February 2001 Therapeutics Letter

Feb 2001                                             Bruce H. Woolley, Pharm.D., Editor                                        Vol. 8, No. 2
Kenneth J. Hunt, Associate Editor

Stroke is one of the most preventable of all life-threatening health problems. Many of the risk factors for stroke are controllable, including hypertension, heart disease and lifestyle factors. Patients having one or more of the uncontrollable stroke risk factors are not necessarily fated to have a stroke. Proper attention to controllable stroke risk factors can reduce the impact of uncontrollable factors.

One of the easiest controllable risk factors to modify is hypertension. A recent report in the archives of internal medicine compared beta-blockers, ACE inhibitors, calcium-channel blockers, and thiazide diuretics, finding that thiazide diuretics are associated with a lower risk of ischemic stroke. This may indicate that these medications are the best choice as first-line treatment for hypertension.

Investigators from the Utrecht Institute of Pharmaceutical Sciences, the Netherlands, and a multicenter team collected data on 380 pharmacologically treated hypertensives who had a fatal or nonfatal first ischemic stroke between 1989 and 1996. They compared these patients with a control group of 2790 treated hypertensive patients who had no history of stroke. Reported risk of ischemic stroke was reported as higher among those who used beta-blockers (risk ratio (rr) 2.03), calcium-channel blockers (rr 2.30) or ACE inhibitors (rr 2.79) than among those who used a thiazide diuretic alone.

The article also reports that for single-drug users who had a history of cardiovascular disease, the adjusted risk ratio for stroke was higher for those who used beta-blockers (1.22), calcium-channel blockers (1.18), and ACE inhibitors (1.45), compared with patients who used a thiazide diuretic. These results are consistent with those of previous clinical trials that suggest the benefit of thiazide diuretics in lowering the risk of ischemic stroke.

Arch Intern Med 2001;161:37-43.
National Stroke Association http://www.stroke.org/

Herb Update: Turmeric and Cancer Prevention

Turmeric is a spice commonly used in curry powder that might help prevent and treat bowel cancer. A recent study released in January by the UK botanical pharmaceutical company Phytopharm reported that the spice, a member of the ginger family, is believed to have medicinal properties because it inhibits production of the pro-inflammatory enzyme cyclo-oxygenase 2 (COX-2), which is abnormally high in certain inflammatory diseases and cancers.

Phytopharm reported a trial in which the natural product, P54, had been subjected to a dose escalation study in 15 patients with advanced colorectal cancer at the Leicester Royal Infirmary NHS Trust and the Medical Research Council Center for Mechanisms of Human Toxicology. Five groups of patients were dosed orally once a day with 2, 4, 6, 8 or 10 capsules of P54, for up to 4 months. Several surrogate markers of potential anticancer activity were explored, including the ex vivo induction of COX-2 in whole blood. Antitumour activity was assessed clinically, biochemically and radiologically every 28 days.

The study did not identify a dose-limiting toxicity and all of the patients tolerated their allocated dose without any significant safety issues. The company reports that there was a dose-dependent decrease in COX-2 induction and five patients exhibited stable disease radiologically during 3-4 months of treatment.

Phytopharm is particularly interested in developing P54 as a food product for chemoprevention of bowel cancer, thereby bypassing the normal pharmaceutical regulatory pathway. This represents a tremendous potential market, with 300,000 people with colonic polyps in the UK alone who could start chemo-prevention in their forties and fifties and continue for the rest of their lives.

Two major companies in the United States, American Home Products and Merck, have already launched COX-2 inhibitors for arthritis and cancer indications may follow.

http://pharmacotherapy.medscape.com/reuters/
Biosci Biotechnol Biochem 1999 Dec;63(12):2118-22

GHB-Related Compounds - Addictive and Lethal

Gamma-hydroxybutyrate (GHB)-related compounds are known to produce toxic effects that range from vomiting to respiratory depression to loss of consciousness and death. According to a recent report from the Hennepin County Medical Center in Minneapolis, these compounds are also very addictive.

The authors report, in the January 11 issue of the New England Journal of Medicine, that the abuse of GHB-related compounds is increasing. People ingest GHB-related compounds for a variety of reasons: to get high, to treat insomnia, to improve athletic and sexual performance, and to fight stress and depression. These substances and their primary metabolite, gamma-hydroxybutyrate, are even marketed for the reduction of wrinkles, reversal of baldness, and sharpening of vision.

GHB was initially developed as an anesthetic, but its use is currently limited in the United States to narcolepsy clinical trials. The related compound, 1,4-butanediol, is an industrial solvent, which converts to GHB after ingestion. Gas chromatography is required to measure these compounds in body fluids and in products that are related with them. The authors warn physicians to be aware of the potential for addiction.

A treatment overdose of GHB can result in a patient waking up several hours after treatment and looking fine; the physician may never know what the patient had taken. It is thus important to ask patients if they are taking GHB or a GHB-related substance and to educate them on the dangers of the compound. One difficulty physicians and patients face is that they are marketed under a wide variety of names: anything from Rest-Eze, Zen, Serenity, or Easy Lay to Blue Nitro, BlueRaine, Thunder or Firewater - even Miracle Cleaning Products.

The authors urge emergency physicians to collect a urine specimen and test it for GHB if a patient comes in unconscious or a patient thinks something was slipped into his or her drink. It is often too late if you wait and collect a second specimen as the substance does not remain in the body for long. The website www.ashesonthesea.com/ghb contains GHB information and has a section specifically for GHB withdrawal.

N Engl J Med 2001;344:87-94.

Femara® FDA Approved for Breast Cancer Treatment

Breast cancer is currently the most common of all cancers in women. It is estimated that one in nine women will develop breast cancer in her lifetime. Numerous pharmaceutical companies are putting great effort into developing medications for the prevention and treatment of this common and deadly disease.

In the middle of January 2001, Novartis Pharmaceuticals announced that the FDA had approved the company's letrozole (Femara®/Novartis) tablets as first-line hormonal treatment for advanced breast cancer in postmenopausal women. The approval covers use in women with hormone receptor positive or hormone receptor unknown locally advanced or metastatic breast cancer. A majority of postmenopausal women with advanced breast cancer can be categorized in one to these two classifications.

The FDA's Oncologic Drugs Advisory Committee enthusiastically recommended Femara for approval based on Novartis' research comparing the drug with a generic version of tamoxifen, the gold standard for metastatic breast cancer.

Femara, a nonsteroidal aromatase inhibitor that acts by blocking estrogen synthesis, was initially approved by the FDA in 1997 as second-line treatment for advanced, hormonally dependent breast cancer. It is currently marketed in 75 countries.

J Exp Clin Cancer Res. 2000 Mar;19(1):17-9.
http://www.fda.gov/cder/

Fighting Antimicrobial Resistance

The US Department of Health and Human Services, working with 10 other governmental agencies and departments is beginning to develop a plan of attack on the threat of antimicrobial resistance. The National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda, Maryland, coordinating efforts with pharmaceutical companies and the FDA to focus their attention on public health needs, such as finding alternatives to existing classes of agents and novel means of treating and preventing infections.

Among top priorities are coordination of national, regional, state and local agencies charged with surveillance. The launch of a national public education campaign and preparation of clinical guidelines on best usage of antimicrobials are highlighted in the new action plan.

FDA Issues Warning on Accutane

The director for the FDA's Center for Drug Evaluation and Research, Janet Woodcock, M.D., recently issued a letter to health care providers warning of the risks of the drug Accutane® (isotretinoin). The letter was disbursed in response to inquiries from dermatologists and concerned citizens.

Dr. Woodcock cautions that although Accutane is highly effective for severe nodular cystic acne, is a known human teratogen causing a range of birth defects. There are also some concerns regarding psychiatric adverse events, including depression and suicide. The concerns had been brought before the Dermatologic and Ophthalmic Drugs Advisory Committee on September 18-19, 2000. Committee members concluded that further steps are necessary in addition to the warnings already in place by the manufacturer and the FDA to ensure the safe use of this drug.

The letter addresses three specific issues that had brought to the FDA's attention.

1. Appropriate use of the drug: Additional systematized measures to manage risk and fully inform patients and families should be instituted, given the devastating impact of potential side effects.
2. Educational efforts to prevent pregnancy exposure will be instituted. These will include systems approaches that build in mandated safety checks at critical points, providing much more effective support for prescribers, dispensers, and patients.
3. Psychiatric Events: Although no causal link has been established between Accutane and psychiatric problems, there is reasonable suspicion of an association. Thus, patients should be informed. The FDA recognizes the need for more scientific study of this issue, but also concedes that informative trials would present significant methodologic and ethical challenges.

The FDA is currently working diligently with the manufacturer to address the recommendations made by the advisory committee last year. Transcripts of this meeting can be found on the FDA's web site: http://www.fda.gov/ohrms/dockets/ac/accutane.htm.