Subcutaneous continuous apomorphine infusion in fluctuating patients with Parkinson's disease: long-term results

Fluctuations in motor disability and dyskinesias are the major problem in the long-term treatment of Parkinson's disease (PD). Many authors and ourselves have shown that by giving patients a continuous infusion of levodopa it is possible to control motor fluctuations. Levodopa can be administered continuously only be intravenous, intragastric or intrajejunal delivery. Continuous dopaminergic stimulation an be achieved more easily by infusing dopamine agonists subcutaneously. Apomorphine is a potent water-soluble dopamine receptor agonist that has been shown to successfully control motor fluctuation when subcutaneously infused in complicated parkinsonian patients. We report the clinical data of 30 PD patients having at least five years of treatment with subcutaneous continuous apomorphine infusion.     

Levodopa methyl ester treatment of Parkinson's disease

Intravenously administered levodopa is effective although relatively impractical for the chronic treatment of patients with Parkinson's disease who are disabled by motor fluctuation. In view of its greater solubility, levodopa methyl ester (LDME) was evaluated in seven advanced parkinsonian patients as a potentially more convenient alternative. Compared with oral levodopa, LDME infusions resulted in marked reductions of both plasma levodopa variations and motor response fluctuations in patients with either wearing-off or on-off phenomena. During infusions lasting approximately 1 week, there were no complications except for peripheral vein phlebitis. The results suggest that LDME might be a practical parenteral treatment for those with severe Parkinson's disease. It appears that central venous access or its equivalent will be necessary for its chronic administration.     

Repeated levodopa infusions in fluctuating Parkinson's disease: clinical and pharmacokinetic data

The short-term efficacy of continuous intravenous infusions of levodopa (with oral peripheral decarboxylase inhibitor) in abolishing or reducing "on-off" fluctuations in patients with Parkinson's disease is well established. However, there are suggestions that clinical response may be less good with longer infusions, or infusions on consecutive days. We therefore gave intravenous infusions of levodopa to three such subjects on five consecutive days (6 h on day 1, 12 h/day on days 2 to 5). One subject's symptoms were perfectly controlled, one experienced one "off" period per day, and the third developed one or two off-periods per day. Nevertheless, clinical control in all three subjects was superior with levodopa infusions to that seen on optimum oral therapy. Plasma levodopa concentrations during the infusions could be correlated with off to on, and with on to off switches. In general, subjects needed higher plasma levodopa levels to turn "on" than to keep them mobile once on, and the threshold levels below which off-periods supervened were lower still. These experiments show that repeated intravenous infusions of levodopa are very effective in some parkinsonian subjects, who may be suitable candidates for prolonged parenteral treatment with alternative, more highly soluble, dopaminergic drugs.     

Comparative efficacy of two oral sustained-release preparations of L-dopa in fluctuating Parkinson's disease. Preliminary findings in 20 patients

Summary 20 patients with Parkinson's disease and a fluctuating response to chronic treatment with conventional L-dopa preparations participated in an open randomized trial comparing two sustained-release L-dopa preparations (Madopar HBS, Sinemet CR4). While a majority (15 patients, 7 on Madopar HBS and 8 on Sinemet CR4) showed a favourable response after 2 months of slow-release L-dopa treatment the clinical benefit remained stable in only 2 patients on Madopar HBS and 3 patients on Sinemet CR4 over the entire follow-up period of 12 months. Reasons for treatment failure were increased peak-dose or biphasic dyskinesias or prolonged off-periods. This preliminary study failed to demonstrate clinically significant advantages of one slow-release principle over the other.     

Thermal and mechanical pain thresholds in patients with fluctuating Parkinson's disease

Study results evaluating pain thresholds in patients with Parkinson's disease (PD) vary widely. Thus, we designed our study to determine the effects of levodopa on the thresholds of pressure (PPT), heat (HPT) and cold pain (CPT) in PD patients with motor fluctuations (18 patients: 10 men, 8 women; age: 65 ± 10 years; mean disease duration: 11.6 ± 6 years), six of whom (33%) reported pain related to their disease. We compared these thresholds in patients in the ON and OFF states with those in 18 age- and sex-matched controls. Pain thresholds were assessed over: the frontal bones, C5-C6 zygapophyseal joints and second metacarpals (PPT); the dorsal aspect of the hand (HPT and CPT); and the tibialis anterior (TA) muscles. PD patients in the OFF state had lower PPT thresholds at all sites (P < 0.001) than healthy controls. Moreover, HPT and CPT thresholds were lower at all sites except over the TA muscle (P < 0.01). In the ON state, the PPT and CPT thresholds in PD patients were lower than in controls at all points, except over the TA (CPT) and the second metacarpals (PPT) P < 0.01. Pain thresholds were no different in PD patients in the ON or OFF state (P > 0.10), and the existence of pain did not influence the results. We detected mechanical and thermal pain hypersensitivity in PD patients in the OFF state, and levodopa administration did not increase these thresholds. Thus, while dopamine may modulate pain responses, other mechanisms are likely to be implicated in the modulation of these pain responses in PD patients.     

Cardiovascular effects of lisuride continuous intravenous infusion in fluctuating Parkinson's disease

The cardiovascular effects of a continuous intravenous infusion of lisuride plus oral domperidone were studied in 16 fluctuating parkinsonian patients as compared to their usual oral therapy with levodopa plus carbidopa. The study was performed using a 24-h ambulatory recording and an automatic noninvasive device for blood pressure monitoring. During lisuride infusion, a significant increase of systolic blood pressure was observed; however, in three patients, a decrease of systolic-diastolic blood pressure occurred; furthermore, a mild increase of atrial arrhythmias and, in two patients, a short run of atrial fibrillation were noted. Asymptomatic orthostatic hypotension, observed in seven patients during levodopa therapy, disappeared during lisuride infusion. Paradoxical hypertensive effects and disappearance of orthostatic hypotension observed in our patients seem related to the concurrent administration of domperidone.     

Dementia and treatment with L-dopa in Parkinson's disease

We compared the neuropsychological performance of patients with Parkinson's disease who were young at onset of the disease (mean age, 41.4 years) and had received prolonged L-dopa treatment (mean, 52.1 months) with nontreated patients of the same age. A similar comparison was made for patients who were older at onset of the disease (mean, 62.1 years). There were no significant differences in cognitive and memory functions between the L-Dopa-treated and untreated young patients, whereas the L-Dopa-treated patients in the older age group performed more poorly than untreated patients in some memory tests (Wechsler Memory Scale I: logical and visual) and cognitive functions (Wechsler Adult Intelligence Scale: similarities, block design, and cognitive flexibility). Treatment duration, disease duration, and mean L-Dopa dose were comparable for the two age groups. After linear effects of age and disease duration had been eliminated, the duration of L-Dopa treatment did not correlate with the cognitive variables studied. These observations suggest that treatment with L-Dopa may not be the cause of cognitive impairment in Parkinson's disease.     

A novel sublingual apomorphine treatment for patients with fluctuating Parkinson's disease.

We tested a novel preparation of a sublingual apomorphine hydrochloride tablet (APO) in 10 patients with advanced Parkinson's disease complicated by motor fluctuations. After a dose titration, patients took either 40 mg APO three times per day alternating with levodopa doses (eight patients) or six doses of 20 mg APO taken concurrently with levodopa doses (two patients) for 3 months. Assessments included timed tapping and ambulation tests, Unified Parkinson's Disease Rating Scale (UPDRS), and patient diaries. Tapping speed while taking only APO (12 hours after stopping levodopa) was faster than while taking only levodopa (p <0.05). The daily levodopa dose decreased by 32.1% (p <0.01), yet the total "on" time increased from 73.5% +/- 10.2% to 81.5% +/- 7.5% of the day (p <0.01) after starting APO. "On" UPDRS part II scores (p <0.05) and "on" UPDRS part III (motor examination) scores (p <0.05) also improved. Adverse events such as nausea, orthostatic hypotension, and disagreeable taste did not limit the dose of APO in any case. The short-term benefit and tolerability demonstrated in this study warrant further study of this new APO preparation.     

Effects of long-term L-dopa therapy on carbohydrate metabolism in patients with Parkinson's disease.

Carbohydrate metabolism and insulin secretion were investigated in 26 patients with Parkinson's disease before and during L-dopa treatment. Oral glucose tolerance tests were performed on 13 patients treated with L-dopa alone and on 7 patients treated with L-dopa combined with Carbidopa. Intravenous glucose tolerance tests were performed on additional 6 patients treated with L-dopa alone. Results indicate that chronic L-dopa administration does not modify glucose metabolism. It was observed only a significant decrease of insulin secretion after oral glucose in the early phase (15th day) of treatment with L-dopa alone. This temporary effect may be related to the peripheral conversion of L-dopa to dopamine since insulin secretion during combined therapy was normal. The mechanism by which L-dopa transiently inhibits insulin release is not clear. Perhaps the oral administration of L-dopa alone causes an alteration in some gastrointestinal functions which are involved in the handling of oral glucose.     

COMT genotype and effectiveness of entacapone in patients with fluctuating Parkinson's disease

OBJECTIVE: To investigate the relationship between the catechol-O-methyltransferase (COMT) genotype and the therapeutic efficacy of entacapone. METHODS: The efficacy of 2 months of entacapone treatment in 65 patients with PD with end-of-dose deterioration was studied. The efficacy of entacapone was assessed using the Unified Parkinson's Disease Rating Scale (UPDRS) score, the daily levodopa dosage, and the patients' diary card. RESULTS: Thirty-six patients (55.4%) had a high-activity COMT gene (COMT(HH)), 22 (33.8%) had an intermediate-activity COMT gene (COMT(HL)), and 7 patients (10.8%) had a low-activity COMT gene (COMT(LL)). Two months of entacapone treatment resulted in a significant increase in "on" time, a reduction in "off" time, and a reduction in the total UPDRS score, but these results were independent of the COMT genotype of the patient. There was no significant difference in the frequency or severity of dyskinesias between the patients with different COMT genotypes. CONCLUSION: The COMT genotype seems to be a minor factor in judging the beneficial effects of entacapone administration.     

Effect of L-dopa on visual evoked potential in patients with Parkinson's disease

In 47 patients with Parkinson's disease, we studied the visual evoked potential (VEP) using the pattern-reversal checkerboard (CBVEP) and the grating (GVEP) stimuli before and after 3 months of L-dopa therapy. The P100 latency in both CBVEP and GVEP was prolonged before L-dopa therapy, usually commensurate with the degree of motor disability. Clinical improvement of the parkinsonian state after L-dopa therapy was associated with shortening of the P100 latency in CBVEP, but not significantly in GVEP.     

Entacapone and selegiline with L-dopa in patients with Parkinson's disease: an interaction study

Both the catechol-O-methyltransferase (COMT) inhibitor entacapone and the monoamine oxidase B (MAO-B) inhibitor selegiline are L-dopa extenders. Both are used, often simultaneously, as adjuncts to L-dopa/dopa decarboxylase (DDC) inhibitor treatment of Parkinson's disease (PD). Their possible interactions have not been previously studied in a double-blind manner.We studied clinical response, tolerability, haemodynamics and cardiac rhythm in 16 PD patients with end-of-dose-type motor fluctuations. The patients' individual L-dopa/DDC inhibitor treatment was stabilized before the experimental treatments. This was followed by three consecutive, randomized, double-blind 2-week treatment periods with entacapone (200mg with each L-dopa dose), selegiline (10mg o.d.) or both entacapone and selegiline with the L-dopa/DDC inhibitor medication. Clinical efficacy (L-dopa test with repeated motor and dyskinesia scoring) and safety (orthostatic test, 24-h ambulatory ECG, haematological and clinical chemistry variables and adverse events) evaluations were performed before each treatment (control) and at the end of each treatment period.All three treatments, entacapone, selegiline, and entacapone+selegiline as adjunct to L-dopa/DDC inhibitor improved (p<0.05) clinical disability compared to L-dopa only but they did not differ significantly from each other. Dyskinesias increased with all the treatments, statistically significantly (p<0.01) with entacapone+selegiline. No significant differences in haemodynamics were observed between control and any of the experimental treatments, or between the experimental treatments in the orthostatic test. One patient already had symptomatic orthostatism before experimental treatments (control). In two other patients orthostatism emerged after the introduction of selegiline, and in one after every experimental treatment. Twenty-four-hour ECG did not show any differences in supraventricular or ventricular extrasystoles or heart rate between treatments. No statistically significant differences were observed in adverse events or in haematology and clinical chemistry variables. One patient treated with entacapone+selegiline discontinued the study due to dizziness and insomnia. Our results suggest that co-administration of entacapone with L-dopa/DDC inhibitor, with or without selegiline, improves clinical disability, is safe, but may also enhance dopamine-related adverse events to some extent in PD patients with end-of-dose type motor fluctuations.     

Absence of relationships between L-dopa plasma levels and therapeutic effect in Parkinson's disease treated with L-dopa.

The plasma concentration of dopa was studied in 15 parkinsonian patients after a single administration of L-dopa. The study was undertaken in order to determine if correlation between plasma dopa concentration and clinical performance as a result of the tests carried out before and after a single dose of dopa, was present. Our data confirm the absolute absence of correlation between dopa levels in plasma and clinical improvement during long-term treatment. Moreover, clinical responses to the performance tests were not related to the concentration of circulating L-dopa in the plasma. Therefore dopa levels cannot be useful in clinical practice but only for the prevention of too high concentrations of plasma L-dopa which often cause a few side-effects.     

The L-dopa test in Parkinson's disease

Seventy parkinsonian patients (mean age: 59.6 +/- 1.2 years; duration of disease: 9 +/- 0.6 years) with severe fluctuations of disability under L-Dopa treatment received a single dose of L-Dopa (200 mg + benserazide, a peripheral decarboxylase inhibitor) after 24-72 h interruption of treatment. The delay and duration of action of a single dose of L-Dopa, and the percentage of improvement of the parkinsonian symptoms were 39 +/- 2 and 162 +/- 6 minutes, and 57 +/- 2 p. 100 respectively. Estimation of the difference between the basal parkinsonian score and the score during maximum clinical improvement under levodopa treatment, and the score under levodopa treatment may reflect the severity of dopaminergic and of non dopaminergic lesions in the brain respectively. Modification of the treatment to obtain continuous clinical improvement can be performed according to the delay and duration of action of a single dose of L-Dopa.     

Chronic administration of L-dopa affects the movement-related cortical potentials of patients with Parkinson's disease.

The chronic effect of L-Dopa administration on the movement-related cortical potentials (MRCPs) was studied in two groups of patients with Parkinson's disease (PD): patients de novo (DN) and patients with on-off fluctuations. The BP and NS' premovement components of MRCPs associated with wrist flexion were assessed by their gradients and by their distribution on the midline (CZ) and the ipsilateral and contralateral hand sensorimotor areas. The treatment efficacy was controlled by a decrease in PD score (Columbia University Rating Scale). The BP component was absent in four out of nine patients DN. After 3 months of treatment, BP and NS' were recorded in six out of seven patients, and the NS' slope was significantly increased in all patients. In the off phase, MRCPs from patients with on-off fluctuations did not present a BP component. In the on phase, the NS' slope was increased and the BP was recorded in two out of nine patients. These patients exhibited an earlier PD stage (Hoehn and Yahr, stage 3). These two patterns of changes in the MRCPs induced by L-Dopa treatment suggest that the BP component was recorded in patients DN when a partial resolution of the nigrostriatal activity could occur. In patients with severe fluctuations, the dopaminergic striatal pathway was more severely affected and the increase of the NS' component demonstrated the activation of extrastriatal dopamine sites within the central nervous system (limbic and cortical structures, in particular).     

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.