On Target - Weekly Journal, Issue September 24, 2000

I		WHAT'S NEW New Appointment Female Sexual Function Forum Meeting
II	..	HISTORY OF MEDICINE Ulcers
III		ASTHMA New Genes Can Help Determine Treatment Response
IV		HIV/AIDS New Drug Approval Urinary Crystals
V		UROLOGY Prostate Cancer
VI		CARDIOLOGY Identifying Risk Factors
VII		FDA New Antibiotic Labeling
		TARGET HEALTH INC.

TARGET HEALTH is pleased to announce the appointment of Mr. Joon You as Manager of Systems and Applications Development. Mr. You's mandate is to expand the growth of TARGET HEALTHs web-based technology. A major Phase 3 trial begins in October using Target e*CRF, followed closely by a Phase 3B program for the NDA which is being submitted this month. Other projects include four postmarketing studies with a novel device to be used in a spinal surgery setting. Please contact Mr. You for additional information jyou@targethealth.com .

TARGET HEALTH is pleased to announce that it is a sponsor of the Female Sexual Function Forum (FSFF) Scientific Meeting to be held in Boston October 26 - 29, 2000. This year TARGET HEALTH, in collaboration with Zonagen, Inc. and Bayer, A.G. completed the Phase 2 validation of the Female Sexual Function Index. The questionnaire can be found at http://www.fsfi-questionnaire.com/ and was recently published in the Journal of Sex and Marital therapy. Dr. Cindy Meston, of the University of Texas, Austin, will be presenting the results of the study. Dr. Ralph D'Agostino, who managed all of the statistical analyses, will also be attending.

Indigestion and heartburn have been described for thousands of years, but it was only in the 16th century that peptic ulcer disease was established by autopsy. At first, only gastric ulcers were identified. In the 18th century, duodenal ulcers were seen, most of which were fatal cases after perforation or hemorrhage. In the 19th century, when autopsy became a common and even routine hospital procedure, uncomplicated acute and chronic ulcers were found and then correlated with symptoms. Thus, our current clinical understanding dates from the 1820s, by which time peptic ulcers were being reported in the U.S. It is unclear why gastric ulcers were not diagnosed at The Mount Sinai Hospital (NYC) until 1873 and duodenal ulcers until 1885. However, after that time both conditions were diagnosed frequently, and they rapidly became common and were treated medically and surgically.

Asthma is a disease process where the bronchial airway contracts, causing wheezing and difficulty in breathing. Often it is caused by an allergy reaction to air pollutants, smoke or other substances. It can also be prompted in some people by exercise or even by emotion. About 17 million Americans suffer from asthma and about 5,000 die from the disease annually. Albuterol is the asthma drug most commonly used to control acute attacks. It works by blocking the beta-2-adrenergic receptor which causes muscles to relax and allows bronchial tubes to dilate, aiding the flow of air to the lungs.

According to an article published in the Proceedings of the National Academy of Sciences (Proc. Natl. Acad. Sci. USA, 2000, 97, 10483-10488), out of thousands of variations in a single gene, 12 genes have been identified that determine how well asthma patients respond to albuterol, a drug commonly used to prevent or to control acute asthmatic attacks. It is hoped that identifying the genes that affect the way a person responds to a drug, will help to tailor prescriptions for individual patients. In the study, the authors composed a profile of the gene associated with the beta-2 adrenergic receptor, which is the target of albuterol. A genetic variability was found that could lead to 8,192 combinations and 12 of the combinations were identified that directly affected the response to albuterol. These results were generated from drug response tests of 121 patients from different ethnic and racial backgrounds. According to the authors, based on the genetic patterns, it is now possible to identify asthma sufferers who have a high probability to respond well to albuterol and those who have a low probability of being helped. The authors said that similar genetic studies are now underway for all of the classes of drugs used to treat asthma.

A Phase 2 study in HIV/AIDS begins in October and new project for the treatment of diarrhea due to protease therapy is imminent. TARGET HEALTH is working closely with Dr. Bernie Bihari, one of the leading clinical researchers in the area of HIV/AIDS

FDA today issued an accelerated approval for Kaletra, a protease inhibitor, for adults and children greater than 6 months of age with HIV. Kaletra is a combination of lopinavir and ritonavir, (a previously approved protease inhibitor). Lopinavir's antiviral properties are combined with a low dose of ritonavir that inhibits lopinavir's metabolism. This results in blood levels of lopinavir that enhance its effectiveness against HIV. The new drug is used in combination with other anti-HIV drugs. It should be taken with food to increase absorption into the blood stream. The usual dose for adults is three capsules or 5.0 mL twice a day. Dosing for children ages 6 months to 12 years, determined by the child's weight, is also given twice daily. Side-effects associated with Kaletra are diarrhea, fatigue, headache, and nausea. Kaletra also produces increases in blood lipid levels (cholesterol and triglycerides) which in some patients may be large enough to require treatment. In addition, infrequent cases of pancreatitis have been observed among patients receiving antiretroviral regimens that included Kaletra. People with high levels of triglycerides in the blood can be at risk for pancreatitis. As observed with other protease inhibitors, Kaletra may also be associated with other significant or serious adverse events including increases in blood glucose, redistribution of body fat, and potentially serious or life-threatening drug interactions. Kaletra was studied in six controlled and one expanded access clinical trials and is manufactured by Abbott Laboratories, North Chicago, IL.

According to an article published in American Journal of Kidney Diseases (Am J Kidney Dis 2000;36:507-515), an unexpectedly high proportion of HIV-infected patients treated with indinavir develop crystalluria at some point during their first year of treatment. According to the authors, the study establishes the importance of standard urinalysis, including microscopy, in showing the presence of indinavir crystalluria. For the study, 54 asymptomatic indinavir-naive HIV-infected patients were monitored during their first year of indinavir therapy. Patients underwent urinalysis at day 3, week 1, week 2, and monthly thereafter. During the year, 67% of patients tested positive for indinavir crystalluria at least once. After the first 2 weeks, approximately one quarter of the patients tested positive at each time point during the study. According to the authors, these results may actually be underestimates, because in a controlled study, patients were probably unusually compliant with recommendations about water intake. Other urinalysis abnormalities were also common. In particular, most urinalysis tests showed low pH and high specific gravity. The authors stated that although the low urine pH may protect against indinavir crystalluria, the high urine specific gravity likely constitutes a major risk factor for the development of crystalluria. Since sufficient hydration could play a large role in preventing indinavir crystalluria and its potential consequences, the authors recommend that the current management of indinavir-treated individuals should include significantly increased water intake, particularly at the time of and during the first 4 hours after indinavir dosing.

TARGET HEALTH just completed a major Phase 2 study for a drug in the area of Urology. Target Health monitored the 12-center study, provided all data management and biostatistical services and is writing the study report in ICH format.

Recent results of in vitro studies have suggested that COX-2 inhibitors may have both anti-tumor and anti-angiogenic effects. Now, according to an article published in The Journal of Urology (J Urol 2000;164:820-825), NS398, a selective cyclooxygenase (COX)-2 inhibitor, suppresses growth of human prostate cancer cells in nude mice. In the study, the activity of NS398 was evaluated against the androgen-independent PC-3 human prostate cancer cell line in vitro and in nude mice. Results showed that, in vitro, NS398 significantly and dose-dependently reduced the viability of PC-3 cells to levels 23% and 11% of control after 4 and 5 days of treatment, respectively, by inducing widespread apoptosis (cell death). Similarly, when administered 3 times weekly to nude mice inoculated with PC-3 cells, NS398 produced a sustained inhibition of tumor growth, including complete remission of tumors in three of 14 mice. The authors also found that NS398-treated tumors had significantly decreased microvessel density (a measure of angiogenesis) compared with control tumors. Additional experiments demonstrated a 2.5-fold reduction in tumor levels of vascular endothelial growth factor (VEGF) after 9 consecutive weeks of NS398 treatment. According to the authors, these phenomena can be explained by the combination of direct (induction of tumor cell apoptosis) and indirect (reduction of tumor VEGF with resultant decreased angiogenesis) effects of the inhibitor. They additionally stated that these data provide a rationale for the use of currently available second generation COX-2 inhibitors as safe and effective chemotherapeutic agents for the treatment of prostate cancer.

TARGET HEALTH has just completed two manuscripts in the area of hypertension for a major blockbuster. The writing team included Anita Islam, Ph.D., Daisy Sun, M.S. and John McMurdo, MB. B.Ch (MD equivalent). Dr. Islam wrote the two ICH study reports supporting the manuscripts.

According to an article published in The New England Journal of Medicine (N Engl J Med 2000;343:826-833,879-880), asymptomatic men who have frequent premature ventricular depolarizations during exercise testing are at increased risk of death from cardiovascular disease. Frequent premature ventricular depolarization is defined as a run of two or more consecutive premature ventricular depolarizations or premature ventricular depolarizations constituting more than 10% of all ventricular depolarizations during any of the 30-second electrocardiographic recordings. For the study, data were analyzed from the Paris Prospective Study I which is comprised of 6,101 asymptomatic men who underwent exercise testing between 1967 and 1972 at 42 to 53 years of age. Of these subjects, 138 men were identified who had frequent premature ventricular depolarizations during exercise testing. Results showed that after 23 years of followup, these subjects had a higher risk of death from cardiovascular causes than men without frequent premature ventricular depolarizations during exercise (relative risk, 2.67). According to an accompanying editorial in the journal, Dr. Hugh Calkins, from Johns Hopkins University School of Medicine, Baltimore, Maryland, said that the increase in long-term cardiovascular mortality by a factor of more than 2.5 that is associated with the presence of frequent premature ventricular depolarizations during exercise is too great to be ignored and that these patients need aggressive risk modification and careful followup.

TARGET HEALTH excels in Regulatory Affairs and works closely with many of its clients and FDA. A pre-IND meeting is scheduled for the first week in October. 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. For additional information, please contact Dr. Jules T. Mitchel at TARGET HEALTH.

Many bacteria, such as those that cause pneumonia and other respiratory infections, meningitis, and sexually transmitted diseases, are becoming increasingly resistant to antibiotics used to treat them. Several bacterial species have developed strains that are resistant to multiple anti-microbial drugs. An important component of a comprehensive program to address the problem of bacterial resistance is decreasing the unnecessary use of antibacterial drugs. Over-prescribing and inappropriate use of antibiotics have contributed to a dramatic increase in drug-resistant bacterial infections. As a result, the FDA has just proposed that all systemic antibacterial drug products intended for human use contain additional labeling information about the emergence of drug-resistant bacterial strains. The proposal is intended to encourage physicians to prescribe systemic antibiotics only when clinically necessary. It also encourages physicians to counsel their patients on the importance of taking them exactly as directed.

FDA is proposing to require that the labeling for systemic antibacterial drug products include certain statements about the inappropriate use of antimicrobials and the link between inappropriate use and the emergence of drug-resistant bacterial strains. Under the proposal the labeling would state the following:

� Antibacterial drugs should only be used in situations where a bacterial infection is either proven or strongly suspected. Anti-bacterials do not treat viral infections.
� The type of bacteria involved in an illness and its antimicrobial susceptibility pattern should be used to direct the initial choice of an antibacterial.
� Antimicrobial therapy should be modified once microbiologic results are available.
� Patients should be counseled about the proper use of antibacterials and the importance of taking them only as directed.

A final rule based on this proposal would become effective one year after the date of its publication in the Federal Register. After that date, all systemic antibacterial new drugs and generic drugs (including drugs that have already been approved and are currently on the market) would have to comply with the labeling requirements.

TARGET HEALTH INC. is a full service CRO with full-time staff dedicated to all aspects of Regulatory Affairs, including IND, IDE, NDA, and PMA submissions, Clinical Research Management, Medical Writing, Biostatistics, Data Management, Strategic Planning and Drug and Device Development. TARGET HEATH's Pharmaceutical Advisory Dream Team (PADT) assists companies in strategic planning from discovery to market launch. Let us help you on your next project.

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