatment of comorbid ADHD
and tics over either medication alone. Clinical guidelines for each of these
agents, as well as their use in combination with stimulants in comorbid
conditions, will be discussed.
Prabhakar, R., P. E. Siegbahn, et al. (2003). "A theoretical study of the
dioxygen activation by glucose oxidase and copper amine oxidase." Biochim
Biophys Acta 1647(1-2): 173-8.
Glucose oxidase (GO) and copper amine oxidase (CAO) catalyze the reduction of
molecular oxygen to hydrogen peroxide. If a closed-shell cofactor (like FADH(2)
in GO and topaquinone (TPQ) in CAO) is electron donor in dioxygen reduction, the
formation of a closed-shell species (H(2)O(2)) is a spin forbidden process. Both
in GO and CAO, formation of a superoxide ion that leads to the creation of a
radical pair is experimentally suggested to be the rate-limiting step in the
dioxygen reduction process. The present density functional theory (DFT) studies
suggest that in GO, the creation of the radical pair induces a spin transition
by spin orbit coupling (SOC) in O(2)(-)(rad), whereas in CAO, it is induced by
exchange interaction with the paramagnetic metal ion (Cu(II)). In the
rate-limiting step, this spin-transition is suggested to transform the
O(2)(-)(rad)-FADH(2)(+)(rad) radical pair in GO and the Cu(II)-TPQ (triplet)
species in CAO, from a triplet (T) to a singlet (S) state. For CAO, a mechanism
for the O[bond]O cleavage step in the biogenesis of TPQ is also suggested.
Rao, M. L. and H. Kolsch (2003). "Effects of estrogen on brain development and
neuroprotection--implications for negative symptoms in schizophrenia."
Psychoneuroendocrinology 28 Suppl 2: 83-96.
Increasing evidence during the last few years suggests that there are
gender-specific differences in schizophrenia, influencing the age of onset,
treatment outcome and the prevalence of negative symptoms. With respect to the
latter in postmortem brain and cerebrospinal fluid of schizophrenic patients
with negative symptoms a reduction of dopaminergic activity became evident.
Measures of noradrenergic activity, dopamine beta-hydroxylase and the metabolite
MHPG, appear to decrease with brain atrophy seen in patients with negative
symptoms. Serotonergic activity tends to be low in patients with impaired
cognitive function as is seen in negative schizophrenia. In these patients
ventricular enlargement is associated with the severity of negative symptoms,
low monoamine activity and low cerebral glucose metabolism.On the other hand
atypical antipsychotic drugs that modulate also glutamate receptor activity,
suggest an additional alternative mechanism of antipsychotic action beyond
aminergic neurotransmitters. These drugs improve glutamatergic transmission and
decrease negative symptoms; this suggests a glutamatergic deficiency as an
extension of the dopamine model.The glutamate-dopamine interaction illustrates
the importance of cross-talk between projections to the cortex, striatum, and
lower brainstem for the expression of negative symptomatology. On the other
hand, estradiol-17beta the most potent female sex hormone influences not only
primary and secondary sexual characteristics but also embryonal and fetal growth
as well as development of the brain aminergic networks, which are involved in
schizophrenia. Estradiol-l7beta possesses neuroprotective properties, which are
relevant for the course of schizophrenia and this may explain the pronounced
gender differences with respect to progression and therapeutic response of
schizophrenia. The present review attempts an update and synthesis of the
information about the hormonal influence on neuronal pathways in negative
symptoms of schizophrenia. It shows that estradiol-l7beta influences
transporters and receptors as well as the morphological appearance of neuronal
systems and that it may be an integral part of the neuroprotective system
ameliorating schizophrenia.
Reif, A. and K. P. Lesch (2003). "Toward a molecular architecture of
personality." Behav Brain Res 139(1-2): 1-20.
Epidemiological studies provided a large body of evidence that personality
dimensions are influenced by genetic factors and that the genetic component is
highly complex, polygenic, and epistatic. However, consistent findings on the
genetic basis of personality have yet remained sparse. In recent years,
molecular genetics has begun to identify specific genes coding in particular for
components of the serotonergic and dopaminergic neurotransmitter systems
representing quantitative trait loci (QTLs) for behavioral traits. The QTL
concept suggests that complex traits are not attributable to single genes.
According to this polygenic model, the genetic basis of personality and behavior
and its pathological variations thus results from additive or nonadditive
interactions of various genes. As the number of suitable candidate genes
constantly increases, the QTL model provides a reasonable explanation for the
genetic basis of personality and its disorders. In this review, the current
knowledge on the impact of a large number of candidate gene polymorphisms (e.g.
variations in serotonin and dopamine receptor and serotonin transporter genes)
on personality and temperament is summarized. Additionally, investigations of
gene-gene and gene-environment interactions in humans and animals, which
currently intensify the identification of genes that underlie behavioral
variations, are examined. The findings converge on the notion that a
probabilistic rather than deterministic impact of genes on the expression of
behavior will contribute to the demystification of behavioral disorders.
Richard, I., B. Perrouin-Verbe, et al. (2003). "[Pharmacological treatment of
post-traumatic behavioural disorders]." Ann Readapt Med Phys 46(1):
49-57.
OBJECTIVE: Literature review of the data concerning pharmacologic treatment of
post-traumatic behavioural disorders. This review is limited to the treatment of
agitation, excitation, mood lability, hostility and agressivity as defined by
the NRS and excludes pharmacologic treatment of mental slowness, cognitive
disorders and depression. METHODS: Medline interrogation using keywords
Traumatic Brain Injury, Agitation, Agressivity, Behaviour, Pharmacology,
Neuroleptics, Benzodiazepines, Carbamazepine, Valproate, Buspirone, SSRI,
Propanolol, Methylphenidate and review of recent contents. The data finally
includes 29 original studies. RESULTS: The overall level of evidence is quite
low as the data mainly consist in open studies and case reports. These data and
data from reviews or didactic articles suggest the efficiency of a variety of
treatments. Mood-stabilizing antiepileptics, and specially carbamazepine
constitute together with SSRI antidepressants the first choices. Some data
suggest efficiency of buspirone, methylphenidate and atypic neuroleptics.
Lithium requires close monitoring but is probably efficient. It is difficult to
conclude concerning propanolol. CONCLUSION: The available data is in favour of
the use of CBZ and SSRI antidepressants. Further studies are required. It is
necessary to establish clear evidence of the efficiency of CBZ and assess the
effects of methylphenidate, which is almost not prescribed in France.
Rotzinger, S. and F. J. Vaccarino (2003). "Cholecystokinin receptor subtypes:
role in the modulation of anxiety-related and reward-related behaviours in
animal models." J Psychiatry Neurosci 28(3): 171-81.
Cholecystokinin (CCK) is an abundant and widely distributed neuropeptide that
plays a modulatory role in a variety of behaviours. This paper focuses on the
role of CCK in modulating anxiety-related and reward-related behaviours in key
brain regions of the amygdala and mesolimbic dopamine system, respectively. The
role of CCK in mediating aspects of these behaviours has been studied in a
variety of behavioural paradigms, but inconsistent results have led to confusion
regarding the precise role of the receptor subtypes in mediating behaviour. The
confusion in the literature may come in part from the diverse behavioural
paradigms that are used, the differences in regional effects of CCK
manipulations in different areas and at different receptor subtypes in these
areas and the dependence of the behavioural outcome on the baseline state of
arousal of the animal. Evidence on the role of CCK in anxiety-related and
reward-related behaviours in various animal models indicates that CCK-B
receptors in the basolateral amygdala are important mediators of anxiety-related
behaviours and that CCK-A and CCK-B receptors in the nucleus accumbens are
important in mediating different aspects of reward-related behaviour. Emphasis
is placed upon the role of CCK as a neuromodulator that is recruited only under
conditions of high frequency neuronal firing.
Safer, D. J., J. M. Zito, et al. (2003). "Concomitant psychotropic medication
for youths." Am J Psychiatry 160(3): 438-49.
OBJECTIVE: This study reviewed the clinical research and practice literature
relating to the prevalence and patterns of concomitant psychotropic medication
given to youths with emotional and behavioral disorders. METHOD: A MEDLINE
search from 1996 through spring 2002, including a review of references from
relevant published articles and reports, was undertaken to identify available
information on concomitant psychotropic medication for youths. RESULTS: The data
supporting concomitant psychotropic medication for youths are almost exclusively
based on case reports and small-scale, nonblind assessments. In the mid-1990s,
over 20% of outpatient youths treated in community mental health centers and
over 40% of youths treated in inpatient psychiatric facilities were given
concomitant psychotropic medication. The rate has since increased. Psychiatrists
more than primary care physicians prescribe concomitant psychotropic medication,
and they show great variability in their prescribing habits. Youths with
aggressive behavior, male gender, severe emotional illness, and disabling social
maladjustment are most likely to receive concomitant psychotropic medication.
CONCLUSIONS: Substantive systematic evidence is needed to clarify this
increasingly common, inadequately researched child psychopharmacologic practice.
Saint-Cyr, J. A. (2003). "Frontal-striatal circuit functions: context, sequence,
and consequence." J Int Neuropsychol Soc 9(1): 103-27.
The exact role of the basal ganglia in both the motor and non-motor domains has
proven elusive since it is virtually impossible to refer to its function in
isolation of cortical, and especially frontal cortical circuits. The result is
that we often speak of frontal-striatal circuits and functions but this still
leaves us in the dark when trying to specify basal ganglia information
processing. A critical review of the data from both basic science and clinical
studies suggests that we should break down processing along a temporal
continuum, including the domains of context, sequential information processing,
and feedback or reinforcement (i.e., the consequences of action). This analysis
would cut across other theoretical constructs, such as attention, central
executive, memory, and learning functions, traditionally employed in the
neuropsychological literature. Under specified behavioral constraint, the basal
ganglia can then be seen to be involved in fundamental aspects of attentional
control (often covert), in the guidance of the early stages of learning
(especially reinforcement-based, but also encoding strategies in explicit
paradigms), and in the associative binding of reward to cue salience and
response sequences via dopaminergic mechanisms. Parkinson's disease is
considered to offer only a limited view of basal ganglia function due to partial
striatal depletion of dopamine and the potential involvement of other structures
and transmitters in its pathology. It is hoped that the present formulation will
suggest new heuristic research strategies for basal ganglia research, permitting
a closer link to be established between neurophysiological, functional imaging
and neuropsychological paradigms.
Salamone, J. D., M. Correa, et al. (2003). "Nucleus accumbens dopamine and the
regulation of effort in food-seeking behavior: implications for studies of
natural motivation, psychiatry, and drug abuse." J Pharmacol Exp Ther
305(1): 1-8.
For several decades, it has been suggested that dopamine (DA), especially in
nucleus accumbens, mediates the primary reinforcing characteristics of natural
stimuli such as food, as well as drugs of abuse. Yet, several fundamental
aspects of primary food reinforcement, motivation, and appetite are left intact
after interference with accumbens DA transmission. Recent studies have shown
that accumbens DA is involved in responsiveness to conditioned stimuli and
activational aspects of motivation. In concurrent choice tasks, accumbens DA
depletions cause animals to reallocate their choice behavior in the direction of
instrumental behaviors that involve less effort. Also, an emerging body of
evidence has demonstrated that the effects of accumbens DA depletions on
instrumental food-seeking behavior can vary greatly depending upon the task. For
example, some schedules of reinforcement are insensitive to the effects of DA
depletions, whereas others are highly sensitive (e.g., large fixed ratios).
Accumbens DA depletions slow the rate of operant responding, blunt the
rate-facilitating effects of moderate-sized ratios, and enhance the
rate-suppressing effects of very large ratios (i.e., produce ratio strain).
Accumbens DA may be important for enabling rats to overcome behavioral
constraints, such as work-related response costs, and may be critical for the
behavioral organization and conditioning processes that enable animals to engage
in vigorous responses, such as barrier climbing, or to emit large numbers of
responses in ratio schedules in the absence of primary reinforcement. The
involvement of accumbens DA in activational aspects of motivation has
implications for energy-related disorders in psychiatry, as well as aspects of
drug-seeking behavior.
Salter, M. W. (2003). "D1 and NMDA receptors hook up: expanding on an emerging
theme." Trends Neurosci 26(5): 235-7.
In the dominant paradigm for functional interactions between G-protein-coupled
receptors (GPCRs) and ligand-gated ion channels, the mantra is that the
interactions are indirect, indirect, indirect. It is commonly understood that
activating GPCRs engages one or more sets of intracellular signaling cascades
that indirectly affect the function or localization of a cohort of ligand-gated
ion channels. Conversely, stimulating ligand-gated channels, particularly those
that are permeable to Ca(2+), indirectly produces effects on GPCRs and/or on
GPCR-activated signaling cascades. The foundation of this dichotomous world-view
shook (just a little) when it was discovered that D5 dopamine receptors bind
directly to GABA(A) receptors, and that this direct interaction reciprocally
affects the signaling of both types of receptor. Now, D1 dopamine receptors also
have got into the act!
Schapira, A. H. and C. W. Olanow (2003). "Rationale for the use of dopamine
agonists as neuroprotective agents in Parkinson's disease." Ann Neurol
53 Suppl 3: S149-57; discussion S157-9.
Schmidt, U. (2003). "Aetiology of eating disorders in the 21(st) century: new
answers to old questions." Eur Child Adolesc Psychiatry 12 Suppl 1:
I30-7.
This paper reviews the aetiology of the eating disorders, anorexia nervosa and
bulimia nervosa, which is generally thought of as multi-factorial in nature. In
recent years with the advent of new bio-technologies interest in the exploration
of the contribution of biological, in particular genetic factors to the origins
of these disorders has been revived. The challenge for the future is to
understand better the relative importance of biological and psychosocial
risk-factors and how these factors interact. Moreover, there is a need for a
greater appreciation of the developmental perspective in the origins of eating
disorders.
See, R. E., R. A. Fuchs, et al. (2003). "Drug addiction, relapse, and the
amygdala." Ann N Y Acad Sci 985: 294-307.
Evidence has extensively implicated the amygdala in the associative learning
process for appetitive reinforcers. Recent interest has focused on the role of
the amygdala in the learned associations that occur during the process of drug
addiction and relapse. Using an animal model of relapse after chronic cocaine
self-administration, we found that rats reinstate extinguished lever responding
for conditioned stimuli (tone + light) previously paired with cocaine or heroin
("conditioned-cued reinstatement"). The basolateral amygdala (BLA) complex plays
a critical role in this behavior, because permanent lesions or reversible
pharmacologic inactivation of the BLA attenuates conditioned-cued reinstatement
without affecting cocaine self-administration or cocaine-primed reinstatement.
Conditioned-cued reinstatement appears to be mediated in part by dopamine inputs
to the BLA, as intra-BLA infusion of a dopamine D1 receptor antagonist blocks
reinstatement, whereas intra-BLA infusion of amphetamine potentiates
reinstatement. Furthermore, the BLA is also necessary for acquisition of
associative learning with cocaine-paired stimuli. Disruption of neural activity
within the BLA by sodium channel blockade or muscarinic receptor blockade just
before acquisition of stimulus-cocaine associations blocks the ability of
conditioned stimuli to elicit conditioned-cued reinstatement after extinction.
Together, these results reveal the importance of the amygdala as part of a
corticolimbic circuit mediating both the acquisition and the expression of
conditioning that plays a critical role in relapse to drug-seeking behavior.
Shabsigh, R. and A. G. Anastasiadis (2003). "Erectile dysfunction." Annu Rev
Med 54: 153-68.
Erectile dysfunction (ED) is a highly prevalent and often undertreated
condition. It may be a symptom of underlying, chronic illness and can have a
negative impact on quality of life, psychosocial health, and relationships. The
aging of the population, as well as the introduction of new treatment options,
such as sildenafil, has led to increased public awareness of this disorder. New
oral therapeutic agents are on the horizon. This article provides an overview of
the physiology of erection, the pathophysiology of ED, and modern patient
evaluation. Management options, including traditional therapeutic approaches as
well as the new generation of oral agents, are also presented.
Shale, J. H., C. M. Shale, et al. (2003). "A review of the safety and efficacy
of droperidol for the rapid sedation of severely agitated and violent patients."
J Clin Psychiatry 64(5): 500-5.
BACKGROUND: Droperidol had become a standard treatment for sedating severely
agitated or violent patients in both psychiatric and medical emergency
departments. However, several recent articles have suggested that droperidol may
have a quinidine-like effect similar to that of thioridazine in inducing
dysrhythmia. METHOD: In view of the recent U.S. Food and Drug Administration
(FDA) position regarding the use of thioridazine, the authors reviewed the
literature regarding droperidol and dysrhythmia in a MEDLINE search for the
years 1960-2002 using the search terms droperidol, dysrhythmia, QTc interval,
and sudden death as well as their own experience in using droperidol in a busy
psychiatric emergency department. This review was done before the FDA's very
recent and peremptory warning about droperidol. RESULTS: The authors report
that, in treating approximately 12,000 patients over the past decade, they have
never experienced a clinically significant adverse dysrhythmic event using
droperidol to sedate severely agitated or violent patients. CONCLUSION: The
authors conclude that, in clinical practice, droperidol is an extremely
effective and safe method for treating severely agitated or violent patients.
While in theory droperidol may prolong the QT interval to an extent similar to
thioridazine, in clinical use there is no pattern of sudden deaths analogous to
those that provoked the FDA warning about thioridazine.
Sheinbaum, R., C. Ignacio, et al. (2003). "Contemporary strategies to preserve
renal function during cardiac and vascular surgery." Rev Cardiovasc Med
4 Suppl 1: S21-8.
Mortality rates associated with perioperative acute renal failure (ARF) range
from 60% to 90%. The major causes of ARF are prerenal factors that decrease
renal blood flow; intrarenal factors that have a direct effect on tubules,
interstitium, or glomeruli; and postrenal factors that obstruct urine outflow.
Current strategies to provide perioperative renal protection include maintaining
adequate renal O2 delivery, suppressing renovascular vasoconstriction,
renovascular vasodilatation, maintaining tubular flow, decreasing renal cellular
O2 consumption, and attenuating reperfusion injury. A study of patients
undergoing elective repair of a thoracoabdominal aortic aneurysm (TAAA) found
that the use of the selective dopamine-1 receptor agonist fenoldopam was
associated with reductions in mortality, dialysis requirements, and lengths of
stay in the hospital and intensive care unit. The study authors suggest that the
improved patient outcomes and hospital-utilization data resulting from the use
of fenoldopam were directly related to the protection of renal function during
surgery and a reduction of postoperative renal complications.
Shim, H. and Z. L. Harris (2003). "Genetic defects in copper metabolism." J
Nutr 133(5 Suppl 1): 1527S-31S.
Genetic defects in copper metabolism highlight the delicate balance mammalian
systems have developed to maintain normal copper homeostasis. Menkes disease,
the mottled mouse, the Atox-1-deficient mouse and the ctr1 knockout mouse reveal
the importance of adequate copper intake during embryogenesis and early
development, especially in the central nervous system. The toxicity associated
with excess copper as manifest in Wilson disease, the toxic milk mouse, the LEC
rat and copper toxicosis in the Bedlington terrier demonstrate the profound
cellular susceptibility to copper overload, in particular, in the brain and
liver. Ceruloplasmin (Cp) contains 95% of the copper found in human serum, and
inherited loss of this protein results in diabetes, retinal degeneration and
neurodegeneration. Despite normal copper metabolism, aceruloplasminemic patients
and the Cp knockout mouse have disturbed iron homeostasis and mild hepatic
copper retention. These genetic disorders of copper metabolism provide valuable
insight into the mechanisms regulating copper homeostasis and models to further
dissect the role of this essential metal in health and disease.
Siderowf, A. and M. Stern (2003). "Update on Parkinson disease." Ann Intern
Med 138(8): 651-8.
This Update reviews developments in the pathophysiology and treatment of
Parkinson disease during the past several years. In the area of pathophysiology,
studies have addressed the contribution of environmental factors such as
caffeine and pesticides. Large-scale epidemiologic studies have also expanded
the role genetic factors are thought to play. Detailed studies of kindreds with
familial Parkinson disease due to alpha-synuclein and parkin have catalyzed
basic science investigations into the pathologic mechanisms of the disease.
These studies have led to the development of a pathophysiologic model of
Parkinson disease that emphasizes abnormal protein aggregation. Studies of
treatment have clarified the relative roles of l-dopa and dopamine agonists in
early Parkinson disease and shown the potential for surgical interventions,
particularly deep-brain stimulation, to relieve the symptoms of advanced,
medically refractory disease.
Silverdale, M. A., S. H. Fox, et al. (2003). "Potential nondopaminergic drugs
for Parkinson's disease." Adv Neurol 91: 273-91.
Smith, R., J. Lotharius, et al. (2003). "[Free radicals and ailing proteins--the
culprits behind Parkinson disease?]." Lakartidningen 100(15):
1324-6, 1329-30.
Parkinson's disease is one of the most common neurodegenerative diseases, and
affects approximately 1% of the population over 65 years of age. Many different
insults appear to be involved in the etiology of the disease, among them
environmental toxins and mitochondrial dysfunction. During the past five years,
mutations in five different genes have been linked to rare, familial forms of
Parkinson's disease. One of the mutated proteins, alpha-synuclein is normally
implicated in synaptic plasticity and vesicle function. Dysfunction of this
protein might lead to increased cytoplasmic dopamine levels. Since cytoplasmic
dopamine is readily prone to autooxidation and enzymatic degradation--processes
which generate reactive oxygen species--failure to properly store dopamine into
vesicles might lead to oxidative stress. Indeed, nigral tissue from idiopathic
Parkinson's disease patients shows signs of oxidative damage. In this article we
propose that dopamine-induced oxidative stress might be a common final pathway
in the pathogenesis of the disease.
Soares, B. G., M. S. Lima, et al. (2003). "Dopamine agonists for cocaine
dependence." Cochrane Database Syst Rev(2): CD003352.
BACKGROUND: Cocaine dependence is a common and serious condition, which has
become nowadays a substantial public health problem. There is a wide and well
documented range of consequences associated to chronic use of this drug, such as
medical, psychological and social problems, including the spread of infectious
diseases (e.g. AIDS, hepatitis and tuberculosis), crime, violence and neonatal
drug exposure. Therapeutic management of the cocaine addicts includes an initial
period of abstinence from the drug. During this phase the subjects may
experience, besides the intense craving for cocaine, symptoms such as
depression, fatigue, irritability, anorexia, and sleep disturbances. It was
demonstrated that the acute use of cocaine may enhance dopamine transmission and
chronically it decreases dopamine concentrations in the brain. Pharmacological
treatment that affects dopamine could theoretically reduce these symptoms and
contribute to a more successful therapeutic approach. OBJECTIVES: To evaluate
the efficacy and acceptability of dopamine agonists for treating cocaine
dependence. SEARCH STRATEGY: Electronic searches of Cochrane Library, EMBASE,
MEDLINE, PsycLIT, Biological Abstracts and LILACS; reference searching; personal
communication; conference abstracts; unpublished trials from pharmaceutical
industry; book chapters on treatment of cocaine dependence, was performed for
the primary version of this review in 2001. Another search of the electronic
databases was done in December of 2002 for this update. The specialised register
of trials of the Cochrane Group on Drugs and Alcohol was searched until February
2003. SELECTION CRITERIA: The inclusion criteria for all randomised controlled
trials were that they should focus on the use of dopamine agonists on the
treatment of cocaine dependence. DATA COLLECTION AND ANALYSIS: The reviewers
extracted the data independently and Relative Risks, weighted mean difference
and number needed to treat were estimated. The reviewers assumed that people who
died or dropped out had no improvement and tested the sensitivity of the final
results to this assumption. MAIN RESULTS: Seventeen studies were included, with
1224 participants randomised. Amantadine, bromocriptine, and pergolide were the
drugs evaluated. The main outcomes evaluated were positive urine sample for
cocaine metabolites, for efficacy, and retention in treatment, as an
acceptability measure. There were no significant differences between
interventions, and in trials where participants had primary cocaine dependence
or had additional diagnosis of opioid dependence and/or were in methadone
maintenance treatment. REVIEWER'S CONCLUSIONS: Current evidence does not support
the clinical use of dopamine agonists in the treatment of cocaine dependence.
Given the high rate of dropouts in this population, clinicians may consider
adding other supportive measures aiming to keep patients in treatment.
Steketee, J. D. (2003). "Neurotransmitter systems of the medial prefrontal
cortex: potential role in sensitization to psychostimulants." Brain Res Brain
Res Rev 41(2-3): 203-28.
The mesocorticolimbic dopamine system, which arises in the ventral tegmental
area and innervates the nucleus accumbens, among numerous other regions, has
been implicated in processes associated with drug addiction, including
behavioral sensitization. Behavioral sensitization is the enhanced
motor-stimulant response that occurs with repeated exposure to psychostimulants.
The medial prefrontal cortex (mPFC), defined as the cortical region that has a
reciprocal innervation with the mediodorsal nucleus of the thalamus, is also a
terminal region of the mesocorticolimbic dopamine system. The mPFC contains
pyramidal glutamatergic neurons that serve as the primary output of this region.
These pyramidal neurons are modulated by numerous neurotransmitter systems,
including gamma-aminobutyric acidergic interneurons and dopaminergic,
noradrenergic, serotonergic, glutamatergic, cholinergic and peptidergic
afferents. Changes in interactions between these various neurotransmitter
systems in the mPFC may lead to alterations in behavioral responses. For
example, recent studies have demonstrated a role for decreased mPFC dopaminergic
transmission in the development of psychostimulant-induced behavioral
sensitization. The present review will discuss the anatomical organization of
the mPFC including descriptions of innervation patterns and receptor
localization of the various neurotransmitter systems of this region. Data
supporting or suggesting a role for each of these mPFC transmitter systems in
the development of behavioral sensitization to cocaine and amphetamine will be
presented. Finally a model of the mPFC that may be useful in directing future
research efforts on the cortical mechanisms involved in the development of
sensitization will be proposed.
Stewart, D. E. (2003). "Physical symptoms of depression: unmet needs in special
populations." J Clin Psychiatry 64 Suppl 7: 12-6.
Over two thirds of people suffering from depression complain of pain with or
without reporting psychological symptoms. Many people have trouble expressing
internal emotions, consider mental illness to be a stigma, or simply assume
depressive symptoms relate to their personal situations and therefore do not
seek treatment. Physical symptoms are more prevalent among women, the elderly,
the poor, children, culturally diverse populations, the medically ill, and the
imprisoned. Because of a dual mechanism of action, medications such as
duloxetine and venlafaxine may be useful in treating the physical symptoms as
well as depressive symptoms in these special populations.
Stewart, P. M. (2003). "Pegvisomant: an advance in clinical efficacy in
acromegaly." Eur J Endocrinol 148 Suppl 2: S27-32.
Acromegaly is a chronic disorder invariably caused by a growth hormone
(GH)-secreting pituitary tumour and is characterised by disabling symptoms
(sweating, arthralgia, headache, paraesthesiae, fatigue), significant
comorbidities (diabetes mellitus, hypertension, sleep apnoea), and premature
mortality. Symptomatic control can be achieved by lowering insulin-like growth
factor-I (IGF-I) concentrations to within the age-adjusted normal range, and
survival can be improved to match that of the general population. However, even
with optimal surgery and current medical therapies (dopamine agonists,
somatostatin analogues), 30% to 50% of patients do not achieve target
concentrations of IGF-I and GH. Pegvisomant is a new GH-receptor antagonist that
blocks GH activity by inhibiting functional dimerisation of GH-receptors. Given
as subcutaneous injections at dosages of 10 mg, 15 mg, or 20 mg/day for 3
Months, pegvisomant normalised serum IGF-I concentrations in, respectively, 54%,
81%, and 89% of acromegalic patients. Moreover, long-term pegvisomant therapy
normalised IGF-I concentrations in 97% of patients treated for 12 Months or
longer, with no evidence of tachyphylaxis. Pegvisomant is the most effective
medical therapy, reported to date, in terms of normalisation of circulating
IGF-I concentrations. In addition, pegvisomant appears to be safe and well
tolerated. Although additional long-term studies are required to further assess
safety, the introduction of this innovative treatment should allow for optimal
disease control in patients with acromegaly.
Stiver, G. (2003). "The treatment of influenza with antiviral drugs." Cmaj
168(1): 49-56.
Influenza vaccination with current inactivated vaccines homologous to the
prevalent wild-type virus can reduce influenza illness in 75%-80% of healthy
adults. Vaccine is recommended for all individuals with chronic underlying
diseases and for those aged 65 years or older. Although influenza vaccination is
still advocated for patients with blunted immunity, protection rates are not as
high, running at 40% for frail institutionalized elderly people. The influenza
antiviral agents amantadine or rimantadine, zanamivir and oseltamivir can modify
the severity of illness and reduce the duration of illness by about 1.5-2.5
days. Amantadine inhibits only influenza A. Resistant virus may emerge in up to
33% of amantadine-treated patients in the first 5 days of treatment and be
transmitted to susceptible close contacts. Side effects are usually mild in
short courses of treatment. The neuraminidase inhibitor drugs zanamivir and
oseltamivir act on both influenza A and B. Treatment is most effective when
given within 30-36 hours after the onset of illness, and the earlier the better.
Influenza should be treated with antiviral drugs in unvaccinated and vaccinated
high-risk patients, as well as immunosuppressed patients with influenza-like
illness, in periods of confirmed influenza prevalence. These drugs may be of
great value in the event of a major viral antigenic shift that causes pandemic
influenza, if an adequate supply can be sustained.
Stocchi, F. and C. W. Olanow (2003). "Neuroprotection in Parkinson's disease:
clinical trials." Ann Neurol 53 Suppl 3: S87-97; discussion S97-9.
Advances in our understanding of the cause and pathogenesis of Parkinson's
disease (PD) have permitted the rational selection of putative neuroprotective
agents for study in PD. However, the list of agents that might provide
neuroprotective effects derived from laboratory studies is daunting, and we face
the challenge of determining which agents to bring to the clinic and how to find
the resources (patients and funds) to properly study so many promising
therapeutic opportunities.1 Appropriate outcome variables that are not
confounded by any symptomatic effect of the drug and are acceptable to
clinicians and regulatory authorities also remain to be defined. The first
clinical trials designed to test the capacity of putative neuroprotective agents
to alter the natural history of PD have now been performed and illustrate some
of these problems. The DATATOP (Deprenyl and Tocopherol Antioxidant Therapy of
PD) study used the time to reach a disease milestone in untreated PD patients
(ie, need for levodopa) as the primary end point. However, interpretation of
results was confounded by the drug's symptomatic effect. The SINDEPAR
(Sinemet-Deprenyl-Parlodel) study used the change in motor score between initial
visit and final visit after washout of all study medications as the primary end
point. However, here too there were concerns about confounding symptomatic
effects, because antiparkinsonian medications have now been shown to have a long
duration response that can persist for weeks and perhaps even months after
withdrawal. More recent studies have used surrogate markers of the integrity of
nigrostriatal function such as striatal uptake of fluorodopa on positron
emission tomography (PET) or beta-CIT-on single-photon emission computerized
tomography (SPECT) as primary outcome measures. However, it has not yet been
confirmed that striatal uptake of these isotopes does in fact correlate with the
remaining number of dopamine neurons or terminals, and the possibility of a
confounding pharmacological effect has not yet been completely excluded. To
date, no drug has been established to have a neuroprotective effect in PD, and
none has been approved for a neuroprotective indication. Furthermore, regulatory
agencies have not yet agreed that any of the outcome measures currently used
will be acceptable for approval of a new drug. Resolution of these issues is of
critical importance to convince pharmaceutical companies to expend the hundreds
of millions of dollars necessary to bring a new drug to market. Drugs that
already have been approved in PD for their symptomatic effects, such as dopamine
agonists or propargylamines (eg, selegiline), offer the best opportunity for
establishing that a drug is neuroprotective in PD in the immediate future, but
herein also lies the difficulty of establishing that any benefits observed are
not solely because of the drug's symptomatic properties. Currently, this will
most likely entail demonstrating that the drug provides benefit for PD patients
for both imaging and clinical markers of disease progression.
Stocchi, F., L. Vacca, et al. (2003). "Are there clinically significant
differences between dopamine agonists." Adv Neurol 91: 259-66.
Stoessl, A. J. and R. de la Fuente-Fernandez (2003). "Dopamine receptors in
Parkinson's disease: imaging studies." Adv Neurol 91: 65-71.
Sugaya, N. (2003). "[Influenza]." Nippon Rinsho 61 Suppl 2:
135-40.
Sulkava, R. (2003). "Differential diagnosis between early Parkinson's disease
and dementia with Lewy bodies." Adv Neurol 91: 411-3.
Swann, A. C. (2003). "Neuroreceptor mechanisms of aggression and its treatment."
J Clin Psychiatry 64 Suppl 4: 26-35.
Aggression results from the interaction of multiple systems. It can be
classified as predatory, impulsive, or based on a medical condition. The
likelihood of aggression is increased by environmental overstimulation or
stress, transmitter balances favoring dopamine and excitatory amino acid
transmission over serotonin and gamma-aminobutyric acid transmission, and the
presence of problems related to impulsivity. Treatments for aggression are based
on the underlying causes and generally should combine pharmacologic and
environmental or psychotherapeutic measures. Useful pharmacologic agents include
mood stabilizers and atypical antipsychotics that combine dopaminergic and
serotonergic actions. Drugs acting on nicotine receptors may deserve further
attention. Nonpharmacologic measures include behavioral techniques aimed at
reducing impulsivity, relapse prevention techniques for substance abuse, and
anger management techniques.
Takeguchi, Y., Y. Miyamoto, et al. (2003). "[Severe hypotension during
anesthesia in a patient on long-term antidepressant therapy]." Masui
52(3): 284-7.
A 71-year-old woman on chronic therapy with mianserine and amantadine was
scheduled to undergo abdominal hysterectomy under spinal anesthesia. Following
spinal anesthesia she developed hypotension refractory to continuous intravenous
fluid infusion as well as multiple boluses of ephedrine. Because the maximum
level of analgesia was T 8, general anesthesia was added using laryngeal mask
airway. Immediately after anesthetic induction, a marked hypotension occurred.
Blood pressure again did not respond to ephedrine but went up excessively to a
small dose of epinephrine without any changes in heart rate. Epinephrine
infusion at a low dose rate was needed to sustain the blood pressure during
surgery. Both depletion of presynaptic norepinephrine store and down-regulation
of postsynaptic beta-receptor may have led to abnormal response to
catecholamines in this case.
Takimoto, Y., A. Inui, et al. (2003). "Orexigenic/anorexigenic signals in
bulimia nervosa." Curr Mol Med 3(4): 349-60.
Bulimia nervosa (BN) and Anorexia Nervosa (AN) are currently classified as
eating disorders (ED). Both disorders are the product of complex interaction
between physiological and psychological and social processes; they are
characterized by abnormal eating behavior. However, patients with BN differ from
AN in their nutritional state and response of treatment with serotonin-selective
reuptake inhibitor (SSRI) as well as frequency of comorbidity of mood and
anxiety disorders. Although biological mechanisms of both BN and AN are largely
unknown, excess of both feeding-stimulatory and feeding inhibitory signaling in
AN have been indicated. This report reviews data that point to the hypothesis
that dysregulation of monoaminergic and new peptidergic circuitry controlling
food intake and energy expenditure play a major role in the eating behavior of
BN.
Talley, N. J. (2003). "Update on the role of drug therapy in non-ulcer
dyspepsia." Rev Gastroenterol Disord 3(1): 25-30.
Non-ulcer dyspepsia is common and is often confused with other diagnoses. It
remains a condition identified by exclusion, and continues to be a challenge to
manage. Currently, only a limited number of pharmacological options are
available. Antacids are no more effective than placebo in treating nonulcer
dyspepsia. H2-receptor antagonists appear to be superior to placebo in efficacy,
but many of the studies suggesting this finding have had a suboptimal study
design. Proton pump inhibitors have been shown to be superior to placebo,
although questions remain as to whether the only subgroup that responds is
comprised of patients with unrecognized gastroesophageal reflux disease. Studies
have found that prokinetic agents are superior to placebo, but currently only a
very limited number of agents within this class can be prescribed in the United
States. Sparse data support the role of metoclopramide and its side effects
limit its use even further. The eradication of Helicobacter pylori has a small
but positive therapeutic benefit in non-ulcer dyspepsia, and can be considered
in those confirmed to be infected. Sucralfate is unlikely to be effective, and
misoprostol is ineffective. Bismuth alone is probably not efficacious. Tricyclic
antidepressants may have a therapeutic role, but this is not firmly established
and this class of medication should be reserved for resistant cases. Emerging
therapies include drugs that relax the gastric fundus, such as buspirone or
sumatriptan, and the new prokinetic tegaserod. Psychological therapies may play
a role but studies of these therapies are limited. Therapy for non-ulcer
dyspepsia remains challenging and is usually empiric; it will remain so until
the mechanisms that induce symptoms of dyspepsia are better understood.
Tan, R. S. (2003). "Novel treatment options for overlapping yet distinct
erectile dysfunction and andropause syndromes." Curr Opin Investig Drugs
4(4): 435-8.
The Food & Drug Administration has recently approved, or is in the process of
approving newer drugs such as the phosphodiesterase inhibitors and apomorphine
to treat men's health issues including erectile dysfunction. Increasing age
results in a gradual hypogonadal state in men, for which different novel
delivery systems of androgens are currently offered for the symptomatic patient.
As such, many men are presenting to healthcare practitioners for the first time.
The age of presentation for erectile dysfunction and andropause often overlaps,
typically in the fifties and beyond, therefore, it makes sense to screen for
erectile dysfunction in andropause patients and vice versa. Erectile dysfunction
is usually a harbinger for other illnesses, such as coronary heart disease and
depression. The hypogonadal state, likewise, could be a harbinger for other ill
health states in men, including obesity, depression, osteoporosis and possibly
memory loss. While the newer treatments for erectile dysfunction and andropause
are distinctly different and targeted at symptom relief, the presentation of the
patient with erectile dysfunction or andropause offers an excellent opportunity
for screening for other health states and health education strategies.
Tan, S., B. Hermann, et al. (2003). "Dopaminergic mouse mutants: investigating
the roles of the different dopamine receptor subtypes and the dopamine
transporter." Int Rev Neurobiol 54: 145-97.
Taylor, D. (2003). "Ziprasidone in the management of schizophrenia : the QT
interval issue in context." CNS Drugs 17(6): 423-30.
Ziprasidone is a new atypical antipsychotic recently marketed in a number of
countries. Its main advantage over other atypical and typical drugs is its low
propensity for causing weight gain. However, ziprasidone has been shown to
prolong to some extent the cardiac corrected QT (QTc) interval, a property
shared by a number of other antipsychotics.Prolongation of the QTc interval is
linked to the ventricular tachyarrhythmia torsade de pointes, which is
occasionally fatal, although the precise association between QTc changes and
risk of sudden cardiac death has not been determined. QTc prolongation is
certainly linked in some way to an increased risk of sudden cardiac death, and
this may explain the recent, somewhat preliminary, reports of increased risk
associated with use of some antipsychotics. Ziprasidone prolongs QTc to a
moderate degree, though to a greater extent than quetiapine, risperidone,
olanzapine and haloperidol. There is also preliminary evidence that ziprasidone
blocks the delayed potassium rectifier channel in cardiac cells. Because of
this, and despite the fact that no increased risk of arrhythmia or sudden death
has been demonstrated for ziprasidone, some caution is required. Ziprasidone
should be avoided in patients with some types of cardiac disease and with
uncontrolled electrolyte disturbance. Coprescription of ziprasidone with other
drugs that prolong the QT interval should be avoided where possible. When
cross-tapering with other antipsychotics, care should be taken to avoid high
total load of antipsychotics, and cross-tapering with drugs known to prolong QT
interval at normal clinical doses should be avoided. Under most clinical
circumstances, however, ziprasidone may be safely used without ECG monitoring or
other special precautions. Its effect on QT interval and possible effect on risk
of arrhythmia should be balanced with the observation that the drug has a more
favourable effect on bodyweight and glucose homeostasis (and so perhaps cardiac
risk) than many other antipsychotics.
Teismann, P., K. Tieu, et al. (2003). "Pathogenic role of glial cells in
Parkinson's disease." Mov Disord 18(2): 121-9.
Parkinson's disease (PD) is a common neurodegenerative disorder characterized by
the progressive loss of the dopaminergic neurons in the substantia nigra pars
compacta (SNpc). The loss of these neurons is associated with a glial response
composed mainly of activated microglial cells and, to a lesser extent, of
reactive astrocytes. This glial response may be the source of trophic factors
and can protect against reactive oxygen species and glutamate. Alternatively,
this glial response can also mediate a variety of deleterious events related to
the production of pro-oxidant reactive species, and pro-inflammatory
prostaglandin and cytokines. We discuss the potential protective and deleterious
effects of glial cells in the SNpc of PD and examine how those factors may
contribute to the pathogenesis of this disease.
Thomas, M. J. and R. C. Malenka (2003). "Synaptic plasticity in the mesolimbic
dopamine system." Philos Trans R Soc Lond B Biol Sci 358(1432):
815-9.
Long-term potentiation (LTP) and long-term depression (LTD) are thought to be
critical mechanisms that contribute to the neural circuit modifications that
mediate all forms of experience-dependent plasticity. It has, however, been
difficult to demonstrate directly that experience causes long-lasting changes in
synaptic strength and that these mediate changes in behaviour. To address these
potential functional roles of LTP and LTD, we have taken advantage of the
powerful in vivo effects of drugs of abuse that exert their behavioural effects
in large part by acting in the nucleus accumbens (NAc) and ventral tegmental
area (VTA); the two major components of the mesolimbic dopamine system. Our
studies suggest that in vivo drugs of abuse such as cocaine cause long-lasting
changes at excitatory synapses in the NAc and VTA owing to activation of the
mechanisms that underlie LTP and LTD in these structures. Thus, administration
of drugs of abuse provides a distinctive model for further investigating the
mechanisms and functions of synaptic plasticity in brain regions that play
important roles in the control of motivated behaviour, and one with considerable
practical implications.
Thomson, C. C. and N. A. Rigotti (2003). "Hospital- and clinic-based smoking
cessation interventions for smokers with cardiovascular disease." Prog
Cardiovasc Dis 45(6): 459-79.
Cigarette smoking is the leading preventable cause of death in the United States
and a major risk factor for cardiovascular disease (CVD). Large observational
epidemiologic studies conducted in diverse populations have demonstrated a
strong association between smoking and CVD morbidity and mortality.
Observational epidemiologic studies have also demonstrated a substantial benefit
of smoking cessation on cardiovascular morbidity and mortality. Smoking
cessation after myocardial infarction reduces subsequent cardiovascular
mortality by nearly 50%. Therefore, the use of effective strategies to reduce
the prevalence of tobacco use is a high priority for both the primary and
secondary prevention of CVD. Effective smoking cessation interventions have been
identified in randomized controlled trials in the general population of smokers.
These methods, which include behavioral counseling and pharmacotherapy, are
incorporated into clinical practice guidelines for physicians in the United
States and Great Britain. A smaller but still substantial body of evidence
demonstrates the efficacy of these interventions in hospital- and clinic-based
settings for smokers with CVD. This evidence is sufficient to support the
routine implementation of these smoking cessation methods in inpatient and
outpatient settings for smokers with CVD.
Tierney, A. J., T. Kim, et al. (2003). "Dopamine in crayfish and other
crustaceans: distribution in the central nervous system and physiological
functions." Microsc Res Tech 60(3): 325-35.
Dopamine is widely distributed in the crustacean nervous system and has a
diverse array of physiological effects. Immunocytochemical studies of several
species have shown that dopamine- and/or tyrosine hydroxylase-containing cells
occur in all ganglia of the central nervous system and that processes from some
of these cells link ganglia of the ventral nerve cord. This study describes the
distribution of tyrosine hydroxylase-containing cells in the central nervous
system of a crayfish (Orconectes rusticus) and compares this information to
available data from other species. The distribution of tyrosine hydroxylase (an
enzyme in the synthetic pathway between tyrosine and dopamine) in O. rusticus is
similar to that reported for marine species. However, differences were observed
in the number of neurons in some ganglia and in the axonal projections of the L
cell, which were more extensive in O. rusticus than in other species studied
thus far. We also review the physiological effects of dopamine in crayfish and
other crustaceans, focusing on the amine's actions in the endocrine,
cardiovascular, and nervous systems, and on behavior when injected into
freely-moving animals.
Tosini, G. and C. Fukuhara (2003). "Photic and circadian regulation of retinal
melatonin in mammals." J Neuroendocrinol 15(4): 364-9.
Several studies have established that melatonin synthesis occurs in the retina
of vertebrates, including mammals. In mammals, a subpopulation of photoreceptors
(probably the cones) synthesize melatonin. Melatonin synthesis in the retina is
elevated at night and reduced during the day in a fashion similar to events in
the pineal gland. Both the MT1 and MT2 melatonin receptors are present in the
retina and retinal melatonin does not contribute to circulating levels,
suggesting that retinal melatonin acts locally as a neurohormone and/or
neuromodulator. Melatonin synthesis in the retina of mammals is under the
control of a circadian oscillator, and circadian rhythms in melatonin synthesis
and/or release have been described for several species of mammals. These rhythms
are present in vivo, persist in vitro, are entrained by light and are
temperature compensated. The cloning of the gene responsible for the synthesis
of the enzyme arylalkylamine N-acetyltransferase (the key enzyme in the
melatonin biosynthetic pathway) has allowed studies of the molecular mechanisms
responsible for the generation of retinal melatonin rhythmicity. The present
review focuses on the cellular and molecular mechanisms that regulate melatonin
synthesis. In particular, we discuss how the photic environment and the
circadian clock interact in determining melatonin levels, in addition to the
role that melatonin plays in retinal physiology.
Tozzi, F. and C. M. Bulik (2003). "Candidate genes in eating disorders." Curr
Drug Target CNS Neurol Disord 2(1): 31-9.
Environmental influences, as well as biological and genetic factors influence
risk for eating disorders. Family and twin studies have shown that eating
disorders are familial and suggest the influence of genetic factors on their
etiology. Positive associations have been observed for some candidate genes that
have been studied (such as 5HT2A receptor gene); however, the field has been
plagued by nonreplications. In this paper we review the extant association
studies of eating disorders.
Tsui, J. K. (2003). "Treatment of dystonia in Parkinson's disease." Adv
Neurol 91: 361-4.
Tyl, R. W. and M. A. Friedman (2003). "Effects of acrylamide on rodent
reproductive performance." Reprod Toxicol 17(1): 1-13.
Acrylamide monomer causes peripheral neurotoxicity, mutagenicity,
clastogenicity, male reproductive toxicity, prenatal lethality, and
endocrine-related tumors in rodents. Acrylamide (and/or its metabolite
glycidamide) binds to dopamine receptors and spermatid protamines and inhibits
activity of kinesin and dyneine, resulting in interference with neuronal
intracellular transport and sperm motility. Glycidamide binds to various
proteins and DNA. Acrylamide at low doses decreases litter size, with rats more
sensitive than mice. At higher doses, sperm morphology and motility and
neurotoxicity are affected, which decreases mating frequency. Acrylamide does
not affect female reproduction (females exhibit neurotoxicity). Dominant lethal
mutations cause decreased newborn litter size. The mechanisms of action appear
to be: (1) acrylamide/glycidamide binding to spermatid protamines, causing
dominant lethality and effects on sperm morphology; and (2) acrylamide binding
to motor proteins, causing distal axonopathy, including hindlimb
weakness/paresis, and effects on mounting, sperm motility, and intromission.
Glycidamide-induced mutations appear to play no role in reproductive or
neurologic toxicity.
Ueno, K., H. Togashi, et al. (2003). "[Behavioral and pharmacological studies of
juvenile stroke-prone spontaneously hypertensive rats as an animal model of
attention-deficit/hyperactivity disorder]." Nihon Shinkei Seishin Yakurigaku
Zasshi 23(1): 47-55.
The present study was undertaken to evaluate juvenile stroke-prone spontaneously
hypertensive rats (SHRSP) as an animal model of attention-deficit/hyperactivity
disorder (AD/HD). Juvenile SHRSP showed significant increases in horizontal
ambulatory activity and vertical rearing activity in the open field as compared
with genetic control Wistar-Kyoto rats (WKY). Anxiety-related behavior assessed
by elevated plus-maze as an index of impulsivity, the entries into open arms and
the spent time in the open arms of SHRSP were significantly higher than those of
WKY. Spontaneous alternation behavior requiring attention and working memory in
the Y-maze was significantly impaired in male, but not female, SHRSP when
compared with sex-matched WKY. Hippocampal long-term potentiation formation, a
cellular model of learning and memory, was not impaired in SHRSP.
Methylphenidate, a first choice psychostimulant for AD/HD, significantly
alleviated the hyperactivity in SHRSP. However, intense impulsivity of SHRSP was
not improved by methylphenidate. Methylphenidate dose-dependently and
significantly ameliorated the impaired spontaneous alteration behavior in male
SHRSP. These results suggest that juvenile male SHRSP manifest problematic
behavior resembling ADHD, namely inattention, hyperactivity and impulsivity.
Methylphenidate alleviates the behavioral symptoms of hyperactivity and
inattention. Thus, juvenile male SHRSP might be a useful behavioral animal model
of AD/HD, from behavioral and pharmacological perspectives.
Ueno, S. (2003). "Genetic polymorphisms of serotonin and dopamine transporters
in mental disorders." J Med Invest 50(1-2): 25-31.
Transporter-assisted uptake of serotonin (5-HT) and dopamine (DA) has been
accounted for activities in human behavior or mental status, because they are
the sites of action of widely used antidepressant and psychoactive drugs. Both
the human serotonin transporter (5-HTT) and human dopamine transporter (DAT1)
genes are good candidates for etiological involvement in various psychiatric
conditions. The serotonin transporter gene has two types of functional
polymorphisms. One is serotonin transporter linked polymorphic region (5-HTTLPR)
consisting of length variation of the repetitive sequence containing
20-23-bp-long repeat elements in the 5'-upstream region of the gene. Another
polymorphism is that serotonin transporter variable number of tandem repeats
(5-HTTVNTR) in its second intron. Both polymorphisms affect the transcription
ratio of 5-HTT gene and may modify neuronal transmission by changing its protein
expression. On the other hand, DAT1 gene has a variable number of tandem repeats
type polymorphism (DAT1VNTR) in the 3'-untranslated region of the mRNA, which
was also reported to change its gene expression. So polymorphic variations of
transporters would change the behavioral and neuropathological tendency. Here,
the feature of those two transporters and their relations to psychiatric
disorders are described.
Uitti, R. J. and Z. K. Wszolek (2003). "Dopamine agonists, sleep disorders, and
driving in Parkinson's disease." Adv Neurol 91: 343-9.
Uyeki, T. M. (2003). "Influenza diagnosis and treatment in children: a review of
studies on clinically useful tests and antiviral treatment for influenza."
Pediatr Infect Dis J 22(2): 164-77.
BACKGROUND: Prompt testing for influenza can help guide clinical management of
patients with suspected influenza. Three antiviral medications, amantadine,
oseltamivir and zanamivir, are approved for treatment of influenza in children.
Rimantadine and ribavirin have also been used. OBJECTIVES: To review the
published evidence on clinically useful diagnostic tests and antiviral treatment
for influenza virus infections in children. METHODS: Studies published from 1966
through September 2002 were reviewed on clinical diagnosis, immunofluorescence
and rapid influenza tests and on antiviral treatment of influenza virus
infections among pediatric populations. RESULTS: No studies assessed the
accuracy of clinical diagnosis of influenza in children compared with viral
culture. Compared with viral culture, direct immunofluorescence antibody and
indirect immunofluorescence antibody tests for influenza had fair to moderate
median sensitivities and high median specificities, whereas rapid influenza
diagnostic tests had moderate median sensitivities and moderately high median
specificities. No randomized, placebo-controlled studies were found of
amantadine or rimantadine for treatment of influenza A. In a few separate
controlled studies, oseltamivir, zanamivir and ribavirin each reduced symptom
duration of influenza compared with placebo. CONCLUSIONS: Additional data are
needed about the accuracy of clinical diagnosis of influenza in children.
Although direct immunofluorescence antibody staining, indirect
immunofluorescence antibody staining and rapid tests are moderately to
reasonably accurate in detecting influenza virus infections in children,
physicians should use clinical judgment and local surveillance data about
circulating influenza viruses when interpreting test results. Further controlled
studies of the efficacy, adverse effects and emergence of antiviral resistance
during treatment of influenza are needed for all of the antiviral drugs.
van Laar, T. (2003). "Levodopa-induced response fluctuations in patients with
Parkinson's disease: strategies for management." CNS Drugs 17(7):
475-89.
Fluctuations in response to levodopa in patients in the advanced stages of
idiopathic Parkinson's disease occur frequently and are a difficult problem to
treat. Patients who are treated with levodopa have an additional 10% risk of
experiencing response fluctuations with each year of treatment: 50% of patients
have this problem after 5 years of receiving levodopa therapy and almost 100% of
patients after 10 years.The mechanisms by which response fluctuations occur are
only partially understood and can be divided into three main types: (i)
presynaptic neuronal degeneration leading to a lack of buffering of released
levodopa, which is mainly related to wearing-off phenomena; (ii) postsynaptic
changes in dopamine receptor sensitivity and number, partially caused by the
presynaptic changes, which are clinically related to at-random response
fluctuations; and (iii) pharmacokinetic and pharmacodynamic influences of
exogenously administered dopaminergic agents.Several oral and parenteral
treatment strategies are recommended to manage response fluctuations, such as
optimisation of dopamine receptor agonist therapy in combination with a
reduction of the levodopa load; use of slow-release levodopa formulations; use
of catechol-O-methyltransferase inhibitors; an increase of levodopa dose
frequency; use of high-dose amantadine; and intermittent or continuous use of
apomorphine and/or levodopa. Continuous stimulation of dopamine receptors with
dopaminergic agents is one of the crucial basic steps in the treatment of
patients at an advanced stage of Parkinson's disease, and the preferential use
of dopamine receptor agonists has proven to be successful in the prevention and
treatment of response fluctuations.
van Vloten, W. A. (2003). "Pimozide: use in dermatology." Dermatol Online J
9(2): 3.
Pimozide is widely used in psychiatry for chronic psychoses, schizophrenia, the
syndrome of Gilles de la Tourette and to a certain extent, also in dermatology.
The only dermatological indication is for delusions of parasitosis. Though there
is a good rationale for using pimozide in this disease, the majority of the
studies on pimozide in dermatology are uncontrolled trials and case reports.
Vance, M. L. (2003). "Medical treatment of functional pituitary tumors."
Neurosurg Clin N Am 14(1): 81-7.
Medical therapy with a dopamine agonist is the most effective for treatment of a
prolactin-producing adenoma and is considered as primary treatment. Surgery and
pituitary radiation are reserved for patients who either do not tolerate or do
not respond to a dopamine agonist drug. A somatostatin analogue is effective
medical therapy for patients with acromegaly, and this is usually administered
if there is persistent GH hypersecretion after surgical resection. Medical
treatment for patients with Cushing's disease is directed at the adrenal glands
to reduce cortisol hypersecretion. Unfortunately, there is no effective medical
therapy to reduce pituitary corticotropin production. Medical therapy for a
gonadotrope adenoma with a dopamine agonist or somatostatin analogue has limited
utility but is employed in patients who are unable to undergo surgery and may
delay or prevent additional tumor growth. Many patients with a pituitary adenoma
can be successfully treated with one treatment, either a dopamine agonist for a
prolactinoma or surgery for other types of tumors. A substantial number of
patients require multimodality therapy, however, including medical therapy,
surgery, and pituitary radiation. Because the biologic behavior of pituitary
adenomas varies considerably, a patient with a pituitary adenoma requires
lifelong regular monitoring for hormone hypersecretion, tumor recurrence, and
development of new pituitary hormone deficiency. A coordinated plan of care
among endocrinologists, neurosurgeons, neuroophthalmologists, and radiation
therapists is necessary to provide optimal care for these patients.
Vieyra, G., M. Moraga, et al. (2003). "[Distribution of DRD4 and DAT1 alleles
from dopaminergic system in a mixed Chilean population]." Rev Med Chil
131(2): 135-43.
BACKGROUND: Genes for dopamine receptor DRD4 and dopamine transporter DAT1 are
highly polymorphic. Two alleles of these genes, namely the DRD4.7 and the DAT1*9
are frequently associated to the attention deficit disorder with hyperactivity.
In Europe, the allele for DRD4 receptor with four repetitions (DRD4.4) has the
highest frequency, with a median of 69%, followed by DRD4.7, with a frequency of
15%. South American indigenous populations have higher frequencies for DRD4.7
(61%) than for DRD4.4 (29%). The ten repetition allele for DAT1 transporter has
a high frequency among Europeans (72%) and Amerindians (100%). The allele DAT1*9
is the second most frequent allele. AIM: To study the frequency of DRD4 and DAT1
alleles in a Chilean population sample. MATERIAL AND METHODS: One hundred serum
samples were obtained from blood donors in two public hospitals in Santiago.
Polymorphic regions for DRD4 and DAT1 were amplified by polymerase chain
reaction. RESULTS: The allele DRD4.4 had a frequency of 59% and DRD4.7 a
frequency of 27%. The allele DAT1*10 had a frequency of 74%, followed by DAT
1*9, with a frequency of 23%. DISCUSSION: In a Chilean population sample, the
frequency of DRD4 and DAT1 alleles was very similar to that of European
populations.
Vila, M. and S. Przedborski (2003). "Targeting programmed cell death in
neurodegenerative diseases." Nat Rev Neurosci 4(5): 365-75.
Wahlsten, D., P. Metten, et al. (2003). "Different data from different labs:
lessons from studies of gene-environment interaction." J Neurobiol 54(1):
283-311.
It is sometimes supposed that standardizing tests of mouse behavior will ensure
similar results in different laboratories. We evaluated this supposition by
conducting behavioral tests with identical apparatus and test protocols in
independent laboratories. Eight genetic groups of mice, including equal numbers
of males and females, were either bred locally or shipped from the supplier and
then tested on six behaviors simultaneously in three laboratories (Albany, NY;
Edmonton, AB; Portland, OR). The behaviors included locomotor activity in a
small box, the elevated plus maze, accelerating rotarod, visible platform water
escape, cocaine activation of locomotor activity, and ethanol preference in a
two-bottle test. A preliminary report of this study presented a conventional
analysis of conventional measures that revealed strong effects of both genotype
and laboratory as well as noteworthy interactions between genotype and
laboratory. We now report a more detailed analysis of additional measures and
view the data for each test in different ways. Whether mice were shipped from a
supplier or bred locally had negligible effects for almost every measure in the
six tests, and sex differences were also absent or very small for most
behaviors, whereas genetic effects were almost always large. For locomotor
activity, cocaine activation, and elevated plus maze, the analysis demonstrated
the strong dependence of genetic differences in behavior on the laboratory
giving the tests. For ethanol preference and water escape learning, on the other
hand, the three labs obtained essentially the same results for key indicators of
behavior. Thus, it is clear that the strong dependence of results on the
specific laboratory is itself dependent on the task in question. Our results
suggest that there may be advantages of test standardization, but laboratory
environments probably can never be made sufficiently similar to guarantee
identical results on a wide range of tests in a wide range of labs.
Interpretations of our results by colleagues in neuroscience as well as the mass
media are reviewed. Pessimistic views, prevalent in the media but relatively
uncommon among neuroscientists, of mouse behavioral tests as being highly
unreliable are contradicted by our data. Despite the presence of noteworthy
interactions between genotype and lab environment, most of the larger
differences between inbred strains were replicated across the three labs. Strain
differences of moderate effects size, on the other hand, often differed markedly
among labs, especially those involving three 129-derived strains. Implications
for behavioral screening of targeted and induced mutations in mice are
discussed.
Wells, S. and D. Murphy (2003). "Transgenic studies on the regulation of the
anterior pituitary gland function by the hypothalamus." Front Neuroendocrinol
24(1): 11-26.
The anterior pituitary gland is composed of five different cell types secreting
hormones whose functions include the regulation of post-natal growth (growth
hormone, GH), lactation (prolactin, PRL), reproduction (luteinising hormone, LH,
and follicle stimulating hormone, FSH), metabolism (thyroid stimulating hormone,
TSH), and stress (adrenocorticotrophic hormone, ACTH). The synthesis and
secretion of the anterior pituitary hormones is under the control of
neuropeptides released from the hypothalamus into a capillary portal plexus
which flows through the external zone of the median eminence to the anterior
lobe. This review describes the ways that gene transfer technologies have been
applied to whole animals in order to study the regulation of anterior pituitary
function by the hypothalamus. The extensive studies on these neuronal systems,
within the context of the physiological integrity of the intact organism, not
only exemplify the successful application of transgenic technologies to
neuroendocrine systems, but also illustrate the problems that have been
encountered, and the challenges that lie ahead.
West, R. (2003). "Bupropion SR for smoking cessation." Expert Opin
Pharmacother 4(4): 533-40.
Cigarette dependence is recognised as a life-threatening disorder which can be
treated by behavioural support and/or medication. Bupropion hydrochloride
sustained-release (Zyban trade mark, GlaxoSmithKline) is licensed in many
countries including the US, Canada, UK, Australia and continental Europe to aid
smoking cessation. The usual recommended dose is 150 mg b.i.d. taken for 7 - 14
days prior to the quit date, and then 6 - 8 weeks afterwards (figures vary
across countries). Evidence from seven double-blind, placebo-controlled,
randomised trials shows that it improves success at staying off cigarettes for
at least 12 months by 9 - 10 percentage points. Taking into account estimates of
subsequent cessation and relapse patterns in treated and untreated smokers, and
the improvement in life-expectancy of smokers who manage to stop, the estimated
cost/life/year saved from an episode of use of the medication is approximately
UK pound 1000 or US$1500. Bupropion has CNS stimulant properties; the common
side effects are dry mouth and sleep disturbance. Rare but serious side effects
are anaphylactic/hypersensitivity reaction and seizure (both estimated at 1 in a
1000). The drug is contraindicated in patients with hypersensitivity to the drug
or its metabolites, any seizure disorder, eating disorder, severe hepatic
cirrhosis, history of bipolar disorder or in patients taking monoamine oxidase
inhibitors. Extreme caution is advised where there are any predisposing factors
that may reduce the seizure threshold. Bupropion sustained-release and nicotine
replacement therapies are both considered as first-line treatments to aid
smoking cessation. Ideally patients should also enrol in a structured
behavioural support programme to boost their chances of success.
Wichmann, T. and M. R. DeLong (2003). "Functional neuroanatomy of the basal
ganglia in Parkinson's disease." Adv Neurol 91: 9-18.
Widner, H. (2003). "Strategies to modify levodopa treatment." Adv Neurol
91: 229-36.
Wolf, F. W. and U. Heberlein (2003). "Invertebrate models of drug abuse." J
Neurobiol 54(1): 161-78.
Susceptibility to drug addiction depends on genetic and environmental factors
and their complex interactions. Studies with mammalian models have identified
molecular targets, neurochemical systems, and brain regions that mediate some of
the addictive properties of abused drugs. Yet, our understanding of how the
primary effects of drugs lead to addiction remains incomplete. Recently,
researchers have turned to the invertebrate model systems Drosophila
melanogaster and Caenorhabditis elegans to dissect the mechanisms by which
abused drugs modulate behavior. Due to their sophisticated genetics, relatively
simple anatomy, and their remarkable molecular similarity to mammals, these
invertebrate models should provide useful insights into the mechanisms of drug
action. Here we review recent behavioral and genetic studies in flies and worms
on the effects of ethanol, cocaine, and nicotine, three of the most widely
abused drugs in the world.
Yoshimura, N. (2003). "[New insights into neural mechanisms controlling the
micturition reflex]." Nippon Yakurigaku Zasshi 121(5): 290-8.
The functions of the lower urinary tract, to store and periodically release
urine, are dependent on the activity of smooth and striated muscles in the
bladder, urethra, and external urethral sphincter. This activity is in turn
controlled by neural circuits in the brain, spinal cord, and peripheral ganglia.
During urine storage, the outlet is closed and the bladder smooth muscle is
quiescent. When bladder volume reaches the micturition threshold, activation of
a micturition center in the dorsolateral pons (the pontine micturition center)
induces a bladder contraction and a reciprocal relaxation of the urethra,
leading to bladder emptying. During voiding, sacral parasympathetic (pelvic)
nerves provide an excitatory input (cholinergic and purinergic) to the bladder
and inhibitory input (nitrergic) to the urethra. The brain rostral to the pons
(diencephalon and cerebral cortex) is also involved in excitatory and inhibitory
regulation of the micturition reflex. Various transmitters including dopamine,
serotonin, norepinephrine, GABA, excitatory and inhibitory amino acids, opioids,
acetylcholine, and neuropeptides are implicated in the modulation of the
micturition reflex in the central nervous system. Therefore, injury or diseases
of the nervous system, as well as drugs and disorders of the peripheral organs,
can produce bladder and urethral dysfunctions such as urinary frequency, urgency
and incontinence, or inefficient bladder emptying.
Yu, Q., D. F. Larson, et al. (2003). "Heart disease, methamphetamine and AIDS."
Life Sci 73(2): 129-40.
Methamphetamine (MA) not only affects the nervous system but also has cardiac
toxicity and immunosuppressive properties. This manuscript will provide support
that there is a relationship between MA use and heart disease as well as immune
dysfunction. The cardiovascular manifestations of acute MA use include
tachycardia, atrioventricular arrhythmias, myocardial ischemia, myocardial
ischemia and hypertension, resulting in cardiac lesions. Chronic use of MA
causes cardiomyopathy including cellular infiltration, myocardial hypertrophy,
myocardium rupture and fibrosis. The increased catecholamine levels are
responsible for the cardiac lesions induced by MA. The additional problem with
MA use is its potential to disrupt the immune system function leading to
suppression of mitogen-stimulated lymphocyte, a reduction in circulating
lymphocyte numbers and alternation T-lymphocyte cytokine secretion as well as B
cell proinflammatory cytokine secretion. Concomitant MA use and Human
Immunodeficiency Virus (HIV) infection not only enhances immunosuppression
associated with HIV but also increases the heart disease occurrence with a
coincidentally complication of AIDS or AIDS medications.
Zeuzem, S. (2003). "[Combination therapy for chronic viral hepatitis C]."
Dtsch Med Wochenschr 128(8): 370-4.
Zhou, F. M., C. Wilson, et al. (2003). "Muscarinic and nicotinic cholinergic
mechanisms in the mesostriatal dopamine systems." Neuroscientist 9(1):
23-36.
The striatum and its dense dopaminergic innervation originating in the midbrain,
primarily from the substantia nigra pars compacta and the ventral tegmental
area, compose the mesostriatal dopamine (DA) systems. The nigrostriatal system
is involved mainly in motor coordination and in disorders such as Tourette's
syndrome, Huntington's disease, and Parkinson's disease. The dopaminergic
projections from the ventral tegmental area to the striatum participate more in
the processes that shape behaviors leading to reward, and addictive drugs act
upon this mesolimbic system. The midbrain DA areas receive cholinergic
innervation from the pedunculopontine tegmentum and the laterodorsal pontine
tegmentum, whereas the striatum receives dense cholinergic innervation from
local interneurons. The various neurons of the mesostriatal systems express
multiple types of muscarinic and nicotinic acetylcholine receptors as well as DA
receptors. Especially in the striatum, the dense mingling of dopaminergic and
cholinergic constituents enables potent interactions. Evidence indicates that
cholinergic and dopaminergic systems work together to produce the coordinated
functioning of the striatum. Loss of that cooperative activity contributes to
the dysfunction underlying Parkinson's disease.
Zolk, O. and N. Thurauf (2003). "[Risperidone]." Dtsch Med Wochenschr
128(24): 1353-6.