Fenfluramine/phentermine

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Fenfluramine/phentermine
Fenfluramine and phentermine.svg
Fenphen3D.png
Combination of
Fenfluramine Serotoninergic
Phentermine Adrenergic, dopaminergic, serotoninergic
Clinical data
Routes of
administration 		Oral
ATC code
  • none
Legal status
Legal status
  • Withdrawn
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The drug combination fenfluramine/phentermine, usually called fen-phen, was an anti-obesity treatment in the early 1990s that utilized two anorectics. Fenfluramine was marketed by American Home Products (later known as Wyeth) as Pondimin, but was shown to cause potentially fatal pulmonary hypertension and heart valve problems, which eventually led to its withdrawal in 1997 and legal damages of over $13 billion. [1] Phentermine was not shown to have harmful effects. [1]

Contents

Fenfluramine acts as a serotonin releasing agent, [2] phentermine as primarily a norepinephrine releasing agent. Phentermine also induces the release of serotonin and dopamine, although to a far lesser extent than it induces the release of norepinephrine. [3]

History

Fenfluramine as a single drug was first introduced in the 1970s, but was not popular because it only temporarily reduced weight. [1] A 1984 study found a weight loss of 7.5 kg on average in 24 weeks, as compared to 4.4 kg under placebo. [4] It sold modestly until the 1990s, when it was combined with phentermine and heavily marketed. [1]

Testing on children in New York City

The New York Psychiatric Institute, associated with Columbia University, the Research Foundation of the City University of New York, and Mount Sinai Medical Center tested fenfluramine intravenously on more than 100 Black and Hispanic boys between the ages of 6 and 10, with delinquent older brothers, to test the theory that delinquent behavior could be predicted by serotonin levels. These studies were conducted before the drug was pulled from the market in September 1997. In 1998, CNN reported that these organizations were under "evaluation" by the Office for Protection from Research Risks, an arm of the National Institutes of Health. [5] An article in Nature reports that these tests were published as a study in Archives of General Psychiatry in 1997 and that "The New York trial, funded largely by the Lowenstein Foundation, with some support from the National Institute of Mental Health, was halted in 1995, two years before the drug was withdrawn." [6] In 1999 the New York Times reported that the Mount Sinai School of Medicine and the Research Foundation of the City University of New York were officially faulted by Federal research-ethics officials for conducting these tests. The article reports that the yearlong investigation found no misconduct by New York State Psychiatric Institute for these tests. This article reports the number of children involved in the study as 150, and states that none were harmed. [7]

Harm and litigation

A similar drug, aminorex, had caused severe lung damage and "provided reason to worry that similar drugs ... could increase the risk of a rare but often fatal lung disease, pulmonary hypertension." [1] In 1994, Wyeth official Fred Wilson expressed concerns about fenfluramine's labeling containing only four cases of pulmonary hypertension when a total of 41 had been observed, but no action was taken until 1996. [1] In 1995, Wyeth introduced dexfenfluramine (the dextro isomer, marketed as Redux), which it hoped would cause fewer adverse effects. However, the medical officer of the Food and Drug Administration (FDA), Leo Lutwak, insisted upon a black box warning of pulmonary hypertension risks. After Lutwak refused to approve the drug, the FDA management had James Milton Bilstad, FDA Senior Drug Evaluator, sign it and approved the drug with no black box warning for marketing in 1996. [1] European regulators required a major warning of pulmonary hypertension risks. [1]

In 1996, a 30-year-old woman developed heart problems after a month of using fenfluramine/phentermine; when she died in February 1997, the Boston Herald devoted a front-page article to her. [8] In August 1997 a paper in the New England Journal of Medicine (NEJM) from the Mayo Clinic discussed clinical findings in 24 people who had taken fen-phen. The authors noted that their findings suggested a possible correlation between mitral valve dysfunction and the use of these anorectic agents. [9] The FDA alerted medical practitioners that it had received nine additional reports of the same type, and requested all health care professionals to report any such cases to the agency’s MedWatch program, or to their respective pharmaceutical manufacturers. The FDA subsequently received over a hundred additional reports of valvular heart disease in people taking fen-phen, fenfluramine alone or dexfenfluramine alone. [10] The FDA requested that the manufacturers of fenfluramine and dexfenfluramine stress the potential risk to the heart in the drugs' labeling and in package inserts. [11] The FDA continued to receive reports in 1997 of valvular heart disease in people who had taken these drugs. This disease typically involves the aortic and mitral valves.

After reports of valvular heart disease and pulmonary hypertension, primarily in women who had been undergoing treatment with fen-phen or (dex)fenfluramine, the FDA requested its withdrawal from the market in September 1997. [10] [12] The action was based on findings from doctors who had evaluated people taking these two drugs with echocardiograms, a procedure that can test the functioning of heart valves. The findings indicated that approximately 30 percent of people who had taken the combination for up to 24 months had abnormal echocardiograms, even though they had no symptoms. This percentage of abnormal test results was much higher than would be expected from a sample of the population who had not been exposed to either fenfluramine or dexfenfluramine. [9] [13] Follow-up studies showed that for people who took the combination for 3 months or less, the rate of heart valve complications was less than 3%. [13]

Aftermath

Upon the release of the information regarding fen-phen's cardiac risks, the Association of Trial Lawyers of America formed a large trial lawyer group to seek damages from American Home Products, the distributor of fenfluramine and dexfenfluramine. [14]

Fen-phen is no longer widely available. In April 2005, American Lawyer magazine ran a cover story on the wave of fen-phen litigation, reporting that more than 50,000 product liability lawsuits had been filed by alleged fen-phen victims. Total liability was estimated to be as high as $14 billion. Wyeth was still in negotiations with injured parties in February 2005, 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. [15] One plaintiff's attorney said that "the payments [were] not going to be large enough to cover medical expenses." [16] Thousands of injured persons rejected these offers. [15] At the time, Wyeth announced it had set aside $21.1 billion (U.S.) to cover the cost of the lawsuits. [15]

Possible uses

Obesity

In 1984, researchers at the University of Rochester Medical Center 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 (8.4±1.1 kg) than in those receiving placebo (4.4±0.9 kg) and equivalent to that of those receiving fenfluramine (7.5±1.2 kg) or phentermine alone (10.0±1.2 kg). This amounts to an additional weight loss of 4±2 kg over the course of 24 weeks. Adverse effects were less frequent with the combination regimen than with the other active (non-placebo) 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. [4]

Addiction remission

The term fen-phen was defined/termed/labeled 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 precursors might share this therapeutic potential. [17] [18] Subsequent experiments in rats supported these preliminary reports. [19] [20] In 2006 it was confirmed that the combination of phentermine and the serotonin precursor 5-hydroxytryptophan (5-HTP), in place of fenfluramine, significantly decreased alcohol withdrawal seizures in rats. [21]

Intramural National Institutes of Health (NIH) double-blind protocols to demonstrate the efficacy of fen-phen in alcohol and cocaine addiction were designed, [22] but never performed.

Adverse effects of serotonin

The findings on fen-phen, specifically fenfluramine, causing valvular heart disease and pulmonary hypertension prompted a renewed interest in the deleterious effects of systemic serotonin. It had already been 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 the serotonin receptor subtype 5-HT2B. [23] [24]

See also

Related Research Articles

An anorectic or anorexic is a drug which reduces appetite, resulting in lower food consumption, leading to weight loss. These substances work by affecting the central nervous system or certain neurotransmitters to create a feeling of fullness or reduce the desire to eat. The understanding of anorexiant effects is crucial in the development of interventions for weight management, eating disorders, and related health concerns. The anorexiant effect can be induced through diverse mechanisms, ranging from hormonal regulation to neural signaling. Ghrelin, leptin, and peptide YY are among the hormones involved in appetite control. Additionally, neurotransmitters such as serotonin and dopamine in the central nervous system contribute significantly to the regulation of food intake.

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<span class="mw-page-title-main">Fenfluramine</span> Medication used to treat seizures

Fenfluramine, sold under the brand name Fintepla, is a serotonergic medication used for the treatment of seizures associated with Dravet syndrome and Lennox–Gastaut syndrome. It was formerly used as an appetite suppressant in the treatment of obesity, but was discontinued for this use due to cardiovascular toxicity before being repurposed for new indications. Fenfluramine was used for weight loss both alone under the brand name Pondimin and in combination with phentermine commonly known as fen-phen.

<span class="mw-page-title-main">Anti-obesity medication</span> Class of pharmacological agents

Anti-obesity medication or weight loss medications are pharmacological agents that reduce or control excess body fat. These medications alter one of the fundamental processes of the human body, weight regulation, by: reducing appetite and consequently energy intake, increasing energy expenditure, redirecting nutrients from adipose to lean tissue, or interfering with the absorption of calories.

<span class="mw-page-title-main">Phentermine</span> Weight loss medication

Phentermine (phenyl-tertiary-butylamine), with several brand names including Ionamin and Sentis, is a medication used together with diet and exercise to treat obesity. It is taken by mouth for up to a few weeks at a time, after which the benefits subside. It is also available as the combination phentermine/topiramate.

<span class="mw-page-title-main">Sibutramine</span> Appetite suppressant

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<span class="mw-page-title-main">Cabergoline</span> Chemical compound

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<span class="mw-page-title-main">4-Methylaminorex</span> Group of stereoisomers

4-Methylaminorex is a stimulant drug of the 2-amino-5-aryloxazoline class that was first synthesized in 1960 by McNeil Laboratories. It is also known by its street name "U4Euh" ("Euphoria"). It is banned in many countries as a stimulant.

<span class="mw-page-title-main">Dexfenfluramine</span> Serotonergic anorectic medication

Dexfenfluramine, marketed as dexfenfluramine hydrochloride under the name Redux, is a serotonergic anorectic drug: it reduces appetite by increasing the amount of extracellular serotonin in the brain. It is the d-enantiomer of fenfluramine and is structurally similar to amphetamine, but lacks any psychologically stimulating effects.

<span class="mw-page-title-main">Chlorphentermine</span> Weight loss medication

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<span class="mw-page-title-main">Naphthylaminopropane</span> Chemical compound

Naphthylaminopropane (PAL-287) is an experimental drug under investigation as of 2007 for the treatment of alcohol and stimulant addiction.

Benfluorex, sold under the brand name Mediator, is an anorectic and hypolipidemic agent that is structurally related to fenfluramine. It may improve glycemic control and decrease insulin resistance in people with poorly controlled type-2 diabetes.

5-HT<sub>2B</sub> receptor Mammalian protein found in Homo sapiens

5-Hydroxytryptamine receptor 2B (5-HT2B) also known as serotonin receptor 2B is a protein that in humans is encoded by the HTR2B gene. 5-HT2B is a member of the 5-HT2 receptor family that binds the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT). Like all 5-HT2 receptors, the 5-HT2B receptor is Gq/G11-protein coupled, leading to downstream activation of phospholipase C.

<span class="mw-page-title-main">Monoamine releasing agent</span> Class of compounds

A monoamine releasing agent (MRA), or simply monoamine releaser, is a drug that induces the release of a monoamine neurotransmitter from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrations of the neurotransmitter. Many drugs induce their effects in the body and/or brain via the release of monoamine neurotransmitters, e.g., trace amines, many substituted amphetamines, and related compounds.

A serotonin releasing agent (SRA) is a type of drug that induces the release of serotonin into the neuronal synaptic cleft. A selective serotonin releasing agent (SSRA) is an SRA with less significant or no efficacy in producing neurotransmitter efflux at other types of monoamine neurons.

<span class="mw-page-title-main">Serotonin–norepinephrine releasing agent</span> Drug class

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<span class="mw-page-title-main">Wyeth</span> American pharmaceutical company

Wyeth was a pharmaceutical company until it was purchased by Pfizer in 2009. The company was founded in Philadelphia, Pennsylvania, in 1860 as John Wyeth and Brother. Its headquarters moved to Collegeville, Pennsylvania, and Madison, New Jersey, before its headquarters were consolidated with Pfizer's in New York City after the 2009 merger.

<span class="mw-page-title-main">Levofenfluramine</span> Non-marketed drug of the amphetamine class

Levofenfluramine (INN), or (−)-3-trifluoromethyl-N-ethylamphetamine, also known as (−)-fenfluramine or (R)-fenfluramine, is a drug of the amphetamine family that, itself (i.e., in enantiopure form), was never marketed. It is the levorotatory enantiomer of fenfluramine, the racemic form of the compound, whereas the dextrorotatory enantiomer is dexfenfluramine. Both fenfluramine and dexfenfluramine are anorectic agents that have been used clinically in the treatment of obesity (and hence, levofenfluramine has been as well since it is a component of fenfluramine). However, they have since been discontinued due to reports of causing cardiovascular conditions such as valvular heart disease and pulmonary hypertension, adverse effects that are likely to be caused by excessive stimulation of 5-HT2B receptors expressed on heart valves.

5-HT2C receptor agonists are a class of drugs that activate 5-HT2C receptors. They have been investigated for the treatment of a number of conditions including obesity, psychiatric disorders, sexual dysfunction and urinary incontinence.

References

  1. 1 2 3 4 5 6 7 8 Avorn J. (2004). Powerful Medicines, pp. 71-84. Alfred A. Knopf.
  2. ↑ Nestler, Eric J. "Molecular Neuropharmacology: A Foundation for Clinical Neuroscience" McGraw-Hill, 2001.
  3. ↑ Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, Partilla JS (January 2001). "Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin". Synapse. 39 (1): 32–41. doi:10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3. PMID   11071707. S2CID   15573624.
  4. 1 2 Weintraub M, Hasday JD, Mushlin AI, Lockwood DH (June 1984). "A double-blind clinical trial in weight control. Use of fenfluramine and phentermine alone and in combination". Archives of Internal Medicine. 144 (6): 1143–8. doi:10.1001/archinte.144.6.1143. PMID   6375610.
  5. ↑ "Groups say children subjected to unethical medical tests". CNN. April 14, 1998. Retrieved September 23, 2023.
  6. ↑ Wadman, Meredith (April 1, 1998). "Row erupts over child aggression study". Nature. Retrieved September 23, 2023.
  7. ↑ Bernstein, Nina (June 12, 1999). "2 Institutions Faulted for Tests on Children". The New York Times. p. 21. Retrieved September 23, 2023.
  8. ↑ Hayward E (6 May 1997). "Diet to Death". Boston Herald. p. 1. Archived from the original on 15 June 2011. Retrieved 3 September 2009.
  9. 1 2 Connolly HM, Crary JL, McGoon MD, Hensrud DD, Edwards BS, Edwards WD, Schaff HV (August 1997). "Valvular heart disease associated with fenfluramine-phentermine". The New England Journal of Medicine. 337 (9): 581–8. doi: 10.1056/NEJM199708283370901 . PMID   9271479.
  10. 1 2 Centers for Disease Control Prevention (CDC) (November 1997). "Cardiac valvulopathy associated with exposure to fenfluramine or dexfenfluramine: U.S. Department of Health and Human Services interim public health recommendations, November 1997". MMWR. Morbidity and Mortality Weekly Report. 46 (45): 1061–6. PMID   9385873.
  11. ↑ ""Fen-Phen" Update (Fenfluramine, Phentermine, Dexfenfluramine)". Food and Drug Administration . 2009-11-04. Archived from the original on 2009-11-04. Retrieved 2019-04-19.
  12. ↑ "Press release: FDA Announces Withdrawal Fenfluramine and Dexfenfluramine (Fen-Phen)". FDA. September 15, 1997. Archived from the original on 4 November 2009.
  13. 1 2 Weigle DS (June 2003). "Pharmacological therapy of obesity: past, present, and future". The Journal of Clinical Endocrinology and Metabolism. 88 (6): 2462–9. doi: 10.1210/jc.2003-030151 . PMID   12788841.
  14. ↑ "After Fen-Phen", Karen Springen and Geoffrey Cowley, Newsweek , September 29, 1997
  15. 1 2 3 New York Times: Fen-Phen Case Lawyers Say They'll Reject Wyeth Offer, Feb. 17, 2005.
  16. ↑ Morrow DJ (8 October 1999). "Fen-Phen Maker to Pay Billions In Settlement of Diet-Injury Cases". The New York Times.
  17. ↑ Hitzig P (1994). "Combined serotonin and dopamine indirect agonists correct alcohol craving and alcohol-associated neuroses" (PDF). Journal of Substance Abuse Treatment. 11 (5): 489–90. doi:10.1016/0740-5472(94)90103-1. PMID   7869471.
  18. ↑ Rothman RB, Gendron T, Hitzig P (1994). "Hypothesis that mesolimbic dopamine (DA) plays a key role in mediating the reinforcing effects of drugs of abuse as well as the rewarding effects of ingestive behaviors". Journal of Substance Abuse Treatment. 11 (3): 273–5. doi: 10.1016/0740-5472(94)90086-8 . PMID   8072057.
  19. ↑ Yu YL, Fisher H, Sekowski A, Wagner GC (1997). "Amphetamine and fenfluramine suppress ethanol intake in ethanol-dependent rats". Alcohol. 14 (1): 45–8. doi:10.1016/s0741-8329(96)00110-3. PMID   9014023.
  20. ↑ Glatz AC, Ehrlich M, Bae RS, Clarke MJ, Quinlan PA, Brown EC, et al. (2002). "Inhibition of cocaine self-administration by fluoxetine or D-fenfluramine combined with phentermine". Pharmacology, Biochemistry, and Behavior. 71 (1–2): 197–204. doi:10.1016/S0091-3057(01)00657-8. PMID   11812523. S2CID   188983.
  21. ↑ Halladay AK, Wagner GC, Sekowski A, Rothman RB, Baumann MH, Fisher H (April 2006). "Alterations in alcohol consumption, withdrawal seizures, and monoamine transmission in rats treated with phentermine and 5-hydroxy-L-tryptophan". Synapse. 59 (5): 277–89. doi:10.1002/syn.20239. PMID   16416445. S2CID   30453212.
  22. ↑ "Google Sites: Sign-in". accounts.google.com. Retrieved 20 August 2023.
  23. ↑ Rothman RB, Baumann MH, Savage JE, Rauser L, McBride A, Hufeisen SJ, Roth BL (December 2000). "Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications". Circulation. 102 (23): 2836–41. doi: 10.1161/01.CIR.102.23.2836 . PMID   11104741.
  24. ↑ Hutcheson JD, Setola V, Roth BL, Merryman WD (November 2011). "Serotonin receptors and heart valve disease--it was meant 2B". Pharmacology & Therapeutics. 132 (2): 146–57. doi:10.1016/j.pharmthera.2011.03.008. PMC   3179857 . PMID   21440001.
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