Christine A. Haller

Adverse Cardiovascular and Central Nervous System Events Associated with Dietary Supplements Containing Ephedra Alkaloids

Background Dietary supplements that contain ephedra alkaloids (sometimes called ma huang) are widely promoted and used in the United States as a means of losing weight and increasing energy. In the light of recently reported adverse events related to use of these products, the Food and Drug Administration (FDA) has proposed limits on the dose and duration of use of such supplements. The FDA requested an independent review of reports of adverse events related to the use of supplements that contained ephedra alkaloids to assess causation and to estimate the level of risk the use of these supplements poses to consumers. Methods We reviewed 140 reports of adverse events related to the use of dietary supplements containing ephedra alkaloids that were submitted to the FDA between June 1, 1997, and March 31, 1999. A standardized rating system for assessing causation was applied to each adverse event. Results Thirty-one percent of cases were considered to be definitely or probably related to the use of supplement...

Adverse events associated with dietary supplements: an observational study

BACKGROUND Adverse events associated with dietary supplements are difficult to monitor in the USA, because such products are not registered before sale, and there is little information about their content and safety. METHODS In 1998, 11 poison control centres in the USA recorded details of 2332 telephone calls about 1466 ingestions of dietary supplements, in 784 of which patients had symptoms. We used a multitiered review process (kappa 0.42) to select 489 cases for whom we were at least 50% certain that their negative events were associated with dietary supplements. We aimed to assess the effects of multiple ingredients and long-term use, and collated data for patterns of use and information resources. FINDINGS A third of events were of greater than mild severity. We noted both new and previously reported associations that included myocardial infarction, liver failure, bleeding, seizures, and death. Increased symptom severity was associated with use of several ingredients, long-term use, and age. Paediatric exposures were more often unintentional than were adult ingestions, and treatment of disease was the reason for supplement use in at least 28% of reports. Most products and ingredients were not identified in the information database (Poisindex) used by poison control centres, and specific adverse events were reported variably among five additional sources. INTERPRETATION Dietary supplements are associated with adverse events that include all levels of severity, organ systems, and age groups. Associations between adverse events and ingredients are difficult to verify if a product has more than one ingredient, and because of incomplete information systems. Research into hazards and risks of dietary supplements should be a priority.

Dosing algorithm for warfarin using CYP2C9 and VKORC1 genotyping from a multi-ethnic population: comparison with other equations

OBJECTIVES Polymorphism in the genes for cytochrome (CYP)2C9 and the vitamin K epoxide reductase complex subunit 1 (VKORC1) affect the pharmacokinetics and pharmacodynamics of warfarin. We developed and validated a warfarin-dosing algorithm for a multi-ethnic population that predicts the best dose for stable anticoagulation, and compared its performance against other regression equations. METHODS We determined the allele and haplotype frequencies of genes for CYP2C9 and VKORC1 on 167 Caucasian, African-American, Asian and Hispanic patients on warfarin. On a subset where complete data were available (n=92), we developed a dosing equation that predicts the actual dose needed to maintain target anticoagulation using demographic variables and genotypes. This regression was validated against an independent group of subjects. We also applied our data to five other published warfarin-dosing equations. RESULTS The allele frequency for CYP2C9*2 and *3 and the A allele for VKORC1 3673 was similar to previously published reports. For Caucasians and Asians, VKORC1 SNPs were in Hardy-Weinberg linkage equilibrium. Some VKORC1 SNPs among the African-American population and one SNP among Hispanics were not in equilibrium. The linear regression of predicted versus actual warfarin dose produced r-values of 0.71 for the training set and 0.67 for the validation set. The regression coefficient improved (to r=0.78 and 0.75, respectively) when rare genotypes were eliminated or when the 7566 VKORC1 genotype was added to the model. All of the regression models tested produced a similar degree of correlation. The exclusion of rare genotypes that are more associated with certain ethnicities improved the model. CONCLUSION Minor improvements in algorithms can be observed with the inclusion of ethnicity and more CYP2C9 and VKORC1 SNPs as variables. Major improvements will likely require the identification of new gene associations with warfarin dosing.

Pharmacology of ephedra alkaloids and caffeine after single‐dose dietary supplement use

Serious cardiovascular toxicity has been reported in people taking dietary supplements that contain ma huang (Ephedra) and guarana (caffeine). We assessed the pharmacokinetics and pharmacodynamics of a dietary supplement that contains these herbal stimulants.

Enhanced Stimulant and Metabolic Effects of Combined Ephedrine and Caffeine

Herbal weight loss and athletic performance–enhancing supplements that contain ephedrine and caffeine have been associated with serious adverse health events. We sought to determine whether ephedrine and caffeine have clinically significant pharmacologic interactions that explain these toxicities.

Prevalence of Smoking Assessed Biochemically in an Urban Public Hospital: A Rationale for Routine Cotinine Screening

Cotinine, a metabolite of nicotine, has been used to study tobacco smoke exposure in population studies, but the authors are unaware of its use to screen hospitalized patients. The authors measured serum cotinine levels in 948 patients admitted to an urban public hospital in San Francisco, California, between September 2005 and July 2006. On the basis of cotinine levels, they classified patients as active smokers (cotinine > or = 14 ng/mL), recent smokers or significantly exposed to secondhand smoke (SHS) (0.5-13.9 ng/mL), lightly exposed to SHS (0.05-0.49 ng/mL), or unexposed (<0.05 ng/mL). In contrast to the 13% prevalence of smoking in the general population of San Francisco, 40% of patients were active smokers; 15% were recent smokers or heavily exposed to SHS; 25% had low-level exposure to SHS; and 20% were unexposed. Active smoking or heavy SHS exposure was particularly high among African Americans (77%), the uninsured (65%), self-reported alcohol drinkers (77%), and illicit drug users (90%). Of people who denied smoking, 32% were found to have had significant exposure. If serum cotinine measurement became part of routine screening at urban public hospitals, cotinine levels would be abnormal in many patients and would provide objective evidence of tobacco smoke exposure, probably resulting in more intensive intervention to encourage patients to stop smoking and avoid SHS.

Human pharmacology of a performance-enhancing dietary supplement under resting and exercise conditions

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Performance-enhancing dietary supplements have not been clinically tested for safety or efficacy. In clinical trials performed under resting conditions, performance-enhancing supplements raise blood pressure and affect glucose homeostasis. The effect of exercise on the pharmacokinetics and pharmacodynamics of stimulant herbals is unknown. WHAT THIS STUDY ADDS Supplement-induced effects on blood pressure and glucose levels are not ameliorated by exercise. Exercise does not affect the kinetics of stimulant ingredients, caffeine and synephrine. Performance-enhancing supplement use modestly improves exercise tolerance. AIMS Dietary supplements (DS) promoted to enhance athletic performance often contain herbal sympathomimetics such as Citrus aurantium (synephrine) and caffeine. We aimed to characterize the pharmacology of a performance-enhancing DS in the setting of exercise. METHODS Ten healthy adults (three women) aged 20-31 years participated in a three-arm, double-blind, placebo-controlled, crossover study. Subjects ingested one dose of DS (Ripped Fuel Extreme Cut(R) with 21 mg synephrine and 304 mg caffeine by analysis) under resting conditions and 1 h prior to moderately intense exercise (30 min on cycle ergometer at 75-80% HR(max)), with a placebo (PLC)/exercise control. Plasma synephrine and caffeine concentrations were measured over 12 h, and vital signs, serum electrolytes, oxygen consumption and perceived exercise exertion were monitored. RESULTS No significant adverse events occurred. Synephrine and caffeine pharmacokinetics were unaffected by exercise. Post-exercise diastolic blood pressure was higher after DS (peak mean 71.7 +/- 8.7 mmHg) than PLC (63.0 +/- 4.9 mmHg) (p = 0.007). There were no substantial treatment-related differences in post-exercise HR, systolic blood pressure, or temperature. Postprandial plasma glucose increased to 121.0 +/- 31.6 mg dl(-1) with DS and exercise vs. 103.7 +/- 25.5 mg dl(-1) with PLC and exercise (P = 0.004). No treatment differences in exercise-related oxygen consumption, serum lactate, or insulin were observed. Exercise was rated less difficult with DS than PLC (P = 0.001). CONCLUSIONS Blood pressure and plasma glucose increased post-exercise with DS use, which could be detrimental in some people. Exercise was perceived as less strenuous after DS, presumably due to the stimulant effects of caffeine.

Gamma-hydroxybutyrate and ethanol effects and interactions in humans

Background: Gamma-hydroxybutyrate (GHB) is a common drug of abuse that can produce serious toxicity, particularly when used with other sedatives. We examined the individual and combined effects of GHB and ethanol in human volunteers. Methods: Sixteen healthy adults (7 men) were given 50 mg/kg GHB (Xyrem), 0.6 g/kg ethanol in 2 doses, alone and combined in a double-blind, placebo-controlled, crossover study. Plasma concentrations, heart rate (HR), blood pressure (BP), and oxygen saturation (O2sat) were serially monitored for 24 hours. Results: Adverse events included 2 instances of hypotension and 6 episodes of vomiting with GHB-plus-ethanol ingestion. Oxygen saturation was decreased by GHB and ethanol individually, and maximally decreased by the drugs combined (max −2.1% ± 0.3%, P < 0.0001 vs placebo). Compared with baseline, systolic and diastolic BP were significantly decreased, and HR was increased by ethanol but not affected by GHB alone (maximum systolic BP change −15.7 ± 3.0 mm Hg, P = 0.0006; maximum HR change 13.5 ± 2.3 beats per minute, P = 0.006). Ethanol coingestion resulted in 16% higher GHB maximal plasma concentration and 29% longer elimination half-life, indicating possible enhanced bioavailability or reduced clearance of GHB caused by ethanol, however, these effects were not statistically significant. Conclusions: Modest doses of GHB do not affect hemodynamic function, but O2sat was decreased. Gamma-hydroxybutyrate-plus-ethanol resulted in more adverse effects, including gastrointestinal disturbances, hypotension, and decreased O2sat, but only minimal pharmacokinetic interactions were observed.

Dietary supplement adverse events: report of a one-year poison center surveillance project.

BackgroundThe safety and efficacy of dietary supplements is of growing concern to regulators, health-care providers and consumers. Few scientific data exist on clinical effects and potential toxicities of marketed products. Harmful supplements may not be identified for months or years with existing adverse event monitoring mechanisms. Retrospective review of poison center statistics to capture supplement-associated toxicity also has limitations.MethodsWe collaborated with the FDA Center for Food Safety and Nutrition (CFSAN) to conduct a 1-year prospective surveillance study of dietary supplement-related poison control center calls in 2006. Prompt follow-up of symptomatic cases, laboratory analysis of implicated dietary supplements, and causality assessment by a case review expert panel were performed.ResultsOf 275 dietary supplements calls, 41% involved symptomatic exposures; and two-thirds were rated as probably or possibly related to supplement use. Eight adverse events required hospital admission. Sympathomimetic toxicity was most common, with caffeine products accounting for 47%, and yohimbe products accounting for 18% of supplement-related symptomatic cases. Suspected drug-herb interactions occurred in 6 cases, including yohimbe co-ingested with buproprion (1) and methamphetamine (3), and additive anticoagulant/antiplatelet effects of NSAIDs taken with fish oils (1) and ginkgo (1). Laboratory analysis identified a pharmacologically active substance in 4 cases; supplement toxicity was ruled unlikely when analytical testing was negative in 5 cases.ConclusionMost supplement-related adverse events were minor. Clinically significant toxic effects were most frequently reported with caffeine and yohimbe-containing products. Active surveillance of poison control center reports of dietary supplement adverse events enables rapid detection of potentially harmful products, which may facilitate regulatory oversight.

Short-term metabolic and hemodynamic effects of ephedra and guarana combinations.

Serious adverse health events have been reported with the use of dietary supplements containing ephedra and guarana. We sought to determine whether repeated dosing and multi‐ingredient formulations contribute to the adverse effects of these supplements.