Govindan Gopinathan

Bromocriptine in Parkinson disease Further studies

Bronnocriptine was administered to 66 patients with advanced Parkinson disease (PD) and increasing disability despite optimal treatment with levodopakarbidopa (Sinemet®). Forty-five patients tolerated at least 25 mg per day of bromocriptine (the “adequately treated” group) in addition to Sinemet and had significantly decreased rigidity, tremor, bradykinesia, gait disturbance, and total score, but increased involuntary movements. Twenty-five of these 45 patients improved by at least one stage. Among the 45 patients, 27 had “on-off” effects, and in 19 the “on-off” effects decreased on bromocriptine. The mean dose ofbromocriptine in adequately treated patients was 47 mg, permitting a 10 percent reduction in the dose of levodopa. Twelve adequately treated patients received bromocriptine for at least 1 year, and 8 continued for longer than this. Bromocriptine was discontinued in 29 of 66 patients because of adverse effects, including mental changes (14 patients) and involuntary movements (9 patients). All adverse effects were reversible. Despite adverse effects, expense, and scarcity, bromocriptine, when added to levodopa, is useful in patients with advanced disease who no longer respond satisfactorily to levodopa, and for whom no other treatment is available.

Further studies with pergolide in Parkinson disease

Pergolide was administered to 56 patients with advanced Parkinson disease who were no longer satisfactorily reponding to levodopa. The group included 45 patients with on-off phenomena. Pergolide, when combined with levodopa, resulted in a 44% decrease in disability as assessed in the on period, a 15% decrease in disability as assessed in the off period, and a 148% increase in the number of hours in which patients were on (from 4.6 ± 0.3 hours to 11.4 ± 0.6 hours). All these changes were significant at 1%. Forty-one of the 56 patients (59%) improved when pergolide was added to levodopa. Mean dose of pergolide was 2.5 mg (range, 0.2 to 10.0 mg). Mean duration of the study was 13 months (range, 1 day to 34 months). Maximum improvement occurred within 2 months and began to decline, usually after 6 months. The major adverse effects necessitating discontinuing pergolide were the occurrence of an organic confusional syndrome (six patients), increased dyskinesias (four patients), and cardiovascular abnormalities (three patients). Nine patients discontinued pergolide because of a lack of effect or declining effect.

Cardiac effects of pergolide

We examined the effect of pergolide, a semi synthetic ergot alkaloid, alone or combined with carbidopa and levodopa (Sinemet), on the cardiac rhythm of 12 patients with Parkinsons disease. The patients were selected on the basis of severe Parkinsons disease and stable cardiac rhythm as determined by I to 5 days of Hoher monitoring. Monitoring was then carried out for an additional period of between 2 and 10 wk while the patients were on pergolide. Seven of the 12 patients had repetitive ventricular rhythms (RVRs). These were isolated, infrequent, and not associated with increases in premature ventricular contractions. The dose at which the RVRs occurred may be a function of the presence or absence of heart disease, but the significance of RVRs remains to be determined.

Long‐term treatment with pergolide Decreased efficacy with time

We studied the effect of pergolide (combined with levodopa) in 17 patients with Parkinsons disease, including 15 with “wearing off” or on-off phenomena, who had been taking pergolide for at least 2 years. Mean duration of the study was 27.8 months. All 17 patients improved initially, but the improvement later faded. Mean disability score, which decreased initially by 60% (significant), was decreased only by 20% after 2 years (not significant). Wearing off and on-off phenomena, which improved initially, became prominent again. Four patients lost all the improvement, nine patients lost much of the improvement, and four maintained much of the improvement. Mean dose of pergolide was 2.2 mg (range, 0.8 to 5.0 mg).

Lisuride combined with levodopa in advanced Parkinson disease

lisuride, a semisynthetic ergoline and potent central dopamine and serotinin agonist, was combined with levodopa in 20 patients with advanced Parkinson disease who were no longer responding satisfactorily to levodopa, including 14 patients with “on-off” phenomena. Every patient who completed the week trial improved significantly (p <0.01), with a decrease in all symptoms. The mean dose of lisuride was 2.4 mg per day. The dose of levodopa (mg of levodopa in Sinemet) was reduced from 1030 to 920 mg. Among the patients with “on-off” phenomena, there was a significant increase in the time in which they were “on” (mobile) from 4.6 to 9.6 hours. In 5 of 10 patients who have been on lisuride for at least 1 year, there has been no decline in efficacy.

Lergotrile in Parkinson disease Further studies

Lergotrile was administered to 53 patients with advanced Parkinson disease (PD), who had increasing disability despite optimal treatment with levodopa/carbidopa (Sinemet®). Thirty-nine patients who could tolerate at least 20 mg per day lergotrile (thus considered “adequately treated”) had significant decreases in rigidity, tremor, bradykinesia, gait disturbance, and total score without increased involuntary movements. Twenty-one of these 39 patients improved by at least one stage. Among the 39 patients, 23 had “on-off” effects, and in 13 of these the “on-off” effects decreased on lergotrile. The mean daily dose of lergotrile in adequately treated patients was 49 mg, permitting a 10 percent reduction in the dose of levodopa. Lergotrile was discontinued in 33 of the 53 patients because of adverse effects, including hepatotoxicity (11 patients), mental changes (12 patients) and orthostatic hypotension (8 patients). Although lergotrile, when added to levodopa, has a definite antiparkinsonian effect, the incidence of adverse effects, particularly hepatotoxicity, makes it unlikely that this ergot alkaloid will become widely available for the treatment of PD. Analogues of lergotrile have been synthesized, and it is hoped that they will duplicate the antiparkinsonian effect of this drug without its toxicity.

Comparative effectiveness of two extracerebral DOPA decarboxylase inhibitors in Parkinson disease

In four patients with Parkinson disease, we compared carbidopa combined with levodopa (Sinemet®) and benserazide combined with levodopa (Madopar®). All of these patients had responded to treatment, first with levodopa and then with Sinemet; after 6 years two continued to show a good response, while two developed marked “on-off” phenomena. Clinically, Sinemet and Madopar were similar; however, DOPA levels were higher, but with a shorter half-life, on Madopar. The higher DOPA levels may have been offset by the shorter half-life, resulting in no clinical change. DOPA levels were lower and half-life was shorter in patients with on-off phenomena. These differences may be responsible in part for the on-off phenomena.

Combined use of benserazide and carbidopa in Parkinson's disease

The pharmacokinetics of levodopa differs when it is combined with benserazide or carbidopa. Peak dopa levels are higher, occur sooner, but decline more rapidly with benserazide. Although many patients respond better to one drug than the other, we sought to exploit the differences in pharmacokinetics by giving both drugs to the same patient. Benserazide was combined with carbidopa in 38 patients who were experiencing a diminished response to carbidopa, including 22 patients with diurnal oscillations in performance, “wearing off” or on-off phenomena. Previous attempts to change the dose, sequence, or ratio of levodopa to carbidopa in these patients had been unrewarding. Ten of the patients improved on the combination of benserazide and carbidopa, with a 30% decline in disability. The mean dose of 1evodopa:carbidopa before benserazide was 910:l00 (9 to 1 ratio); the mean dose of 1evodopa:benserazide was 355:90 (4 to 1 ratio). The mean dose of evodopa:carbidopa + benserazide was 925:155 (6 to 1 ratio). The combination of carbidopa with benserazide is useful in some parkinsonian patients.

Advanced Parkinson's disease Use of partial dopamine agonist, ciladopa

Ciladopa is a partial dopamine agonist that is effective in patients with advanced Parkinsons disease who are no longer satisfactorily responding to levodopa. Thirty-one patients participated in a double-blind randomized study of ciladopa (added to levodopa) versus placebo. Among 21 patients randomized to treatment with ciladopa and levodopa, there was a 32% decrease in symptoms on the Modified Columbia University Disability Scale. This change was significant, p ≤ 0.05. Eight of the 21 patients (38%) improved by at least 50%. The mean number of hours “on” increased by 20%. This change was significant, p ≤ 0.05. Five of the 21 patients (24%) were on for at least 4 hours more than at baseline. Dyakinesias were not increased. The mean dose of ciladopa was 19.5 mg/d. The mean dose of levodopa in Sinemet was decreased by 10%. Studies with ciladopa in humans had to be discontinued because of the occurrence of microscopic testicular tumors in some rodents. Although improvement in patients taking ciladopa was modest, there were few adverse effects. These results are encouraging, because two other partial agonists are now available, and they may be as effective ae ciladopa.

MODIFICATION OF THE “ON-OFF” EFFECT WITH BROMOCRIPTINE AND LERGOTRILE

ABSTRACT Twenty patients with advanced Parkinson disease and “on-off” phenomena were treated at different times with bromocriptine and lergotrile in addition to levodopa. When either bromocriptine or lergotrile was added to levodopa there was a significant decrease in total score and an increase in time spent in “on” periods. Thirteen of 20 patients improved by at least one-stage. Comparable improvement was not seen in “off” periods. Bromocriptine and lergotrile are useful in the treatment of advanced Parkinson disease, particularly in patients with “on-off” phenomena.