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Biomedical subjects

J G Nutt

Publications and source records attributed to J G Nutt.

At least 73 records · Page 4Linked 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↗
PubMed1990

L-dopa pharmacokinetics in plasma and cisternal and lumbar cerebrospinal fluid of monkeys.

The pharmacokinetics of levodopa (L-dopa) in plasma and in cisternal and lumbar cerebrospinal fluid (CSF) were studied in Rhesus monkeys that were given 2- to 3-hour intravenous infusions of L-dopa. Steady-state L-dopa concentrations in cisternal CSF correlated well with plasma levels, and yielded a CSF:plasma ratio of 0.17. The disappearance of L-dopa from plasma and cisternal CSF compartments fits an open, two-compartment pharmacokinetic model. Although slower, the distribution and elimination half-lives for L-dopa from cisternal CSF (8.9 and 49.2 minutes, respectively) were of a similar magnitude to those from plasma (4.9 and 33.2 minutes, respectively). If cisternal CSF reflects brain extracellular fluid, then plasma pharmacokinetics of L-dopa are a reasonable approximation of those in the brain. In contrast to cisternal CSF, the disappearance of L-dopa from lumbar CSF fits an open, one-compartment model with an elimination half-life of 100 minutes. This indicates that the lumbar CSF compartment is unsuitable for investigation of the pharmacokinetics of L-dopa in the brain.

Animals↗
PubMed1990

The short-duration response to apomorphine: implications for the mechanism of dopaminergic effects in parkinsonism.

The pharmacological basis of the short-duration response to dopaminergic stimulation in parkinsonism is not completely understood. Whereas it is generally assumed that the response reflects concurrent dopamine receptor occupancy, it is also possible that receptor activation triggers events that outlast the time that receptors are occupied by agonist. To distinguish between these two possibilities, we administered apomorphine, a mixed D1-D2 agonist with rapid equilibration between plasma and brain, to patients with parkinsonism. The clinical response to apomorphine injections lagged behind peak plasma concentrations and persisted beyond the time plasma concentrations following ineffective doses. We conclude that dopaminergic stimulation triggers effects that outlast the period of receptor occupancy by agonist. Understanding these steps may offer new pharmacological therapies for parkinsonism.

Aged↗
PubMed1989

Peripheral pharmacokinetics of apomorphine in humans.

Apomorphine, a potent dopamine agonist, has been used in acute and chronic studies of parkinsonism and other neurological disorders. To define its peripheral pharmacokinetics, we administered apomorphine by subcutaneous injection, by subcutaneous infusion, and by intravenous infusion to 15 patients with parkinsonism and measured plasma apomorphine levels by high-performance liquid chromatography with electrochemical detection. The peak drug levels and area under the curve were closely correlated with the dose administered; time to peak was brief and was independent of dose. The variation in absorption was high between subjects but low within individual subjects. In 11 of 15 subjects, the disappearance of drug could be described by a two-compartment model, with a distribution half-life of 5 minutes and an elimination half-life of 33 minutes. The drug absorption, volume of distribution, plasma clearance, and half-lives were similar for subcutaneous injection, subcutaneous infusion, and intravenous infusion. We conclude that apomorphine is rapidly and completely absorbed from subcutaneous tissue, correlating with the rapid onset of clinical effects, and that the brief duration of clinical action of the drug is explained by its rapid clearance.

Adult↗
PubMed1989

Localisation in PET images: direct fitting of the intercommissural (AC-PC) line.

A technique is described for estimating the position of the intercommisural line (AC-PC line) directly from landmarks on positron emission tomographic (PET) images, namely the ventral aspects of the anterior and posterior corpus callosum, the thalamus, and occipital pole. The relationship of this estimate to the true AC-PC line, fitted through the centres of the anterior and posterior commissures, showed minimal vertical and angular displacement when measured on magnetic resonance imaging (MRI) scans. Using regression analysis, the ease and reliability of fitting to these points was found to be high. This directly derived AC-PC line estimate was validated in terms of the assumptions used in the method of Fox et al. The ratio of distance between the AC-PC line and a line passing through the base of the inion (GI line) to total brain height was 0.21, as predicted. The technique has been further validated by localizing focal activation of the sensorimotor cortex. The technique is discussed in terms of absolute limits to localization of structures in the brain using noninvasive tomographic techniques in general and PET in particular.

Brain↗
PubMed1989

Influence of fluctuations of plasma large neutral amino acids with normal diets on the clinical response to levodopa.

Plasma large neutral amino acids (LNAAs) compete with levodopa for entry into the brain. Fluctuations in plasma LNAA concentrations could therefore contribute to variability in clinical response to levodopa. The hourly plasma levodopa, plasma LNAAs and clinical response were investigated in 11 fluctuating Parkinsonian patients on a regular hospital diet. The fluctuations in plasma levodopa were 2 to 3 times greater than the fluctuations of plasma LNAAs. The correlation between clinical response and plasma levodopa was substantially improved in only one patient by considering plasma LNAAs and calculating relative levodopa flux into brain. Although plasma LNAAs significantly increased during the day, the patients' clinical status did not uniformly deteriorate and mean afternoon clinical scores correlated better with mean plasma levodopa and levodopa flux than with mean plasma LNAAs. Minimum effective concentrations of levodopa for clinical response did not correlate with 9 am LNAA concentrations. It is concluded that in most patients, the relatively small variation in plasma LNAAs in comparison with the large variations in plasma levodopa indicates that fluctuations in LNAA are not an important contributor to the fluctuating response to levodopa.

Adult↗
PubMed1989

Amount and distribution of dietary protein affects clinical response to levodopa in Parkinson's disease.

Reducing dietary protein improves the effectiveness of levodopa (LD) but the most effective distribution of a low-protein diet (0.8 g/kg) is unclear. We compared a 1.6 g/kg protein diet, a 0.8 g/kg diet with protein evenly distributed between meals, and a 0.8 g/kg diet with protein restricted to the evening meal in 5 parkinsonian patients with motor fluctuations. We monitored clinical response, plasma LD, and plasma large amino acids (LNAAs) hourly throughout the day. Mean "on" times were 51% (1.6 g/kg diet), 67% (0.8 g/kg evenly distributed), and 77% (0.8 g/kg restricted). Hourly averages of plasma LD did not differ between the diets. The mean plasma LNAAs were 732 nmol/ml (1.6 g/kg diet), 640 (0.8 g/kg distributed), and 542 (0.8 g/kg restricted), and the diurnal pattern reflected the distribution of protein intake. In conclusion, the amount and distribution of dietary protein affect clinical response to LD. These effects are not related to LD absorption but are explained by the variation in plasma LNAAs.

Aged↗
PubMed1988

Duodenal and gastric delivery of levodopa in parkinsonism.

To clarify the influence of gastric emptying on levodopa-related motor fluctuations in Parkinson's disease, we assessed mobility and plasma levodopa concentrations in 10 patients during five modes of levodopa administration: (1) standard intermittent oral (SIO), (2) intermittent duodenal (ID), (3) continuous duodenal infusion (CDI), (4) continuous gastric infusion (CGI), and (5) controlled-release Sinemet (CR-4). The rank order from greatest to least for both percentage of time "on" and average mobility score was CDI, CGI, ID, CR-4, and SIO. The rank order for variance of means, a measure of fluctuation, from least to greatest for mobility was CDI, CGI, CR-4, ID, SIO, and for plasma levodopa concentrations was CDI, CGI, ID, SIO, and CR-4. The results demonstrate that it is possible to produce very steady plasma concentrations of levodopa with a corresponding reduction in motor fluctuations by continuous intraduodenal administration of the drug. This mode of delivery is an ideal model for the development of optimal continuous-release preparations of levodopa. Other enteral routes have produced a more variable plasma levodopa concentration and clinical response.

Administration, Oral↗