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Biomedical subjects

J G Nutt

Publications and source records attributed to J G Nutt.

At least 37 records · Page 2Linked to original sources
PubMed1999

ABT-431, a D1 receptor agonist prodrug, has efficacy in Parkinson's disease.

Studies in animal models show a selective D1 receptor agonist with full functional efficacy compared with dopamine to have antiparkinsonian efficacy of similar magnitude to levodopa, without the same propensity for inducing dyskinesia. To date, no such agent has been tested in humans. ABT-431 is the prodrug of A-86929, a full, selective D1 receptor agonist. Subjects (n = 14) with levodopa-responsive Parkinson's disease received five doses of ABT-431 (5, 10, 20, 30, and 40 mg) and one of placebo after a 12-hour levodopa holiday. Response was assessed by using the Unified Parkinson's Disease Rating Scale motor subsection. Dyskinesia was separately graded. ABT-431 showed efficacy significantly superior to placebo at doses of 10 mg and more, and of similar magnitude to that seen with levodopa. Dyskinesia was reduced in several patients after receiving ABT-431. There were no serious adverse events, the most common minor events being nausea and emesis, dizziness, and hypotension. Assuming that ABT-431 is not transformed in humans into an unknown active D2 metabolite, and remains selective for D1 receptors, it is the first dopamine D1 receptor agonist to demonstrate a full antiparkinsonian effect in patients with Parkinson's disease. These preliminary findings also suggest that it may exhibit a reduced tendency to provoke dyskinesia. The emergence of a well-tolerated D1 agonist should allow for the development of a better understanding of the relation between motor efficacy and dyskinesia in Parkinson's disease.

Aged↗
PubMed1998

Verbal fluency task affects gait in Parkinson's disease with motor freezing.

We examined the effects of a simultaneous verbal fluency task on walking in Parkinson's disease (PD) patients with freezing of gait (PD-F) compared to nonfreezing patients (PD-NF) or control subjects (C). Effects of antiparkinsonian medications on gait in PD-F were examined. PD-F patients exhibited a greater increase in the number of steps to complete the walk with verbal fluency, even when the effect of medication was taken into account (mean increase +/- SD): PD-F = 4.2 +/- 4.6, n = 10; PD-NF = 0.1 +/- 1.6, n = 9; C = 1.5 +/- 1.5, n = 19; P = .007. Medications improved walking in PD-F patients by decreasing the number of steps, the time to walk, and freezing. PD-F patients may be more dependent on attention for walking.

Aged↗
PubMed1998

Mood response to levodopa infusion in early Parkinson's disease.

Mood response to levodopa infusion was studied in 18 Parkinson's disease (PD) patients during the first year of levodopa therapy before and after 2-hour (1.0 mg/kg/h) levodopa infusions at baseline and 6- and 12-month follow-up. Mood elevation was greatest after a 2-day levodopa holiday at the 6- and 12-month assessments. Age, sex, duration and severity of PD, and ongoing oral levodopa dose did not correlate with mood response. Mood response in these patients differs from that seen in advanced patients, possibly because of sensitization to levodopa's mood effects.

Affect↗
PubMed1997

Short- and long-duration responses to levodopa during the first year of levodopa therapy.

We examined the response to 2-hour levodopa infusions in 18 Parkinson's disease subjects before starting long-term levodopa treatment and after 6 and 12 months of treatment using tapping speed as an index of bradykinesia. The long-duration response (LDR), measured as the increase in baseline (overnight without levodopa) tapping speed, increased by 29 +/- 18 at 6 months and by 35 +/- 24 at 12 months. The magnitude of the short-duration response (SDR) to a 2-hour levodopa infusion after an overnight levodopa withdrawal did not differ at 6 and 12 months (16 +/- 8 and 20 +/- 13 taps/min) from that before long-term levodopa (21 +/- taps/min). However, when levodopa was withheld for 3 days, it was evident that the SDR magnitude was increasing in magnitude (19, 23, and 31 taps/min at 0, 6, and 12 months). Duration of SDR did not change. A diurnal motor pattern with faster tapping speeds in the morning and slower in the evening was apparent on the days no levodopa was administered. These observations indicate (1) the LDR is responsible for much of the sustained response to levodopa during the first year of treatment, (2) the SDR magnitude increases but is obscured by the LDR, and (3) a diurnal pattern of motor function is present that may be partially responsible for the poorer motor function in the afternoons and evenings.

Adult↗
PubMed1997

Step initiation in Parkinson's disease: influence of levodopa and external sensory triggers.

We studied anticipatory postural adjustments contributing to gait initiation deficits in patients with Parkinson's disease (PD) to determine if these deficits could be improved by administration of levodopa or by external stimuli. Ground reaction forces and body kinematics were recorded for self-generated and cutaneous cue-triggered step initiation in normal subjects and in PD subjects when OFF and when ON. The effects of assisting anticipatory postural sway with a surface translation coupled with a cutaneous cue were also examined. Decreased force production, decreased velocity of movement, and slowed execution of the anticipatory postural adjustments for self-generated step characterized step initiation in PD subjects when OFF. These impairments were significantly less evident when the PD subjects were ON. Both PD and normal subjects increased force and velocity of movement when a cutaneous cue was used as a go signal. When subjects voluntarily initiated a step in response to the surface translation, both PD and normal subjects executed the anticipatory postural adjustments for step more rapidly, but the PD subjects, both ON and OFF, failed to increase force to execute push-off more rapidly. In conclusion, dopaminergic therapy and an external stimulus similarly improve the deficient force production for the anticipatory postural adjustments associated with step initiation in PD. The findings also suggest that force production during the postural adjustment phase of self-generated, but not externally triggered, step initiation is influenced by dopaminergic pathways.

Aged↗
PubMed1997

Motor fluctuations during continuous levodopa infusions in patients with Parkinson's disease.

The cause of motor fluctuations occurring during constant-rate levodopa infusions is unknown. We examined whether known pharmacokinetic factors could explain the fluctuations and looked for clues to pharmacodynamic causes. Eleven subjects with stage III-V Parkinson's disease (PD) and a fluctuating response to levodopa underwent constant-rate infusions for 36-110 h. Levodopa, 3-O-methyldopa (3-OMD), and plasma large neutral amino acids (LNAAs) were measured at 2- to 6-h intervals and PD was monitored hourly from 07:00 to 22:00 h with tapping speed. Ten subjects had motor fluctuations during the infusions. Zero to 68% of the variability of tapping speed could be explained by variation in plasma LNAA concentrations in individual subjects. Fluctuations occurred more commonly later in the day, which may be related to the tendency for LNAAs to increase during the day. Motor fluctuations were not associated with minor variations in levodopa or 3-OMD concentrations. Fluctuations during constant infusions were more marked in patients using larger daily doses of oral levodopa; severity of PD did not predict fluctuations during the infusions. There was no trend for fluctuations or dyskinesia to decrease or increase during several days of constant-rate levodopa infusion. A portion of motor fluctuations occurring during constant levodopa infusions can be explained by peripheral pharmacokinetic mechanisms. Fluctuations are more prominent in subjects who have taken larger daily doses of levodopa, implicating pharmacodynamic factors as well.

Adult↗
PubMed1996

The response to levodopa in Parkinson's disease: imposing pharmacological law and order.

The seemingly unpredictable response to levodopa in patients with Parkinson's disease can be understood as an interaction between several distinct pharmacological effects of levodopa. The most important are a short-duration response with a half-life of minutes to hours and a long-duration response with a half-life of days, superimposed on diurnal motor variation. A negative response characterized by brief worsening before and after the short-duration response and dyskinesia accentuate the short-duration response. These various responses are modified by disease progression and long-term levodopa therapy. Pharmacodynamic modeling of the short-duration response indicates that with time, the response becomes less graded and small changes in levodopa concentrations can produce big changes in response. In this setting, unpredictability arises from the variation in absorption and distribution of levodopa.

Circadian Rhythm↗
PubMed1996

Apomorphine tolerance in Parkinson's disease: lack of a dose effect.

The development of tolerance to dopaminergic drugs may be important in the long-term therapy of Parkinson's disease. In this study, we sought to determine whether tolerance developed during infusions of apomorphine and if there was evidence of any dose dependency. Eight patients with Parkinson's disease received 4- to 6-h infusions of apomorphine at low, medium, and high rates on consecutive days. Before and after each infusion, test boluses of apomorphine were administered to measure sensitivity to the drug. The duration of motor effects after the postinfusion boluses were reduced in comparison to those of the preinfusion boluses, indicating that tolerance developed during the infusions. The infusion rate did not affect the responses to the postinfusion test boluses. Our observations indicate that tolerance develops to the antiparkinsonian effect of apomorphine after several hours of its constant infusion, but is not influenced by the dose of drug administered.

Antiparkinson Agents↗
PubMed1995

Apomorphine infusional therapy in Parkinson's disease: clinical utility and lack of tolerance.

We assessed the clinical utility of apomorphine infusional therapy in patients with parkinsonism and motor fluctuations and sought evidence for alterations in drug response resulting from chronic treatment. Six patients with Parkinson's disease were treated for 3 months with s.c. infusions of apomorphine administered during waking hours. At the beginning and the end of the study, test doses of apomorphine (12.5-100 micrograms/kg) were administered to establish a dose-response curve. Over the study, the patients reported a significant improvement in the number of "on" hours experienced per day and substantially reduced the dose and frequency of levodopa and other antiparkinsonian medications. No average change in apomorphine dose-response relationships or pharmacokinetics was observed during the study. However, two patients lowered the infusion rate during the 3-month observation and exhibited higher drug levels and longer responses following test doses of apomorphine given at the end of the study. Although pragmatic concerns with the use of infusion pumps solutions and adverse effects limited the overall benefit afforded by the treatment, this kind of drug treatment may be useful in selected patients with severe parkinsonism and fluctuations.

Administration, Cutaneous↗