31 August 2003

I. WHAT'S NEW?
  Approval - Orphan Drug Designation
II. HISTORY OF MEDICINE
  Roswell Park, M.D.
III. CARDIOLOGY
  Chronic Use of NSAIDs May Negate Aspirin's Effect on First MI
IV. WOMEN'S HEALTH
  Low Dose Estrogen and Improved Bone Mineral Density
V. EPIDEMIOLOGY
  Mercury in Fish - How Toxic Is It?
VI. NUTRITION
  Dark Chocolate vs. Milk Chocolate
VII. FDA
   Electronic Submissions of Annual Reports for NDA's and ANDA's

I. WHAT'S NEW?

Approval - Orphan Drug Designation

Target Health Inc. is pleased to announce that it has once again assisted a client in obtaining Orphan Drug Designation for its drug product. This is the second time that we have been successful in obtaining Orphan Drug Designation. A new request was submitted last month for a third client. We are optimistic that this submission will be smooth sailing. Target Health performs all FDA submissions and will be preparing for 2 pre-IND meetings, submitting 3 IND's, and assembling one PMA over the next several months. Please let us know if you need any assistance in Regulatory Affairs.

II. HISTORY OF MEDICINE

Roswell Park, M.D.

Roswell Park, M.D., (1852-1914) is remembered for founding the world's first cancer institute a century ago, named The Roswell Park Cancer Institute. However, Dr. Park's accomplishments as a pioneer American neurosurgeon have been overlooked. After Park was appointed as Chair of Surgery at the University of Buffalo in 1884, he became the first American surgeon precisely to localize and remove a posttraumatic epileptic focus in the absence of external scars. Park introduced American physicians and surgeons to David Ferrier's research on localization of cerebral cortical function and Victor Horsley's techniques for extirpating epileptic foci. In 1895, Park became the first American surgeon to successfully treat spina bifida. In the same year, he wrote the first American monograph on surgery of the head. Park's case reports of successful operations on patients deemed almost incurable reveal boldness and ingenuity.

III. CARDIOLOGY

Chronic Use of NSAIDs May Negate Aspirin's Effect on First MI

Aspirin most likely reduces heart attack risk by irreversibly blocking the enzyme COX-1, thereby impairing the ability of platelets in the blood to form clots. Nonsteroidal anti-inflammatory drugs (NSAIDs) also lock on to COX-1, but the effect is reversible. There is clear evidence from numerous randomized trials and their meta-analyses that aspirin reduces risks of first myocardial infarction (MI). However, recent data have suggested that other NSAIDs may interfere with this benefit of aspirin. As a result, a subgroup analysis, published in the online edition of the journal Circulation (August 25, 2003), was performed from a 5-year randomized, double-blind, placebo-controlled trial of 325 mg aspirin on alternate days among 22,071 apparently healthy US male physicians with prospective observational data on their use of NSAIDs. During the course of the study, a total of 378 MIs were confirmed. Of these cases, 139 occurred in the aspirin group and 239 in the placebo group. It was clearly showed that subjects taking aspirin had a 44% (P<0.00001) reduction in risk of first MI. Results of the subgroup analysis showed that subjects taking an NSAID up to 59 times during the course of a year had no effect on the likelihood of a heart attack in either group. Also, taking an NSAID more often had no effect among the men taking a placebo. However, in the group taking aspirin, those who also took an NSAID on at least 60 days per year had a 2.8-fold higher risk of having an MI. According to the authors, these data suggest that regular, but not intermittent, use of NSAIDs inhibits the clinical benefits of aspirin. The authors added that chance, bias, and confounding still remain plausible alternative explanations, despite the prospective design and adjustment for covariates. Nonetheless, the authors felt that the most plausible interpretation of the data to be that regular but not intermittent use of NSAIDs inhibits the clinical benefit of aspirin on first MI.

IV. WOMEN'S HEALTH

 Low Dose Estrogen and Improved Bone Mineral Density

Estrogen therapy is known to prevent osteoporosis, but studies have shown that conventional doses increase adverse events. Whether lower doses, one quarter of standard treatment, prevent bone loss is not known. As a result, a study published in the Journal of the American Medical Association (2003;290:1042-1048) was performed to examine the effect of 3 years of treatment with 0.25 mg/day of micronized 17 beta-estradiol on bone mineral density (BMD) and bone turnover in healthy older postmenopausal women. The study was a randomized, double-blind, placebo-controlled trial conducted at a university general clinical research center in the United States. Subjects included healthy, community-dwelling women (N = 167) who were older than 65 years at the time of enrollment. The subjects received either 0.25 mg/day of micronized 17 best-estradiol (n = 83) or placebo (n = 84). All women who had not had a hysterectomy received 100 mg/day of oral micronized progesterone for 2-week periods every 6 months. The main outcome measures were the BMD of the hip, spine, wrist, and total body, measured annually for 3 years. Serum and urine biochemical markers of bone resorption and formation and sex hormones were measured at baseline, 3 months, and during years 1 and 3 of treatment. Results of the study showed that BMD increased at all sites for participants taking low-dose estrogen (17 beta-estradiol) compared with placebo (P<.001). Compared with participants receiving placebo, participants taking low-dose estrogen had BMD increases of 2.6% for the femoral neck; 3.6%, total hip; 2.8%, spine; and 1.2%, total body. Markers of bone turnover, N-telopeptides of type 1 collagen, and bone alkaline phosphatase decreased significantly (P<.001) in participants taking low-dose estrogen compared with placebo. Estradiol, estrone, and sex hormone-binding globulin levels increased in the estrogen-treated group compared with placebo. The adverse effect profile was similar between the study groups; specifically, there were no statistically significant differences in breast tenderness, changes in endometrial thickness or pathological effects, or annual mammographic results between the 2 groups. The number of abnormal mammograms over 3 years was 15 for the low-dose estrogen group and 10 for the placebo group (8 occurred at baseline) (P = .26). There were no reports of breast cancer during the study. The authors concluded that in older women, a dosage of 0.25 mg/day of 17 beta-estradiol increased bone density of the hip, spine, and total body, and reduced bone turnover, with minimal adverse effects. The authors recommended that future studies evaluating the effect of low-dose estrogen on fractures are indicated.

V. EPIDEMIOLOGY

Mercury in Fish - How Toxic Is It?

Mercury is a potent neurotoxin that is especially harmful to developing fetuses. Mercury can cause sensory loss, tremors, loss of muscular coordination, speech, hearing, and visual problems, as well as increased risk of heart attack. As a metal, mercury can build up in tissues. Mercury gets into the environment when toxic waste is burned and the mercury molecules fall from the smoke onto the ground and into water. There it builds up in the bodies of animals that eat contaminated plants and drink contaminated water. Predatory fish, such as tuna, swordfish and lake bass, are especially likely to have high levels of mercury in their flesh. For this reason, the U.S. government advises pregnant women to limit the amount of fish they should eat. Environmental toxicology studies have presumed that mercury is bound in its methylated form. The methylated form is highly toxic. According to an article published in the journal Science (2003;301:1203), the mercury that builds up in fish may be less dangerous than people feared. This finding which may come as good news to pregnant women and others who routinely eat fish, indicated the structure of the mercury compounds may make them less toxic to people. Results of the study demonstrated that the mercury in fish is actually attached to both a carbon atom and a sulfur atom. Since sulfur attaches more tightly to other elements than methyl groups do, it is possible that this mechanism would make the mercury less likely to be metabolized, or taken up, by the body. For the study, X-ray absorption spectroscopy was used to look at the physical structure of the mercury compounds in fish muscle tissue. When day-old zebra fish larvae were exposed to the two types of mercury salts, it was found the sulfur-mercury compound was less toxic than methylmercury chloride, the compound often used to determine the toxicity of mercury in fish. According to the authors, while methylmercury chloride has been used to model the toxic properties of mercury in fish, once it is understood how mercury is bound in mammalian tissues, there may be the possibility to better inform the public of its potential toxicity.

VI. NUTRITION

Dark Chocolate vs. Milk Chocolate

There has some speculation that dietary flavonoids from chocolate, in particular (-)epicatechin, may promote cardiovascular health as a result of direct antioxidant effects or through antithrombotic mechanisms. According to an article published in the journal Nature (2003;424;1013), a study was performed which demonstrated that consumption of plain, dark chocolate results in an increase in both the total antioxidant capacity and the (-)epicatechin content of blood plasma. However, these effects were markedly reduced when the chocolate was consumed with milk or if milk was incorporated as milk chocolate. For the study, 12 healthy volunteers who, on different days, ate either 100 grams (about 3 ounces) of dark chocolate alone, 100 grams of dark chocolate with milk, or 200 grams of milk chocolate. Blood analysis one-hour after dark chocolate was eaten showed a significant rise in antioxidant levels, including levels of (-)epicatechin. In contrast, not much change in antioxidant levels was seen after eating of milk chocolate or dark chocolate with milk. Moreover, (-)epicatechin absorption was much lower than when dark chocolate was eaten alone. According to the authors, the findings indicate that milk may interfere with the absorption of antioxidants from chocolate and may, therefore, negate the potential health benefits that can be derived from eating moderate amounts of dark chocolate.

VII. FDA

TARGET HEALTH excels in Regulatory Affairs and works closely with many of its clients and FDA and performs all FDA submissions. TARGET HEALTH receives daily updates of new developments at FDA. Each week, highlights of what is going on at FDA are shared to assure that new information is expeditiously made available.

Electronic Submissions of Annual Reports for NDA's and ANDA's

The FDA has issued a Draft Guidance for Industry: Providing Regulatory Submissions in Electronic Format--Annual Reports for New Drug Applications and Abbreviated New Drug Applications. This draft guidance is one of a series of guidances to assist applicants wishing to make electronic submissions to the FDA. The guidance addresses issues related to submissions in electronic format of Annual Reports for New Drug Applications and Abbreviated New Drug Applications. The draft guidance addresses two general issues: 1) if an electronic copy is submitted as the archival copy, there is no need to send a paper copy; and 2) until the FDA has developed procedures for electronic signatures, all signature pages still need to be sent in paper format. The draft guidance also provides rules on how to structure the submission. For a copy of the Guidance please contact (julesmitchel@targethealth.com).

VIII. TARGET HEALTH

TARGET HEALTH INC. (www.targethealth.com) is a full service e*CRO with fulltime staff dedicated to all aspects of drug and device development. Areas of expertise include Regulatory Affairs, comprising, but not limited to, IND, IDE, NDA, PMA and 510(k) submissions, execution of Clinical Trials, Project Management, Biostatistics and Data Management, Web Trials, utilizing Target e*CRF™™, our proprietary Internet-based Remote Data Entry (I-RDE? system, and Medical Writing. TARGET HEALTH's Pharmaceutical Advisory Dream Team (PADT) assists companies in strategic planning from Discovery to Market Launch. Let us help you on our next project.

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