On Target - Weekly Journal, Issue March 12, 2000

I	..	WHAT'S NEW New Services From TARGET HEALTH
II		HISTORY OF MEDICINE Early Germans, Celts and Others
III		UROLOGY Race Differences in PSA Drug Approval
IV		ALLERGY Diphenhydramine Impairs Driving Performance
V		PUBLIC HEALTH New York is Again Being Attacked By Egypt from the West (Nile)
VI		CLINICAL TRIALS Expansion of the Cooperative Group System Hypertension - ALLHAT Trial Stopped
VII		FDA Fluoride Testing - Animal Caries Reduction Test
VIII		TARGET HEALTH INC.

TARGET HEALTH is pleased to announce that its Marketing Department will now provide expert design services to the pharmaceutical industry. This expansion is being led by TARGET HEALTH's VP of Marketing, Joyce Hays. The team also includes Nick Ozkan, Erwin Trace and Mui Ying Kwan. The department has created web pages, scientific posters, brochures, flyers, computer graphics, etc. For more information, please contact Joyce Hays (joycehays@targethealth.com) at 212-681-2100 to see what we can do for you.

Before the Roman conquests, the medicine of the Germans was mainly mystical or domestic. Demons were expelled from the body and sacrifices were given to appease the gods. The medicine man Kedfinger would touch the patient with a finger dipped in the blood of the victim to effect cures. Magic stones, and herbs collected on special days along with spells were the mainstay of medical care. Women had a special place in Pre-Roman Germanic medicine. l Tacitus wrote of the ancient Germans, "Ad Matres, ad coniuges vulnera ferunt, nec illae numerare et exigere plagus parent (they take their injuries to their mothers and wives, who do not fear to examine and treat their wounds)." Some groups of women healers were reported to have supernatural powers. After the fall of the Roman Empire, some areas that were not under the control of the Christian Church returned to the more primitive forms of medicine. The Gallo-Celtic peoples used this system until the monks christianized all of Europe and brought with them Roman-style medicine. Although mysticism remained, there was more reliance on herbalism and empirical medicine than before. During the Dark Ages, men completely controlled the practice of medicine. The office of healer was considered holy and reserved for the caste of Druids. They controlled medicine as well as science and religion for their people until the Benedictines and other monks changed them all forever.

Dr. Mitchel will be attending the annual meeting in Atlanta at the end of April. Please let us know if you will be attending.

Prostate Specific Antigen (PSA) is an enzyme made by prostate cells and is normally just secreted into semen. Both cancer and a number of benign conditions can change the architecture of the prostate so PSA gets secreted into the bloodstream. Once circulating, PSA can exist either free or bound to proteins. The standard PSA test measures both forms while the free PSA test looks at the ratio of free form to the total.

African-Americans have the highest rate of prostate cancer in the world which is approximately one-third greater than for whites. African-Americans also have higher PSA values when the cancer is diagnosed. The free prostate specific antigen test (fPSA) is a more sensitive test for cancer risk than the standard PSA test. fPSA was approved two years ago, based on a national trial of 773 men who had both tests as well as prostate biopsies. This earlier trial showed that fPSA detected 95% of the cancers and has reduced unnecessary prostate biopsies after the standard PSA test. Since its approval, the fPSA is becoming a follow-up test for men whose PSA falls in a "diagnostic gray zone" of moderately elevated levels (4-10 ng/mL). The risk of prostate cancer in this group is 25% in Caucasian and 30 to 50% in African-Americans.

According to an article published in the March 2000 issue of the journal Urology, fPSA provides improved accuracy in detecting prostate cancer in African-Americans. A review of data from a recent nationwide trial of the fPSA showed that fPSA is accurate in revealing cancer risk in African-Americans as it is in Whites. It also shows that many African-Americans could now be spared the expense and trauma of prostate biopsies. A variety of races took part in the original fPSA trial, but because the trial was comprised mostly of White men, there was a need to re-analyze the data specifically for the subset of African-Americans, who are at far higher risk for prostate cancer. The new analysis showed that no significant differences exist between Blacks and Whites in the performance of the fPSA test.

Leuprolide is currently used for palliative treatment of advanced prostate cancer, but until now, the drug had to be administered through frequent injections. Just recently, the FDA has approved ALZA's Viadur (leuprolide acetate implant), an annual palliative treatment for advanced prostate cancer. Viadur is the first product that provides continuous, 12-month testosterone suppression with a single treatment. The drug is also the first to incorporate ALZA's Duros implant technology. ALZA developed the once-yearly implant through a worldwide license from CRESCENDO PHARMACEUTICALS. CRESCENDO was formed by ALZA in 1997 to develop drugs and license them to ALZA.

Allergies are the sixth leading cause of chronic disease in the US and cost the health care system more than $10 billion annually.

According to an article published in the Annals of Internal Medicine (Ann Intern Med 2000;132:354-363,405-407), the first-generation antihistamine diphenhydramine impairs driving performance more than alcohol, in driving-simulator studies. In contrast, the newer medication fexofenadine does not differ from placebo. In this double-blind, crossover, randomized study, the effects of fexofenadine (60 mg), diphenhydramine (50 mg), alcohol and placebo were compared in 40 subjects in a 8-minute test on a driving simulator. After baseline evaluations, participants performed the driving exercise once a week for 4 weeks. It was reported that diphenhydramine was associated with significantly poorer driving coherence, the ability to maintain appropriate velocity based on a lead car that varied its speed, compared with alcohol, fexofenadine and placebo. The study also indicated that patients were more likely to cross the center line of the road while under the influence of alcohol or diphenhydramine than after taking fexofenadine or placebo. While subjects reported feeling drowsiest after taking diphenhydramine, it was reported that self-reported drowsiness was not associated with some measures of driving performance and only weakly predicted others. This suggested that drivers who use alcohol or diphenhydramine may probably be mistaken if they believe that lack of drowsiness means that they will be able to drive without impairment. The authors noted that some health programs prefer older antihistamines over newer medications, but that the cost savings of these programs should be weighed against the potential increased risk to the driving public.

According to the CDC, following the 1999 West Nile encephalitis outbreak in New York, guidelines were developed to direct surveillance, prevention, and control efforts. New York City and New York State were to develop comprehensive West Nile virus (WNV) surveillance and control programs, which included collecting overwintering Culex mosquitoes to determine whether WNV might persist throughout the winter. As part of this surveillance effort, adult Culex mosquitoes were collected during January-February 2000. Mosquitoes were sought from sites within the city's storm and sanitary sewer system, historic sites at Fort Totten in northeastern Queens, hangars and other locations at the abandoned Flushing Airport, and utility rooms under the Whitestone Bridge and under municipal swimming pools. Mosquitoes were pooled and then tested for the presence of WNV using vero cell plaque assay and a fluorogenic real-time PCR that focused on three different primer pairs: the envelope protein and the NS-1 and NS-5 regions. No pools produced live virus isolates. However, three of the 67 pools containing Culex spp. mosquitoes, all of which were collected from Fort Totten, reproducibly demonstrated low but detectable levels of WNV RNA.

TARGET HEALTH excels in the management of clinical trials and is currently managing several multicenter clinical trials. Our team is championed by Anita Islam, Ph.D. and Nicole Eland, BS and has just completed major projects in the areas of cardiovascular surgery and sexual dysfunction. A new Project Manager, with over 20 years of experience in cardiovascular clinical trials, will be joining TARGET HEALTH in April.

Phase III cancer clinical trials are the most reliable way to evaluate new treatments. The Cooperative Group system, established in 1955, yearly enrolls some 20,000 patients in NCI-supported multicenter clinical trials. Unfortunately, relatively few patients could participate in studies since, traditionally, only physicians who are members of NCI Cooperative Groups could enrol patients. To enable more patients and physicians to participate, the National Cancer Institute (NCI) is conducting a pilot project, the Expanded Participation Project (EPP). The EPP complements this system by extending clinical trials privileges to other qualified oncologists, with simplified administration as well as direct reimbursement for the time and effort involved in enrolling patients and collecting data. One obstacle, the paperwork typically required for each study participant, is lessened by the EPP's Internet-based data entry system. Patient information and study data are entered directly into the Internet, thus reducing time spent on paperwork. TARGET HEALTH has also developed an Internet-based data retrieval system and the potential is quite spectacular. EPP partners are provided $1,500 per patient to cover research-related costs.

About 50 million Americans have hypertension (HTN) and about 52 million have high blood cholesterol. Both conditions are major risk factors for coronary heart disease (CHD). HTN is also the chief risk factor for both congestive heart failure (CHF) and stroke. Treatment for both HTN and high cholesterol typically starts with lifestyle changes, including increased physical activity and weight loss. A healthy, low-saturated fat, low- cholesterol diet is advised for elevated cholesterol and, for HTN, the diet should avoid excess salt, sodium, and alcohol.

The National Heart, Lung, and Blood Institute (NHLBI) has stopped one part of a large HTN study because one of the drugs doxazosin (Cardura�), an alpha-adrenergic blocker, was found less effective than the diuretic (chlorthalidone) in reducing some forms of cardiovascular disease. The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was designed to compare newer drug treatments for HTN and elevated cholesterol with a more conventional and less costly treatment. The NHLBI acted after an independent data review showed that patients treated with doxazosin had 25% more CV events and were twice as likely to be hospitalized for CHF than users of chlorthalidone. The drugs were similarly effective in preventing heart attacks and in reducing the risk of death from all causes. Of the approximately 24 million Americans who take medication to treat HTN, about 1 million use an alpha blocker. Other alpha blockers used for HTN are terazosin (Hytrin) and prazosin (Minipres). Due to the finding, NHLBI is advising patients with HTN who now take an alpha-adrenergic blocker drug to consult with their doctors.

ALLHAT enrolled 42,448 patients, in 623 study centers Upon enrollment into the study, participants had been diagnosed with systolic and/or diastolic hypertension (140 mm Hg or higher and 90 mm Hg or higher, respectively), and had at least one added risk factor for coronary heart disease, such as diabetes, cigarette smoking, and a low level of high- density lipoprotein (HDL cholesterol), or had a history of (but no recent) heart attack or stroke.

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.

The FDA has received many requests to eliminate the animal caries reduction test as one of the testing requirements for fluoride in toothpastes (Final Monograph for OTC Anticaries Drug Products, Oct. 6, 1995). This monograph established conditions under which OTC anticaries drug products are generally recognized as safe and effective and not misbranded. FDA had concluded that differences in individual product formulations could greatly influence the effectiveness of fluoride toothpastes. Because inactive ingredients can affect the bioavailability, the FDA was concerned that newer formulations might reduce fluoride bioavailability during brushing. Because the animal caries reduction test directly measures effectiveness, FDA concluded that this test gave a more complete assessment compared with chemical tests. Although FDA has encouraged the development of alternative testing procedures, it has not yet received sufficient data to include a standard substitute test. Although testing in human subjects wearing a removable dental appliance containing enamel chips (intra-oral test) appears to offer certain advantages, there is disagreement as to whether this test is an appropriate substitute. The FDA will continue to accept petitions to allow substitute tests and will review each test on a product-specific basis.

TARGET HEALTH INC. is a full service CRO with full-time staff dedicated to all aspects of Regulatory Affairs, Clinical Research Management, Biostatistics, Data Management, Strategic Planning and Drug and Device Development. TARGET HEALTH also has a group of specialized advisors in the areas of Toxicology, Analytical Methods Validation, Product and Process Development, Quality Assurance, Manufacturing and Animal Health. Let us be of help to you on your next project.

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Last modified: March 15, 2000