Brain serotonin neurotoxicity and primary pulmonary hypertension from fenfluramine and dexfenfluramine. A systematic review of the evidence

OBJECTIVES: Obesity is an important clinical problem, and the use of dexfenfluramine hydrochloride for weight reduction has been widely publicized since its approval by the Food and Drug Administration. However, animal and human studies have demonstrated toxic effects of fenfluramines that clinicians should be aware of when considering prescribing the drugs. Our purpose was to systematically review data on brain serotonin neurotoxicity in animals treated with fenfluramines and the evidence linking fenfluramines to primary pulmonary hypertension (PPH). DATA SOURCES: Archival articles and reviews identified through a computerized search of MEDLINE from 1966 to April 1997 using "fenfluramine(s)," "serotonin," "neurotoxicity," "behavior," "anorexigens," "weight loss," and "primary pulmonary hypertension" as index terms. STUDY SELECTION: Reports dealing with long-term effects of fenfluramines on brain serotonin neurons, body weight, and pulmonary function in animals and humans. DATA EXTRACTION: Reports were reviewed by individuals with expertise in serotonin neurobiology, neurotoxicity, neuropsychiatry, and pulmonary medicine and evaluated for appropriateness for inclusion in this review. DATA SYNTHESIS: Fenfluramines cause dose-related, long-lasting reductions in serotonin axonal markers in all the animal species tested and with all the routes of drug administration used. Doses of fenfluramines that produce signs of brain serotonin neurotoxicity in animals are on the same order as those used to treat humans for weight loss when one takes into account known relations between body mass and drug clearance. However, no human studies have been conducted, and the pathological and clinical potential for neurotoxicity in humans is unknown. Appetite suppressants-most commonly fenfluramines-increase the risk of developing PPH (odds ratio, 6.3), particularly when used for more than 3 months (odds ratio, >20). CONCLUSIONS: Fenfluramine and dexfenfluramine have been demonstrated to damage brain serotonin neurons in animal studies. It is not known if such damage occurs in humans or if there are clinical consequences. Use of fenfluramines is associated with an increased risk of PPH. Future studies should address the long-term consequences of prolonged use of fenfluramines.     

Adverse life events and resilience

OBJECTIVE: Adverse life events are well-documented risk factors of psychopathology and psychological dysfunction in children and adolescents. Youth with good adjustment despite high levels of adverse life events are considered resilient. This study identifies factors that characterize resilience. METHOD: Household probability samples of youth aged 9 through 17 years at four sites were used. Main and interaction effects of 11 factors were examined to assess their impact on youth adjustment. RESULTS: Children at risk because of higher levels of adverse life events exhibited a greater degree of resilience when they had a higher IQ, better family functioning, closer parental monitoring, more adults in the household, and higher educational aspiration. The interaction between maternal psychopathology and adversity was significant, and the interaction between IQ and adversity approached significance. CONCLUSION: Resilient youth received more guidance and supervision by their parents and lived in higher-functioning families. Other adults in the family probably complemented the parents in providing guidance and support to the youth and in enhancing youth adjustment. Higher educational aspirations might have provided high-risk youth with a sense of direction and hope. Although IQ had no impact in youth at low risk, youth at high risk who had a higher IQ might have coped better.     

Risk for valvular heart disease among users of fenfluramine and dexfenfluramine who underwent echocardiography before use of medication

BACKGROUND: Because uncontrolled echocardiographic surveys suggested that up to 30% to 38% of users of fenfluramine and dexfenfluramine had valvular disease, these drugs were withdrawn from the market. OBJECTIVE: To determine the risk for new or worsening valvular abnormalities among users of fenfluramine or dexfenfluramine who underwent echocardiography before they began to take these medications. DESIGN: Cohort study. SETTING: Academic primary care practices. PATIENTS: 46 patients who used fenfluramine or dexfenfluramine for 14 days or more and had echocardiograms obtained before therapy. MEASUREMENTS: Follow-up echocardiography. The primary outcome was new or worsening valvulopathy, defined as progression of either aortic or mitral regurgitation by at least one degree of severity and disease that met U.S. Food and Drug Administration criteria (at least mild aortic regurgitation or moderate mitral regurgitation). RESULTS: Two patients (4.3% [95% CI, 0.6% to 14.8%]) receiving fenfluramine-phentermine developed valvular heart disease. One had baseline bicuspid aortic valve and mild aortic regurgitation that progressed to moderate regurgitation. The second patient developed new moderate aortic insufficiency. CONCLUSION: Users of diet medications are at risk for valvular heart disease. However, the incidence may be lower than that reported previously.     

Adverse drug events in hospitalized elderly

BACKGROUND: The study objectives were (a) to describe the occurrence, types, and preventability of adverse drug events (ADEs) in hospitalized patients 70 years of age and older; (b) to examine the association between potential risk factors and ADEs; and (c) to examine the relationship of an ADE occurrence and hospital length of stay (LOS) and functional decline. METHOD: Consecutive general medical admissions (n = 157) of community-dwelling persons were prospectively monitored daily for ADE occurrence. Admission assessment included demographic factors, cognition, preadmission medication use, and functional status. Discharge assessment included functional status. LOS, discharge diagnoses, and medication use during the hospitalization. RESULTS: Twenty-three patients (14.6%) experienced 28 probable ADEs, of which 54.2% (13/24) were judged to be potentially preventable. Patients experiencing an ADE had a significantly lower mean Mini-Mental State Examination score (23.6 +/- 4.3 vs 25.5 +/- 3.6, p = .039) and were prescribed significantly more new inpatient medications (4.0 +/- 2.3 vs 2.6 +/- 1.7, p = .01) compared to non-ADE patients. Age, gender, functional status prior to admission, percent with more than four active diagnoses, or number of preadmission medications were not associated with ADE status. Upon discharge, 50.0% of ADE patients experienced a decline in one or more activities of daily living (ADLs), compared with 24.1% of non-ADE patients (p = .017). ADE patients had a longer LOS (8.7 +/- 4.9 vs 6.6 +/- 3.0 days, p = .022) compared to non-ADE patients. CONCLUSIONS: ADEs were associated with number of new inpatient medications and admission cognitive status, but not demographic, disease, or physical function variables. Patients experiencing an ADE were more likely to experience a longer LOS and to decline in ADL function. ADEs may be one factor contributing to functional decline during hospitalization. Future research in this area should include larger samples and multivariable analyses controlling for potential confounders.     

Adverse drugs reactions associated with glaucoma medications

We undertook a non-concurrent prospective study of 191 Puerto Rican patients from August 1993 to April 1994. All patients had open angle glaucoma (OAG) (age ranged from 50 to 80 yrs; mean = 65 yrs). Patient's symptomatology associated to side effects of their glaucoma medicadons was reviewed. Incidence percent of ocular and/or systemic side effects per medication were: levobunolol 45.0%; betaxolol 42.0%; timolol 27.3%; pilocarpine 100%; dipivefrin 14.0%; and acetazolamide 250 mg 64.1%. Incidence percent of ocular and/or systemic side effects of topical beta-blockers used with concomittant medications were determined. Ocular side effects were more frequent in patients using levobunolol 44.2% than in those patients using betaxolol 42.0%, 8.5% of patients using levobunolol did report systemic side effects. No systemic side effects were reported by patients using betaxolol. Ocular side effects in patients using pilocarpine were frequent (100%); whereas the frequency of systemic side effects was low (6.1%). Systemic side effects were common in patients using carbonic anhydrase inhibitors. These results suggest that non-selective and cardio-selective topical Beta-blockers, differ in their ocular or systemic side effects.     

Adverse effects associated with influenza vaccine in pediatrics

To investigate mechanisms of capillary network remodeling, we developed a serum-free angiogenesis in vitro system in three-dimensional fibrin matrices which allows the study of directional growth of endothelial sprouts, anastomosis, and remodeling ('pruning') of the primitive plexus toward more elaborated capillary trees. To follow the movements of living endothelial cells by inverse-fluorescence microscopy, we cocultured unlabeled endothelial cells with endothelial cells labeled with the carbocyanine dye 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI). We show that elongation and retraction of neighboring capillary sprouts occurs simultaneously, resembling a tug-of-war by which endothelial cells are withdrawn from shortening sprouts to become incorporated in other sprouts nearby. For the first time, we directly demonstrate the long-suspected parallel sliding movement of endothelial cells. We show that cell migration persists within immature capillaries even after sprouts have merged to continuous capillary loops, leading to overlapping growth of opposing sprout tips. As a novel concept of capillary remodeling, we distinguish two types of endothelial cell migration: sprouting and guided migration. Sprouting is the de novo invasion of a matrix by endothelial cells, and guided migration is the locomotion of cells along preexistent capillary-like structures. We show that guided migration leads to remodeling of immature capillary networks and to the retraction of sprouts. We describe a method for quantification of sprouting versus guided migration in DiI-mosaic-labeled capillary networks, and we present evidence that endothelial cell-derived basic fibroblast growth factor serves as a chemotactic signal for other cells to migrate along a preestablished capillary-like structure.     

Adverse effects and drug interactions associated with local and regional anaesthesia

Systemic and localised adverse effects of local anaesthetic drugs usually occur because of excessive dosage, rapid absorption or inadvertent intravascular injection. Small children are more prone than adults to methaemoglobinaemia, and the combination of sulfonamides and prilocaine, even when correctly administered, should be avoided in this age group. The incidence of true allergy to local anaesthetics is rare. All local anaesthetics can cause CNS toxicity and cardiovascular toxicity if their plasma concentrations are increased by accidental intravenous injection or an absolute overdose. Excitation of the CNS may be manifested by numbness of the tongue and perioral area, and restlessness, which may progress to seizures, respiratory failure and coma. Bupivacaine is the local anaesthetic most frequently associated with seizures. Treatment of CNS toxicity includes maintaining adequate ventilation and oxygenation, and controlling seizures with the administration of thiopental sodium or benzodiazepines. Cardiovascular toxicity generally begins after signs of CNS toxicity have occurred. Bupivacaine and etidocaine appear to be more cardiotoxic than most other commonly used local anaesthetics. Sudden onset of profound bradycardia and asystole during neuraxial blockade is of great concern and the mechanism(s) remains largely unknown. Treatment of cardiovascular toxicity depends on the severity of effects. Cardiac arrest caused by local anaesthetics should be treated with cardiopulmonary resuscitation procedures, but bupivacaine-induced dysrhythmias may be refractory to treatment. Many recent reports of permanent neurological complications involved patients who had received continuous spinal anaesthesia through a microcatheter. Injection of local anaesthetic through microcatheters and possibly small-gauge spinal needles results in poor CSF mixing and accumulation of high concentrations of local anaesthetic in the areas of the lumbosacral nerve roots. In contrast to bupivacaine, the hyperbaric lidocaine (lignocaine) formulation carries a substantial risk of neurotoxicity when given intrathecally. Drugs altering plasma cholinesterase activity have the potential to decrease hydrolysis of ester-type local anaesthetics. Drugs inhibiting hepatic microsomal enzymes, such as cimetidine, may allow the accumulation of unexpectedly high (possibly toxic) blood concentrations of lidocaine. Reduction of hepatic blood flow by drugs or hypotension will decrease the hepatic clearance of amide local anaesthetics. Special caution must be exercised in patients taking digoxin, calcium antagonists and/or beta-blockers.     

Adverse political events and psychological adjustment: two cross-cultural studies

OBJECTIVE: The life events model was extended to the political arena to enable the comparison of children's adjustment reactions to political stress. The cross-cultural impact of adverse political events on psychological adjustment was examined for two closely matched research samples, Arab and Jewish children and Palestinian and Israeli children. METHOD: All children completed the Political Life Events scale and the Brief Symptom Inventory in their home languages. RESULTS: The hypothesis of a linear relation between adverse events and psychological distress was not confirmed in both studies. In study 1, a direct relation emerged for both Jewish and Arab Israeli children. However, in study 2, when separated by nationality, results revealed opposite trends for each nation. For Israelis there was a linear relation, but for Palestinians there was a consistent inverse relation between increased severity of political life events exposure and distress, both for the global index and for specific symptomatology. CONCLUSION: It is proposed that these cross-cultural results stem from differential mediating coping mechanisms, specifically passive versus active strategies, which intervene between the stressor-adjustment link. The need to address short- and long-term consequences of political stress on children's mental health is discussed.     

Cerebral ischemic events associated with prolapsing mitral valve

Twelve patients who had no evidence of arteriosclerotic cerebral vascular disease, lacked hypertension or coagulation defect, and had not been receiving contraceptive therapy had recurrent transient cerebral ischemic attacks (TIAs) and partial nonprogressive strokes. All had prolapsing mitral valve proved by angiocardiography. The average age was 38 years, compared with 62 years in a larger series of patients with TIA associated with arteriosclerosis. We propose that the ischemic events are related to emboli emanating from the abnormal mitral valve with or without an associated paroxysmal cardiac arrhythmia.     

Proportion of hospital deaths associated with adverse events

OBJECTIVES: To determine the fraction of hospital deaths potentially associated with the occurrence of adverse events (AE). DESIGN: A paired (1:1) case-control study. SETTING: An 800-bed, teaching tertiary care hospital. PATIENTS: All patients older than 14 years admitted to the hospital between January 1, 1990, and January 1, 1991, were eligible. All 524 consecutive deaths (death rate of 3.74%) that occurred in the hospital comprised the case group. For each case, a control patient was matched for both primary diagnosis on admission and admission date. MEASUREMENTS: The proportion of hospital deaths associated with adverse events (defined as problems of any nature and seriousness faced by the patient during hospitalization, and potentially traceable to clinical or administrative management) was estimated from attributable risks adjusted for age, sex, service, severity of illness, length of stay, and quality of the medical record. RESULTS: For stays longer than 48 hours, the adjusted attributable risk for all adverse events was estimated to be 0.51 (0.40-0.61). When the data were stratified according to the category of adverse event, the attributable risks remained significant except for administrative problems. The greatest proportion of deaths associated with adverse events was observed for surgical adverse events [0.56 (0.38-0.71)] and nosocomial infection [0.22 (0.14-0.28)]. CONCLUSIONS: A significant proportion of intrahospital deaths were associated with AE. These results suggest the need to consider programs focused on the prevention of mortality from AE.     

Perinatal events associated with maternal smoking during pregnancy

To identify components of smoking-related increased perinatal mortality, detailed analyses of data from the Ontario Perinatal Mortality Study (50,000 births, 1,300 deaths, 1960-1961) measured the relationship of maternal smoking to birth weight, gestation, placental complications, and perinatal mortality. Cross-tabulations with other factors and multiple adjustment showed increases with amount smoked of birth weights less than 2500 gm, gestations less than 38 weeks, placenta previa, abruptio placentae, and perinatal mortality. These significant, smoking-related increases were independent of mother's height, weight, hospital status, age-parity group, birthplace, previous pregnancy history, weight gain, time of registration, and sex of child. Maternal smoking had the strongest effect on birthweight in the 8 factor regression, and birth less than 2500 gm increased directly with smoking level from 20% to 340% in 37 data subgroups. Births less than 38 weeks increased 20% and 50% and perinatal mortality increased 20% and 35% for less than 1 pack and 1 + pack smokers, respectively, adjusted for 7 other factors. Placental complications increased consistently with smoking level in all of 37 subgroups except for primiparous less than 1 pack smokers. Adjusted rates increased 25% and 92% for placenta previa, 23% and 86% for abruptions among smokers of less than 1 pack and 1 + packs, respectively. These complications carry high perinatal mortality risk, and account for one-third to one-half of the perinatal deaths attributable to maternal smoking.     

Adverse events with radiographic contrast agents: results of the SCVIR Contrast Agent Registry

The role of lipopolysaccharide (LPS) and Shiga-like toxin (SLT) in the pathogenesis of hemolytic uremic syndrome (HUS) was studied in a mouse model. Mice inoculated intragastrically with Escherichia coli O157:H7 developed gastrointestinal, neurologic, and systemic symptoms, necrotic foci in the colon, glomerular and tubular histopathology, and fragmented erythrocytes. LPS-responder (C3H/HeN) mice developed a combination of neurologic and systemic symptoms, whereas LPS-nonresponder (C3H/HeJ) mice had a biphasic course of disease, first developing systemic symptoms and later severe neurologic symptoms. Mice inoculated with SLT-II-positive strains developed severe neurotoxic symptoms and a higher frequency of systemic symptoms and glomerular pathology compared with SLT-II-negative strains. Anti-SLT-II antibodies protected against these symptoms and pathology. These results demonstrate that this model could be used to study aspects of human HUS and that both LPS and SLT are important for disease development.