Search PubMed⌕ Search

Biomedical subjects

S Fahn

Publications and source records attributed to S Fahn.

At least 325 records · Page 18Linked to original sources
PubMed1983

Long-term treatment of tardive dyskinesia with presynaptically acting dopamine-depleting agents.

Fourteen patients with TD, all but one also having tardive akathisia, were evaluated on presynaptically acting dopamine-depleting drugs, reserpine, TBZ, and AMT. Initially, the drugs were evaluated individually, but later AMT was used in combination with reserpine and with TBZ, since their different mechanisms of action allowed for increased potency when they were used in this combination. All but one patient responded to this therapeutic approach. Parkinsonism was easily induced, however. Most patients varied during the day between mild parkinsonism and mild dyskinesia-akathisia. It was difficult to have patients at the normal level between these two conditions. The addition of carbidopa/levodopa in one patient not only relieved the side effect of parkinsonism but may have also accelerated a remission from TD and akathisia. Although postural hypotension was a common adverse effect in patients receiving reserpine, especially in combination with AMT, it did not develop in patients taking TBZ, either alone or in combination with AMT. This observation suggests that TBZ may be less effective depleting monoamines in the periphery than in the central nervous system. Since reserpine is available commercially in the United States whereas TBZ is not, reserpine may be the drug of choice in treating patients with TD or tardive akathisia. The addition of AMT will increase the potency of this form of treatment.

Adult↗
PubMed1983

Tetrabenazine, an amine-depleting drug, also blocks dopamine receptors in rat brain.

Tetrabenazine (TBZ) is used in the treatment of hyperkinetic movement disorders. Its effect is thought to be mediated by depletion of dopamine (DA) stores. We studied other possible mechanisms of action of this drug. TBZ decreased DA concentration in rat striatum and nucleus accumbens in a dose-dependent manner with an IC50 of approximately 1.2 mg.kg-1. Maximal depletion was obtained within 30 min with only partial recovery at 8 hr. TBZ induced (at 40 mg . kg-1) 5- to 8-fold increases in 3,4-dihydroxyphenylacetic acid and homovanillic acid concentrations in both brain regions. Unlike reserpine, TBZ completely abolished the apomorphine-induced inhibition of DA synthesis under conditions in which this effect is mediated by presynaptic DA receptors. Both TBZ (5 mg . kg-1) and reserpine (5 mg . kg-1) depleted, at 1 hr, striatal DA content by approximately 90%. However, TBZ, but not reserpine, significantly stimulated in vivo tyrosine hydroxylase activity. TBZ also inhibited [3H]spiperone binding in the striatum with Ki = 2.1 X 10(-6) M. In rats, with unilateral destruction of the nigrostriatal pathway with 6-hydroxydopamine, pretreatment with TBZ significantly reduced the number of rotations induced by apomorphine. Finally, in rats treated with either TBZ (5 mg . kg-1) or reserpine (5 mg . kg-1), prolactin levels significantly increased as compared to control values. TBZ, but not reserpine, blocked apomorphine inhibition of prolactin secretion. We conclude that, in addition to depleting monoamines, TBZ also blocks both presynaptic and postsynaptic DA receptors in rat brain.

Animals↗
PubMed1982

Effect of 3',4'-dihydroxy-2-methyl-propriophenone (U-0521) on catechol-O-methyltransferase activity and on DOPA accumulation in rat red blood cells and corpus striatum.

The effects of the catechol-O-methyltransferase (COMT) inhibitor 3',4'-dihydroxy-2-methyl-propriophenone (U-0521) were studied in red blood cells (RBC) and corpus striatum in the rat. In vitro U-0521 inhibited RBC COMT activity in a dose-dependent manner with an IC50 of 6 x 10(-6)M. In vivo maximum inhibition (90%) of enzyme activity in RBC was obtained with 250 mg/kg with a peak effect at 5 min and enzyme recovery within 90 min. In U-0521-pretreated rats L-3,4-dihydroxyphenylalanine (L-DOPA) accumulation in RBC and corpus striatum, after injection of L-DOPA, was significantly higher than in nonpretreated rats. The use of COMT inhibitor along with L-DOPA may be of benefit in the treatment of Parkinson's disease.

Animals↗
PubMed1982

Chlorpromazine methiodide-induced barrel rotation: an antimuscarinic effect.

Barrel rotation is a motor response observed in rats in which the animal twists about its long axis and rolls laterally. This response was first described following intracerebroventricular injection of somatostatin. The pharmacologic specificity of the response has been questioned, and its physiologic basis is unknown. Recently, barrel rotation following intraventricular injection of quaternary chlorpromazine, chlorpromazine methiodide (CPZMI), has been reported. We have studied the specificity and pharmacologic basis of CPZMI-induced barrel rotation. The response was not induced by 26 compounds injected as controls, and was induced by 6 anti-muscarinic compounds. Dose-response relationships for onset, duration and magnitude of CPZMI-induced barrel rotation response were studied; number of rotations increased linearly with CPZMI dose up to 20 micrograms, after which number of rotations decreased and toxic effects (sedation, seizures) occurred. CPZMI barrel rotation was inhibited by intraventricular injection of the muscarinic agonist carbachol and enhanced by intraventricular or systemic atropine. Muscarinic and dopamine receptor studies indicated that CPZMI has high affinity for the muscarinic cholinergic receptor and low affinity for the spiperone binding site. Modified Scatchard analysis of CPZMI displacement of [3H]QNB at the muscarinic receptor is consistent with muscarinic antagonist properties. We conclude that CPZMI-induced barrel rotation has a specific pharmacologic basis, that of muscarinic cholinergic antagonism.

Animals↗
PubMed1982

The effect of chronic L-dopa administration on supersensitive pre- and postsynaptic dopaminergic receptors in rat brain.

Chronic administration of haloperidol induced supersensitivity of the pre- and postsynaptic dopaminergic receptors in rat brain. The response of the presynaptic receptors was determined by an enhanced inhibitory effect of apomorphine on dopamine synthesis after gamma-butyrolactone injection. This change in the receptor function was detected both in the nigrostriatal and mesolimbic pathways. Haloperidol also increased the 3H-spiperone binding sites in striatal membranes, indicating supersensitivity of the postsynaptic receptors. Subsequent prolonged treatment with high doses of L-DOPA/carbidopa resulted in a decrease in 3H-spiperone binding sites, but had no effect on the supersensitive presynaptic receptors. It is suggested that tardive dyskinesia may be a state of both pre- and postsynaptic dopamine receptor supersensitivity and that chronic L-DOPA treatment may have a differential effect on these sites.

Animals↗
PubMed1982

3-O-methyldopa blocks dopa metabolism in rat corpus striatum.

3-O-Methyldopa (OMD) given to rats inhibits striatal uptake and utilization of L-dopa. Thus, the accumulation of L-dopa, dopamine, 3,4-dihydroxyphenylacetic acid, and homovanillic acid in OMD-pretreated rats after L-dopa injection is significantly lower compared with control rats. This effect of OMD is dose-dependent. OMD inhibits L-dopa accumulation in the striatum after inhibition of aromatic amino acid decarboxylase activity with 3-hydroxybenzylhydrazine-HCL. This effect is not mediated through inhibition of firing in dopaminergic neurons, since the accumulation of dopamine in the striatum after gamma-butyrolactone injection was also significantly reduced by OMD. It is suggested that OMD competes with L-dopa and tyrosine uptake into the brain. These findings are in line with clinical observations which indicate that high plasma levels of OMD in parkinsonian patients are associated with poor response to L-dopa. The data presented here indicate that use of catechol-O-methyltransferase inhibitors with L-dopa may be of value in the treatment of parkinsonian patients.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1982

Catechol-O-methyltransferase inhibition by U-0521 increases striatal utilization of levodopa.

The effects of U-0521, a catechol-O-methyltransferase (COMT) inhibitor, were studied on this enzyme activity and on Dopa metabolism in rat striatum. In vivo maximal inhibition (95%) of COMT activity was obtained at 5 min with enzyme recovery to 64% of basal activity at 120 min. When injected in increasing doses U-0521 (200 mg . kg-1) inhibited, at 10 min, COMT activity by 85% with an IC50 = 80 mg . kg-1. In rats pretreated with U-0521 and then with DOPA the accumulation of 3-O-methyldopa-(OMD) in the plasma was essentially blocked while Dopa, dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) accumulation in the striatum was significantly higher than in DOPA treated controls. U-0521, a potent COMT inhibitor, enhances the availability and utilization of levodopa in the brain and may thus be helpful in future treatment of parkinsonian patients.

Animals↗
PubMed1982

Paroxysmal dystonic choreoathetosis in a patient with familial ataxia.

A patient with paroxysmal dystonic choreoathetosis also had familial ataxia. His brother was similarly affected but had rare paroxysmal episodes. No secondary or symptomatic forms of this type of paroxysmal dyskinesia have ever been reported. Episodes were briefly controlled with acetazolamide and were almost completely eliminated by clonazepam therapy.

Adult↗
PubMed1982

Tardive dystonia: late-onset and persistent dystonia caused by antipsychotic drugs.

It is not widely recognized that antipsychotic drugs can cause late-onset and persistent dystonia. This dystonia, which we call tardive dystonia, is to be distinguished from acute dystonic reactions, which are transient, and from classic tardive dyskinesia, which is a choreic disorder that predominantly affects the oral region. We present 42 patients with tardive dystonia. The age of onset of dystonia was 13 to 60 years. Symptoms began after 3 days to 11 years of antipsychotic therapy. Younger patients tended to have more generalized dystonia. In a few patients, spontaneous remission occurred, but dystonia persisted for years in most. Therapy was rarely a complete success. The most frequently helpful medications were tetrabenazine (68% of patients improved) and anticholinergics (39% improved).

Adolescent↗
PubMed1982

"Tip-of-the-tongue" phenomenon in Parkinson disease.

Articulatory disturbances are frequently described in Parkinson disease, but language disorders are not. We have occasionally encountered parkinsonian patients with word-finding difficulty unrelated to memory loss, intellectual impairment, or dysarthria. To examine this, 22 medically stable parkinsonian patients were given the vocabulary subtest of the WAIS, the Boston Naming Test, measures of verbal fluency, and sentence repetition. Signs and symptoms of parkinsonism were rated. WAIS vocabulary subtest scores were above the mean for normal aged subjects, but confrontation naming was one standard deviation below norms for age and education. Naming was facilitated by cues in most patients. Only sentence repetition correlated with dysarthria. Category naming was impaired and correlated significantly with the severity of parkinsonism, especially bradykinesia. This suggests that a type of anomia may occur in Parkinson disease. it shares the clinical characteristics of the "tip-of-the-tongue" phenomenon and "word production anomia" seen in some aphasics.

Anomia↗