Obesity phentermine

Pemoline [2152-34-3] (24), stmcturally dissimilar to amphetamine or methylphenidate, appears to share the CNS-stimulating properties. As a consequence, pemoline is employed in the treatment of ADHD and of narcolepsy. There are several other compounds that are stmcturally related to amphetamines, although not as potent and, presumably, without as much abuse potential. These compounds also have anorexic effects and are used to treat obesity. Some of the compounds available are phentermine [122-09-8] fenfluramine [458-24-2] and an agent that is available over-the-counter, phenylpropanolamine [1483815-4] (26). 

Problem Suggest a synthesis of ketone (11), used in the manufacture of phentermine, a drug used to control obesity. 

Phentermine decreases food intake, and hence weight, by increasing norepinephrine and dopamine release in the central nervous system. This drug is indicated for short-term use—no more than a few weeks—in addition to lifestyle modifications in obese patients with a BMI of 30 kg/m2 or greater or a BMI of 27 kg/m2" or greater in the presence of other risk factors.38... 

On September 15,1997, FDA asked the manufacturers of dexfenfluramine (Redux manufactured for Intemeuron Pharmaceuticals by Wyeth-Ayerst) and fenfluramine (Pondimin Wyeth-Ayerst) to voluntarily withdraw both treatments from the market because of findings that indicate approximately 30% of patients taking the combined drugs had abnormal echocardiograms, even if they had no symptoms. Both companies agreed. FDA is not requesting the withdrawal of phentermine, the third widely used medication for obesity. 

The newest appetite suppressant, sibutramine (Meridia), works by blocking the reuptake of both serotonin and norepinephrine. It does not stimulate nerve cells to release serotonin, as do fenfluramine and dexfenfluramine. Administered at 20 mg/ day, sibutramine effectively reduces weight in obese patients, but its use has not been assessed in eating disorder patients. The most common side effects of this medication are insomnia, dry mouth, and constipation. It has not been associated with the more serious heart and lung complications observed with fenfluramine and dexfenfluramine. Because sibutramine acts in part through modulation of norepinephrine, there is no rational basis for coadministering phentermine, which acts via this same mechanism. 

Fenfluramine (Pondimin) and phentermine (Adipex-P, Fastin) are anorexigenic drugs that produce depression of the CNS and at one time were used (Fen-phen) in the treatment of obesity. Sibutramine (Meridia) is also available for the treatment of obesity. 

These findings precipitated the widespread use of a fenfluramine-phentermine combination therapy that came to be known as Fen-Phen. The combined use of the two anorexigens had never been approved by the FDA, nor had the longterm safety of the therapy ever been established. Nevertheless, weight loss clinics specializing in Fen-Phen therapy were established throughout the country. In 1996, the FDA narrowly approved the more potent, less adverse-effect-prone (+)stereoisomer of fenfluramine, dexfenfluramine, for less-than-l-yr use in the treatment of obesity. The New York Times reported that in 1996, 18 million prescriptions had been written for fenfluramine alone or in combination with phentermine and that about 6 million Americans took the drug (37). 

Fenfluramine, dexfenfluramine, and phentermine have been used alone or in combination as an alternative to diet and surgery in the management of obesity. This therapy was halted in 1997 after reports of valvular lesions affecting almost one-third of patients treated with these drugs. The combination of fenfluramine and phentermine is called fen-phen. 

A 47-year-old mildly obese woman began a weight-reduction program that included anorectic therapy with phentermine and phendimetrazine. She had normal renal function at the start of therapy. After 3 weeks of treatment she fell ill and discontinued treatment. She was subsequently found to have leukocyturia, a rash on her face and chest, and a rise in serum creatinine from 67 to 175 pmol/l (0.8-2.1 mg/dl). Renal biopsy confirmed the diagnosis of acute interstitial nephritis. She was treated with corticosteroids and her renal function returned to normal. 

Steel JM, Munro JF, Duncan LJ. A comparative trial of different regimens of fenfluramine and phentermine in obesity. Practitioner 1973 211(262) 232-6. 

Despite the withdrawal of the fenfluramines, the appetite suppressants phendimetrazine and phentermine have remained in widespread use for the treatment of obesity. 

Following the withdrawal of the fenfluramines, alternative combinations have been explored as appetite suppressants. In an open study of a combination of phentermine + fluoxetine in 16 obese patients with... 

New pharmacological treatments have been developed for the treatment of obesity. These include the combination of phentermine and fenfluramine (phen-fen) and, alternatively, dexfenfluramine (Redux). Phentermine (Fastin, lonamin) is a stimulant and fenfluramine (Pondimin) is a serotonin agonist. In combination they have persistent appetite suppression and weight loss effects. These medications can cause anxiety and insomnia and must be used with extreme caution if taken with antidepressants, especially SSRIs. Dexfenfluramine works similarly, but avoids the side effect of increased anxiety, and instead tends to cause diarrhea, dry mouth, and somnolence. There have also been reports of pulmonary hypertension, a potentially fatal condition, especially when taken for longer than three months. Some researchers (Ricuarte et al. 1991 McCann et al. 1994) have expressed concern because rats given these medications showed evidence of neuronal toxicity. Thus, they are effective medications, but must be used with caution. 

There have been 17 double-blind placebo-controlled trials of phentermine 30 mg daily in obesity, involving some 1000 patients. In every single one of these trials the mean weight loss among those taking phentermine was at least twice as great as among those on placebo. 

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