PPA Literature Relevance To Ephedra Supplement Safety Questioned

Structural and pharmacological differences between phenylpropanolamine and other ephedrine alkaloids negate FDA's heavy reliance on PPA literature in its analysis of adverse health effects caused by dietary supplements, industry consultants asserted at an Aug. 8-9 Public Health Service meeting in Washington, D.C.

San Francisco County Assistant Medical Examiner Steven Karch, MD, stated that while FDA has identified 56 references to primary research regarding the cardiovascular effects of ephedrine alkaloids, the bulk of these references pertain to PPA.

"It is clear...that the FDA considers all isomers of ephedrine to be equivalent, both in terms of effects exerted and toxicity produced. This is clearly not the case," said Karch, who was retained by the Ephedra Education Council.

A Center for Food Safety & Applied Nutrition review of the published literature on the physiological, pharmacological and toxicological effects of ephedrine alkaloids was made available in April, concurrent with FDA's release of new adverse event reports and accompanying analyses.

"There are new, fairly recent in vitro studies demonstrating, for example, that a naturally occurring 1R,2S isomer [of ephedrine] has much greater affinity for beta-1 and beta-2 receptors than does a synthetic pseudoephedrine, and that conversely [PPA] has much less affinity," Karch said.

"In spite of all these very clear differences at the molecular level, the FDA relies heavily on [PPA] data to raise questions about the safety of ephedrine, and I feel that is inappropriate," he added.

Norbert Page, an EEC toxicologist and principal in the consulting firm ToxaChemica International, said PPA, also known as norephedrine, is present in only a small number of ephedra supplements, and only in trace amounts, usually representing less than 5% of total ephedrine alkaloid content.

Ephedrine and pseudoephedrine are the two primary alkaloids found in supplements, he noted, contending the PPA literature "is not relevant to this analysis of ephedra products."

EEC representatives, as well as the Consumer Healthcare Products Association, also contended the results of Yale University's study on PPA and hemorrhagic stroke are inconclusive and irrelevant to FDA's consideration of the safety of ephedrine alkaloid-containing supplements.

The study, released in May, found the use of OTC cough/cold remedies or appetite suppressants containing PPA increased the odds of hemorrhagic stroke by a factor of 1.49 (¹ (Also see "PPA Increases Hemorrhagic Stroke Risk - Yale Study" - Pink Sheet, 29 May, 2000.)).

The HSP report, which has not yet been peer-reviewed or published, was based on a study of 702 stroke survivors, ages 18-49, and 1,376 control subjects matched by gender and geography. Twenty-seven case subjects (3.8%) reported PPA use within three days of onset of initial stroke symptoms, compared to 33 control subjects (2.4%) reporting PPA use within the corresponding three-day window.

In reopening the comment period on the newly released AERs from Aug. 10 until Sept. 30, FDA invited public input on the HSP report and its relevance in assessing the safety of ephedra supplements. The agency expects to hold a future public meeting on the findings.

CHPA consultant Charles Hennekens, MD, University of Miami School of Medicine, said the HSP study "has numerous methodologic issues that limit its interpretability." Among the confounding factors Hennekens pointed to are "marked differences in the characteristics between the cases and controls," particularly with regard to socio-economic status, cigarette smoking, hypertension history and alcohol consumption.

Selection and observation bias also may have influenced the results, Hennekens opined. "The small number of exposed cases limits the ability to statistically control for even the available confounding variables in this study. This situation also greatly increases the possibility that chance alone could be a plausible alternative explanation for any apparent association between use of PPA and subsequent development of hemorrhagic stroke," he said.

"There were no direct questions concerning ephedra and other dietary supplements asked in the HSP," Hennekens continued, stating there is a "lack of relevance of the HSP to ephedra alkaloids." Hennekens was the lead researcher in Harvard's Physician Health Study II and Women's Health Study.