3 February 2008
I. WHAT'S NEW?
Clinical Research at Target Health is Fully Integrated with EDC
II. QUIZ - (Fill In The Blanks)
Skin Biology
III. HISTORY OF MEDICINE
Hippocratic Treatise On Fractures (ca 400 BCE)
IV. CARDIOLOGY
Chlorthalidone (old diuretic) Superior Treatment of Hypertension in Metabolic Syndrome
V. ONCOLOGY
Genes Expression Shows Racial Differences in Prostate Cancer
VI. PULMONOLOGY
Snoring and Risk of Bronchitis
VII.
REGULATORY AFFAIRS
FDA Approves Drug-Eluting Stent
VIII. TARGET HEALTH
Clinical Research at Target Health is Fully Integrated with EDC
Target Health is pleased to announce that it has received a contract in the GI area to prepare the IND, perform protocol design, monitor the study, use Target e*CRF® for EDC and data management, perform the statistical analysis and write the study report. We are also winding down a 1,500 patient study at 45 sites for which we are also providing full CRO/EDC services. With Target e*CRF, and our excellent data management team, it has been painless to meet our time lines. We now have additional project management features integrated with Target e*CRF which reduces and/or eliminates the need for a separate CTMS.Skin Biology
Flamozil Ag is a gentle wound treatment developed by the Belgium Biotech company, Oystershell. This novel gel, combines a carbomer hydrogel for dry and exsudating wounds, with other novel ingredients. Carbomers, in organic chemistry, are expanded 1) ___, also called carbon-molecules. Without parabens, chemicals used as preservatives, Flamozil Ag is preserved by a patented silver dihydrogen citrate complex. Silver has a residual biological effect on skin fibroblasts and accelerates 2) ___ healing. Unlike other woundcare hydrogels, Flamozil Ag is not neutralized with arginine or NaOH. Instead the intrinsic skin factor L-Carnosine is used to stabilize the gel. 3) ___ are becoming increasingly aware of the potential adverse effects of parabens on skin. Methylparaben potentiates UV-induced damage of skin keratinocytes, decreases the proliferating ability of keratinocytes and changes the cell morphology in vitro. 4) ___ also decrease the expression of hyaluronan synthase 1 and 2 and type IV collagen and affect the epidermal differentiation of the skin. Following these concerns the Scientific Committee on Consumer Products (SCCP) of the EU has issued several reports trying to balance the issue and ended with a request to industry for more trial data. In wound care, where the 5) ___ barrier is no longer intact, many researchers believe, it is better to avoid parabens. The silver citrate in this new gel, kills microorganisms by two modes of action: 1) the silver ion deactivates structural and metabolic membrane proteins leading to microbial death; 2) the microorganisms view the silver citrate as a 6) ___ source and internalize it, thus allowing the silver ion to enter as well. Once inside the organism, the silver ion denatures DNA, which halts the microorganisms' ability to replicate, leading to its death. This dual action makes silver citrate highly and quickly effective against a broad spectrum of 7) ___. In addition, it is aqueous, colorless, odorless, non-irritating, with a long shelf life. Closer to skin 8) ___, by using L-carnosine in the manufacturing (patent pending), a biological buffer is incorporated in the product. L-carnosine is a natural skin factor and has been proven to scavenge ROS (radical oxygen species) as well as unsaturated aldehydes formed from peroxidation of cell membrane fatty acids during oxidative stress. Carnosine also interferes with skin protein cross-linking and glycation phenomena (7) facilitating wound healing. Based on the EPA toxicity categorization, the silver citrate concentration used, is rated in the lowest toxicity category. It is expected that Flamozil Ag, while not an antimicrobial treatment per se, will have a beneficial effect by protecting the wound from microbial infection.IV. CARDIOLOGY
Chlorthalidone (old diuretic) Superior Treatment of Hypertension in Metabolic Syndrome
People with metabolic syndrome have three or more risk factors for heart disease including elevated blood pressure (130/85 mmHg or higher), low HDL (good cholesterol) levels (HDL less than 40 mg/dL in men or less than 50 mg/dL in women), and diabetes or pre-diabetes (fasting blood glucose of 100 mg/dL or greater). A study, published in the Archives of Internal Medicine (2008;168:207-217) has shown that in people with high blood pressure as part of metabolic syndrome, diuretics offer greater protection against cardiovascular disease, including heart failure, and are at least as effective for lowering blood pressure as newer, more expensive medications. The findings run counter to current medical practices that favor ACE-inhibitors, alpha-blockers, and calcium channel blockers for treatment of high blood pressure in those with metabolic syndrome. In addition, the results provide important new evidence supporting the use of diuretics for initial blood pressure-lowering therapy in African- American patients with metabolic syndrome. The results come from the latest findings from the "Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial" or ALLHAT, sponsored by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health. ALLHAT is the largest study to compare a diuretic (chlorthalidone) with three newer classes of medications to treat high blood pressure: a calcium-channel blocker (amlodipine besylate), an alpha-blocker (doxazosin mesylate), and an angiotensin-converting enzyme (ACE) inhibitor (lisinopril). The ALLHAT study was a randomized, double-blind trial involving 42,418 participants, ages 55 and older with high blood pressure (140/90 mm Hg or greater) and at least one other risk factor for heart disease. Of those, 23,077 had metabolic syndrome at the time of enrollment. Roughly 35% of the study participants were black. Each drug was used to start treatment and other medications could be added if necessary to control blood pressure. The study originally reported in 2002 that diuretics were the most beneficial of the drug classes studied for treating high blood pressure and for protecting against adverse cardiovascular outcomes. This latest analysis shows that even among men and women with metabolic syndrome, and for both black and non-black (Caucasians, Hispanics, Asians/Pacific Islanders and American/Alaskan Natives) participants, the less costly diuretics consistently control blood pressure, are equally beneficial in preventing heart attack and coronary heart disease death. They are also more beneficial than newer medications in preventing one or more other forms of cardiovascular disease including heart failure and stroke. When compared with those taking diuretics, African-Americans with metabolic syndrome receiving ACE-inhibitors had poorer blood pressure control and a 24% greater risk of overall cardiovascular disease. This included a 19% greater risk of coronary heart disease, a 37% greater risk of stroke, and a 49% greater risk of heart failure. They also had a 70% greater risk of kidney failure.V. ONCOLOGY
Genes Expression Shows Racial Differences in Prostate Cancer
Prostate cancer is the second leading cause of cancer-related death among all men in the United States. However, incidence and mortality rates for this disease vary substantially among geographic areas and ethnic groups. Most notably, African-American men in the U.S. have the highest risk of developing prostate cancer, and, due to the development of more aggressive disease, they have more than twice the mortality rate observed for other racial and ethnic groups. According to an article published online in Cancer Research (1 February 2008), differences have been identified in gene expression (the degree to which individual genes are turned on or off) in prostate tumors between African-American and European-American men. These differences show the existence of distinct tumor microenvironments (the area that includes the tumor and the surrounding non-cancerous tissue) in these two patient groups. Since many of the genes that are differentially expressed between the tumors of African-American and European American men are related to the immune system, the results suggest that biological differences may, in part, underlie the disparity in prostate cancer survival rates observed between these groups. The study analyzed differences in gene expression in prostate tumors from 33 African-American and 36 European-American men. The analysis revealed higher expression of numerous genes that influence immune responses and the spread of cancer (metastasis) in the tumors of African-American men compared with European-American men. Among the genes with elevated expression in prostate tumors from African-American men were genes that encode different types of chemokines and their receptors. Chemokines are proteins released by cells to regulate both immune system function and cell migration. Two of these genes, CXCR4 and CCR7, have been linked to cancer metastasis and encode proteins that are commonly produced during inflammation and infection. In addition, expression of a number of genes that are induced by a cytokine called interferon was found to be elevated in the African-American prostate tumor tissues. Interferon is produced by cells in response to various pathogens, including viruses. This observation suggests the possibility that viral infections could be associated with the development of prostate tumors in African-Americans. As part of the study, the team also analyzed the expression of genes in non-cancerous prostate tissue from African-American and European-American men. They found that differences in the expression of genes related to immune system function were more prominent in the tumor microenvironment than in non-cancerous prostate tissue. Having uncovered genes that were expressed at different levels in tumors from these two ethnic populations, the researchers asked if the converse were true: Can differences uncovered in the profiles be used in a blind test to identify the ethnic origin of a prostate tumor sample? The researchers identified two potential candidate genes for successfully differentiating between tumors from African-American and European-American men. The genes, PSPHL and CRYBB2, were more highly expressed in the prostate tumors of African-Americans compared with European-Americans. While little is known about the functions of the two genes, PSPHL is located in a chromosomal region related to advanced tumor stage in prostate cancer.VI. PULMONOLOGY
Snoring and Risk of Bronchitis
It is well known that snoring is more prevalent in patients with chronic bronchitis than in persons without it. However, few studies have examined the effect of snoring on chronic bronchitis. As a result, a study published in the Archives of Internal Medicine (2008;168:167-173), was performed to prospectively investigate the association between snoring and the incidence of chronic bronchitis. The study cohort consisted of 5,015 male and female Korean citizens aged 40 to 69 years at baseline who participated in a comprehensive health examination and on-site interviews at Korea University Ansan Hospital. Of these, 4,270 participants (52% men and 48% women) entered the analysis for the first 2-year follow-up, and those who met the same inclusion criteria, remained in the analysis for a second 2-year follow-up period. Information was collected on snoring at baseline as well as incident cases of chronic bronchitis during a 4-year follow-up period. On the baseline questionnaire, participants were excluded who reported the presence of cough and sputum production on most days for at least 3 months a year. Results showed that during 4 years of follow-up, there were 314 documented new cases of chronic bronchitis (27.1 cases per 1000 person-years). After taking into account age, smoking, and other risk factors for chronic bronchitis, the multivariate relative risks of chronic bronchitis, compared with never snorers, were 1.25 for persons snoring 5 times per week or less, and 1.68 for those snoring 6 to 7 times per week (P for trend = .049). The analyses stratified by risk factors, including smoking, occupation, and body mass index, showed a stronger association among never smokers, house workers, and overweight persons. In analysis for the joint effect of smoking and snoring, the relative risks of chronic bronchitis were 1.39 for nonsmoking and snoring, 2.31 for smoking and never snoring, and 2.86 for smoking and snoring compared with nonsmoking and never snoring. It was concluded that snoring is associated with chronic bronchitis and that the findings provide support for the hypothesis that snoring influences the development of chronic bronchitis.VII. REGULATORY AFFAIRS
TARGET HEALTH excels in Regulatory Affairs and works closely with many of its clients performing 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.FDA Approves Drug-Eluting Stent
The FDA approved the Endeavor Zotarolimus-Eluting Coronary Stent for use in treating patients with narrowed coronary arteries. The Endeavor is the first drug-eluting stent approved since 2004 and the first since FDA convened its Circulatory System Devices Panel in 2006 to discuss evidence of the rare risk of blood clots occurring in patients who receive drug-eluting stents. Manufactured by Medtronic, Inc., of Minneapolis, the device is a tiny metal mesh tube coated with a small amount of a new drug, zotarolimus, developed only for use on a stent. It is crimped around a balloon and delivered to the narrowed section of the coronary artery via a long thin catheter during a procedure known as an angioplasty. Once the stent is positioned, the balloon is inflated, expanding into the vessel wall where it will remain in place, acting as a mechanical scaffold to keep the artery open. Slow release of zotarolimus over time prevents the artery from re-narrowing when new tissue begins to form. This process, known as restenosis, can eventually require a repeat angioplasty. Medtronic provided data from seven clinical trials in its marketing application. Studies showed that the Endeavor significantly reduced the number of major coronary events – heart attack, cardiac death and repeat procedures to re-open the artery – compared to a bare-metal stent (a stent without a drug coating). It also cut the restenosis rate by about half. Imaging studies on a subset of patients indicated that the Endeavor’s restenosis rate was higher than what is seen in currently marketed drug-eluting stents. However, the Endeavor had a similar number of coronary events when compared to one of these stents. The number of adverse events experienced by patients implanted with the Endeavor stent was similar to those that occurred in patients implanted with bare-metal stents and existing drug-eluting stents. Based on recent concerns over the rare but serious side effect of blood clots or stent thrombosis, FDA asked Medtronic to combine data from all Endeavor trials to determine how often this happened at various points in time following stent implantation. The stent thrombosis rate was 0.4 percent at one year and 0.5 percent at two years, a rate similar to that for bare-metal stents. To reduce such clotting risk, patients receiving the Endeavor will need to take blood-thinning medication for at least six months after implantation and should consider continuing this regimen for 12 months if they are not at an increased risk for bleeding complications. Patients who are allergic to zotarolimus or to cobalt, nickel, chromium, or molybdenum should not receive an Endeavor stent. Caution is also recommended for people who have had recent cardiac surgery and for women who are nursing or who may be pregnant. Medtronic will continue to follow patients enrolled in six of the Endeavor trials for five years. Additionally, the company will conduct a 2,000-patient U.S. post-approval study, which will be combined with 3,300 patients from a study conducted outside the United States, to assess the long-term safety and effectiveness of the Endeavor stent and to look for rare adverse events such as stent thrombosis. Medtronic will also collect clinical data to identify the optimal duration of blood-thinning medication.VIII. TARGET HEALTH
TARGET HEALTH INC. (www.targethealth.com) is a full service eCRO with full-time 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 Clinical Trial System, and Medical Writing. TARGET HEALTH's Pharmaceutical Advisory Dream Team assists companies in strategic planning from Discovery to Market Launch. Let us help you on your next project.TARGET
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