Researchers from MIT and the Massachusetts College of Pharmacy and Allied Health Sciences (MCP/AHS) said today at the International Congress of Obesity that the diet drug duo known as "fen-phen" was potentially toxic because the two drugs taken together destroy the body's ability to control the amount of serotonin in blood plasma.
Too much serotonin damages blood vessels, particularly in the lungs, and may also harm heart valves. Such damage may have led to primary pulmonary hypertension and heart valve lesions in a small number of the millions of Americans who took the anti-obesity drug combination from 1992 until 1997, when one of the drugs, fen-fluramine, was voluntarily withdrawn by its manufacturer.
The other drug, phentermine, is still used to treat obesity. Because the two drugs were never in one pill, their use in combination didn't require US Food and Drug Administration approval.
The two drugs should never have been prescribed together, say researchers Timothy J. Maher, the Sawyer Professor of Pharmaceutical Sciences and director of the Division of Pharmaceutical Sciences at MCP and a lecturer in MIT's Department of Brain and Cognitive Sciences; MIT visiting scientist Dr. Ismail H. Ulus, professor of pharmacology at the University of Uludag in Bursa, Turkey; and Dr. Richard J. Wurtman, the C.H. Green Distinguished Professor at MIT and director of the Clinical Research Center.
Because of omissions on drug labels, similarly dangerous side effects may result from pairing antidepressants such as Prozac with phentermine, as well as with over-the-counter cold remedies that contain ingredients such as pseudoephedrine (found in Sudafed), phenylpropanolamine (found in Accutrim) and ephedrine, the researchers found.
SEROTONIN MECHANISMS
The body has two mechanisms for removing serotonin: absorption into platelets, which use it for clotting, and the serotonin-destroying enzyme monoamine oxidase (MAO). Some drugs block serotonin from being taken in by platelets; others inhibit the activity of MAO. By using two of these drugs at the same time, the body's ability to keep serotonin levels in check is virtually wiped out.
Fenfluramine, like many antidepressant drugs, 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. Neither drug has caused these problems when taken alone.
That the two drugs taken in tandem would lead to a dangerous excess of serotonin would have been obvious to any physician or pharmacist who knew that phentermine is an MAO inhibitor. But apparently few paid much attention to this, even though scientific papers published in the 1970s first demonstrated it, because the drug's label doesn't say it.
"These new findings show that it's critically important that drug labels be complete and up to date, and that there can be great harm when they're not. The fact that phentermine is an MAO inhibitor should have been stated on its label," Professor Wurtman said.
Professor Maher said that the information that appears on drug labels, in the Physician's Desk Reference and on package inserts that reach consumers is negotiated between the manufacturer and the FDA.
"When the labels for phentermine and Sudafed were negotiated, their MAO inhibitory activity was not known or appreciated or considered to be important. And apparently there was no requirement for phentermine's label to be updated 20 years ago when it was first shown to be an MAO inhibitor," he said.
"The new findings also probably explain why only a handful of the tens of millions of patients outside America who took drugs in the fenfluramine family without phentermine developed pulmonary hypertension or heart valve lesions, and almost all of these people were also taking other drugs that we have found are unrecognized MAO inhibitors," Professor Wurtman said.
He 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, although there was little evidence that Redux given alone caused heart or lung damage.
The researchers also found that common over-the-counter remedies for colds and obesity that contain ingredients such as pseudoephedrine (found in Sudafed), phenyl-propanolamine (found in Accutrim) and ephedrine also act as MAO inhibitors, although they are not labeled as such. This could be damaging to patients who also take antidepressants such as Prozac, Effexor, Zoloft or Paxil, which, like the fenfluramines, inhibit serotonin uptake, and whose labels state that they should never be taken with MAO inhibitors.
Because the label on phentermine didn't say anything about its ability to inhibit MAO, "people didn't recognize that phentermine had significant MAO inhibiting activity," Professor Maher said. "Because this information is still omitted from the drug's label, many patients are now taking it with another serotonin-uptake blocker, Prozac, to lose weight."
Herbs, which are unregulated, are another complicating factor, Maher said. St. John's Wort and ma huang--both taken for mood elevation and weight loss--may also be MAO inhibitors, he said.
Although nobody has been identified as having developed lung or heart diseases after taking Prozac and Sudafed, for instance, Professor Maher said this possibility needs to be investigated carefully.
"Until now, there was no particular reason to think that these classes of drugs would interact in the blood, and physicians examining patients with pulmonary hypertension or heart valve disease might not have asked specifically about how often the patients took the drugs," he said.
FEN-PHEN HISTORY
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. They were joined "for what they did to the brain, and not analyzed for their consequences for the blood," Professor Wurtman said.
Serotonin in brain cells is involved in transmitting nerve impulses, and the antidepressant and anti-obesity drugs that block serotonin uptake into platelets are designed to enhance this effect. The serotonin in blood plasma, made by special cells in the intestines, is the only source of serotonin for the platelets, which release the chemical when they form clots to stop bleeding but are unable to make it themselves.
A rare intestinal tumor called carcinoid releases enormous amounts of serotonin into the plasma, swamping the body's two mechanisms for removing serotonin. Carcinoid causes the same pulmonary hypertension and heart valve lesions found in a small number of people taking fen-phen.
About two years ago, Professor Maher started to look more closely at the problems seemingly tied to fen-phen. In a search of literature that is readily available to physicians, pharmacists and students, he quickly discovered that articles published in the 1970s identify phentermine as an MAO inhibitor.
While the labels on fenfluramines and other serotonin uptake-blockers clearly warn against combining these drugs with MAO inhibitors, no red flags about phentermine's MAO-inhibiting ability were raised because the bible of drug facts -- the Physician's Desk Reference -- and the drug's own FDA-approved label don't list it as an MAO inhibitor.
"To this day, if you ask 1,000 physicians or pharmacists if phen-termine is an MAO inhibitor, they will say no. This information was buried. It never surfaced after the 1970s and we're reconfirming it now," Professor Maher said.
The authors' rediscovery of phentermine's MAO-inhibiting effect was partly accidental. Professor Wurtman wanted to see whether phentermine affected another blood chemical, dopamine. After he gave a low dose of phentermine to volunteers, he found that their dopamine levels increased. As a control, he also measured serotonin in platelets, and was surprised to find that platelet serotonin increased much more, an effect that could only have resulted from MAO inhibition. Dr. Ulus then confirmed this action in lungs and other tissues in rats.
Professor Maher has no commercial associations related to fenflur-amines or phentermine. Dr. Ulus has no commercial associations. Redux was licensed to several companies, including Interneuron Pharmaceuticals Inc. of Lexington, of which Professor Wurtman is a director.
These studies were supported in part by grants from the National Institutes of Health and the Center for Brain Sciences and Metabolism Charitable Trust.
