Search

Objective: To study the possible relationship between central levodopa influx and short-term antiparkinsonian and dyskinetic responses to levodopa in patients with Parkinson disease., Methods: The clinical response to a single oral dose of standard and controlled-release levodopa/carbidopa was assessed in 12 patients with Parkinson disease complicated with motor fluctuations and dyskinesias. Plasma concentrations of levodopa and large neutral amino acids were determined, and the theoretical central levodopa influx was calculated using a model based on competitive inhibition of substrates to cross the blood-brain barrier., Results: The mean (SD) central levodopa influxes at the onset of the antiparkinsonian clinical effect were 19.7 (10.9 x 10(-3) and 19.1 (7.4 x 10(-3) nmol min(-1) g(-)1 (P >0.1) for standard and controlled-release levodopa, respectively. The mean (SD) central levodopa influxes at the onset of choreic dyskinesias were 20.1 (8.2 x 10 (-3) and 19.9 (10.8 x 10(-3) nmol min (-1) g(-)1 (P 9 0.1) for standard and controlled-release levodopa, respectively. During the tests, choreic dyskinesias were associated with a central levodopa influx of 10 x 10(-3) nmol min(-1) g(-1) or greater, and foot dystonia occurred with a central levodopa influx less than 9 x 10(-3) nmol min(-1) g(-1)., Conclusions: The clinical response to levodopa in patients with advanced Parkinson disease may be related to central levodopa influx. We found no differences in the central levodopa influx threshold for clinical improvement with different levodopa formulations. The central levodopa influxes at the onset of choreic dyskinesias and antiparkinsonian effect were similar. Choreic dyskinesias and foot dystonia were associated with high and low central levodopa influx, respectively.

We present the results of an open, prospective, multicentric study including 450 patients with mild to moderate Parkinson's disease (PD) converted from standard Sinemet to Sinemet CR (controlled release; Dupont Pharma, Pavia, Italy). Patients with complex fluctuations and diphasic dyskinesias were excluded and the conversion was made after some recommendations, depending on the clinical problems and the daily dosage and administration schedule of standard (STD) Sinemet. The condition of more than 60% of the patients improved after the change and 80% of them preferred the CR formulation by the end of the study. We found a moderate, but significant, improvement in most of the efficacy parameters used, such as the Unified Parkinson's Disease Rating Scale (UPDRS), the Schawb and England scale, and dyskinesias and sleep questionnaires. Forty-five patients (10%) discontinued the study due to adverse effects (mainly gastrointestinal disturbances, functional deterioration, and dyskinesias). We conclude that Sinemet CR is a useful and safe therapeutic option in patients with mild and moderate PD. Selection of the patients is the most important outcome factor.

To determine whether Botulinum Toxin Type A (BTXA) has an effect on the Central Nervous System, the authors studied the excitability of the blink reflex recovery cycle in 12 patients with blepharospasm before and 3 weeks after unilateral BTXA injections. To avoid recording from severely denervated muscles, the R2 response of the blink reflex was obtained from the untreated orbicularis oculi with both ipsilateral and contralateral supraorbital nerve stimulation. Baseline recovery curves were compared with a control group (n = 11) and showed an enhanced recovery of the R2 component. There were no significant differences between the recovery curves of the R2 component of the blink reflex taken before BTXA treatment and those taken after treatment. This finding confirms that BTXA does not modify the excitability of brainstem interneurons that mediate the bilateral R2 response of the blink reflex in patients with blepharospasm.

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.

Recent studies giving subcutaneous apomorphine or intravenous levodopa boluses have not found clear evidence of behavioral hyposensitivity to repeated dopaminergic stimulation in Parkinson's 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.

Ten patients with Parkinson's disease (PD) with motor fluctuations under levodopa treatment were given repeated equal subcutaneous injections of apomorphine [minimal effective dose (MED)] in 1 day. The MED was defined as the dose of apomorphine necessary to induce at least 60% reduction of motor disability for a minimum period of 10 min. MED was found for each patient in previous study days. In eight a subcutaneous infusion of apomorphine was performed on a different day. Four patients with simple fluctuations ("wearing off") showed a progressive reduction of the motor response to apomorphine injections, but three of the four had a stable response (continuous "on") to apomorphine infusion. Six patients with complicated fluctuations also exhibited a decreasing response to successive apomorphine injections and often completely failed to respond to some of the boluses. The response to a subcutaneous infusion of apomorphine was unstable in three of four cases. These findings indicate that a reduction of striatal dopaminergic receptor sensitivity is associated with repeated "pulsatile" apomorphine administration in parkinsonian patients with oscillations of motor performance. It is suggested that altered regulation of dopaminergic receptor sensitivity following pulsatile stimulation with levodopa may be a relevant phenomenon in the pathogenesis of motor fluctuations in PD.

Fluctuations and dyskinesias are the 2 main motor complications associated with chronic levodopa therapy. Striatal denervation following degeneration of the substantia nigra dopaminergic projections is probably the major pathophysiologic mechanism underlying motor fluctuations. In addition, pathologic modification of striatal receptors, partially related to the nonphysiologic delivery of levodopa in a discontinuous pulsatile mode, may be responsible for the various types of dyskinesias and sudden "off" episodes. Drugs capable of providing a stable dopaminergic stimulation should be particularly useful for preventing the development of motor complications in patients not yet treated. At the other end of the clinical spectrum, patients with complex fluctuations are the least likely to improve with slow-release levodopa preparations.