J. Vaamonde

Levodopa and 3-O-methyldopa plasma levels in parkinsonian patients with stable and fluctuating motor response.

Many parkinsonian patients with motor fluctuations in response to levodopa show a good response to initial morning doses but fail to respond in the afternoon and evening. We have studied levodopa and 3-O-methyldopa (3-OM-dopa) plasma profiles in 21 patients with fluctuations and eight patients with stable motor function throughout the day. Levodopa plasma peaks and valleys were similar for both group of patients. No significant difference for levodopa absorption index [defined as levodopa plasma levels after each dose divided by the quantity (mg) of ingested levodopa] was found between the first and the second levodopa-carbidopa dose in either group of patients. Even in patients who failed to improve after the second levodopa-carbidopa tablet (p.o.) on the day of the study, no significant variation in levodopa absorption index was observed. 3-OM-dopa values depended mainly upon levodopa consumption and were not different for patients with fluctuating or stable motor response. These findings provide further evidence of the prime role of central pharmacokinetic and pharmacodynamic factors in the pathogenesis of motor fluctuations in Parkinsons disease.

Acetazolamide Improves Action Myoclonus in Ramsay Hunt Syndrome

The myoclonus of two patients with Ramsay Hunt syndrome was only partially controlled under treatment with clonazepam, sodium valproate, primidone, and piracetam. Acetazolamide (200 mg daily) was added to these drugs, resulting in a dramatic improvement. Placebo substitution (one patient) and withdrawal of acetazolamide in the other patient resulted in marked aggravation of the myoclonus. The mechanism of action of acetazolamide in myoclonus is unknown. Acetazolamide may be an additional therapeutic possibility for patients with severe action myoclonus.

The Duration of the Motor Response to Apomorphine Boluses Is Conditioned by the Length of a Prior Infusion in Parkinson's Disease

“Pulsatile” administration of levodopa has been invocated a relevant factor for motor fluctuations in Parkinsons disease (PD). We studied dopaminergic sensitivity to apomorphine in 10 parkinsonian patients with motor fluctuations. Patients were tested as follows: the minimal effective dose of apomorphine (MED‐1) was administered in the morning to induce an on response. Fifteen minutes after this motor response had disappeared, an apomorphine infusion was initiated and maintained to ensure on periods of three different durations on different days. Infusion lasted for ∼30, 60 and 90 minutes. Subsequently, the infusion was stopped, and after 15 minutes in the off state, a second bolus of apomorphine (MED‐2) was given. The mean infusion doses were 49.2 ± 5.4, 108.4 ± 10.3, and 150 ± 8.2 mg. These elicited on periods of 48.2 ± 4.1, 110 ± 4.5, and 195 ± 3.8 minutes. The MED‐2 elicited on responses with a duration of 30 ± 4.5, 18.4 ± 3.2, and 11.2 ± 4.1 minutes. The duration of the on response induced by the apomorphine infusions correlated inversely (P < 0.01) with the on induced by the MED‐2 of apomorphine. Our findings indicate that a continuous dopaminergic stimulus may induce pharmacodynamic changes associated with tolerance in PD patients.

Motor Response to Repeated Dopaminergic Stimulation in Parkinsonʼs Disease

Recent studies giving subcutaneous apomorphine or intravenous levodopa boluses have not found clear evidence of behavioral hyposensitivity to repeated dopaminergic stimulation in Parkinsons disease (PD). Here we analyze that data, and review experimental findings in animal models and our previous experience with parkinsonian patients. We conclude that acute tolerance to pulsatile stimulation is likely to play a role in the pathophysiology of motor fluctuations in PD.