Pilot and Feasibility Program Supplements
Cross-sectional Study of Pulmonary Artery Pressure and Cardiac Valvular Function Measured by Transthoracic Echocardiography with or without Doppler Signal Enhancement in Patients Receiving Varying Degrees of Single or Multiple Appetite Suppressant Therapy
Mehmood Khan, M.D.
Division of Endocrinology, Metabolism and Nutrition
Hennepin County Medical Center, Minneapolis, MN
Fenfluramine, Phentermine and other appetite suppressant agents have been used for many years in the short-term treatment of obesity. One of the most serious potential effects of appetite suppressant use appears to be an increased risk for developing primary pulmonary hypertension (PPH). An FDA Public Health Advisory was released in July 1997, outlining 33 reported cases of unusual valvular morphology and regurgitation involving the mitral, aortic and/or tricuspid valves following variable exposure (1->16 months) of the combination of fenfluramine and phentermine. This study will utilize noninvasive transthoracic echocardiographic Doppler studies to document in patients from three existing open-label treatment trials who have been exposed to various combinations of appetite suppressant therapy for time periods ranging from 3 - 36 months.
Potential Risk Factors for Developing Valvular Disease in Patients Treated with Fenfluramine and Phentermine
E. Kenneth Weir, M.D.
Cardiology; VA Medical Center, Minneapolis, MN
Cardiac valvular heart disease has been reported in patients taking fenfluramine and phentermine, and in patients taking dexfenfluramine alone. We have found that dexfenfluramine causes serotonin release from platelets and inhibits reuptake. Thus it is possible that, in susceptible individuals, dexfenfluramine may increase plasma levels of serotonin. Additionally, dexfenfluramine inhibits potassium current, causes membrane depolarization and elevates cytosolic calcium in megakaryocytes, used as a model for platelets.
Obese patients who have been treated with fenfluramine and phentermine who have been found to have cardiac valve abnormalities will be studied to determine:
- levels of the metabolite of serotonin, 5 hydroxyindole-acetic acid (5HIAA) in the urine;
- uptake and release of serotonin by platelets in response to dexfenfluramine;
- level of serotonin in the platelets and plasma;
- ion channel activity and cytosolic calcium in platelets in response to dexfenfluramine;
- and levels of breath nitric oxide.
The Effect of Dexfenfluramine on Dog Platelet Serotonin, Cardiac Valves and Pulmonary Artery Pressure
Gerhard J. Johnson, M.D.
VA Medical Center, Minneapolis, MN
Fenfluramine and its active enantiomer, dexfenfluramine, are anorectic agents that were extensively used, often with phentermine, for treatment of obesity prior to their withdrawal from clinical use because of cardiopulmonary toxicity. Cardiac valve abnormalities were observed in some persons taking fenfluramine or dexfenfluramine, and pulmonary hypertension developed in others. Anorexia induced by fenfluramine and dexfenfluramine is considered to be due primarily to serotonin (5-HT) release and secondarily to blockade of 5-HT reuptake by neurons. The cause of the cardiac valve lesions and pulmonary hypertension have not been defined, but the close resemblance of the cardiac valve lesions to those seen in carcinoid syndrome suggests that elevated plasma 5-HT may be responsible. In support of the potential role of 5-HT are the observations that plasma 5-HT is increased and platelet 5-HT is decreased in patients with pulmonary hypertension.
Platelets rapidly take up 5-HT via the 5-HT transporter (SERT). Nearly all blood 5-HT is found in platelets where it is stored in dense granules. Transport into dense granules is active and dependent upon a transmembrane proton gradient.
Because dexfenfluramine affects cellular uptake and release of 5-HT, we postulated that its cardiopulmonary toxicity may be due to secretion of 5-HT and/or impaired uptake of 5-HT by platelets. The resulting increase in plasma 5-HT could then exert toxic effects on vascular tissues.
Foodborne Transmission of Uropathogenic Escherichia coli
James R. Johnson, M.D.
Infectious Diseases Section
VA Medical Center, Minneapolis, MN
Urinary tract infection (UTI) is a common and costly health problem for which better preventive measures are needed. Although much is known about the virulence traits of the distinctive Escherichia coli that cause UTI and about the mechanisms whereby such strains emerge from the host's intestine and enter the urinary tract to cause infection, little is known about how these strains come to colonize the host's intestine in the first place. Since a better understanding of the sources and acquisition pathways of uropathogenic E. coli could lead to better methods to prevent the initial colonization step in UTI pathogenesis, and since the food supply is a known source for acquisition of other virulent E. coli strains, the food supply will be evaluated as a possible source for acquisition of uropathogenic E. coli. First, the prevalence of uropathogenic E. coli strains in foods from retail markets will be determined. Then, the E. coli content of a household's food supply will be characterized and compared with the intestinal E. coli flora of household members who have consumed the foods.