On Target - Weekly Journal, Issue January 1st, 2000

I	..	WHAT'S NEW
II		HISTORY OF MEDICINE Hippocrates
III		BASIC RESEARCH Jelly Fish Genes COX-2 Inhibition
IV		CARDIOLOGY Natriuretic Peptide and Ace Inhibition ACE Inhibition and Cardiac Workload
V		DENTAL DISEASE Caries Prevention
VI		NATURAL PRODUCTS Green Tea Beta Carotene
VII		FDA ColorMax Lenses
VIII		TARGET HEALTH INC.

Please visit our new Target Health Publications page where you will find recent abstracts, articles and slide presentations prepared by TARGET HEALTH

Hippocrates of Cos was a Greek physician who lived around the 5th and 4th centuries B.C. Although he believed that "humors" and "foul vapors" caused disease, many of his teachings are consistent with modern medicine. Hippocrates believed that nature healed all wounds and the physician was a modifier of that natural healing. He taught that medications could produce a countereffect to the symptoms of a disease, "opposite through opposite". Although public opinion during his time condemned dissections of the human body, Hippocrates did perform them to a limited extent. He also emphasized the observation of external signs and symptoms in establishing diagnoses. In addition, Hippocrates dealt well with fractures and was a master in the use of splints. He even treated fractures of the skull with trepanning (removing a circular area of bone) and urged his students to be careful not to mistake suture lines for fractures. Most of all, Hippocrates was a good observer. This can best be demonstrated by his "Aphorisms" or his advice to physicians.

TARGET HEALTH has current programs early in the drug development process. These projects are offshoots of basic research in leading research centers. The strength of the pharmaceutical industry is its ability to translate basic research into marketed products.

According to an article published in Molecular Human Reproduction, jellyfish genes have been successfully placed into rhesus monkey embryos, a step that could lead to a better understanding of genetic diseases in humans. The jellyfish gene was chosen because it instructs cells to make a green protein that makes it relatively easy to track whether the gene has been transferred into a target embryo. The cells actually emit a green glow under certain lighting. According to the article, more than one-third of the monkey embryos produced by using the technique took up the jellyfish gene and began producing the green protein within two days. Seven embryo transfers were then attempted. One of the transfers resulted in a birth of a monkey named George. George, now 6 months, is reported to be a normal, happy frisky monkey. The jury is still out as to whether George is pure monkey, pure jellyfish or a hybrid.

According to an article published in Laboratory Investigation (Lab Invest 1999;79:1469-1477), specific inhibitors of cyclooxygenase (COX)-1 and -2 suppress angiogenesis (blood vessel growth) and tumor growth in rats with cancer grafts from different species (xenograft). The study examined the effects of COX-1 and COX-2 expression and inhibition on gastrointestinal tumor growth and angiogenesis in rats. In rats grafted with a COX-2-overexpressing tumor, oral treatment with either COX-2-specific inhibitors, such as NS-398, or nonspecific COX inhibitors, like indomethacin, suppressed the expression of several potent angiogenesis factors, as well as vascular endothelial growth factor and basic fibroblast growth factor. The inhibitors reduced angiogenesis and growth, induced apoptosis, and suppressed cell replication of the COX-2 overexpressing cancer xenografts in a dose-dependent manner. Even in a non-COX-expressing tumor xenograft, a nonspecific COX inhibitor reduced growth and angiogenesis by inhibiting COX-1 in vascular endothelial cells. By contrast, a COX-2-specific inhibitor had no effect in this model. As anti-cancer agents, specific COX-1 and COX-2 inhibitors appear to offer advantages over nonspecific COX inhibitors, in that COX-2-specific inhibitors are thought to exert anti-inflammatory and anticancerous effects with less toxicity than nonspecific COX inhibitors.

TARGET HEALTH has completed two abstracts to be submitted for publication in the area of hypertension. The abstracts are based on ICH study reports prepared by the medical writing group at TARGET HEALTH. Full publications are in preparation.

According to an article published in the American Heart Journal (Am Heart J 1999 ;138 :1005 -1006, 1126 -1132), levels of brain natriuretic peptide can be used to titrate the dosage of angiotensin-converting enzyme (ACE) inhibitors to optimal levels in patients with mild to moderate chronic heart failure. In the study, the efficacy of titrating ACE inhibitor dosage based on plasma brain natriuretic peptide, versus optimal empiric therapy, was examined in 20 patients with mild to moderate chronic heart failure receiving stable conventional therapy including an ACE inhibitor. Patients were randomized to one of the two treatments for 8 weeks. Plasma brain natriuretic peptide levels were reduced significantly compared with baseline throughout the study in patients randomized to the titration protocol, and were significantly suppressed relative to patients in the empiric therapy group after 4 weeks. Moreover, titration was associated with more profound inhibition of the renin-angiotensin-aldosterone system even in patients receiving apparently optimal ACE inhibitor therapy. While both treatment strategies were well tolerated and associated with favorable neurohormonal and hemodynamic changes, patients in the titration group had significantly greater mean decreases in heart rate and increases in plasma renin activity.

According to an article published in the American Journal of Hypertension (Am J Hypertens 1999;1188-1194), treatment with an ACE inhibitor, such as ramipril, not only lowers blood pressure but also appears to reduce cardiac workload during stress in patients with mild to moderate hypertension. In the study, blood pressure and heart rate responses during mental stress and a cold pressor test were measured in 28 patients with mild to moderate hypertension during a three-part study. During the first two phases of the study, patients were randomly crossed-over to either ramipril, 5 mg daily, or placebo for 6 weeks. During the last phase of the study, all patients received ramipril for 6 months. The unique finding of this study was that circulatory responses to mental stress (i.e., the relative increases in blood pressure and the increase in heart rate) were attenuated by ramipril. Specifically, ramipril reduced heart rate and systolic, but not diastolic, blood pressure during mental stress. In addition, both systolic and diastolic blood pressures were lower during the cold pressor test when patients were using ramipril than when they were using placebo. Heart rate responses, on the other hand, were reduced during the cold pressor test when patients used ramipril compared with placebo. Cardiac workload, defined as heart rate multiplied by systolic blood pressure, was reduced by ramipril during both the cold pressor test and mental stress. Also, the effects of ramipril on circulatory responses to stress increased with duration of treatment. According to the authors, the findings may indicate that ACE inhibitors may offer a significant advantage over other antihypertensive drugs in treating mild to moderate hypertension.

Dental disease is a major risk factor for cardiac disease. TARGET HEALTH was recently involved in a study in caries prevention through direct action of an antimicrobial agent against Streptococcus mutans.

According to an article published in Infection and Immunity (Infect Immun 1999;67:6543-6549), intranasal immunization with the glucan-binding region of glucosyltransferase from Streptococcus mutans protects against dental caries in mice. In the report, the mechanism explored was the synthesis of glucans from sucrose, mediated by the extracellular glucosyltransferase enzymes for the development of smooth-surface carious lesions. In the study, a chimeric vaccine was used in which the glucan-binding domain of S. mutans glucosyltransferase was fused with the thioredoxin unit of Escherichia coli, a step which increases the solubility of co-expressed recombinant proteins and stimulates proliferation of murine T cells. Control groups were immunized with the glucan-binding domain alone and with a sham vaccine. All vaccines were administered intranasally. Results showed that both immunogens produced sustained responses in serum, saliva, and the vaginal mucosa. Furthermore, mice immunized with the chimeric vaccine had a reduction in S. mutans colonization of more than 85% by 3 weeks. Animals immunized with the glucan-binding domain alone, however, required 5 weeks to show reductions of 50% or more. According to the study, animals immunized with either vaccine had significantly fewer carious lesions in the buccal enamel or dentinal surfaces than the sham-immunized animals. Although the chimeric vaccine was not significantly better than the glucan-binding domain alone in stimulating salivary IgA responses and in protecting against dental caries, the finding that the glucan-binding domain polypeptide alone is protective against disease offers a promising and safe strategy for the development of a vaccine against caries.

According to an article published in the American Journal of Clinical Nutrition (Am J Clin Nutr 1999;70:1040-1045), green tea extract may be useful in controlling body composition by activation of thermogenesis or fat oxidation. In the study, the 24-hour energy expenditure, respiratory quotient, and urinary excretion of nitrogen and catecholamines was measured in 10 healthy men randomly assigned to receive either placebo, caffeine alone or green tea extract. Subjects had measurements taken on three separate occasions in a respiratory chamber. Compared with placebo, treatment with green tea significantly increased 24-hour energy expenditure, significantly decreased the 24-hour respiratory quotient, and increased 24-hour urinary norepinephrine excretion. The effects did not appear to be due to caffeine, since subjects receiving amounts of caffeine similar to that found in green tea had no changes in any of the measurements. Green tea extract contains a high amount of catechin polyphenols and the authors suggest that because the catechins inhibit the norepinephrine-degrading enzyme catechol O-methyltransferase, and caffeine inhibits the cyclic AMP-degrading phosphodiesterases, green tea extract may have a more sustained effect of norepinephrine on thermogenesis. Stimulation of thermogenesis and fat oxidation by the green tea extract was not accompanied by an increase in heart rate, which might make green tea distinct from sympathomimetic drugs which can have adverse cardiovascular effects.

According to an article published in the Journal of the National Cancer Institute (J Natl Cancer Inst 1999;91:2068-2069,2102-2106), beta-carotene supplementation for 2 years produces neither benefit nor detriment in the prevention of cardiovascular disease or cancer in women. In the study, data were analyzed from the Women's Health Study to assess the effects of 50-mg beta-carotene supplementation on alternate days in healthy women aged 45 and older. It was reported that beta-carotene supplementation had no overall effect in preventing invasive cancer. Similarly there was no statistically significant evidence of an effect of beta-carotene on myocardial infarction, stroke, death from cardiovascular causes, the combined endpoint of all important cardiovascular events, or death from any cause. Because of previous studies suggesting that beta-carotene supplementation may be harmful to smokers, the authors examined the subset of women who smoked cigarettes (2,635 receiving beta-carotene and 2,600 receiving placebo). There were no differences in the number of confirmed cases of invasive cancer or in the combined endpoint of all important cardiovascular events. With the exception of skin yellowing, which was more prevalent in the beta-carotene group, there were no differences in side effects between the two groups of women

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.

Most people with color vision problems have partial color vision deficiencies that make it difficult to distinguish between red and green or between yellow and blue. ColorMax lenses (Color Vision Technologies, Inc., Tustin, CA) are coated with colored filters using a technology similar to that used to apply anti-reflection coatings on spectacles and colored coatings on prescription sunglasses. Although ColorMax lenses are the first such lenses to be cleared by FDA for commercial marketing in the United States, the idea is far from new. The use of colored filters as an optical aid for color deficiency has been reported in the scientific literature since the 1850's, and at least two textbooks on color vision deficiencies contain entire chapters on the subject. FDA marketing clearance for ColorMax Lenses is limited to red-green color deficiencies, and does not include yellow-blue deficiencies or total color blindness. The FDA has received a number of inquiries about ColorMax eyeglass lenses which are being promoted widely as a way to correct color blindness. Some of the claims in these promotions may be misleading. Contrary to reports, no special class of devices was created by FDA for these products.

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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