Anoxic Auguring: Neurological Prognostication After Cardiopulmonary Resuscitation
Three neurological diseases respond to treatment with L-dopa
Transcript of Three neurological diseases respond to treatment with L-dopa
Three neurological diseases respond to treatment with L-dopa
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44 C&EN JUNE 23, 1969
Dystonia musculorum deformans, a rare crippling congenital disease is the third and latest neurological disease to respond to treatment with the experimental drug L-dopa. Dr. George C. Cotzias of Brookhaven National Laboratory and Dr. M. Baze-lon Coleman of Children's Hospital, Washington, D . C , told the American Neurology Association meeting in Los Angeles that the experimental drug L-dopa (L-3,4-dihydroxyphenylalanine) has also been used with success to treat victims of Parkinson's disease and manganese poisoning.
There is little doubt that L-dopa brings relief to victims of three of the most debilitating diseases known to afflict mankind. Data on more than 350 patients suffering from Parkinsonism alone bear witness to the fact that dramatic improvements in what is an incurable disease have been recorded. More important than the results that have been chalked up to date for the drug is the fact that a whole new approach may be opened up to treatment of diseases of organs protected by blood barriers such as brain and skin.
The work of investigators with L-dopa on Parkinson's disease indicates that parts of the human body may be starved for a biogenic amine while other areas are surfeited. This principle was proposed by Dr. Linus Pauling and put to practice by Dr. George C. Cotzias and coworkers at Brook-haven in the treatment of Parkinsonism. The principle seems to be holding true. Dr. Cotzias finds that mammoth doses, by pharmacological standards, of L-dopa had to be given patients afflicted with Parkinsonism before sufficient quantities of the dopamine precursor saturated body pools and penetrated the blood-brain barrier to bring relief from the crippling symptoms of the disease.
These findings promise a new era in the treatment of chronic diseases of the nervous system. Dr. Cotzias says that L-dopa and a serotonine precursor, 5-hydroxytrophane, are basic tools with the potential for much wider investigations in the fight against neurologically based diseases such as palsy. In addition, he says, "Many drugs that theoretically held strong promise but failed to pass therapeutic tests may fall into the domain of having been given in insufficient dosage to saturate body pools and might merit systematic reinvestigation." One such drug, he adds, is glutamic acid.
Neurologists and biochemists are excited about the potential for this kind of therapeutic approach. Dr.
David C. Poskanzer of Massachusetts General Hospital calls the Brookhaven team's work "the most important contribution to medical therapy of a neurologic disease in the past 50 years because of its usefulness in the treatment of Parkinsonism."
Dr. Cotzias expains that the thought process used to determine that L-dopa holds promise in modifying the symptoms of Parkinsonism, manganism, and dystonia is rational as opposed to intuitive. Initial studies, in collaboration with Dr. Ismael Mena, Catholic University, Santiago, Chile, were directed at finding a treatment for managanese poisoning, which affects some miners after only a few months in the mines and occurs as a result of inhalation and subsequent ingestion of dust particles. Once afflicted, a miner cannot perform any physical tasks for the rest of his life.
Studies soon shifted to Parkinson's disease because of the similarity of the symptoms, the fact that both were diseases that attack the central nervous system of the brain (extrapyramidal centers), and the practical reason that more data on Parkinsonism were available.
Parkinson's disease is far more prevalent than is generally recognized. Estimates of the number of victims in the U.S. range from 500,000 to 1 million. Each year 43,000 new cases of Parkinsonism occur in the U.S. alone. Even though the patient generally dies of another malady, Parkinsonism is a devastating disease in man and results in major disability within five years of onset.
Dr. Cotzias tells C&EN that he was initially interested by two flagrant characteristics of Parkinsonism discovered by others: depigmentation (loss of melanin) of the substantia nigra (black center in the brain), and the decrease of certain biogenic amines (dopamine) in the striatum (grey cellular matter) . Attempts to improve the melanin concentration in the brain of patients with melanophore-stim-ulating hormone only aggravated some of the symptoms of Parkinsonism, and Dr. Cotzias shifted to the amino acid approach. The brain will not accept dopamine directly because dopamine won't penetrate the blood-brain barrier. The brain will accept the precursor L-dopa and convert it to dopamine with the action of the enzyme dopa decarboxylase.
Investigators in the early 1960's reported short-lived improvements in muscular rigidity of Parkinson's disease patients after a dopamine precursor was injected into the blood stream,
but these favorable results were disputed and the treatment practically abandoned. Dr. Cotzias reasoned that L-dopa (initial studies were conducted with the racemic mixture D, L-dopa) might have to be given in very large amounts.
Dr. Cotzias, Dr. Paul S. Papavasil-iou, and Rosemary Gellene "titrated" individual patients with gradually increasing doses. The slow titration often circumvents nausea, vomiting, and fainting which this drug otherwise induces, Dr. Cotzias explains. The doses necessary for improvement with D,L-dopa were massive, namely from eight to 16 grams per day, he adds. Even today, doses of the less toxic L-dopa are in the four to eight gram-per-day range. An inhibitor, decarboxylase, blocks the formation of dopamine in other parts of the body but cannot penetrate the brain where the dopamine is needed. The inhibitor permits diminution of the dose of L-dopa [New Engl J. Med., 280, 7, 337 (1969)] .
The potential market for L-dopa is large. At present, the drug is listed as experimental and any doctor wishing to administer it must petition the Food and Drug Administration. The National Institute of Neurologic Disease and Stroke (NINDS) and a group of physicians headed by Dr. Melvin Yahr, Columbia Presbyterian Medical Center, who have been using the drug (it has been given to more than 350 patients to date) , are attempting to pool available data to see
if existing information warrants the issuance of a new drug application ( N D A ) b y F D A .
FDA is under considerable pressure to release the drug and a number of individual drug companies have submitted their own new drug applications. One of these is Nutritional Biochemicals Corp., Cleveland, Ohio, which says it has developed a completely synthetic route to manufacturing L-dopa and expects its present price of 40 cents a gram to fall to 5 cents within two years if FDA gives an early approval.
Eaton Laboratories (Norwich Phar-macal Co. ) says it will attempt to make the drug available to the medical profession as soon as possible. Hoffmann-La Roche, Nutley, N.J., and Premium Chemicals, Oceanside, N.Y., also plan to produce the drug (C&EN, March 10, page 13).
The cause of Parkinsonism isn't known. The disease can afflict anyone and symptoms usually appear in middle age. Dr. Robert S. Schwab and Dr. Poskanzer at Massachusetts General have suggested that Parkinsonism might be directly connected to the influenza epidemic of 1917. The reason is that the virus inverted in 1930 and that few born after 1930 will ever contract the disease. About 89% of the victims of Parkinson's disease have been found to have had the flu in the 1917-30 period, according to Dr. Schwab. When final results are in, this number may be much higher.
TREATMENT. Dr. George C. Cotzias has found that L-dopa is useful in treating dystonia musculorum deformans, Parkinson's disease, and manganese poisoning
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JUNE 23, 1969 C&EN 45