Showing papers in "Clinical Neuropharmacology in 1992"

The neurobiology of the opsoclonus-myoclonus syndrome.

Abstract: SummaryOpsoclonus-myoclonus is a pervasive neurological syndrome of children and adults. Although rare, it raises important clinical and neurobiological issues. This article provides an overview of the clinical and laboratory features, differential diagnosis, treatment, and outcome of opsoclonus-myo

Clinical and pharmacokinetic effects of a diet rich in insoluble fiber on Parkinson disease.

Abstract: In this study, the effects of a diet rich in insoluble fiber (DRIF) on motor disability and the peripheral pharmacokinetics of orally administered L-dopa in Parkinsonian patients with marked constipation are analyzed. We found a useful effect of a DRIF on plasma L-dopa concentration and motor function. The greatest effect on the plasma L-dopa levels was found early (at 30 and 60 min) after oral administration. There was a relationship between the improvement of constipation and the higher bioavailability of L-dopa. DRIF can be a coadjuvant treatment in patients with Parkinson's disease.

Nitrous oxide abuse in perspective.

Abstract: I present evidence that certain health professionals have a higher liability to drug abuse than does the general population. In view of this, data are presented in which the extremely limited contribution of nitrous oxide to this problem is assessed. I demonstrate on the basis of the limited published data now available that pure nitrous oxide addiction is very rare among health professionals, being the rarest drug of abuse among them. When used by the latter, it is most commonly part of a polydrug abuse pattern, not being a major component of the addiction in these cases. It is clear that nitrous oxide addiction is even less of a problem in the general population. Furthermore, after almost 200 years of use, its very minor addictive potential should by now have clarified itself. It would appear that it is unlikely to become, has never been, nor is it the moment of any real significance as a drug of abuse when compared with the many currently available addictive drugs, which clearly pose a much more serious problem.

Serotonergic and dopaminergic involvement in ethanol intake.

Abstract: Ethanol, being a simple molecule, is known to influence the activity of a number of biological systems and therefore it is not suprising that ethanol has a very complex psychopharmacodynamic profile. The understanding of the neurochemical basis of these various pharmacological effects is of course imperative for the development of new pharmacological treatment strategies for decreasing alcohol consumption in man. All the diverse effects of ethanol can in all probability not be related to one single neurotransmitter system. In fact, as indicated by data from our research group as well as from others, we have to consider that different neurotransmitters and perhaps also hormones are involved in the mediation of the pharmacological effects of ethanol (fig. 1). To what degree they participate in the regulation of ethanol consumption is one of many challenges we have to face in ethanol research. One way to view this is that multiple neurotransmitters and hormones collectively orchestrate the reward profile of ethanol, ethanol being the conductor and every instrument/transmitter being able to play the reward tune to some degree, but not until all instruments are playing together the full reward symphony will be experienced. Furthermore, adding to the complexity, we also have to take into account that the various biological systems may be differentially sensitive to ethanol i.e. they display different dose-response ranges (cf. Engel and Liljequist, 1983).

Baclofen in the treatment of dystonia.

Abstract: Dystonia refers to involuntary, prolonged muscle contractions leading to sustained, often twisting, postures. High dose anticholinergic therapy for childhood onset dystonia, botulinum toxin injections for focal dystonia, and levodopa for diurnal dystonia provide symptomatic relief for some patients. Despite this, treatment of both idiopathic and secondary dystonia remains inadequate for many patients. Baclofen, a pre-synaptic acting GABA agonist, has been reported to benefit dystonia in a number of retrospective studies. Dramatic improvement in symptoms, especially in gait, was found in almost 30% of 31 children and adolescents with idiopathic dystonia in one retrospective study using doses ranging from 40 to 180 mg daily. The response to baclofen of adults with focal dystonia is less dramatic. One series of 60 adults with cranial dystonia found sustained benefit in 18%. Smaller series have not consistently found significant benefit in adults. Baclofen has been used to treat several secondary dystonias: tardive dystonia has occasionally been reported to improve and there are isolated reports of improvement in dystonia occurring in Parkinson's disease and in glutaric aciduria.

Exacerbation of parkinsonism by tacrine.

Abstract: A patient with Alzheimer's disease and mild features of parkinsonism was treated with tacrine. Tremor and gait dysfunction worsened but responded to the addition of levodopa without adversely affecting cognitive function. The implications for experimental treatment strategies of patients with combined Alzheimer's and Parkinson's disease are discussed.

GABA-active steroids: endogenous modulators of GABA-gated chloride ion conductance.

Abstract: Naturally occurring 3-alpha-hydroxy ring A-reduced metabolites of progesterone and deoxycorticosterone and their synthetic analogues bind to specific sites within the hydrophobic channel domain of the GABAA receptor complex. Acting at these sites, these ligands function as positive allosteric effectors of the complex; they potentiate GABA-stimulated membrane chloride ion conductance, enhance the binding of [3H]muscimol and [3H]flunitrazepam, and displace the binding of [35S]t-butylbicyclophosphorothionate ([35S]TBPS), a channel ligand that is a specific marker of the GABA-associated chloride ionophore. Moreover, steroid metabolites (namely pregnenolone sulfate and dehydroepiandrosterone sulfate) have been identified that display properties of GABA-negative allosteric effectors. The identification of this membrane-associated steroid binding should stimulate development of new classes of anxiolytic, sedative-hypnotic, anticonvulsant, anesthetic, and muscle-relaxant medications that may be devoid of many of the side effects associated with benzodiazepines and barbiturates. Also, elucidation of the physiologic role of this binding site should contribute both to our understanding of endogenous mechanisms for modulating inhibitory neurotransmission, and the pathophysiologic role of the GABAA receptor complex in a variety of neuropsychiatric disorders.

Baclofen intoxication: report of four cases and review of the literature

Abstract: Four cases of baclofen intoxication are reported, with a review of 33 cases from the literature. Analysis of these 37 cases suggests that there are two types of baclofen intoxication syndrome. Patients with acute intoxication present with four major clinical manifestations: encephalopathy (disturbance of consciousness and/or seizure), respiratory depression, muscular hypotonia, and generalized hyporeflexia. Patients with chronic intoxication present with hallucinosis, impaired memory, catatonia, or acute mania. The acute intoxication syndrome has a faster onset, shorter duration, more severe clinical manifestations, and higher incidence of seizures than the chronic intoxication syndrome. Baclofen intoxication, although it may cause grave encephalopathic manifestations and electroencephalographic findings, has a benign outcome if actively managed.

Clinical, immunopathologic, and therapeutic considerations of inflammatory myopathies.

Abstract: The inflammatory myopathies encompass a group of heterogenous muscle diseases which have in common an acquired myopathy with histological signs of endomysial inflammation. We present evidence based on recently emerged clinical, histologic, immunopathologic, demographic and therapeutic observations that these myopathies comprise three major and distinct groups: polymyositis (PM), dermatomyositis (DM), and inclusion-body myositis (IBM). Immune-mediated mechanisms characteristic for each group appear to play a primary role in the pathogenesis of these diseases. In DM there is an intramuscular microangiopathy mediated by the C5b-9 membranolytic attack complex, leading sequentially to loss of capillaries, muscle ischemia, muscle fiber necrosis and perifascicular atrophy. In contrast, in PM and IBM the muscle fiber injury is initiated by sensitized CD8+ cytotoxic T cells that recognize MHC-I restricted muscle antigens, leading to phagocytosis and fiber necrosis. Among the viruses implicated in the cause of inflammatory myopathies, only the retroviruses, HIV, HTLV-1 and simian retroviruses, have been convincingly associated with PM. Retroviruses, therefore, appear to be the leading group of viruses capable of triggering these diseases. The treatment of inflammatory myopathies has been largely empirical. A detailed therapeutic plan based on our experience with a large number of patients is presented. Patients with bona fide PM or DM respond to steroids to some degree and for some period of time. In contrast, patients with IBM do not respond to any therapy and the disease should be suspected when a patient with presumed PM has failed treatment. Methotrexate and cyclophosphamide are disappointing. Cyclosporine and Azathioprine are commonly used but they are of uncertain benefit. Plasmapheresis is ineffective. High-dose intravenous immunoglobulin is a promising new therapeutic modality.

Pharmacology of benzodiazepine receptors: an update.

Abstract: Benzodiazepine receptors are allosteric modulatory sites on GABAA receptors. GABAA receptors are probably composed of five protein subunits, at least some of which belong to different subunit classes. So far six alpha-, four beta-, three gamma-, and delta- and two rho = p subunits of GABAA receptors have been identified. A large number of different subunit combinations, each of which will result in a GABAA receptor with distinct electrophysiological and pharmacological properties, are therefore possible. Many compounds from different chemical classes which are able to bind to benzodiazepine receptors have been identified. Depending on their individual efficacy, binding of these compounds either enhances, reduces or does not influence GABAergic transmission. However, the individual efficacy of the benzodiazepine receptor ligands changes with the subunit composition of the GABAA receptor. The investigation of the regional distribution, subunit composition and pharmacology of GABAA receptors will result in the development of new and more selective compounds for psychiatry.

Synaptic plasticity in the rat striatum following chronic haloperidol treatment.

Abstract: Administration of the dopamine (DA) antagonist haloperidol leads to the development of behavioral hypersensitivity as well as enhanced neuronal growth when striatal extracts from these animals are incubated with mesencephalic cultures. For determining if alterations in neuronal growth also occur in vivo, the ultrastructure of the neuropil in the dorsolateral quadrant of the striatum from rats treated (24 days) with haloperidol (1.25 mg/kg) was examined by electron microscopy. Haloperidol-treated rats developed statistically significant behavioral hypersensitivity relative to vehicle-treated controls (p < 0.01). Evaluation of the neuropil revealed that haloperidol treatment enhanced, relative to vehicle-treated controls, the overall number of synaptic boutons by 9% (p < 0.01). The number of perforated synaptic profiles as well as the number of double synapses was increased by 20 and 50%, respectively, although this increase was not statistically significant. The number of myelinated axons remained unchanged, while the number of dendritic spines was increased by 21% (p < 0.05). These data suggest that chronic haloperidol treatment enhanced the growth and possible sprouting of presynaptic neurons and also induced postsynaptic plastic changes. These ultrastructural changes may contribute in part to hypersensitivity behaviors.

Parkinsonism associated with calcium channel blockers: a prospective follow-up study.

Abstract: Parkinsonism is a well-known side effect of some calcium channel blockers (CCB). Its long-term evolution, however, is unknown. To clarify this issue, we performed a prospective follow-up study involving 32 patients diagnosed with CCB-induced parkinsonism. After the baseline examination, the CCB were discontinued and serial evaluations were carried out according to the same protocol. Despite a global improvement, cognitive and mood disturbances subsided slowly, and tremor persisted in most patients. After 18 months of CCB withdrawal, 44% of patients had depression, 88% had tremor, and 33% still had criteria for diagnosis of parkinsonism. During the survey, only three patients were found to be fully recovered. The improvement of some clinical symptoms was related to age: Patients younger than 73 years recovered better than older patients did. Our data indicate that CCB-induced parkinsonism is not the benign condition previously thought, and suggest an age-related prognosis of this entity.

Cerebral amyloid angiopathy with granulomatous angiitis ameliorated by steroid-cytoxan treatment.

Abstract: We report a case of a 62-year-old black woman who, 8 months prior to death, developed confusion, apraxias, disorientation, and difficulties with her vision. There was no dementia. Computed tomography (CT) scan and magnetic resonance imaging (MRI) suggested a tumor in the right posterior parietal white matter. A biopsy of the lesion displayed granulomatous angiitis and severe cerebrovascular amyloidosis, but no tumor was identified. Chronic inflammation with an occasional multinucleated giant cell was seen about the amyloid-infiltrated vessels. The cortex demonstrated gliosis but no plaques or tangles. Subsequently, the patient was treated with steroids and Cytoxan, with an improvement in her neurologic status. She died of opportunistic bronchopneumonia 8 months after the initial onset of her symptoms. On postmortem examination, the biopsied area of the brain showed atrophy with gliosis. Amyloid angiopathy was present but in much lesser degree than in the biopsy. Scant perivascular inflammatory infiltrates were seen only focally, and no giant cells were observed. The amyloid, both in the biopsy and autopsy material, was of the Alzheimer A4 type. This case suggests that steroid and cytoxan treatment ameliorated the angiitis and the amyloid angiopathy as well. The pertinent literature is discussed.

The role of drugs in the etiology of stroke.

Abstract: Drugs of many classes have been implicated in hemorrhagic and ischemic stroke. Alcohol in moderation may have a protective effect although in greater doses may predispose to stroke. Drugs such as cocaine, amphetamines and heroin have been associated with stroke by a number of mechanisms. Antiplatelet, anticoagulant and thrombolytic therapy carry risk of hemorrhagic complications. Oral contraceptives appear to slightly increase stroke risk whereas estrogen replacement therapy may decrease it. Anabolic steroid use in athletes has been linked to stroke. The antineoplastic agent L-asparaginase has been associated with cerebral hemorrhage, ischemic infarction and venous sinus thrombosis. Infarction has been reported in association with cisplatin-based combination chemotherapy. Stroke is an infrequent but recognized complication of some forms of drug therapy and drug abuse.

Pharmacologic controversy of CNS stimulants in Gilles de la Tourette's syndrome.

Abstract: The controversy of the use of stimulants in Gilles de la Tourette's syndrome (GTS) can only be understood by examining the relationship between GTS and attention deficit-hyperactivity disorder (ADHD), because the relationship between the two disorders is complex, and stimulants are used in the one (ADHD) and may be contraindicated in the other (GTS). This relationship therefore has to be viewed from several perspectives, including clinical, genetic, neurobiochemical, neurophysiological, and treatment strategies, to highlight the complexities involved, and reasons for controversy. The present review will examine these relationships, and thus the evidence for and against the treatment of GTS with stimulants.

Cigarette smoking and parkinson disease : the illusion of a neuroprotective effect

Abstract: Repeated studies have demonstrated a negative association between cigarette smoking and Parkinson disease. This negative association has led many investigators to suggest that some facet of cigarette smoking exerts a neuroprotective influence with respect to developing Parkinson disease. Longitudinal Gompertzian analysis demonstrates that no neuroprotective influence is necessary to account for the negative association between Parkinson disease and cigarette smoking. Indeed, the only assumption that needs to be made is that smokers experience earlier mortality than nonsmokers. The example of cigarette smoking and Parkinson disease illustrates a limitation with current risk factor analysis, i.e., disease patterns are typically interpreted using only two dimensions: genetics and the environment. However, longitudinal Gompertzian analysis demonstrates that disease mortality patterns and trends are actually three-dimensional phenomenon, with competition being the third dimension.

Effects of selective activation or blockade of the histamine h3 receptor on sleep and wakefulness

Abstract: The effects of the histamine H3 receptor agonist, (R)-alpha-methylhistamine were compared with those of the histamine H3 antagonist, thioperamide, in rats implanted with electrodes for chronic sleep recordings. (R)-alpha-Methylhistamine (1.0-4.0 micrograms) injected bilaterally into the premammillary area where histamine immunoreactive neurons have been detected increased slow wave sleep, whereas wakefulness and REM sleep were decreased. No significant effects were observed when (R)-alpha-methylhistamine (1.0-8.0 mg/kg) was administered i.p. Thioperamide (1.0-4.0 mg/kg i.p.) increased wakefulness and decreased slow wave sleep and REM sleep. Pretreatment with thioperamide (4.0 mg/kg) prevented the effects of (R)-alpha-methylhistamine (2.0 micrograms) on slow wave sleep and wakefulness. Our results further support an active role for histamine in the control of the waking state.

Dihydroergotamine: a review of its use in the treatment of migraine and other headaches.

Abstract: Dihydroergotamine has been one of the main drugs used in the treatment of migraine for greater than 40 years. The recent introduction of the more selective 5-HT antagonist sumatriptan will challenge the place of dihydroergotamine in migraine therapy and indicates the need to review the evidence for the use of dihydroergotamine. Although there is little evidence from double-blind clinical trials, dihydroergotamine does appear to be effective in the treatment of acute attacks and in the prevention of migraine. Its place in treatment is in cases where simple analgesics alone or in combination with other agents fail to provide relief. Further studies are necessary to compare dihydroergotamine with sumatriptan for acute migraine and with beta-blockers in prophylaxis to determine its future role in migraine therapy.

Neuroleptic malignant syndrome related to tetrabenazine introduction and haloperidol discontinuation in Huntington's disease.

Abstract: We describe the second reported case of neuroleptic malignant syndrome (NMS) related to tetrabenazine therapy in Huntington's disease. In the previously reported case, factors capable of potentiating NMS included a high dosage of tetrabenazine exceeding the accepted therapeutic range, and co-medication with the dopamine-synthesis inhibitor alpha-methylparatyrosine, while in the present case abrupt introduction of the drug and discontinuation of concomitant neuroleptics may have contributed to this important adverse reaction. Uneventful recovery occurred in both cases without the need for drugs specifically enhancing dopaminergic transmission, while rechallenge by tetrabenazine with conventional doses and slow upward titration was not followed by recurrence of the NMS. Tetrabenazine has proved to be a safe and frequently useful drug in the long-term treatment of approximately 400 dyskinetic patients. We believe that NMS related to this drug is rare, provided that it is properly administered.