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Biomedical subjects

J G Nutt

Publications and source records attributed to J G Nutt.

17 recordsLinked to original sources
PubMed1992

Effect of long-term therapy on the pharmacodynamics of levodopa. Relation to on-off phenomenon.

To determine how the response to levodopa is altered by long-term therapy, we examined the dose response to 2-hour infusions of levodopa in three groups of parkinsonian patients: those who were previously untreated, those who exhibited stable responses, and those who exhibited fluctuating responses to levodopa therapy, using tapping speed as an index of bradykinesia. The baseline tapping speed was greater in the patients with stable responses than in the untreated patients, probably representing a "long-duration response" to levodopa therapy. A "short-duration response," indicated by an increase in tapping speed lasting hours, was observed in most patients in all groups. The onset of the short-duration effect was more rapid and the incremental increase in tapping speed was twice as large in the patients with fluctuating responses compared with the untreated patients and patients with stable responses. The duration of the short-duration effect was greatest in the untreated group but did not differ between the groups with stable and fluctuating responses. Dyskinesia was not observed in any of the de novo patients but was observed in three of 12 patients with stable responses and eight of nine patients with fluctuating responses to levodopa therapy. Dyskinesia appeared before or with the antiparkinsonian effects in patients with stable responses, giving no indication of a higher threshold for dyskinesia in these patients compared with those with fluctuating responses. The plasma half-life clearance, volume of distribution, and maximum plasma concentrations of levodopa did not differ among groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Postural inflexibility in parkinsonian subjects.

In order to identify the types of postural deficits seen in parkinsonian patients with postural instability, we compared the performance of parkinsonian subjects with young and old control subjects in 3 aspects of postural control: (1) the use of sensory information for postural orientation, (2) the coordination of postural movement patterns in response to surface displacements, and (3) the flexible modification of postural response patterns to changes in support conditions. Parkinsonian subjects had very small sway, even under altered sensory conditions. Postural response latencies to displacements were also normal. Postural instability was associated with abnormal patterns of postural responses including excessive antagonist activity and inflexibility in adapting to changing support conditions. Some parkinsonian subjects appeared to have difficulty sequencing motor programs for postural correction. The parkinsonian subjects appeared stiffer since the rate-of-change of sway in response to displacements was reduced. Levodopa improved postural coordination but not the flexible adaptation to changing support conditions.

Adult↗
PubMed1992

Time course of tolerance to apomorphine in parkinsonism.

We sought to determine if tolerance developed to the antiparkinsonian effects of apomorphine and, if so, what temporal factors influenced its development. Seven patients with parkinsonism and motor fluctuations received short (6-hour) and long (22- to 31-hour) apomorphine infusions. Tolerance was evaluated by comparison of the responses to test doses of apomorphine that were administered before and after each infusion. The responses to the test doses that followed either infusion were reduced by 35% after the short infusion and by 68% after the long infusion, although plasma apomorphine levels were similar to or higher than levels achieved with preinfusion test doses. The duration of improvement in parkinsonism after discontinuation of the long infusion was briefer than that after the short infusion. We conclude that tolerance to apomorphine occurs in parkinsonism, and the loss of response is greater after longer periods of drug administration.

Aged↗
PubMed1992

Differences in the motor response to apomorphine between untreated and fluctuating patients with Parkinson's disease.

Behavioral hyposensitivity to repeated apomorphine administration has been observed in fluctuating parkinsonian patients. To investigate whether a similar phenomenon occurs in patients never treated with levodopa, we studied the response to apomorphine in 20 de novo patients with Parkinson's disease. Six patients showed no or minimal improvement after apomorphine injections (maximal dose 3.5 mg). Fourteen patients responded and were then given up to four repeated subcutaneous injections of apomorphine [minimal effective dose (MED)]. The responses of de novo patients were compared with responses in 10 patients with motor fluctuations previously studied by the same protocol. There was no significant difference in latency and duration of motor responses after repeated apomorphine injections in de novo patients. MED was similar in de novo and fluctuating patients, but duration of improvement induced by each apomorphine bolus was longer in the de novo group. These results indicate that response duration to apomorphine is longer in previously untreated patients and that behavioral tolerance associated with pulsatile dopaminergic stimulation by apomorphine occurs mainly in patients with more advanced disease under chronic levodopa therapy.

Adult↗
PubMed1992

Pharmacodynamics of the hypotensive effect of levodopa in parkinsonian patients.

Blood pressure effects of i.v. levodopa were examined in parkinsonian patients with stable and fluctuating responses to levodopa. The magnitude of the hypotensive effect of levodopa was concentration dependent and was fit to an Emax model in fluctuating responders. Stable responders demonstrated a small hypotensive response. Baseline blood pressures were higher in fluctuating patients; a higher baseline blood pressure correlated with greater hypotensive effects. Antiparkinsonian effects of levodopa temporally correlated with blood pressure changes. Phenylalanine, a large neutral amino acid (LNAA) competing with levodopa for transport across the blood-brain barrier, reduced the hypotensive and antiparkinsonian effects of levodopa. We conclude that levodopa has a central hypotensive action that parallels the motor effects in fluctuating patients. The hypotensive effect appears to be related to the higher baseline blood pressure we observed in fluctuating patients relative to stable patients.

Amino Acids↗
PubMed1992

The effect of exercise on levodopa absorption.

We studied the effect of exercise using cycle ergometry on levodopa absorption in ten patients with Parkinson's disease. Oral levodopa was administered during exercise and at rest on separate days. Exercise delayed levodopa absorption in five patients, increased it in three, and did not influence it in two. We conclude that exercise can either increase or decrease levodopa absorption.

Absorption↗
PubMed1991

Absorption of apomorphine by various routes in parkinsonism.

We wanted to determine the absorption and clinical effect of sublingual (SL) and transdermal apomorphine in parkinsonism. Patients received single SL apomorphine doses (N = 7) and the absorption was compared with parenteral (N = 5) and oral (N = 4) doses. One patient received a transdermal dose of apomorphine. The relative bioavailability of SL apomorphine ranged from 10 to 22% of a parenteral apomorphine dose. Oral apomorphine was less than 4% bioavailable, and the transdermal dose did not produce detectable plasma levels. Three patients with motor fluctuations responded to SL apomorphine, with a latency to effect of 20-40 min and a duration of effect of 15-100 min. One patient used SL apomorphine as an adjunct with levodopa, and during 1 month reported a large decrease in "off" periods. We conclude that apomorphine is effectively absorbed by the sublingual route.

Absorption↗
PubMed1979

Thrombocytopenia associated with sodium valproate treatment.

The administration of sodium valproate to 30 patients in daily doses of 1,200 to 3,000 mg was associated with a significant reduction of the platelet count. Thrombocytopenia without any concomitant bleeding abnormalities occurred in 10 of the patients. Platelet counts returned to baseline levels after withdrawal of the drug.

Adult↗
PubMed1979

Linear relationship between plasma concentration and dosage of sodium valproate.

Plasma valproate concentration was studied in 7 hospitalized nonepileptic patients who received sodium valproate at daily doses of up to 60 mg/kg. A linear relationship between dose and plasma concentration of valproate (r = 0.81--0.99) was found in each patient, although the slopes of the regression lines (reflecting clearance rates) varied twofold. This suggests that if the valproate plasma concentrations at two different doses are known and the clearance of valproate is not altered by concomitant administration of other drugs, it should be possible to predict the plasma valproate concentration that will result from further dose increments.

Dose-Response Relationship, Drug↗
PubMed1978

Ergot derivatives for Parkinsonism.

The response of Parkinsonism to three ergot derivatives which modify dopaminergic transmission was studied. CF 25-397 behaved more as an antagonist than an agonist. Lergotrile was an agonist with therapeutic properties marred by prominent hepatotoxicity. Bromocriptine is an effective anti-Parkinsonian agent, particularly useful in patients with prominent dyskinesia or "on-off" reactions to levodopa; in most patients optimal results have been obtained by combining from 40 to 90 mg of bromocriptine daily with approximately 60% of the previous maximal dose of levodopa. Unfortunately, only some 50% of patients tolerate long-term bromocriptine therapy, but all adverse reactions have been dose dependent and reversible.

Bromocriptine↗
PubMed1978

Long-term treatment of parkinsonism with bromocriptine.

92 patients with parkinsonism have been treated with bromocriptine for up to 30 months. 48 continue to receive bromocriptine with benefit; of these, 35 take bromocriptine (mean dose 53 mg daily) in combination with levodopa and 13 take bromocriptine (mean dose 45 mg daily) without levodopa. In those who were originally on levodopa, addition of bromocriptine allowed a mean 41% reduction in the dose of levodopa; the largest group of patients to benefit from bromocriptine entered the study because of excessive dyskinesia or "on-off" phenomena induced by levodopa. In 40 patients bromocriptine was stopped because of adverse reactions, absence of therapeutic response, or non-compliance with the protocol. The main problems were psychiatric disturbance (8 patients) and erythromelalgia (7 patients); these effects tended to occur late (mean 6 months and 10 months, respectively) and with high dosage (mean 66 mg and 115 mg daily). Other frequent adverse effects were dizziness and nausea; these began considerably earlier (at 2 months and 1 month) and with much lower dosage (31 mg and 12 mg daily). 4 patients died, for reasons apparently unrelated to therapy.

Bromocriptine↗
PubMed1978

Effect of an opiate antagonist on movement disorders.

Animal experiments suggest that opiate peptides might play a role in extrapyramidal function. This hypothesis was tested by administering the opiate antagonist, naltrexone, in doses sufficient to antagonize exogenous opiates, to patients with parkinsonism and Huntington's disease. No improvement in the clinical features of either disorder was noted.

Adult↗
PubMed1978

Treatment of Huntington disease with a cholinergic agonist.

The involuntary movements of Huntington disease may be related to cholinergic hypofunction in the striatum. For this reason, the effect of a direct cholinergic agonist, arecoline, was studied in six patients with this disorder. Rather than improving the chorea, arecoline tended to exacerbate the choreic movements. Arecoline did produce significant alterations of blood pressure, heart rate, and body temperature, probably by central cholinergic stimulation.

Adult↗
PubMed1977

Lithium: effects on subjective functioning and morphine-induced euphoria.

The therapeutic usefulness of lithium in decreasing the euphoria and other symptoms associated with manic behavior and the hypothesis of a common final mechanism for elevations in mood have led to speculation that lithium may block the euphoria induced by drugs of abuse. In this study, lithium alone was antieuphoric in drug-free opiate addicts and, further, did not block morphine-induced euphoria.

Clinical Trials as Topic↗
PubMed1975

A comparison of fenfluramine and amphetamine in man.

dl-Fenfluramine hydrochloride (60, 120, 240 mg), d-amphetamine sulfate (20, 40 mg), and placebo were compared in 8 postaddict volunteers, each dose given orally in random sequence at weekly intervals using a double-blind crossover design. Fenfluramine had little effect on blood pressure and temperature, but caused a marked dilation of pupils, whereas amphetamine was a potent vasopressor and a weak mydriatic. While fenfluramine produced euphoria in some subjects, its overall effects were unpleasant, sedative, and qualitatively different from amphetamine. Three subjects given 240 mg of fenfluramine experienced brief but vivid hallucinogenic episodes characterized by olfactory, visual, and somatic hallucinations, abrupt polar changes in mood, time distortion, fleeting paranoia, and sexual ideation. These observations indicate that fenfluramine is a hallucinogenic agent with a pharmacologic profile in man that is not amphetamine-like.

Adult↗