Fen-phen
Encyclopedia
The drug
combination fenfluramine/phentermine, usually called fen-phen, is an anti-obesity
treatment that utilizes two anorectic
s. Fenfluramine
, its S-enantiomer
dexfenfluramine
, and a few other serotonin agonists were shown to cause potentially fatal pulmonary hypertension
and heart valve
problems, which eventually led to their withdrawal and expensive legal settlements.
reported that they had performed a double-blind, controlled clinical trial comparing phentermine alone, fenfluramine alone, a combination of phentermine and fenfluramine, and placebo, for weight loss in humans. Weight loss in those receiving the fen-phen combination was significantly greater than in those receiving placebo and equivalent to that of those receiving fenfluramine or phentermine alone. Furthermore, adverse effects were less frequent with the combination regimen than with other active treatments. The authors felt that combining fenfluramine and phentermine capitalized on their pharmacodynamic differences
, resulting in equivalent weight loss, fewer adverse effects, and better appetite control.
In 1992, the same authors published the results of a 3-year study, demonstrating that prolonged use of fen-phen was markedly efficacious in maintaining a significant weight loss and that when fen-phen was stopped the subjects inevitably regained their weight despite the continuation of other ancillary modes of supportive treatment.
might share this therapeutic potential.
Subsequent murine experiments by Bart Hoebel and Hans Fisher supported these preliminary reports. In 2006, Fisher and his Rutgers University
team confirmed that phentermine and the serotonin
precursor
5-HTP, in place of fenfluramine, combination significantly decreased alcohol withdrawal seizures in rats.
Intramural National Institutes of Health
(NIH) double-blind protocols to demonstrate the efficacy of fen-phen in alcohol and cocaine addiction were designed by a former director of the National Institute on Drug Abuse
, the late Charles (Bob) Schuster and Rothman, also a NIDA senior scientist. The studies were never performed.
tool, demonstrated marked psychiatric improvement in several modalities.
(NEJM).
patients revealed a probable correlation between mitral valve
dysfunction and the use of these anorectic agents.
occurs in patients taking fenfluramine, dexfenfluramine and several other serotonergic agents.
The NEJM articles prompted not only a media blitz and legal action but also a renewed interest in the deleterious effects of systemic serotonin. It was already known for decades that two of the major side-effects of the carcinoid syndrome
in which excessive serotonin is produced endogenously, are valvular disease and pulmonary hypertension. Several centers were able to note a relationship to an excessive activation of a specific 5-HT2B receptor
subtype.
The Food and Drug Administration
(FDA) in late 1997 recommended that fenfluramine and the other serotonergic agents implicated be no longer prescribed.
formed a large trial lawyer group to seek damages from American Home Products, the distributor of fenfluramine (Pondimin) and dexfenfluramine (Redux).
Estimates of total liability ran as high as $14 billion. As of February 2005, Wyeth was still in negotiations with injured parties, offering settlements of $5,000 to $200,000 to some of those who had sued, and stating they might offer more to those who were most seriously injured.
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
combination fenfluramine/phentermine, usually called fen-phen, is an anti-obesity
Obesity
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...
treatment that utilizes two anorectic
Anorectic
An anorectic or anorexic , also known as anorexigenic or appetite suppressant, is a dietary supplement and/or drug which reduces appetite, food consumption, and as a result, causes weight loss to occur.-List of anorectics:Numerous pharmaceutical compounds are marketed as appetite suppressants.The...
s. Fenfluramine
Fenfluramine
Fenfluramine is a drug that was part of the Fen-Phen anti-obesity medication . Fenfluramine was introduced on the U.S. market in 1973. It is the racemic mixture of two enantiomers, dextrofenfluramine and levofenfluramine...
, its S-enantiomer
Enantiomer
In chemistry, an enantiomer is one of two stereoisomers that are mirror images of each other that are non-superposable , much as one's left and right hands are the same except for opposite orientation. It can be clearly understood if you try to place your hands one over the other without...
dexfenfluramine
Dexfenfluramine
Dexfenfluramine, marketed as dexfenfluramine hydrochloride under the name Redux, is a serotoninergic anorectic drug: it reduces appetite by increasing the amount of extracellular serotonin in the brain...
, and a few other serotonin agonists were shown to cause potentially fatal pulmonary hypertension
Pulmonary hypertension
In medicine, pulmonary hypertension is an increase in blood pressure in the pulmonary artery, pulmonary vein, or pulmonary capillaries, together known as the lung vasculature, leading to shortness of breath, dizziness, fainting, and other symptoms, all of which are exacerbated by exertion...
and heart valve
Heart valve
A heart valve normally allows blood flow in only one direction through the heart. The four valves commonly represented in a mammalian heart determine the pathway of blood flow through the heart...
problems, which eventually led to their withdrawal and expensive legal settlements.
Obesity
In 1984, Michael Weintraub, MD, and collaborators at the University of Rochester Medical CenterUniversity of Rochester Medical Center
The University of Rochester Medical Center , located in Rochester, New York, is one of the main campuses of the University of Rochester and comprises the university's primary medical education, research and patient care facilities....
reported that they had performed a double-blind, controlled clinical trial comparing phentermine alone, fenfluramine alone, a combination of phentermine and fenfluramine, and placebo, for weight loss in humans. Weight loss in those receiving the fen-phen combination was significantly greater than in those receiving placebo and equivalent to that of those receiving fenfluramine or phentermine alone. Furthermore, adverse effects were less frequent with the combination regimen than with other active treatments. The authors felt that combining fenfluramine and phentermine capitalized on their pharmacodynamic differences
Pharmacodynamics
Pharmacodynamics is the study of the biochemical and physiological effects of drugs on the body or on microorganisms or parasites within or on the body and the mechanisms of drug action and the relationship between drug concentration and effect...
, resulting in equivalent weight loss, fewer adverse effects, and better appetite control.
In 1992, the same authors published the results of a 3-year study, demonstrating that prolonged use of fen-phen was markedly efficacious in maintaining a significant weight loss and that when fen-phen was stopped the subjects inevitably regained their weight despite the continuation of other ancillary modes of supportive treatment.
Addiction
The term fen-phen was coined in 1994 when Pietr Hitzig and Richard B. Rothman reported that this combination could presumptively remit alcohol and cocaine craving. The authors suggested that other combined dopamine and serotonin agonists or precursorsPrecursor (chemistry)
In chemistry, a precursor is a compound that participates in the chemical reaction that produces another compound. In biochemistry, the term "precursor" is used more specifically to refer to a chemical compound preceding another in a metabolic pathway....
might share this therapeutic potential.
Subsequent murine experiments by Bart Hoebel and Hans Fisher supported these preliminary reports. In 2006, Fisher and his Rutgers University
Rutgers University
Rutgers, The State University of New Jersey , is the largest institution for higher education in New Jersey, United States. It was originally chartered as Queen's College in 1766. It is the eighth-oldest college in the United States and one of the nine Colonial colleges founded before the American...
team confirmed that phentermine and the serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
precursor
Precursor (chemistry)
In chemistry, a precursor is a compound that participates in the chemical reaction that produces another compound. In biochemistry, the term "precursor" is used more specifically to refer to a chemical compound preceding another in a metabolic pathway....
5-HTP, in place of fenfluramine, combination significantly decreased alcohol withdrawal seizures in rats.
Intramural National Institutes of Health
National Institutes of Health
The National Institutes of Health are an agency of the United States Department of Health and Human Services and are the primary agency of the United States government responsible for biomedical and health-related research. Its science and engineering counterpart is the National Science Foundation...
(NIH) double-blind protocols to demonstrate the efficacy of fen-phen in alcohol and cocaine addiction were designed by a former director of the National Institute on Drug Abuse
National Institute on Drug Abuse
The National Institute on Drug Abuse is a United States federal-government research institute whose mission is to "lead the Nation in bringing the power of science to bear on drug abuse and addiction."-History:...
, the late Charles (Bob) Schuster and Rothman, also a NIDA senior scientist. The studies were never performed.
Anxiety and depression
The pilot study cited above, using the psychometric Symptom Checklist 90Symptom Checklist 90
The Symptom Checklist-90-R is a relatively brief self-report psychometric instrument published by the Clinical Assessment division of the Pearson Assessment & Information group. It is designed to evaluate a broad range of psychological problems and symptoms of psychopathology...
tool, demonstrated marked psychiatric improvement in several modalities.
Adverse effects
In 1996, two papers appeared in the New England Journal of MedicineNew England Journal of Medicine
The New England Journal of Medicine is an English-language peer-reviewed medical journal published by the Massachusetts Medical Society. It describes itself as the oldest continuously published medical journal in the world.-History:...
(NEJM).
Cardiac valvulopathy
A clinical study of 24 Mayo ClinicMayo Clinic
Mayo Clinic is a not-for-profit medical practice and medical research group specializing in treating difficult patients . Patients are referred to Mayo Clinic from across the U.S. and the world, and it is known for innovative and effective treatments. Mayo Clinic is known for being at the top of...
patients revealed a probable correlation between mitral valve
Mitral valve
The mitral valve is a dual-flap valve in the heart that lies between the left atrium and the left ventricle...
dysfunction and the use of these anorectic agents.
Pulmonary hypertension
A statistically significant rise in the risk of pulmonary hypertensionPulmonary hypertension
In medicine, pulmonary hypertension is an increase in blood pressure in the pulmonary artery, pulmonary vein, or pulmonary capillaries, together known as the lung vasculature, leading to shortness of breath, dizziness, fainting, and other symptoms, all of which are exacerbated by exertion...
occurs in patients taking fenfluramine, dexfenfluramine and several other serotonergic agents.
The NEJM articles prompted not only a media blitz and legal action but also a renewed interest in the deleterious effects of systemic serotonin. It was already known for decades that two of the major side-effects of the carcinoid syndrome
Carcinoid syndrome
Carcinoid syndrome refers to the array of symptoms that occur secondary to carcinoid tumors. The syndrome includes flushing and diarrhea, and, less frequently, heart failure and bronchoconstriction...
in which excessive serotonin is produced endogenously, are valvular disease and pulmonary hypertension. Several centers were able to note a relationship to an excessive activation of a specific 5-HT2B receptor
5-HT2B receptor
5-hydroxytryptamine receptor 2B, also known as HTR2B, is a 5-HT2 receptor, but also denotes the human gene encoding it.-Function:...
subtype.
The Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) in late 1997 recommended that fenfluramine and the other serotonergic agents implicated be no longer prescribed.
Legal action
Upon the release of the information regarding fenfluramine's cardiac risks, the Association of Trial Lawyers of AmericaAssociation of Trial Lawyers of America
The American Association for Justice , formerly the Association of Trial Lawyers of America is the leading organization for lawyers representing plaintiffs in the United States...
formed a large trial lawyer group to seek damages from American Home Products, the distributor of fenfluramine (Pondimin) and dexfenfluramine (Redux).
Estimates of total liability ran as high as $14 billion. As of February 2005, Wyeth was still in negotiations with injured parties, offering settlements of $5,000 to $200,000 to some of those who had sued, and stating they might offer more to those who were most seriously injured.
External links
- Frontline: Dangerous prescriptions - Interview with Leo Lutwak, M.D., in which he discuses the side effects of Pondimin (Fenfluramine), its successor Redux, and the Fen-Phen combination.
- U.S. FDA Fen-Phen information