New recommendations from the 1999 American College of Cardiology/American Heart Association acute myocardial infarction guidelines.

OBJECTIVE: To review literature relating to significant changes in drug therapy recommendations in the 1999 American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for treating patients with acute myocardial infarction (AMI). DATA SOURCES: 1999 ACC/AHA AMI guidelines, English-language clinical trials, reviews, and editorials researching the role of drug therapy and primary angioplasty for AMI that were referenced in the guidelines were included. Additional data published in 2000 or unpublished were also included if relevant to interpretation of the guidelines. STUDY SELECTION: The articles selected influence AMI treatment recommendations. DATA SYNTHESIS: Many clinicians and health systems use the ACC/AHA AMI guidelines to develop treatment plans for AMI patients. This review highlights important changes in AMI drug therapy recommendations by reviewing the results of recent clinical trials. Insights into evolving drug therapy strategies that may impact future guideline development are also described. CONCLUSIONS: Several changes in drug therapy recommendations were included in the 1999 AMI ACC/AHA guidelines. There is emphasis on administering fibrin-specific thrombolytics secondary to enhanced efficacy. Selection between fibrin-specific agents is unclear at this time. Low response rates to thrombolytics have been noted in the elderly, women, patients with heart failure, and those showing left bundle-branch block on the electrocardiogram. These patient groups should be targeted for improved utilization programs. The use of glycoprotein (GP) IIb/IIIa receptor inhibitors in non-ST-segment elevation MI was emphasized. Small trials combining reduced doses of thrombolytics with GP IIb/IIIa receptor inhibitors have shown promise by increasing reperfusion rates without increasing bleeding risk, but firm conclusions cannot be made until the results of larger trials are known. Primary percutaneous coronary intervention (PCI) trials suggest lower mortality rates for primary PCI when compared with thrombolysis alone. However, primary PCI, including coronary angioplasty, is only available at approximately 13% of US hospitals, making thrombolysis the preferred strategy for most patients. Clopidogrel has supplanted ticlopidine as the recommended antiplatelet agent for patients with aspirin allergy or intolerance following reports of a better safety profile. The recommended dose of unfractionated heparin is lower than previously recommended, necessitating a separate nomogram for patients with acute coronary syndromes. Routine use of warfarin, either alone or in combination with aspirin, is not supported by clinical trials; however, warfarin remains a choice for antithrombotic therapy in patients intolerant to aspirin. Beta-adrenergic receptor blockers continue to be recommended, and emphasis is placed on improving rates of early administration (during hospitalization), even in patients with moderate left ventricular dysfunction. New recommendations for drug treatment of post-AMI patients with low high-density lipoprotein cholesterol and/or elevated triglycerides are included, with either niacin or gemfibrozil recommended as an option. Supplementary antioxidants are not recommended for either primary or secondary prevention of AMI, with new data demonstrating lack of efficacy vitamin E in primary prevention. Estrogen replacement therapy or hormonal replacement therapy should not be initiated solely for prevention of cardiovascular disease, but can be continued in cardiovascular patients already taking long-term therapy for other reasons. Bupropion has been added as a new treatment option for smoking cessation. As drug therapy continues to evolve in treating AMI, more frequent updates of therapy guidelines will be necessary.

Content versus label claims in ephedra-containing dietary supplements.

The content of ephedra alkaloids in herbal dietary supplements containing ephedra (ma huang) was studied. The ephedra alkaloid content of 20 ephedra-containing supplements was determined by high-performance liquid chromatography. Contents of (-)-ephedrine, (+)-pseudoephedrine, (-)-methylephedrine, (-)-norephedrine, and (+)-norpseudoephedrine were measured. Ephedra alkaloid content varied considerably among products. Total alkaloid content ranged from 0.0 to 18.5 mg per dosage unit. Ranges for (-)-ephedrine and (+)-pseudoephedrine were 1.1-15.3 mg and 0.2-9.5 mg, respectively. (+)-Norpseudoephedrine, a Schedule IV controlled substance, was often present. Significant lot-to-lot variations in alkaloid content were observed for four products. For one product, lot-to-lot variations in the content of (-)-ephedrine, (+)-pseudoephedrine, and (-)-methylephedrine exceeded 180%, 250%, and 1000%, respectively. Half of the products exhibited discrepancies between the label claim for ephedra alkaloid content and actual alkaloid content in excess of 20%. One product was devoid of ephedra alkaloids. Assay of 20 ephedra-containing dietary supplements showed that alkaloid content often differed markedly from label claims and was inconsistent between two lots of some products.

Ephedrine pharmacokinetics after the ingestion of nutritional supplements containing Ephedra sinica (ma huang).

Nutritional supplements containing Ephedra sinica (ma huang), a botanical source of ephedrine alkaloids, have been linked to several episodes of ephedrine toxicity and at least 17 deaths, yet these products remain unregulated. Ten subjects were enrolled in a randomized, crossover study aimed at characterizing the pharmacokinetics of ephedrine after the ingestion of three commercially available ma huang products compared with a 25-mg ephedrine capsule. Pharmacokinetic parameters for botanical ephedrine were similar to those for synthetic ephedrine hydrochloride. Gender-based comparisons of Vss/F and CL/F revealed higher values for women than for men (Vss/F, 3.49 +/- 1.04 vs 2.98 +/- 0.73 l/kg; CL/F, 0.48 +/- 0.11 vs 0.37 +/- 0.11 l/hour x kg). The current study suggests that the increased incidence of ma huang toxicity does not stem from differences in the absorption of botanical ephedrine compared with synthetic ephedrine; rather, it results from accidental overdose often prompted by exaggerated off-label claims and a belief that "natural" medicinal agents are inherently safe.

Ephedrine-type alkaloid content of nutritional supplements containing Ephedra sinica (Ma-huang) as determined by high performance liquid chromatography.

Nutritional supplements containing Ephedra sinica (ma-huang), a botanical source of ephedrine-type alkaloids, have been linked to numerous episodes of ephedrine (EPH) toxicity. With passage of the 1994 Dietary Supplement Health and Education Act, nutritional supplements are no longer subject to the same FDA preapproval requirements as food additives, prescription, or nonprescription medications. As a consequence, EPH content is not a label requirement for Ephedra-containing supplements. Less stringent labeling requirements, therefore, may contribute to toxicity associated with these products. A validated HPLC method for the determination of ephedrine-type alkaloids, commonly found in Ephedra supplements, is presented. Nine commercially available supplements exhibited considerable variability in alkaloid content (EPH range: 1.08-13.54 mg). Only three products listed EPH content on the label while one exhibited lot to lot variations in EPH of 137%.

Pharmacokinetics and cardiovascular effects of ma-huang (Ephedra sinica) in normotensive adults.

The purpose of this study was to evaluate heart rate and blood pressure responses to a commercially available source of ma-haung, a natural source of the sympathomimetic substance, ephedrine, and to evaluate the pharmacokinetic properties of the product in normotensive, healthy adults. On day 1, twelve study participants were monitored with an ambulatory blood pressure device between hours 7 and 20. On day 2, they ingested four capsules of powdered ma-huang at hours 8 and 17 while again wearing the monitor between hours 7 and 20. Serial plasma samples were obtained and concentrations of ephedrine were analyzed by high-performance liquid chromatography. Pharmacokinetic parameters of ephedrine were determined from plasma concentration-time profiles. The ephedrine alkaloid content of each capsule was also determined by high-performance liquid chromatography. Six participants experienced a statistically significant increase in heart rate, but the effects on blood pressure were variable. The half-life, volume of distribution, clearance, and maximum concentration in plasma of ephedrine in the ma-huang product were similar to values previously reported for a 20 mg, immediate-release ephedrine tablet. Values for the absorption rate were considerably lower and time to reach maximum concentration was longer for the capsules, compared with the standard tablet. Variability in alkaloid content of ephedrine was low and yielded a mean dose of ephedrine at 19.4 mg; pseudoephedrine at 4.9 mg; and methylephedrine at 1.2 mg for a four-capsule dose. In summary, ma-haung had variable effects on blood pressure and increased heart rate in healthy, normotensive adults. Pharmacokinetic parameters for ephedrine were in agreement with those previously reported; however, the absorption rate was much slower after ingestion of ma-huang.

An assessment of cerebral blood flow and metabolism after fleroxacin therapy.

Cerebral blood flow (CBF), glucose (FDG), and oxygen metabolism (OM) were evaluated by positron emission tomography (PET) in 18 healthy volunteers who were randomized to a 72-hour course of either 600 mg/d of fleroxacin or placebo. Such studies attempted to assess potentially serious, yet unexplained, central nervous system adverse effects of the fluorinated quinolone class. Baseline and postplacebo values for CBF (mL/min/100 g) and FDG (mg/min/100 g) were: 53 +/- 6 and 5.7 +/- 1.8; and 49.6 +/- 4.4, and 5.2 +/- 1.2, respectively. Identical values for fleroxacin were: 53.9 +/- 4.8 and 6.3 +/- 1.1; and 54.4 +/- 2.2 and 6.8 +/- 1.5, respectively. The differences between fleroxacin and placebo were not significant. There was also no effect seen in OM between placebo and the active drug. The authors conclude that short-term administration of fleroxacin does not alter CBF, FDG, or OM in healthy volunteers.