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S T Gancher

Publications and source records attributed to S T Gancher.

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

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↗
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

Gilles de la Tourette syndrome is not linked to D2-dopamine receptor.

Gilles de la Tourette syndrome has an important genetic component; the pathophysiology of this disorder may involve the dopamine system. We tested a D2-dopamine receptor (locus DRD2, recognized by probe hD2G1) for genetic linkage with Gilles de la Tourette syndrome. Using a genetic linkage map of the region of DRD2 on the long arm of chromosome 11 and restriction fragment length polymorphism data from a total of four markers (DRD2 itself, D11S84, D11S29, and PBGD), we were able to exclude linkage of this candidate gene and Gilles de la Tourette syndrome in two extended kindreds segregating for Gilles de la Tourette syndrome. This rules out causation of Gilles de la Tourette syndrome by mutation in DRD2 in the kindreds studied under the genetic assumptions we employed; use of the map and multipoint linkage analyses also allowed us to exclude a Gilles de la Tourette syndrome susceptibility locus from a larger genetic region.

Chromosome Mapping↗
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

Studies of renal function in animals chronically treated with apomorphine.

Based on the observation that orally administered apomorphine may induce nephrotoxicity, we studied the renal effects of a two-week subcutaneous infusion of apomorphine in rats. Drug-treated rats did not exhibit any change in renal cortical uptake of an organic cation (tetraethyl ammonium), organic anion (para-hippuric acid), creatinine clearance, or fractional excretion of sodium and potassium. Renal histology showed no change specific to drug. A small increase in urinary N-acetylglucosaminidase, a tubular enzyme, was measured but a second tubular enzyme showed no change. We conclude that parenterally administered apomorphine is not associated with renal toxicity.

Animals↗
PubMed1988

Movement disorders in multiple sclerosis.

Movement disorders other than cerebellar tremor are rare clinical manifestations of multiple sclerosis (MS). Two cases of parkinsonism and a case of chorea associated with MS are reported, and the literature is reviewed.

Adult↗
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

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

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↗