Search PubMed⌕ Search

Biomedical subjects

S Fahn

Publications and source records attributed to S Fahn.

At least 289 records · Page 16Linked to original sources
PubMed1985

Acetylcholinesterase activity in patients with torsion dystonia. Measurement in erythrocyte membranes.

Anticholinergic therapy provides symptomatic relief in many patients with dystonia. The mechanism underlying this therapeutic action is poorly understood; however, one possibility is that the degradation of acetylcholine is perturbed in these conditions. To investigate this possibility, acetylcholinesterase activity was measured in erythrocyte membranes from healthy volunteers and patients with torsion dystonia. Enzyme activities in erythrocytes from 14 patients with adult-onset, childhood-onset idiopathic, and childhood-onset familial dystonias did not differ significantly from activities measured in erythrocyte membranes from 17 healthy volunteers. Moreover, when blood samples from several members of a family with dominant inheritance of dystonia were assayed simultaneously, similar enzyme activities were found in the affected and unaffected individuals. The data suggest that a generalized acetylcholinesterase deficiency is not involved in the pathogenesis of torsion dystonia.

Acetylcholinesterase↗
PubMed1985

Tetrabenazine induces acute dystonic reactions.

Four patients suffered acute dystonic reactions caused by tetrabenazine. Because dystonic reactions have previously been reported only after dopamine receptor blockade and not with dopamine depletion, it is likely that the ability of tetrabenazine to induce acute dystonia is due to its dopamine receptor blocking properties. Because tetrabenazine can induce acute dystonia even when combined with alpha-methyl-p-tyrosine, presynaptic dopamine stores may not be necessary for these reactions to occur.

Acute Disease↗
PubMed1985

Pharmacokinetics of trihexyphenidyl after short-term and long-term administration to dystonic patients.

Although trihexyphenidyl has been used effectively for many years in the treatment of Parkinson's disease, little is known about its pharmacokinetics. Using a sensitive radioreceptor assay for anticholinergic drugs, we assayed trihexyphenidyl in human serum and studied its pharmacokinetics following short-term and long-term administration to patients with dystonia. Previously untreated patients had a biphasic semilogarithmic plot of serum concentration-time consisting of an initial rapid distribution phase and a later slower elimination phase. Patients on long-term treatment showed only the slower elimination phase. Elimination followed first-order kinetics and was rapid, with a half-life of 3.7 +/- 0.4 (SEM) hours. There was no relationship between half-life and peak serum level, age, duration of therapy, or etiology or severity of dystonia. Although acute anticholinergic side effects paralleled the rise and fall of serum anticholinergic levels, the response of dystonia did not.

Adolescent↗
PubMed1985

Attenuation by electroshock treatment of the haloperidol-induced rise in the binding of 3H-imipramine to rat brain membranes.

Studies were conducted in rats to investigate whether chronic haloperidol treatment, electroshock treatment (EST), or a combination of both affects the high-affinity binding of 3H-imipramine to cerebral membranes. Chronic haloperidol (2 mg/kg SC daily for 28 days) resulted in a significant decrease in the density of binding sites in animals killed 1 h after the last treatment, but binding was markedly enhanced after a "washout" period of 5 days. In animals subjected to EST (20-30 mA, 1.5 s, 60 Hz; three times a week for 4 weeks) and killed 1 h after the last treatment, there were no apparent changes, but when animals were allowed a recovery period of 5 days there appeared to be a slight increase in binding. The marked increase in binding seen after haloperidol withdrawal was no longer apparent in animals treated with both haloperidol and EST, indicating that EST acts to attenuate the increase in binding seen after withdrawal of chronic haloperidol. It is suggested that chronic haloperidol may influence presynaptic recognition sites that regulate serotonin uptake and that EST may interact with haloperidol to "stabilize" these presynaptic sites.

Animals↗
PubMed1985

DL-threo-DOPS as a precursor of noradrenaline.

DL-threo-Dihydroxyphenylserine (DL-threo-DOPS) is a non-physiological precursor of noradrenaline (NA). The formation of NA from DL-threo-DOPS has been reported to occur in various mammalian tissue. Since NA deficiency is thought to be underlying mechanism in several neurological disorders, we studied the role of the DL-threo-DOPS as a precursor of NA. In rats treated with DL-threo-DOPS, heart NA levels increased in a dose-dependent manner with maximal effect obtained 1 h after intraperitoneal injection of the drug. However, no effect of DL-threo-DOPS on brain NA levels or DA metabolism was detected. The effect of DL-threo-DOPS on heart NA levels was completely inhibited in the presence of carbidopa and significantly enhanced in the presence of pargyline. Under these conditions, DL-threo-DOPS had no effect on brain catecholamines. Depletion of catecholamines was obtained by pretreatment with either alpha-methyl-p-tyrosine (AMPT), reserpine or FLA-63. DL-threo-DOPS increased NA levels in the heart but not in the brain. Finally, coadministration of DL-threo-DOPS with levodopa potentiated the effect of levodopa on brain DA metabolism. This effect was independent of peripheral dopa decarboxylase activity and was also shown in circling behaviour in rats with unilateral destruction of the nigrostriatal pathway. In rats, DL-threo-DOPS is an effective peripheral precursor of NA but the drug itself has no effect on brain catecholamines. DL-threo-DOPS may, however, enhance levodopa effects in the brain.

Animals↗
PubMed1985

Clonazepam-induced up-regulation of serotonin1 binding sites in frontal cortex of rat.

Chronic administration of the benzodiazepine, clonazepam, increased the number of [3H]5-hydroxytryptamine (5-HT1) binding sites in the frontal cortex of the rat. The increase reflected a change in the maximum density of binding sites (Bmax) with no change in ligand affinity (Kd). Increased binding occurred after continued exposure (10 days) to large (5.0 mg/kg) doses of clonazepam. The changes in [3H]5-HT binding were regional in that they occurred in membranes from the frontal cortex but not the brainstem. The effects were also at least partially selective for 5-HT receptors since the binding of the beta-adrenergic radioligand, [3H]dihydroalprenolol, was not affected by clonazepam. A second benzodiazepine, diazepam, did not affect the binding of [3H]5-HT at doses of 30 mg/kg per day. The latter data suggest that the effects of benzodiazepines on serotonin 5-HT1 receptors are unique to clonazepam.

Animals↗
PubMed1985

Validity and reliability of a rating scale for the primary torsion dystonias.

For quantitative assessment of the primary torsion dystonias, a rating scale is proposed that has two sections--a Movement Scale, based on examination, and a Disability Scale, based on the patient's statements about seven activities of daily living. We assessed the validity of the Movement Scale by comparing scores with a ranking of patients according to dystonia severity and with ratings of the patients on the Disability Scale. In addition, we assessed the inter-and intra-rater reliability of the scale by comparing independent scorings of patients by four examiners and by comparing scorings by the same examiners performed at different times. We found that the Movement Scale was a valid and reliable indicator of the severity of primary torsion dystonia.

Activities of Daily Living↗
PubMed1985

Serum trihexyphenidyl levels in the treatment of torsion dystonia.

Using a radioreceptor technique, we assayed serum trihexyphenidyl levels in patients with dystonia being treated chronically with high dosage. We found a significant correlation between total daily dose and the daily lowest (trough) serum levels. There was no relationship between serum levels and therapeutic response or toxicity. Toxicity was more closely related to patient age than to serum level. Although levels may be useful to monitor patient compliance, they cannot be used to judge adequacy of therapy.

Animals↗
PubMed1985

A therapeutic approach to tardive dyskinesia.

An approach to treating tardive dyskinesia and tardive akathisia was tested in 33 patients. The common denominator was the elimination of antipsychotic drugs. In 7 of 8 patients with mild tardive dyskinesia and no akathisia who were treated by drug abstinence, gradual lessening of tardive dyskinesia occurred. Complete remission was seen after 2-4 years in 5 of these 8. Treatment with reserpine and discontinuance of antipsychotic drugs was useful for patients with severe symptoms of tardive dyskinesia or akathisia; complete remission with elimination of all drugs was achieved in 4 of 19 treated patients, without recurrence of symptoms. Although tetrabenazine masked symptoms in 5 of 7 patients to whom it was administered, none was able to achieve remission of tardive dyskinesia when taken off the drug. Seven of the total 33 patients received a course of levodopa; 2 of these 7 developed recurrence of their underlying psychosis. This agent should be used with caution.

Adult↗
PubMed1984

Synthesis and dopaminergic activity of 3-(3,4-dihydroxyphenyl)-1-n-propylpyrrolidine hydrobromide.

3-(3,4-Dihydroxyphenyl)-1-n-propylpyrrolidine hydrobromide was synthesized by a six-step reaction sequence and was evaluated, and compared with apomorphine, for central dopaminergic agonist activity. The compound produced behavioral and biochemical changes characteristic of central dopaminergic stimulation. Administration of 3-(3,4-dihydroxyphenyl)-1-n-propylpyrrolidine hydrobromide to rats resulted in the reversal of the reserpine syndrome, stereotypic behavior, contralateral turning following 6-hydroxydopamine lesion of the substantia nigra, a decrease in dopamine turnover, and inhibition of prolactin release. These results indicate that 3-(3,4-dihydroxyphenyl)-1-n-propylpyrrolidine hydrobromide is a dopaminergic agonist. However, the compound exhibited a lower potency but a slightly longer duration of action than apomorphine.

Animals↗
PubMed1984

Lithium does not interact with haloperidol in the dopaminergic pathways of the rat brain.

Prophylactic treatment with lithium has been reported to prevent haloperidol-induced dopamine (DA) receptor supersensitivity. If such an effect exists, then lithium may be useful in the prevention of tardive dyskinesia, which is related to the neuroleptic-induced DA hyperfunction. In the experiments reported here chronic lithium administration had no effect on DA synthesis or utilization in the nigrostriatal, mesolimbic, or mesocortical DA pathways in the rat brain. Similarly, lithium had no effect on the increase in DA metabolism induced by the acute administration of haloperidol. Also, chronic lithium treatment failed to modify the biochemical tolerance which developed after prolonged administration of the neuroleptic drug. Supersensitivity of the presynaptic DA receptors, which was induced by prolonged exposure to haloperidol, likewise was unaffected by prophylactic lithium treatment. We conclude that lithium does not affect changes in DA metabolism or receptor supersensitivity induced by haloperidol. These results do not support the use of lithium in neurological disorders that may be related to neuroleptic-induced DA receptor supersensitivity.

Animals↗
PubMed1984

Electroconvulsive treatment and haloperidol: effects on pre- and postsynaptic dopamine receptors in rat brain.

Electroconvulsive treatment (ECT) has a transitory beneficial effect on patients with Parkinson's disease (PD). The possibility that this effect is mediated by dopamine (DA) receptors was investigated in the rat brain. Repeated ECT or chronic haloperidol treatment induced supersensitivity of putative autoreceptors in the nigrostrital and mesolimbic DA pathways as reflected by enhanced apomorphine-induced inhibition of DA synthesis. Effect of simultaneous administration of ECT plus haloperidol on DA receptor sensitivity were not additive. Chronic haloperidol treatment induced significant elevations in the density of 3[H]-spiperone striatal binding sites. Concurrent administration of ECT had no effect on the neuroleptic-induced supersensitivity. ECT alone was also without effect on 3[H]-spiperone binding. Thus, ECT-induced increases in the sensitivity of presynaptic autoinhibition of DA release was not reflected by changes in the striatal 3[H]-spiperone binding sites. This suggests that effects of ECT on the DA system are not mediated by dopamine D2 receptors.

Animals↗
PubMed1984

Biochemical and behavioral evaluation of pergolide as a dopamine agonist in the rat brain.

The ergot derivative pergolide was evaluated as a dopamine agonist using various behavioral and biochemical analyses. Spontaneous motor activity was decreased by small doses (0.1 mg/kg) of pergolide and increased with larger doses (above 0.5 mg/kg). Hypermotility after larger doses persisted for as long as 24 hr and was succeeded by a period of hypomotility. The doses of drug, sufficient to produce hypermotility, also produced stereotypy. With repeated daily injections (2 weeks), the period of hypermotility decreased and the ensuing period of hypomotility increased. Stereotyped behavior was similarly affected. Chronic administration of pergolide did not alter the magnitude of the behavioral responses. Levels of the dopamine (DA) metabolites, dihydroxyphenylacetate (DOPAC) and homovanillic acid (HVA), in the striatum and mesolimbic regions were decreased during the periods of hypermotility but returned to control levels during subsequent hypomotility. Activation of putative inhibitory presynaptic dopamine receptors by pergolide was studied by following accumulation of DOPA in rats treated with the dopamine neuron inhibiting agent, gamma-butyrolactone (GBL) and a DOPA-decarboxylase inhibitor. Pergolide significantly inhibited both striatal and mesolimbic accumulation of DOPA. In contrast, with changes in behavioral and metabolic indices, pergolide-induced inhibition of tyrosine hydroxylase was not affected by chronic treatment with pergolide. On the basis of both behavioral and biochemical data it is proposed that pergolide acts as a dopamine agonist with particularly long-lasting effects.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1984

Reductions in pain thresholds and morphine analgesia following intracerebroventricular parachlorophenylalanine.

The selective decreases in both basal and analgesic pain thresholds following systemic administration of parachlorophenylalanine (PCPA) has been attributed to the inhibition of tryptophan hydroxylase and subsequent depletion of brain serotonin. These effects only occur at high systemic doses which have other general debilitating effects. The present study examined the relationship between PCPA's nociceptive and serotonin-depleting effects following intracerebroventricular (ICV) administration. The first experiment determined that an ICV dose of 3 mg, but not 1 mg, of PCPA significantly decreased jump thresholds at 0.5, 48 and 120 hr after injection. These effects were not due to osmolarity shifts since hypertonic saline injections failed to alter thresholds. The second experiment demonstrated a time-dependent reduction of morphine (5 mg/kg) analgesia as a function of the interval between ICV PCPA and the systemic morphine injection. PCPA reduced morphine analgesia if it was administered 24 hr prior to the opiate and eliminated morphine analgesia if it was administered 48 hr prior to the opiate. Pretreatment with ICV PCPA either 0.5 or 72 hr prior to the opiate failed to alter morphine analgesia. The third and fourth experiments indicated that hippocampal and spinal levels of either serotonin or 5-hydroxyindoleacetic acid were not significantly affected by ICV PCPA pretreatment. These data indicate that the hyperalgesia and morphine analgesia impairments noted following ICV PCPA do not correspond with changes in serotonin from hippocampal or spinal tissue and such effects are discussed in terms of alternative modes of action.

Animals↗
PubMed1984

Should levodopa therapy for Parkinsonism be started early or late? Evidence against early treatment.

We define the meaning of early and late treatments and present arguments opposed to early treatment with levodopa. These are based on the development of complications with long-term Sinemet which include clinical fluctuations, loss of efficacy, and painful dystonic cramps. By delaying the onset of levodopa therapy until the symptoms require this most potent of antiparkinsonian agents, we can delay the onset of these disabling problems. Also, using as low a dosage as possible should reduce the risk of any long-term complication related to accumulative dose. We also present the serial evaluations of 26 patients followed for as long as 7.5 years before levodopa therapy was initiated. Three scoring scales on these patients are compared. Arguments are presented which suggest that the Columbia University and the ADL scales are superior to the UCLA scale, and more closely approximate the curve of the progressive clinical disability of the disease as assessed by global evaluation. We conclude that the ultimate answer to any clinical debate must come from well-designed, controlled studies to assess the differences between two treatment modalities.

Adult↗
PubMed1984

Genetic linkage analysis in primary torsion dystonia.

We studied five families, each containing two siblings affected with torsion dystonia and having phenotypically normal parents, for linkage of dystonia to 18 marker systems, including HLA. Analysis assumed an autosomal recessive mode of inheritance. Linkage was not found. Two markers, HLA and MN, were excluded from tight linkage, and evidence against tight linkage to ABO, Rh, GC, and GLO was obtained.

Adolescent↗
PubMed1984

Pergolide therapy for Parkinson's disease: neurobehavioral changes.

Pergolide mesylate, a long-acting dopamine agonist, is effective in treating Parkinson's disease. Behavioral change is said to be one adverse effect. We therefore studied 19 parkinsonian patients with neuropsychological tests before and after initiating pergolide therapy. Intellectual and behavioral changes were also monitored clinically for up to 2 years. There was no decline in performance on the neuropsychological tests. Six patients had transient psychiatric or intellectual changes that were controlled by reducing drug dosage. These changes were similar to those seen with other dopamine agonists.

Adult↗