MIT, Mass. College of Pharmacy researchers: Half of drug duo 'fen-phen' inhibits an important enzyme


CAMBRIDGE, Mass.--Even a single, low dose of the diet drug phentermine inhibits an important enzyme in the blood, according to a paper published Friday (Jan. 2) in the British medical journal Lancet by researchers at the Massachusetts College of Pharmacy and Allied Health Sciences (MCP/AHS) and the Massachusetts Institute of Technology (MIT).

Researchers Timothy J. Maher, Sawyer Professor of Pharmaceutical Sciences and director of the Division of Pharmaceutical Sciences at MCP in Boston and lecturer in MIT's Department of Brain and Cognitive Sciences; visiting MIT scientist Dr. Ismail H. Ulus, professor of pharmacology at the University of Uludag in Bursa, Turkey; and Dr. Richard J. Wurtman, C. H. Green Distinguished Professor at MIT in Cambridge, Mass., and director of MIT's Clinical Research Center, also reported these findings in September 1998 at the International Congress of Obesity in Paris.

Although the amphetamine-like phentermine was first used as an appetite suppressant in the 1960s and became available in a generic version around 1980, it got new life in the United States after 1992 when it was paired with another anti-obesity drug, fenfluramine. The drugs were combined to cancel out the tendency of one to act as a stimulant and the other as a depressant.

From 1992 to 1997, millions of Americans were prescribed "fen-phen" for weight control. A small number of people who took the anti-obesity drug combination developed primary pulmonary hypertension and heart valve lesions.

In 1997, half the fen-phen drug duo, fenfluramine, was voluntarily withdrawn by its manufacturer because it was speculated that fenfluramine was responsible for these health problems. The other drug, phentermine, does not seem to cause adverse effects when taken alone. It still is used to treat obesity.

The Lancet article, "Phentermine, and other monoamine-oxidase inhibitors, may increase plasma serotonin when given with fenfluramines," shows that phentermine inhibits the enzyme monoamine oxidase (MAO). MAO helps the body to control the amount of serotonin in the bloodstream.

According to the article, a 15-milligram dose of phentermine led to an increase in platelet serotonin levels in test subjects. The researchers attributed this to an inhibition of the metabolism of MAO. "That phentermine inhibits the MAO that catabolizes serotonin was well known in the early '70s but apparently this information never made its way onto the drug's label," write the researchers.

KEEPING SEROTONIN IN CHECK

Serotonin in brain cells is involved in transmitting nerve impulses, and the antidepressant and anti-obesity drugs are designed to enhance its effect. Serotonin levels in the blood plasma are kept low by two mechanisms: absorption into platelets and the serotonin-destroying MAO enzyme. Too much serotonin appears to harm heart valves and lead to damaged blood vessels in the lungs.

Taking an MAO inhibitor like phentermine with serotonin uptake-blockers like fenfluramines inhibits the body's ability to keep serotonin in check. Fenfluramine stops plasma serotonin from being taken up into platelets. Phentermine, the investigators found, raises serotonin by another chemical action: it inhibits the MAO that destroys serotonin.

Wurtman is the co-inventor of the use of Redux, an MIT-patented drug, to treat obesity. Redux, or dexfenfluramine, is the half of the chemical compound of fenfluramine that directly works on serotonin metabolism. Redux also was withdrawn from the market in 1997 though there was little evidence that Redux given alone caused heart or lung damage. Redux was licensed to several companies, including Interneuron Pharmaceuticals Inc. of Lexington, Mass., of which Wurtman is a director.

Wurtman says that to his knowledge, Redux is no longer being developed as a weight-loss pill, although the researchers contend that taking a serotonin-uptake blocker alone would not be expected to raise serotonin levels or cause heart valve lesions or primary pulmonary hypertension.

"Subsequent to our September report, three reports from various universities have appeared comparing the frequency of cardiac valvular changes in people taking fen-phen or Redux, and in all three, either the frequency was twice as great in the fen-phen group, or there were no cases at all in the Redux group," Wurtman said. "Additionally, a multi-center study conducted by the University of Oregon found that if one omitted from consideration patients who were also taking a drug that inhibits MAO, there were no differences at all in the frequency of valvular changes between people taking Redux and control subjects."


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