Drug Interactions With St. John’s Wort

The National Institute of Health (NIH) recently conducted a study that showed a significant drug interaction between St John's wort (hypericum perforatum), an herbal product sold as a dietary supplement, and indinavir, a protease inhibitor used to treat HIV infection. Concomitant administration of St. John’s wort and indinavir substantially decreased plasma drug concentrations, potentially due to induction of the cytochrome P450 metabolic pathway.

The FDA issued a physician public health advisory against the concamitant use of St. Johns Wort with Indinavir and other antiretroviral agents. Based on the results of the study, it is expected that St John’s wort may significantly decrease blood concentrations of all of the currently marketed HIV protease inhibitors as well as other drugs that are metabolized in the same P450 system. This includes the NNRTIs (see Feb newsletter). The interaction between these drugs will result in suboptimal drug concentrations, leading to loss of virus response and development of resistance or class cross-resistance.

Herbal products are widely used in the United States and are readily available in various forms. It is important that health care professionals ask patients about concomitant use of products that could contain St. John’s wort (hypericum perforatum) or other herbal compounds. The FDA is working closely with drug manufacturers to ensure that product labeling of antiretrovirals is revised to highlight the potential for drug interactions with St. John’s wort.

St. John’s wort appears to be an inducer of the cytochrome P450 pathway. Many prescription drugs are also metabolized by this pathway, including heart disease, depression, seizures, certain cancers, and retrovirals. Health care providers should therefore alert patients about these potential drug interactions to prevent loss of therapeutic effect of any drug that is metabolized via the cytochrome P450 pathway.

As always, the FDA encourages health care professionals to report any serious adverse event associated with the concomitant use of prescription drugs and St. John’s wort products to their MedWatch program at 1-800-FDA-1088 (fax 1-800-FDA-0178).

Thanks to Piscitelli. Lancet 2000; 355(9203) 575-580 and http://www.fda.gov/cder/drug

Androstenedione Demonstrated to Increase Testosterone in Young Men

Androstenedione is a steroid hormone and the major precursor to testosterone is available without prescription in the United States. After home run record-breaker Mark McGuire admitted to using this substance, which is not banned by several professional sports, including Major League Baseball, there was a tremendous surge in popularity for the supplement. It is purported to increase strength and athletic performance, but the hormonal effects of the drug are unknown.

It has been estimated that 4.9% of male and 2.4% of female adolescents in the United States have used illegal androgenic/anabolic steroids. Because androstenedione is readily available as a dietary supplement, its use may be even greater. In 1998, Major League baseball and the NIH funded a randomized study to determine whether androstenedione increases serum testosterone concentrations in Young men

Androstenedione was administered at levels of 100 mg (15 subjects) or 300 mg (14 subjects) per day for 7 days to young, healthy men. Detailed measurements of serum sex-steroid hormone concentrations were made to subjects and controls. When compared with the control group, the change in testosterone levels was significant for the 300-mg/d group (P<.001) but not for the 100-mg/d group (P = .48). Baseline testosterone levels, drawn 24 hours after androstenedione administration, did not change. The change in the estradiol was significant for both the 300-mg/d (P<.001) and 100-mg/d (P = .002) groups. Researchers reported a large variability in individual responses for measured sex steroids.

The study, which was recently published in JAMA suggests that oral androstenedione at doses of 300 mg/day increases serum testosterone and estradiol concentrations in some healthy men. That oral androstenedione administration increases serum testosterone levels suggests that it could have androgenic or anabolic effects. It remains unknown if doses of androstenedione that increase testosterone levels would have significant effects on muscle size and function, though it is suspected that increases in androstenedione itself could have anabolic effects.

There are ongoing studies on androstenedione regarding the substance’s ability to increase muscle mass as well as its adverse effects. Long term studies in this area are required to determine safety and efficacy so that the substance may be classified appropriately.

JAMA. 2000;283:779-782

Management of Seasonal Affective Disorder

Depression and depressive episodes are a major public health concern in the United States. It is estimated that 17% of the general population will experience a depressive episode at some point in their lives. Major depressive disorders rank second only to unstable coronary artery disease in the number of days lost from work and number of days spent in nonpsychiatric hospitals each year. Because depressive disorders are so frequently encountered in society, health professionals should be familiar with the signs and symptoms of the illness, and ensure proper therapy.

Seasonal affective disorder (SAD) is a subtype of major depressive mood disorders characterized by recurrent seasonal patterns, with onset most commonly in fall or winter and remission in spring or summer. Approximately 4%-6% of the population experiences seasonal depression. The Journal of the American Pharmaceutical Association recently published a review of seasonal affective disorder, discussing the epidemiology and treatment of SAD.

The literature review demonstrated that SAD most likely results from a deficiency in serotonin. SAD identified as a subtype of bipolar and major depressive disorder. Diagnosis usually includes identifying prolonged depressive periods occurring during the last 2 years, with episodes generally beginning in fall or winter and remitting in spring. These episodes cannot be explained by seasonal stresses alone (seasonal unemployment). It is generally believed that lack of sunlight in the wintertime is a primary cause of SAD. The epidemiology of the disorder is consistent with this hypothesis as SAD is more prevalent with increasing lattitude (1.4% in Florida; 9.7% in New Hampshire).

Bright light therapy is the most commonly implemented and recommended therapeutic intervention and has the most experience and success. Selective serotonin reuptake inhibitors (SSRIs) and have also shown benefit in treating the disorder and may be preferentially used if patients have responded tot hem in the past or do not respond to light therapy. Some MAOIs and Beta-blockers have also been demonstrated to improve symptoms of SAD.

SAD is an important subtype of major depressive disorder. Clinicians should be familiar with the symptoms and remain vigilant in the diagnosis of the disease in their patients. It is most likely that serotonin is the major etiology, although other hypotheses are likely to contribute. Successful treatment includes light therapy or antidepressants, particularly SSRIs. Appropriate diagnosis and treatment of this disease will improve the quality of life for affected patients

J Am Pharm Assoc 39(6):822-829, 1999

The "B" Vitamins and Atherosclerosis

High concentrations of homocysteine in the blood are associated with an increased risk of premature atherothrombotic events. Researchers in the Netherlands recently published a randomized, placebo-controlled trial to investigate the effects of folic acid and vitamin B6 as a homocysteine-lowering treatment. The effects of the vitamins were studied on markers of subclinical atherosclerosis 158 healthy siblings of patients with premature atherothrombotic disease. Compared to placebo, the vitamin treatment group was associated with a decrease in homocysteine concentrations, and a decreased occurrence of abnormal exercise electrocardiography tests. Folic acid continues to demonstrate beneficial effects in a number of areas, including the prevention of neural tube defects and certain lines of colon cancer.

Lancet 2000; 355: 517 – 522

The dietary supplement industry continues to have more regulations placed on them by the FDA to protect the consumer. In February, the FDA advised dietary supplement manufacturers not to make any claims related to pregnancy on their products. The FDA also urges all pregnant women to consult their health care provider before taking any dietary supplements or medication.

The FDA is advising health care professionals and patients on the use of cisapride (PropulsidÒ /Janssen), a treatment for severe nighttime heartburn in patients with GERD. The new measures are being recommended to help physicians avoid giving cisapride to patients at known risk of rare-- but serious--cardiac events associated with the drug.

Patients who already take the drug are encouraged to ask their doctors about having the recommended tests performed and whether they should pursue other treatment options.

These actions are prompted by continuing reports of heart rhythm disorders and deaths associated mostly with the use of the drug in people who are taking certain other medications or who have underlying conditions that are known risk factors. Approximately 85% of adverse effect reports occurred in patients with identifiable risks.

It is advised that patients with any of the following conditions not take the drug:

• history of irregular heartbeats
• abnormal electrocardiogram (ECG or EKG)
• heart disease
• kidney disease
• lung disease
• low blood levels of potassium, calcium or magnesium
• eating disorder (such as bulimia or anorexia)
• dehydration or persistent vomiting.

Cisapride works by a prokinetic mechanism that moves harmful acids through the digestive tract preventing reflux into the esophagus. Healthcare providers are encouraged to report any adverse events related to cisapride to Janssen Pharmaceutica

(800-526-7736) or the FDA (800-FDA-1088)

FDA Talk Paper http://www.fda.gov/