Programs to facilitate tuberculosis drug discovery: the tuberculosis antimicrobial acquisition and coordinating facility.

There is a real need to discover new drugs that are active on drug-resistant tuberculosis (TB), and for drugs that will shorten the time of therapy. Large pharmaceutical companies have traditionally led the quest for discovering and developing new antiinfective agents but this is not the case when it comes to diseases like tuberculosis that primarily occur in resource restricted countries. Throughout the world many research groups are actively engaged in the scientific discovery of new TB drugs. Unfortunately, most research laboratories do not have the necessary safety facilities or resources for all facets of TB drug discovery. The Tuberculosis Antimicrobial Acquisition and Coordinating Facility (TAACF) was established in order to make comprehensive testing services available at no cost to research laboratories with an interest in discovering new TB drugs. The TAACF is a consortium of contracts managed and funded by the National Institute of Allergy and Infectious Diseases (National Institutes of Health, Bethesda, MD) as a resource to support preclinical drug discovery and development. The core of the TAACF is the Southern Research Institute, Birmingham, AL, which supports compound acquisition, storage, medicinal chemistry, and high throughput assays. Other collaborating groups provide biological data on antimycobacterial activity and cytotoxicity, preliminary in vivo toxicity, oral bioavailability and efficacy in animal models, specialty testing (such as activity against non-replicating persistent bacteria), and assistance in technology transfer for developing comprehensive promotional packages and facilitating partnerships with pharmaceutical companies for drug development. The TAACF program and recent progress that has been publicly disclosed by suppliers is reviewed. There are many aspects promising of the program that will not be discussed due to confidentially.

Chronic treatment with phentermine combined with fenfluramine lowers plasma serotonin.

As expected on the basis of published research in both humans and animals, treatment with phentermine/fenfluramine lowers plasma 5-hydroxytryptamine [corrected], whereas treatment with phentermine had no significant effect. In light of these findings, future research should focus on mechanisms other than increased plasma 5-hydroxytryptamine [corrected] to explain how fenfluramine increases the risk of primary pulmonary hypertension and valvular heart disease.

Pharmacologic induction of weight loss to treat type 2 diabetes.

OBJECTIVE: Most individuals with type 2 diabetes are overweight, and weight loss for them is an important therapeutic objective. However, usual weight-loss strategies have generally not produced sustained weight loss. Pharmacologic agents to assist weight loss might be useful, but no long-term data on their effectiveness and safety in patients with type 2 diabetes are available. We therefore initiated a 2-year placebo-controlled trial of the weight-loss medications fenfluramine and phentermine in type 2 diabetic subjects. RESEARCH DESIGN AND METHODS: A total of 44 overweight (> 120% ideal body weight) subjects with type 2 diabetes were enrolled in a randomized, placebo-controlled, double-blind trial of fenfluramine and phentermine. All subjects received intensive nutrition counseling, an exercise prescription, and instruction in behavior modification. Subjects were randomly assigned to 20 mg fenfluramine three times a day and 37.5 mg phentermine daily (n = 23) or dual placebos (n = 21). Diabetes medications were adjusted as necessary to achieve glycemic goals. Changes in weight, glycemia, lipemia, and blood pressure were assessed every 2 months, as were adverse events. In September 1997, when fenfluramine was withdrawn from the U.S. market, fenfluramine was stopped in all subjects. Thus the length of drug treatment varied, but 16 subjects (8 in each group) reached 12 months of treatment. Only data obtained before the withdrawal of fenfluramine are included in this report. RESULTS: A study termination, diabetes medications had been reduced in 1 subject in the placebo group (5%) and 11 subjects in the drug treatment group (52%) (P = 0.005). Drug treatment resulted in significant reductions in body weight, BMI, and HbA1c at all time points through 6 months. Changes in weight at 6 months were -2.7 +/- 1.4 kg (mean +/- SEM) with placebo treatment and -9.6 +/- 1.5 kg with drug treatment (P = 0.003). Even though more subjects in the drug treatment group required reductions in diabetes medications, at 6 months, changes in HbA1c were -0.3 +/- 0.2% with placebo treatment and -1.6 +/- 0.3% with drug treatment (P = 0.002). Fasting plasma glucose and triglycerides were significantly reduced at some time points with drug treatment. No serious adverse events attributable to study medications were observed. CONCLUSIONS: Premature study termination decreased the power of our study at later time points. However, our data suggest that weight loss medications are an effective treatment for type 2 diabetes during active weight loss. Whether the benefit persists after weight loss has stopped remains to be determined.