2/11/18: PARKINSON’S DISEASE: The Discovery of L-DOPA Treatment; Part Two of Two; Cotzias Ups the Dosage

Parkinsons1

 

(This post concludes an excerpt from my book, “Starting with Serotonin: How a High-Rolling Father of Drug Discovery Repeatedly Beat the Odds.” Important biochemistry basics are explained in Part One, 2/10/18.)

THE EUREKA!

Neurologist George Cotzias and his colleagues had been studying manganese poisoning among Chilean miners since the early 1960s. After chronic exposure to the chemical, the miners suffered Parkinson-like tremors and other extrapyramidal symptoms. Manganese, Cotzias found, accumulated in the miners’ melanin granules.

Intrigued by the relationship between melanogenesis (the cells’ formation of melanin) and extrapyramidal disease, the forty-eight-year-old neurologist set up an in-hospital study of sixteen Parkinson’s patients in which he first tried to ameliorate the disorder’s biochemical abnormalities by giving them a melanocyte-stimulating hormone that increases melanin deposits. It only aggravated their symptoms.

Hypothesizing that the hormone was shifting L-DOPA, which is a precursor of the melanins, as well as the catecholamines, from the brain to the body, Cotzias administered oral L-DOPA to these patients. To saturate the enzymes that form melanin and brain dopamine, he gave huge doses, ranging from 3 to 16 gm, and titrated them over months. The result was a Eureka! In eight of the sixteen patients, the tremors, the rigidity, the muscular weakness, and all of the other disabling symptoms of Parkinsonism completely disappeared or markedly lessened.

Although Canadian clinical pharmacologist Andre Barbeau also had given oral L-DOPA to Parkinson’s patients, he had stopped well short of the effective dosage.

[Said Dad, who was never a fan of the FDA:] Cotzias did this on his own. These massive doses. He didn’t have approval from anybody. He just did it.

The DOPA breakthrough was a happening. Many people had loved ones afflicted with Parkinson’s disease. My father, who had been experimenting clinically with DOPA—the “L” designates an isomer—started getting calls from members of Congress, who did not hesitate to use their influence.

[Dad:] We were not only giving DOPA to people, but we were the only ones in the whole region who knew anything about it. . . .  We had a clinical protocol that we were going to study the effects of DOPA. We were going to give it intravenously, but we never got around to it.

DOPA was a pharmacologically active agent, in terms of being converted to dopamine, so we never thought of giving gram quantities of it, but we should’ve known that you could give it by mouth and get away with it. Suddenly, there’s a big demand for DOPA, and everybody starts to make it. Five companies were trying to beat each other out for the Parkinson’s market. It was wild.

Hoffman-LaRoche was the first to burst out of the starting gate, with its product, Levodopa®, but it would not win the race. It had a handicap. DOPA caused problems.

***

‘YOU NEED TONS OF IT’

In early DOPA trials, about one-third of all Parkinson’s patients failed to improve, and nearly all manifested one or more adverse effects. Initial administration of the drug typically induced nausea and vomiting and occasionally brought on cardiac arrhythmia and hypotension. After long-term use, involuntary movements, usually of the leg and facial muscles, occurred, as did occasional episodes of mental disturbances, such as sleeplessness, irritability, anger, and paranoia.

According to Cotzias, who studied chronic L-DOPA treatment, patients were more apt to experience gastric upset and cardiac irregularities when physicians increased their dosage too quickly. But even those patients whose dosage increased more gradually under the Brookhaven neurologist’s care suffered hypermobility and untoward mental effects.

Besides the drug’s symptomatic downside, the cost to manufacture the massive quantities of Levodopa necessary for efficacy was prohibitive. To get enough Levodopa for all of the patients in the world, you would need tons of it.

In an attempt to enhance L-DOPA’s anti-Parkinsonism effects and reduce its toxicity, Cotzias concomitantly gave three patients a compound made by Merck that was known to block DOPA decarboxylation in the body, but not the brain. Cotzias knew that my father had clinically experimented with this compound, known as MK-485, and that Dad’s biochemist partner, Sidney Udenfriend, had demonstrated that, in combination with L-DOPA, MK-485 increased animal brain dopamine.  (MK-485 eventually was marketed as Carbidopa®.)

Cotzias used L-DOPA and Carbidopa together and achieved encouraging results, but he failed to recognize their significance. Thomas N. Chase of the National Institute of Mental Health had no such myopia.

***

COMBINATION TREATMENT

A reviewer for The New England Journal of Medicine, Chase read about a mini-trial that Cotzias performed with MK-485 in an advance copy of a lengthy, disjointed, and confusing article that Cotzias submitted describing his DOPA-treatment study. Chase, a Yale- and Harvard-educated neurologist, asked Merck for a supply of the compound—and thereafter performed the definitive study for treating Parkinson’s disease with a combination of DOPA and Carbidopa. Along the way, my father lent him a helping hand.

I remember we had this meeting on DOPA at Roche in 1969 or 1970. Cotzias was there. I was going to be chairman of one of the sessions, and I knew that Tom Chase, in the neurology institute at the NIH, had been studying Parkinsonism and the effects of DOPA and had given Carbidopa with DOPA to patients. Chase had found that you could give a lot less DOPA, when you also gave Carbidopa, because Carbidopa blocked decarboxylation of DOPA in the periphery [i.e., the body], so you didn’t waste your DOPA and more got into the brain, as a result. Chase ended up giving very small amounts of DOPA and Carbidopa together, versus 4, 6, or 8 gm. of DOPA, if it’s used alone.

[Carbidopa prevented the conversion of DOPA to dopamine in the body, so more DOPA entered the bloodstream and passed through the blood-brain barrier to reach the brain, where it was converted to dopamine. As I mentioned yesterday, dopamine itself does not pass through the blood-brain barrier, but DOPA, its amino-acid precursor, does.]

Anyway, I’m running this session, and these companies are all competing, because they all want to make money on DOPA. So, I said, maybe it’s relevant if Tom Chase says something about the studies that he’s been doing, and that changed the whole field right there, immediately. Boom.

Chase’s reluctant talk about his early data at this informal meeting, which only about 100 people attended, launched the combination therapy alternative for Parkinson’s disease. Later, after completing a two-year study with fourteen patients, Chase published his findings: He could reduce a patient’s L-DOPA dose by 76 percent when he used Carbidopa as an adjunct. The inhibitor markedly potentiated L-DOPA’s centrally mediated pharmacologic effects, increasing the amount of brain dopamine.

Perhaps even more important, most patients who received Carbidopa with L-DOPA did not suffer intolerable gastrointestinal or cardiovascular effects. As a result, Chase could reach therapeutic levels of L-DOPA dosage within just a few days, as opposed to several weeks, which Cotzias needed with L-DOPA alone.

Merck punctured Roche’s balloon. They had the advantage because they already knew, based on what we had done, that you could give a gram a day of Carbidopa. They ended up using a lot lower levels later in Sinemet®, a combination of DOPA and Carbidopa. Roche came up with a decarboxylase inhibitor similar to Carbidopa, but it didn’t work out.

According to Chase, Melvin D. Yahr, one of Roche’s kingpin neurological advisers, adamantly opposed the combination therapy. Despite the mild success that Andre Barbeau and other international researchers had in treating Parkinson’s patients with Levodopa and Roche’s DOPA-decarboxylase inhibitor, Ro 4-4602 (benserazide), Yahr, an eminent neurologist at Columbia, strongly discouraged the company from using the additive.   . . . He was stubbornly wrong for years.

Carbidopa is the only DOPA-decarboxylase inhibitor clinically available in the United States. Roche’s Ro 4-4602, marketed as Madopar®, can be obtained in Canada and elsewhere. Sinemet, which is Carbidopa-Levodopa, is still the first-line treatment of choice for Parkinson’s disease today.

For other available treatments, see the Mayo Clinic website at https://www.mayoclinic.org/diseases-conditions/parkinsons-disease/diagnosis-treatment/drc-20376062.

Ann, 2/11/18

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