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Ephedra has been used as a natural medicine for thousands of years by numerous cultures with very little concern about toxicity. Its most recent popularity is related to its purported “weight loss” or “performance enhancing” attributes. In spite of that in 2004, concerns over safety resulted in the banning of all over-the-counter (OTC) sales of ephedra-containing dietary supplements by the Food and Drug Administration.

All ephedra plants contain phenylalanine-derived alkaloids, including ephedrine, pseudoephedrine, methylephedrine, and trace amounts of phenylpropanolamine. Previously marketed herbal supplements typically stated total ephedra alkaloid content, although actual levels of individual alkaloid varied depending on raw material and production runs.

A double-blind, placebo-controlled trial by Boozer et al. examined issues of long-term safety and efficacy of ephedra, demonstrating its ability to reduce body weight and body fat while improving blood lipids without significant adverse events. Although other studies have documented a favorable adverse effect profile for appropriately administered doses of ephedra-containing supplements, there have been numerous anecdotal reports of adverse effects. Abuse and misuse of ephedra-containing products likely contributed to spontaneously reported adverse effects and increased concerns over safety.

As with other sympathomimetic agents, theoretical drug interactions with ephedra alkaloids are possible. Despite this potential, only a handful of adverse drug interactions have been reported. This is especially pertinent when considering the extensive use of both ephedra-containing supplements and ephedrineor pseudoephedrine-containing OTC products. The most notable interaction exists between nonselective monoamine oxidase inhibitors and ephedraor ephedrine-containing products.

Kava has a long history of traditional use for the treatment of symptoms related to anxiety, stress, and nervous restlessness and has demonstrated effectiveness for treatment of anxiety in double-blind, randomized, placebo-controlled trials. Lack of both dependence and documented adverse effects contributed to kava’s popularity up through the 1990s. Typical adverse effects have been limited to reversible yellowing of the skin after chronic use and a temporary condition known as kava dermopathy. Subsequent reports of hepatotoxicity in Europe and less frequently in the United States have resulted in a decrease in its popularity as well as regulatory action by various government regulatory bodies against specific formulations. Although subsequent analysis has concluded that “there is no clear evidence that the liver damage reported in the United States and Europe was caused by the consumption of kava” much of the US market for the herb has been diminished.

Controlled studies suggest that administration of (GB) extract has limited effectiveness in improving memory and cognition, either in elderly subjects with dementia or healthy subjects. GB administration does seem to reverse sudden hearing loss in patients with mild cases of this disorder. Additionally, GB administration may blunt the rise in blood pressure in response to stress and may blunt the glycemie response after an oral glucose tolerance test. Despite the lack of evidence of effects on coagulation in vivo, a number of case reports of excessive bleeding in patients taking GB have been reported. Finally, GB does not appear to be prone to causing drug interactions, except for agents metabolized by cytochrome P450 2C19 (in which case, induction is observed).

Valerian is a unique herb with a long history of use through western Europe as a sedative and hypnotic. A variety of pharmacologically active components are likely responsible for its clinical effects including volatile oils, monoterpenes, valepotriates, and sesquiterpenes. Valerenic acid, a sesquiterpene component of valerian, is postulated to produce sedation through inhibition of the breakdown of gamma-amino butyric acid. The herb is well tolerated, and side effects have been mild and self-limiting in most cases. Isolated reports of liver damage have occurred with valerian being a concomitantly consumed agent, yet anecdotal cases of attempted intentional self-poisoning with the herb have not resulted in fatality and long-term follow-up for subsequent hepatotoxicity in a number of these patients has not revealed liver abnormalities. The herb’s postitive safety profile and demonstrated effectiveness in treating insomnia contributes to its popularity.

St. John’s wort has demonstrated clinical efficacy for mild to moderate depression and compares favorably to other more potent or toxic antidepressants. Low side effects and potential benefits warrant its use as a first-line agent for select patients with mild to moderate depression or anxiety-related conditions. Benefits related to other reported uses such as an antimicrobial, agent to treat neuropathic pain, antiinflammatory, treatment alternative for atopic dermatitis, and antioxidant are either not well documented or evidence is encouraging but not conclusive and further study is needed. St. John’s wort has an inherently wide margin of safety when taken by itself, with most reported adverse drug reactions (ADRs) being related to skin reactions. Isolated, but more significant ADRs have been reported in relation to neurological effects, impact on thyroid function, and increased prothrombin time. Of greatest concern is the potential for interactions between St. John’s wort and mainstream pharmaceuticals through induction of cytochrome P450. Patients on concomitant treatment with drugs metabolized through this pathway should be monitored closely for altered drug effect.

Echinacea remains a popular supplement used as an immunostimulant in the prevention and treatment of infection. Despite inconsistent results from clinical trials attempting to assess effectiveness, its relatively wide margin of safety makes the herb an attractive alternative for prevention and treatment of common infections such as upper respiratory infections. Given the herb’s inherent ability to inhibit various CYP450 enzymes, further studies to identify the clinical implications for herb-drug interactions are needed.

Although feverfew has been demonstrated to provide therapeutic benefit to isolated patient groups and at varying dosage levels, its clinical effectiveness has not been consistently reported. A variety of caveats associated with study design, identification or concentration of appropriate substance, or duration of evaluation from previous clinical studies complicate the assessment of the overall benefit of the herb. Despite inconsistent reports of effectiveness, the favorable safety profile and low risk of use suggest a positive risk benefit for patients looking for migraine prophylaxis treatment alternatives.

Garlic possesses a variety of beneficial pharmacological properties affecting most notably the cardiovascular system (lipid management, decreased blood pressure, platelet inhibition, and decreased fibrinolytic activity), and the immune system as an antineoplastic and immunostimulant agent. It is also a potent antioxidant. Although its effects are modest in some clinical applications, its inherent safety and culinary benefits usually support its use when a mild clinical effect is acceptable. There is the potential for interactions with drugs possessing antiplatelet and anticoagulant effects. Additionally, potential induction of various cytochrome P450 enzymes warrants closer monitoring of drugs metabolized through this pathway when garlic is concomitantly administered.

Ginger has been promoted for a variety of medical conditions and is purported to have carminative, diaphoretic, spasmolytic, expectorant, peripheral circulatory stimulant, astringent, appetite stimulant, anti-inflammatory, diuretic, and digestive effects. It is most commonly used in the United States for its antinauseant effects to relieve and prevent motion sickness, and relieve morning sickness in pregnancy. Ginger has compared favorably to a variety of other antinauseant therapeutic agents including metoclopramide, dimenhydrinate, promethazine, and scopolamine. Studies assessing therapeutic benefit for other uses such as an anti-inflammatory or antimutagenic agent are less impressive. Ginger has enjoyed a long history of safe use and concerns over a theoretical interaction with antiplatelet drugs has not been confirmed in clinical practice or adverse event reports.

Administration of saw palmetto can be effective in treating symptoms of benign prostatic hyperplasia, and its use may have benefit in stimulating hair growth. Adverse effects of saw palmetto therapy are usually mild and its use does not appear to result in significant drug interactions.