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Biomedical subjects

J G Nutt

Publications and source records attributed to J G Nutt.

At least 55 records · Page 3Linked to original sources
PubMed1995

Mood and anxiety fluctuation in Parkinson's disease associated with levodopa infusion: preliminary findings.

Pilot data on mood and anxiety changes in 15 Parkinson's disease patients with motor fluctuations are described based on ratings every 30 min for 5 h bracketing a 2-h constant-rate levodopa infusion. Robust mood and anxiety effects slightly preceded but temporally paralleled fluctuations in motor tapping scores. Research nurse ratings blind to patient ratings corroborated the changes. The magnitude of changes in mood and anxiety scores did not correlate with the magnitude of changes in tapping scores. The findings of this uncontrolled study suggest mood and anxiety fluctuations may be a common and potentially important component of levodopa-induced fluctuations.

Affect↗
PubMed1995

Management of parkinsonism and treatment of associated complications.

Management of Parkinson's disease is dominated by the desire to prevent the development of fluctuations, dyskinesia, and psychiatric complications, and to treat effectively these effects when they appear. Advances in the understanding of these complications and methods to manage them are reviewed.

Antiparkinson Agents↗
PubMed1995

Pharmacodynamics of levodopa in Parkinson's disease.

1. Levodopa markedly reduces parkinsonism during the first years of treatment. However, with continued therapy the response to levodopa becomes erratic and is complicated by involuntary movements. To improve the therapy of parkinsonism, the challenge is to understand why fluctuations in response develop and, once developed, what controls the moment to moment motor status. 2. In patients with a fluctuating response to levodopa, three distinct responses can be recognized: a short-duration response, a long-duration response and a negative response. 3. The short-duration response, measured in minutes to hours, has a steep concentration-response relationship such that the response appears 'all or nothing.' The duration of effect is dose-responsive. The short-duration response becomes shorter during chronic therapy, possibly because of tolerance. The onset to effect becomes briefer and the magnitude of the response becomes larger during chronic therapy, possibly because of sensitization. 4. The long-duration response, measured in days to weeks, develops and decays slowly. The rate of decay is proportional to the severity of the parkinsonism and therefore this response may relate to dopamine storage capacity of remaining nerve terminals. 5. The negative response, measured in minutes, is a worsening of motor function as the short-duration improvement wears off. It may reflect a biphasic concentration-response relationship. 6. The response to levodopa in parkinsonian patients is a complex interplay between responses with different time courses and variably affected by sensitization, tolerance and disease progression.

Antiparkinson Agents↗
PubMed1995

Long-duration response to levodopa.

We measured the long-duration response to levodopa by changes in tapping rate in 16 patients with Parkinson's disease undergoing 3 to 5 days of levodopa withdrawal. "Off" tapping rates deteriorated 22% over the course of this holiday, the decline beginning 24 hours after levodopa withdrawal. Deterioration was more pronounced in the more affected hand in asymmetrically affected patients. A 2-hour infusion of levodopa after the levodopa holiday did not restore the long-duration response, although it produced a greater short-duration response than before the holiday. These observations indicate that the long-duration response is an important component of the therapeutic benefit of levodopa and is separable from the short-duration response.

Female↗
PubMed1995

Dose-response relationship of levodopa with mood and anxiety in fluctuating Parkinson's disease: a double-blind, placebo-controlled study.

We investigated the effect of levodopa on mood and anxiety in eight Parkinson's disease patients with motor fluctuations. Each patient received 0.0-, 0.5-, and 1.0-mg/kg/hr levodopa infusions in randomly assigned order under double-blind conditions on consecutive days. Mood elevation and anxiety reduction based on half-hourly patient rating and a corresponding increase in tapping speed occurred with active drug infusion but not placebo infusion. The effects were dose related. The higher-dose infusion rate produced more rapid onset, greater magnitude, and longer duration of response. We conclude that mood and anxiety fluctuations related to levodopa dosing are robust pharmacologic, and not placebo, effects.

Affect↗
PubMed1994

Episodic ataxia/myokymia syndrome is associated with point mutations in the human potassium channel gene, KCNA1.

Episodic ataxia (EA) is a rare, familial disorder producing attacks of generalized ataxia, with normal or near-normal neurological function between attacks. One type of EA is characterized by brief episodes of ataxia with myokymia (rippling of muscles) evident between attacks. Linkage studies in four such families suggested localization of an EA/myokymia gene near the voltage gated K+ channel gene, KCNA1 (Kv1.1), on chromosome 12p. Mutation analysis of the KCNA1 coding region in these families identified four different missense point mutations present in the heterozygous state, indicating that EA/myokymia can result from mutations in this gene.

Amino Acid Sequence↗
PubMed1994

Controlled release levodopa/carbidopa 25/100 (Sinemet CR 25/100): pharmacokinetics and clinical efficacy in untreated parkinsonian patients.

The pharmacokinetics of the clinically determined optimal dose of controlled release levodopa/carbidopa 25/100 (Sinemet CR 25/100) after 12 weeks of therapy was studied in nine parkinsonian patients without prior exposure to levodopa. The pharmacokinetics of single oral doses of controlled release levodopa/carbidopa 25/100 and 50/200 were also compared. As predicted from the plasma half-life (1.7 +/- 0.3 h) and confirmed by morning trough levels, levodopa did not accumulate when controlled released levodopa/carbidopa 25/100 was administered twice daily. The absorption and bioavailability of CR 25/100 are minimally greater than CR 50/200. Controlled released levodopa/carbidopa 25/100 levodopa plasma levels peak slightly faster than controlled release levodopa/carbidopa 50/200.

Absorption↗
PubMed1994

Effect of peripheral catechol-O-methyltransferase inhibition on the pharmacokinetics and pharmacodynamics of levodopa in parkinsonian patients.

Catechol-O-methyltransferase (COMT) metabolizes a portion of administered levodopa and thus makes it unavailable for conversion to dopamine in the brain. In an open-label trail, we examined the effects of entacapone, a peripheral inhibitor of COMT, administered acutely or for 8 weeks, on the pharmacokinetics and pharmacodynamics of levodopa in 15 parkinsonian subjects with a fluctuating response to levodopa. Acutely and chronically administered entacapone similarly decreased the plasma elimination of orally and intravenously administered levodopa. Absorption of levodopa was minimally affected. During chronic entacapone treatment, daily levodopa dosages were reduced by 27% yet mean plasma levodopa concentrations were increased by 23%. Plasma 3-O-methyldopa concentrations were decreased by 60%. Entacapone increased the duration of action of single doses of levodopa by a mean of 56%. The percent of the day "on" after 8 weeks of entacapone treatment was 77%; it dropped to 44% upon withdrawal of entacapone. We conclude that inhibition of COMT by entacapone increases the plasma half-life of levodopa and augments the antiparkinsonian effects of single and repeated doses of levodopa.

Aged↗
PubMed1994

Effect of brief levodopa holidays on the short-duration response to levodopa: evidence for tolerance to the antiparkinsonian effects.

To determine whether tolerance to the antiparkinsonian actions of levodopa develops during longterm levodopa therapy, we compared the response to 2-hour levodopa infusions before and after 2- to 4-day levodopa holidays using tapping and walking speeds and tremor/dyskinesia scores as measures of response in 17 parkinsonian patients with a fluctuating response to levodopa. As expected, motor function deteriorated during the levodopa holiday, but the maximum motor tapping and walking speeds and dyskinesia scores produced by the levodopa infusion before the holiday were the same as those produced by the infusion after the holiday. Because the baseline motor function was lower after the holiday, the increment in tapping and walking speeds (ie, the difference between the baseline and the maximum response) was larger with the postholiday infusion (p < 0.01). The postholiday infusion produced a longer response than did the preholiday infusion as measured by tapping score (p = 0.047), walking speed (p = 0.02), and tremor or dyskinesia scores (p = 0.02). The prolongation of the response was greater in patients receiving larger daily doses of levodopa (r = 0.55; p = 0.03). These changes in the duration of response suggest that progressive shortening of the response to levodopa during long-term therapy is partially caused by development of tolerance to levodopa and not just by loss of dopamine storage sites. Tolerance to levodopa should be considered in establishing oral dosing regimens and in developing new strategies for drug delivery.

Adult↗
PubMed1993

Does tolerance develop to levodopa? Comparison of 2- and 21-H levodopa infusions.

To determine if acute tolerance to levodopa develops, we compared the response to 2- and 21-h levodopa infusions with the rate adjusted during the long infusion to yield the same plasma concentration as at the end of the 2-h infusion. The duration of response after discontinuing the long infusions was briefer than after discontinuing the short infusion, suggesting the development of tolerance. Furthermore, dyskinesia severity was greater during long infusions. We conclude that continuous dopaminergic stimulation with levodopa may not offer optimal control of parkinsonism in patients with response fluctuations.

Aged↗
PubMed1993

Effects of thalamic stimulation on tremor, balance, and step initiation: a single subject study.

This study was conducted to evaluate the clinically apparent balance improvements in a patient with Parkinson's disease who had stimulating electrodes surgically implanted to the VIM nucleus of the right thalamus for control of left-upper-extremity tremor. Experiments were conducted to determine if balance improved simply because the large-amplitude upper-extremity tremor was reduced or if the neural control of balance improved. Using EMGs and forceplate recordings, we quantified the effects of the thalamic stimulation on the contralateral upper-extremity tremor and on the lower-extremity postural muscle activations for quiet stance, step initiation, and equilibrium responses to surface displacements. The results demonstrated that, beside reducing the amplitude and destabilizing effects of the upper-extremity tremor, the thalamic stimulation was also effective in reducing tremor activity of the trunk and contralateral lower-extremity muscles. In addition, the contralateral lower-extremity muscle activation patterns, strengths, and durations for the balance tasks were enhanced during stimulation. These results suggest that thalamic stimulation improved this patient's balance by reducing tremor in the contralateral extremities and by increasing burst duration and magnitude of the tibialis anterior, which functions as the postural prime mover for the step initiation and balance tasks.

Electric Stimulation Therapy↗
PubMed1993

Environmental antecedents of young-onset Parkinson's disease.

We conducted an exploratory study of young-onset Parkinson's disease (YOPD) to examine occupational and environmental factors associated with disease risk. This case-control study included 63 YOPD patients (diagnosis on or before age 50); controls (n = 68) were diagnosed with rheumatoid arthritis. Crude odds ratios (ORs) were computed to identify exposure variables for logistic regression analyses. After controlling for the variables of race, educational level, sex, age, age at diagnosis, and family history of Parkinson's disease (PD), PD was positively associated with insecticide exposure (OR = 5.75, p < 0.001), past residency in a fumigated house (OR = 5.25, p = 0.046), herbicide exposure (OR = 3.22, p = 0.033), rural residency at time of diagnosis (OR = 2.72, p = 0.027), and nuts and seed eating 10 years before diagnosis (OR = 1.49, p = 0.021). PD was inversely associated with cigarette smoking at 5 years (OR = 0.50, p = 0.027), 10 years (OR = 0.43, p = 0.012), and 15 years (OR = 0.37, p = 0.005) before diagnosis, farm residency (OR = 0.38, p = 0.018), and exposure to dimethyl sulfoxide (OR = 0.10, p < 0.001). These findings are consistent with hypotheses linking PD to exposure to pesticide agents.

Adult↗
PubMed1993

The effect of L-dopa infusions with and without phenylalanine challenges in parkinsonian patients: plasma and ventricular CSF L-dopa levels and clinical responses.

We monitored the motor response and plasma and ventricular CSF (CSFv) concentrations of L-dopa during IV infusions of L-dopa in two patients with advanced Parkinson's disease. Concentrations of L-dopa in CSFv mirrored, but lagged behind, those in plasma. In the fasting state, the duration, but not the magnitude, of the motor response was greater with increasing plasma and CSFv levels of L-dopa. During IV infusions of L-dopa following oral administration of phenylalanine, a large neutral amino acid that shares a transport system into the brain with L-dopa, the duration of the motor response was markedly attenuated despite undiminished CSFv levels of L-dopa. These observations suggest that either L-dopa entry into CSFv and the brain are differentially affected by phenylalanine or that phenylalanine affects other steps in the motor response. These observations demonstrate that, except in the fasting state, L-dopa in CSFv is not a reliable predictor of motor response.

Amino Acids↗