The progression of fenfluramine-associated valvular heart disease assessed by echocardiography.

BACKGROUND: An association between the dietary suppressants fenfluramine and dexfenfluramine and valvular heart disease was first described in patients from North Dakota and Minnesota in 1997. Limited data are available on the natural history of this valvulopathy after discontinuation of drug therapy. OBJECTIVE: To follow the progression of fenfluramine-associated valvular heart disease after discontinuation of therapy by using serial echocardiography. DESIGN: Retrospective cohort study. SETTING: Regional medical center in Fargo, North Dakota. PATIENTS: 50 patients with previous exposure to fenfluramines who had at least mild mitral regurgitation or aortic regurgitation after exposure to fenfluramines on serial echocardiography between December 1994 and February 1999 (96% were female, mean body mass index was 36.6 kg/m(2), and mean duration of drug exposure was 447 days). MEASUREMENTS: Serial echocardiograms were reviewed by two echocardiographers who were blinded to the order of image acquisition. The severity of valvular regurgitation and presence or absence of valve leaflet restriction were assessed. RESULTS: As described in the initial report, significant valvular disease on initial postexposure echocardiography was common in this cohort; 38 patients (76%) had at least mild mitral regurgitation and 43 patients (86%) had at least mild aortic regurgitation. On serial echocardiograms obtained an average of 356 days apart, mitral regurgitation improved by at least one grade in 17 patients (P = 0.001) and aortic regurgitation improved by at least one grade in 19 patients (P = 0.004). Nineteen and 22 patients, respectively, experienced no change in severity of mitral and aortic regurgitation. Two patients in each group experienced worsening of regurgitation by at least one grade. Results were similar for tricuspid (P = 0.002) and pulmonic (P = 0.012) regurgitation. CONCLUSION: On serial echocardiography, fenfluramine-associated valvular regurgitation improved or remained stable in most patients after therapy ended. Worsening of valvular regurgitation was uncommon. The potential for stabilization or regression of valvular regurgitation should be taken into account when counseling patients and considering the need for and timing of valve surgery.

Detailed examination of fenfluramine-phentermine users with valve abnormalities identified in Fargo, North Dakota.

Although several studies have reported on valve abnormalities among users of fenfluramine or dexfenfluramine, detailed information on these subjects has not been provided, limiting the ability to understand who may be at risk for valve abnormalities and to generate hypotheses about the etiology and pathogenesis of these abnormalities. This study was a detailed medical record review of 18 previously reported users of fenfluramine and phentermine, all with valve abnormalities on echocardiogram and 2 with surgical pathology. Both clinical characteristics and medication use were recorded by trained abstracters using a standardized data collection form. Two subjects (11%) had other possible etiologies of valve disease: a history of rheumatic fever and prescribed ergotamine. Three subjects (17%) had a history of migraine headaches and 4 (22%) had murmurs noted before using fenfluramine. Use of medications that may affect serotonin receptors was common: ergotamine (1 subject, 5%), selective serotonin reuptake inhibitors (6, 33%), sumatriptan (2, 11%), and mirtazapine (1, 5%). Prior medication and nonmedication allergies were recorded in 6 (33%) and 3 (17%) subjects, respectively. All subjects had symptoms possibly due to fenfluramine or phentermine side effects. This study raises the hypotheses that valvular heart disease among fenfluramine users may be less common than previously estimated, that serotonin excess may play a role in valve pathology, and that a patient's response to anorexigens and other medications may serve as a marker for increased risk. Further study is needed to test these hypotheses.

Valvular heart disease associated with fenfluramine-phentermine.

BACKGROUND: Fenfluramine and phentermine have been individually approved as anorectic agents by the Food and Drug Administration (FDA). When used in combination the drugs may be just as effective as either drug alone, with the added advantages of the need for lower doses of each agent and perhaps fewer side effects. Although the combination has not been approved by the FDA, in 1996 the total number of prescriptions in the United States for fenfluramine and phentermine exceeded 18 million. METHODS: We identified valvular heart disease in 24 women treated with fenfluramine-phentermine who had no history of cardiac disease. The women presented with cardiovascular symptoms or a heart murmur. As increasing numbers of these patients with similar clinical features were identified, there appeared to be an association between these features and fenfluramine-phentermine therapy. RESULTS: Twenty-four women (mean [+/-SD] age, 44+/-8 years) were evaluated 12.3+/-7.1 months after the initiation of fenfluramine-phentermine therapy. Echocardiography demonstrated unusual valvular morphology and regurgitation in all patients. Both right-sided and left-sided heart valves were involved. Eight women also had newly documented pulmonary hypertension. To date, cardiac surgical intervention has been required in five patients. The heart valves had a glistening white appearance. Histopathological findings included plaque-like encasement of the leaflets and chordal structures with intact valve architecture. The histopathological features were identical to those seen in carcinoid or ergotamine-induced valve disease. CONCLUSIONS: These cases arouse concern that fenfluramine-phentermine therapy may be associated with valvular heart disease. Candidates for fenfluramine-phentermine therapy should be informed about serious potential adverse effects, including pulmonary hypertension and valvular heart disease.

Brefeldin A inhibits protein secretion and parasite maturation in the ring stage of Plasmodium falciparum.

The release of all newly synthesized soluble proteins from the ring stage of Plasmodium falciparum-infected erythrocytes was reversibly blocked by brefeldin A, indicating the presence of a conserved step of classical eukaryotic secretory export within the parasite. This implies that proteins exported to the erythrocyte cytosol undergo secretory release at the parasite plasma membrane and subsequent translocation across the vacuolar membrane. Along with inhibiting protein export brefeldin arrested parasite maturation, but the cells remained viable even after 24 h in the presence of the drug. The results suggest that secretory export may be important for development, but not for immediate survival, at the ring stage.

Stage-specific expression of plasmodial proteins containing an antigenic marker of the intraerythrocytic cisternae.

A monoclonal antibody, LWLI, recognized 3 proteins of 45, 50 and 102 kDa in Plasmodium falciparum-infected erythrocytes. The 45- and 50-kDa proteins were parasite-encoded and displayed markedly different peptide maps, indicating that they were distinct plasmodial polypeptides with a common antigenic epitope rather than differentially processed forms of a primary translational product. The 45-kDa protein was present throughout intraerythrocytic growth, while the 50-kDa molecule was not detected earlier than 11 h in the life cycle. The 102-kDa protein was only expressed in trophozoite- and schizont-infected red cells: its structural relationship to the 45- and 50-kDa proteins, if any, remains undefined. By indirect immunofluorescence and immunoelectron microscopy, LWLI bound to flattened intraerythrocytic cisternae exported into the erythrocyte cytoplasm. The results support the theory that proteins recognized by the antibody were concentrated in these compartments and their common antigenic epitope may serve as a marker for the cisternae. Stage-specific expression of LWLI reactive proteins implicates developmental regulation of cisternal functions during asexual parasite development.