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
inv