Richard D. Sweet

Treatment of Parkinson's Syndrome with L Dihydroxyphenylalanine (Levodopa)

Abstract In 1967 Cotzias recommended d, i, dihydroxyphenylalanine (levodopa) for the treatment of Parkinsons syndrome. Since then 100 patients have been treated at Cornell University Medical Colle...

Five Years' Treatment of Parkinson's Disease with Levodopa: Therapeutic Results and Survival of 100 Patients

One hundred patients with Parkinsons disease, who started taking levodopa before the end of 1968, have been assessed after 5 years. Forty-seven patients are still being followed on levodopa, and half of them are at least 25% better than at their pretreatment evaluation. However, the average functional rating is returning toward baseline from its remarkable improvement at 1/2 to 2 years. Abnormal involuntary movements, rapid oscillations in motor performance, postural instability, and dementia have become the major adverse effects. Thirty-two of the 100 patients have died. Life-table analysis shows an excess mortality of 1.9 compared with the U.S. population, a figure that is lower than the 2.9 reported before levodopas use. Despite its inability to cure Parkinsons disease, levodopa provides symptomatic relief for a prolonged time and it remains the single most effective medication for the illness.

Gilles de la Tourette's syndrome Clinical, genetic, psychologic, and biochemical aspects in 21 selected families

Eighty-one patients and relatives with Tourettes syndrome, members of 21 selected families, participated in a 1-day clinic. In 12 of the 13 Jewish families and six of the eight non-Jewish families, there were multiple members with motor and vocal tics by observation or history. Males predominated among those with persistent symptoms, but among those with spontaneous clearing, females predominated. Twelve propositi had troublesome sexual and aggressive impulses, differing only quantitatively from normal. No evidence of abnormality was found in plasma dopamine beta hydroxylase, or norepinephrine levels.

Mental symptoms in Parkinson's disease during chronic treatment with levodopa.

Mental symptoms increased in frequency among 100 patients with parkinsonism treated with levodopa. Dementia was found in about one-third of patients throughout the 6-year treatment period. Thirteen patients became demented during the study, and dementia worsened severely in seven others. Agitated confusion became increasingly frequent and was observed in 60 percent of patients taking levodopa for 6 years. Withdrawal from levodopa decreased agitation, but not dementia. Ten patients received L-tryptophan along with levodopa, but no change in mentation was observed. In view of previous studies of mentation in Parkinsons disease and reports of widespread neuronal changes in the brain of autopsied patients with parkinsonism, our results suggest that the high incidence of dementia in patients with Parkinsons disease who take levodopa reflects prolongation of the course of the illness rather than a direct effect of the medication.

Plasma dopa concentrations and the "on-off" effect after chronic treatment of Parkinson's disease.

Plasma concentrations 01 dopa were measured during “on” (mobile and dyskinetic) and “off” (akinetic and/or tremulous) episodes in 10 patients who had been treated chronically with levodopa for Parkinsons disease. Dopa levels were higher during “on” than “off” spells (1.29 ± 1.08 versus 0.62 ± 0.59 mcg per milliliter; p < 0.01). A diet containing less than 10 gm per day of protein resulted in higher plasma dopa levels (2.05 ± 1.00 versus 1.20 ± 0.92 mcg per milliliter; p <0.001). The “on-off” effect was greatly relieved by low protein diets in 3 of 1 1 patients, possibly because of decreased competition for absorption by dietary amino acids. These results suggest that extracerebral metabolism of levodopa may be important in the “on-off” effect.

Propranolol treatment of essential tremor

Propranolol treatment of patients with essential tremor, selected for chronic, nonresting tremor of hands and head causing functional impairment, benefited only one of nine patients during a double-blind study (320 mg per day). No serious cardiorespiratory complications occurred in this screened patient group, but an elderly man became agitated and depressed. We conclude that propranolol does not benefit all patients with essential tremor and that this disorder may be caused by several biochemical mechanisms.

Enhanced response to low doses of levodopa after withdrawal from chronic treatment

Park insonian patients who respond to levodopa usually require weeks of therapy and graded increases of dose to levels of 2 to 4 gm. per day to show significant clinical benefit. ’ -4 They usually cannot tolerate such large doses immediately because of side effects such as nausea and dyskinesia. However, many patients have no side effects when they reach much higher dose levels of levodopa after a gradual increase. This indicates that they make an adjustment to chronic levodopa intake and develop tolerance to side effects. A second adjustment in response to chronically administered levodopa was suggested to us when 2 patients who temporarily stopped levodopa because of severe dyskinesia improved briefly and dramatically upon restarting the medication. We therefore designed a study to investigate the phenomenon of enhanced motor response to levodopa after withdrawal from chronic levodopa treatment.

Piribedil, a dopamine agonist, in Parkinson's disease.

Piribedil, a dopamine agonist that is thought to act directly on the postsynaptic receptor, was adminisered orally to 32 patients with Parkinsons disease. An initial nonblind study of 12 patients showed improvement in 6, in 4 by 33% or more. Subsequently, a double‐blind trial was conducted in 20 patients. Seven improved more than 25% and 3 of these more than 50%. The mean difference between placebo and piribedil scores was 44%, significant at the 1% level. Tremor improved more than the other major criteria of parkinsonism. Adverse effects included dyskinesia, nausea, drowsiness, and confusion. Though some patients were not helped at all and adverse effects made the medicine difficult to use, the benefit of piribedil for some patients demonstrates that dopamine receptor stimulators are potentially very helpful in the treatment of Parkinsons disease.

Piribedil Its synergistic effect in multidrug regimens for parkinsonism

Piribedil, a dopamine agonist, was administered to 13 patients with long-standing Parkinsons disease whose major symptoms were not well controlled on levodopa, anticholinergics, alpha-methyldopa, amantadine, or a combination of these agents. Twelve of the 13 clearly benefited from the addition of Piribedil although side effects precluded long term use in two cases. Beneficial results were obtained by using a combination of Piribedil, levodopa, and anticholinergic drugs. Side effects (hallucinations, confusion, dyskinesias) were frequent, but were usually reversible by lowering the dosage of levodopa or the accompanying anticholinergic medication. The synergistic effect of Piribedil and other antiparkinsonian drugs emphasizes the need for careful titration of all available medications in difficult cases and demonstrates the usefulness of dopamine receptor stimulators when drugs acting presynaptically have failed.