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Biomedical subjects

J G Nutt

Publications and source records attributed to J G Nutt.

At least 91 records · Page 5Linked to original sources
PubMed1988

Epidemiology of focal and generalized dystonia in Rochester, Minnesota.

The epidemiology of generalized and focal dystonias was investigated in the Rochester, Minnesota, population over the period 1950-1982. The crude incidence of generalized dystonia was 2 per million persons per year, and for all focal dystonias combined, 24 per million per year. The crude prevalence rate was 34 per million persons for generalized dystonia and 295 per million persons for all focal dystonias. Torticollis was the most common focal dystonia; essential blepharospasm, oromandibular dystonia, spasmodic dysphonia, and writer's cramp were less common and had roughly equal incidence and prevalence rates.

Adolescent↗
PubMed1988

The case for and concerns about continuous dopamine stimulation in Parkinson's disease.

Delivery of levodopa or other dopaminergic agents to the striatum is a critical determinant of the clinical response and may account for many of the fluctations in response ("on-off"). This should be manageable with innovative delivery systems for the drugs. However further studies are required to determine if continuous dopaminergic stimulation will be complicated by increased levels of drug metabolites or down regulation of dopaminergic neurotransmission.

Administration, Oral↗
PubMed1988

Does an inhibitory action of levodopa contribute to motor fluctuations?

The possibility that levodopa can both acutely improve as well as worsen motor function was investigated in eight fluctuating parkinsonian patients by administering 2-hour infusions of placebo and of levodopa at suprathreshold, threshold, and subthreshold rates when the subjects had been without medication overnight. Plasma levodopa and clinical status were monitored for an hour before, during, and for 3 hours after the infusions. Placebo infusions were associated with a mild deterioration in motor status during the period of monitoring. Subthreshold infusions were associated with greater motor deterioration than were placebo infusions in five of six subjects, but this deterioration did not occur in any specific temporal relation to the infusion. Threshold infusion rates in three subjects produced a transient improvement in motor function followed by deterioration to below the scores during the hour preceding the infusion and then returned to baseline. Suprathreshold rates in seven of the eight subjects were associated with motor improvement for 1/2 to 3 1/2 hours followed by worsening to below baseline for 30 to 90 minutes and then spontaneous improvement to baseline function. These observations suggest that levodopa causes an acute deterioration in motor function following drug-induced improvement. Thus, the nadir of motor function in levodopa-treated patients may not be simply loss of dopaminergic stimulation and return to the untreated state, but may represent an inhibitory effect of levodopa.

Aged↗
PubMed1988

Erratic gastric emptying of levodopa may cause "random" fluctuations of parkinsonian mobility.

The pathogenesis of "random" fluctuations in parkinsonian mobility, which are not clearly related to the dosing schedule of levodopa, has not been determined. We rated parkinsonian mobility and assayed plasma dopa in one patient with clinically random fluctuations during two modes of administration of levodopa/carbidopa: (1) standard oral route and (2) direct duodenal delivery via nasoduodenal tube. During oral therapy, mobility varied unpredictably in relation to levodopa dosing, suggesting a clinically random pattern. During duodenal delivery, however, a predictable and dramatic pattern of recurrent end-of-dose deterioration was observed; each intraduodenal levodopa dose resulted in 60 to 90 minutes of benefit. Plasma dopa levels correlated closely with mobility ratings for both modes of administration. Our findings indicate that erratic gastric emptying of levodopa is responsible for apparently "random" oscillations in mobility in at least one patient with Parkinson's disease and probably in others.

Absorption↗
PubMed1988

Response to brief levodopa infusions in parkinsonian patients with and without motor fluctuations.

The fluctuating response to levodopa may result from progressive loss of striatal dopamine terminals and consequently increasingly impaired dopamine storage capacity. This hypothesis predicts that the acute response to levodopa would shorten with increasing disease severity. To test this, we compared the duration of improvement in tapping and walking speeds following discontinuation of 2-hour levodopa infusions in nine previously untreated (UT), seven stable (ST), and 17 fluctuating (FL) subjects. Mean Hoehn and Yahr disability in the morning prior to levodopa infusion was 2.8, 2.2, and 4.4 for UT, ST, and FL subjects. Six of nine UT, six of seven ST, and all FL subjects exhibited improvement with the infusions, which produced similar peak plasma levodopa levels in all groups. The duration of the response was similar in the ST and FL groups. The response in the UT group was heterogeneous; in three, the response was of similar length as compared with the ST and FL groups, but was longer in the other three UT subjects. The correlation between disease severity and response duration was poor. The ST and FL groups, while differing in disease severity, exhibited a similar duration of response to levodopa infusion. This does not support a reduced dopamine "storage capacity" as the sole explanation for the length of the short-duration response. Furthermore, motor fluctuations appear to be present from early in treatment, but only become noticeable when "off" disability becomes marked.

Aged↗
PubMed1987

3-O-methyldopa and the response to levodopa in Parkinson's disease.

Plasma 3-O-methyldopa (3OMD) concentrations in parkinsonian patients treated with levodopa on a long-term basis reflect daily levodopa dosage and do not vary markedly during the day. Oral challenges with 3OMD reduce the clinical response to levodopa infusions, but 3OMD is no more potent then phenylalanine in this regard. These observations, plus the fact that 3OMD makes a small contribution to the total concentration of large neutral amino acids competing with levodopa for transport at the blood-brain barrier, support the contention that 3OMD is not an important determinant of clinical response to levodopa.

Administration, Oral↗
PubMed1987

On-off phenomenon: relation to levodopa pharmacokinetics and pharmacodynamics.

Motor function in the moderately to severely affected parkinsonian patient is critically dependent upon delivery of levodopa to the striatum. This, in turn, is influenced by the fluctuating plasma concentrations of levodopa produced by the drug's short half-life and erratic absorption, and by modifiable transport at the blood-brain barrier. Duration of response to a single dose of levodopa is proportional to peak plasma drug levels, and paradoxical responses may occur when plasma concentrations are in the vicinity of minimum effective concentrations. Thus the strategy of administering frequent, small doses of levodopa may contribute additional unpredictability to a fluctuating clinical response imposed by pharmacokinetic factors.

Blood-Brain Barrier↗
PubMed1987

Peripheral pharmacokinetics of levodopa in untreated, stable, and fluctuating parkinsonian patients.

We compared the pharmacokinetics of oral and IV infusions of levodopa in untreated, stable, and fluctuating patients pretreated with carbidopa. After oral dosing, mean peak plasma levodopa levels, time to peak level concentration after oral levodopa, and area under the curve were similar in all groups. Absorption was proportional to dose. Plasma elimination half-lives, clearance rates, and volumes of distribution after levodopa infusions were similar in all groups. 3-O-Methyldopa levels were similar in stable and fluctuating subjects. We conclude that the peripheral pharmacokinetics of levodopa do not differ between untreated, stable, and fluctuating patients, and that altered peripheral kinetics of the drug are unlikely to explain the development of the fluctuating state.

Aged↗
PubMed1987

Diurnal responsiveness to apomorphine.

Many parkinsonian patients respond to L-dopa better in the morning than at other times. To explore the possibility that this phenomenon represents diurnal fluctuations in dopaminergic receptor responsiveness, we compared the effects of subcutaneously administered apomorphine during "off" periods in the mornings and afternoons in nine fluctuating patients. The duration of response and area under the time-response curve, but not the magnitude of improvement, were dose responsive. Response durations to the same dose administered in the morning and afternoon were similar, although at threshold doses three subjects responded only to the afternoon dose. These observations suggest there is no large diurnal change in striatal dopaminergic responsiveness.

Aged↗
PubMed1986

Autosomal dominant episodic ataxia: a heterogeneous syndrome.

We describe six kindreds with autosomal dominant episodic ataxia, apparently representing three distinct syndromes. Four kindreds were characterized by episodic ataxia and response to acetazolamide, and in three, interictal nystagmus. One kindred was characterized by paroxysmal ataxia and in one member, paroxysmal choreoathetosis. The last kindred had brief attacks of ataxia and interictal neuromyotonia. The age of onset and severity of the disorder varied within each kindred. These kindreds illustrate the heterogeneity of episodic ataxia as well as the variable expressivity within each kindred.

Adult↗
PubMed1986

Buspirone in Parkinson's disease.

Buspirone, an anxiolytic unrelated to benzodiazepines that may act at the presynaptic dopamine receptor, was given to 11 patients with Parkinson's disease in an open label study. Seven patients completed the initial 10 week study achieving doses of 50-70 mg/day without any significant change in their clinical status. Six patients continued for an additional 3-11 weeks with increases in dose to 65-100 mg/day. Two of the three most severely affected patients had mild worsening of parkinsonian symptoms. Buspirone is ineffective in the treatment of Parkinson's disease, but at anxiolytic doses (less than 40 mg/day) does not adversely affect parkinsonian disability.

Adult↗
PubMed1986

A case-control study of twin pairs discordant for Parkinson's disease: a search for environmental risk factors.

A previous study of twins with Parkinson's disease (PD) revealed low concordance, suggesting that genetic factors play a minor role in the etiology of PD. To identify possible environmental determinants of PD while maximally controlling for hereditary factors, 31 monozygotic twin pairs discordant for PD were interviewed by telephone. Information about possible risk factors was obtained from systematic and uniform interviews with cases and controls. The only statistically significant result was less cigarette smoking by PD patients (p less than 0.05). Thirteen dizygotic discordant twin pairs were evaluated with the same techniques, but there were no statistically significant differences between affected and unaffected twins.

Female↗
PubMed1986

Levodopa pharmacokinetics and pharmacodynamics in fluctuating parkinsonian patients.

We investigated levodopa intravenous infusion rates, plasma concentrations, and clinical responses in 23 parkinsonian patients with a fluctuating response to the drug. There was a linear relationship between rate of levodopa infusion and plasma concentration when carbidopa was coadministered. Minimum-therapeutically effective plasma concentrations of levodopa ranged from 3 to 12 nmol/ml. The duration, but not the magnitude, of clinical response was linearly related to plasma concentrations. The clinical response lagged behind the rise and fall of plasma levodopa. There was no evidence of idiosyncratic pharmacokinetic or pharmacodynamic responses to levodopa to explain the fluctuating response.

Adult↗
PubMed1986

Clinical and biochemical studies with controlled-release levodopa/carbidopa.

In five patients with parkinsonism, the optimal dosage of a controlled-release levodopa/carbidopa preparation (CR-3) was three times higher than the dosage of Sinemet and produced higher plasma levodopa concentrations, but did not reduce the fluctuations in plasma levodopa or clinical response. Plasma levodopa concentrations were higher and clinical responses better before the first dose of the day with CR-3. CR-3 treatment benefited two patients, reducing the severity of off periods and off dystonia. Two patients were worse on CR-3 despite higher plasma levodopa levels than those adequate for clinical response to Sinemet or levodopa infusions. CR-3 could benefit a few severely affected patients, but it is necessary to understand the factors that affect absorption of levodopa from sustained-release preparations, as well as the consequences of prolonged elevation of plasma levodopa levels.

Aged↗