Droloxifene More Like Estrogen than Other SERMs
By William T. Elliott, MD, FACP
A new selective estrogen receptor modulator (serm), droloxifene, seems more like estrogen with respect to its effect on lipids and vascular endothelium than either tamoxifen or raloxifene. The drug was found to lower LDL 16.6% compared to 12.0% for estrogen. Droloxifene administration, however, had no effect on HDL, while estrogen raised HDL levels by 18.5%. Both drugs reduced Lp(a) and fibrinogen levels. Droloxifene also increased flow-mediated vasodilation by 36.4%, compared to 27.3% for estrogen. Droloxifene is a structural analogue of tamoxifen, and has estrogen-agonistic effects on bone and antagonistic effects on endometrial and breast tissue (Arterioscler Thromb Vasc Biol 2000;20:1606-1612). The drug is still in clinical trials.
RU-486 (mifepristone) is getting closer to market. The controversial abortion drug may be subject to restrictions imposed by the FDA, restrictions that the Population Council, the group that holds the patent for the drug, may be willing to accept. The restrictions include limiting use of the drug to physicians who are trained to perform surgical abortions, can monitor patients using ultrasound, and have easy access to emergency facilities. The Population Council is not happy about the restrictions, but it is anxious to get the drug to market after years of delay.
Infectious Disease
The CDC is starting an aggressive campaign to reduce the overprescribing of antibiotics. The concern is the development of antibiotic resistance, an increasing problem worldwide. The main thrust of the campaign will be to convince the public that antibiotics don’t work on viral infections and to present physicians with guidelines for prescribing antibiotics for respiratory infections. The campaign will start in seven states this summer.
Sexual Medicine
TAP Pharmaceuticals has announced that it is withdrawing its application for approval of apomorphine, a new drug for the treatment of erectile dysfunction (ED) in men. The drug, which was to be named "Uprima," had received a recommendation for approval by an FDA expert committee, but the consumer watchdog group Public Citizen had recently lobbied the FDA to deny approval. Their concern centered on reports of syncope, nausea, and vomiting at the highest dosage. TAP hopes to resubmit the drug for approval after more study. Bayer, on the other hand, is going ahead with plans to seek approval for its own ED drug—vardenalfil. The drug is still in trials, and will not be ready for marketing until at least 2002. Schering-Plough and Zonagen also have a product in the works, as do ICOS and Eli Lilly.
Cardiology
Use of the antiplatelet drug ticlopidine (Ticlid) has plummeted due to concern over thrombotic thombocytopenic purpura (TTP). Now cases of TTP are turning up associated with the use of clopidogrel (Plavix), the drug most physicians have used in place of ticlopidine. Eleven cases of TTP have been reported with use of clopidogrel, of which one patient died. The others responded to plasma exchange. There are some indications that TTP associated with clopidogrel may be more severe and difficult to treat than TTP associated with ticlopidine (N Engl J Med 2000;342:1773-1777,1824-1826).
A new "single bolus" thrombolytic has been approved for use in acute myocardial infarction. Genetech’s tenecteplase (TNKase) can been administered in a rapid IV bolus over five seconds. The drug has a very long half-life compared to other thrombolytics, allowing for a single rapid infusion. Genetech also makes Activase (alteplase, also known as tPA), currently the most commonly used thrombolytic in this country. In a head-to-head study of the two drugs in more than 17,000 patients, outcomes, including side effects, were similar. Tenecteplase should be available this summer.
According to a new study, amiodarone (Cordarone) is effective in terminating atrial fibrillation. A placebo-controlled study from Crete looked at more than 200 patients with new onset atrial fibrillation. Placebo resulted in conversion to normal sinus rhythm (NSR) in 40% of patients while amiodarone converted more than 80% of patients. The high response to placebo was not unexpected, and explains the misconception that drugs such as digoxin or beta-blockers result in conversion of atrial fibrillation, according to an accompanying editorial (Chest 2000;117:1529-1531,1538-1545). In related news, the Agency for Healthcare Research and Quality has just published a guideline entitled "Management of New Onset Atrial Fibrillation." It can be found at www.ahrq.gov/clinic/atrialsum.htm.
Gastroenterology
The FDA is getting closer to approving a second drug for the treatment of irritable bowel syndrome (IBS). The FDA’s Gastrointestinal Drugs Advisory Committee recently recommended the approval of tegaserod (Zelmac—Novartis Pharmaceuticals). Like alosetron (Lotronex), which was recently approved for this same indication, tegaserod is only indicated for women. Alosetron is a selective 5HT3 antagonist, while tegaserod is a 5HT4 antagonist. These serotonin receptors, which are present throughout the bowel, are thought to play a role in pain perception and GI motility. Alosetron was approved for IBS patients whose predominant symptom is diarrhea, but tegaserod may have a slightly different profile, causing diarrhea in 12% of patients in early trials.
Long-term therapy with the proton pump inhibitor omeprazole (Prilosec) appears to be safe. Early animal studies of high-dose omeprazole showed a higher than expected incidence of carcinoid tumors, but no long-term studies have been done in humans. The drug manufacturer recently sponsored a long-term study of omeprazole in patients who took an average of 20-40 mg daily for reflux. Some patients were followed for more than 10 years (average 6.5 years) with yearly endoscopies and gastric biopsies. Three patients exhibited intestinal metaplasia of the gastric mucosa, but none showed dysplasia or cancer (Gastroenterology 2000;118:661-669).
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