31 July 2006

ON TARGET - Weekly Journal from Target Health Inc.

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31 July 2006

I. WHAT'S NEW?
History of Medicine, Volume 1, Is Available
II. QUIZ (Fill In The Blanks)
Stem Cells – Highly Complex Research
III. HISTORY OF MEDICINE
Early Hospitals
IV. HEMATOLOGY
Not All Aspirins Are The Same
V. OPHTHALMOLOGY
AMD Risk Factors - Smoking Yes, Fish Oils No
VI. CARDIOLOGY
High Carbohydrate, Low Glycemic Index Seems To Work?
VII. NEONATOLOGY
Diabetes, Perinatal Mortality and Congenital Abnormalities
VIII. FDA
Drug For Hunter Syndrome Approved - Orphan Drug
IX. Target Health Inc.

I. WHAT'S NEW

History of Medicine, Volume 1, Is Available

Target Health has assembled all of the articles published on History of Medicine, to date, and it is now available to our readers. The the first volume has been prepared as an educational document, free of charge, with no commercial intention. For a copy, please contact Dr. Jules T. Mitchel.

II. QUIZ (Fill In The Blanks)

Stem Cells – Highly Complex Research

Harvard U. is using private funding to develop about 100 new 1) __ cell lines from fertility-clinic embryos. Researchers, desperate for variety, are snapping them up. Not all embryonic-stem-cell lines are created 2) ___. Some cells are more readily driven to a certain lineage, such as heart cells, while others more easily become nerve cells. Scientists don't understand how it happens, but know that cell 3) ___ is needed. One study estimated that at best, a couple hundred cell lines might be derived from leftover 4) __ embryos, which tend to be weaker than those naturally fertilized. The fact that leftover embryos come from infertile couples may mean they are not typical. Also the process of freezing and thawing may be hard on delicate cells. After exhaustive ethical review, Harvard researchers announced that they would develop new cell lines through 5) ___ cell nuclear transfer, or therapeutic cloning. In this process, a cell from a patient with diabetes, for example, is inserted into an 6) ___ egg whose 7) ___ has been removed. The fertilized egg is prodded into growing in a petri dish for a few days until its stem cells can be 8) ___. Unlike fertility-clinic embryos, these cells would match the patient's 9) __, so the body would be less likely to reject a transplant derived from them. More exciting, this technique can yield embryos that serve as the perfect disease in a dish, revealing how a disease unfolds from the very first hours. Long-term promise is boundless, but immediate barriers are high. No one has yet succeeded in creating human-stem-cell lines through nuclear 10) ___. A new possibility doesn't use embryos at all. At Japan’s Kyoto University, studies show success in taking an adult skin cell, exposing it to four growth factors in a petri dish, and then transforming it into an embryo-like entity that could produce stem cells. This process may allow sidestepping the debate over means and ends.

ANSWERS: 1) stem; 2) equal; 3) diversity; 4) IVF; 5) somatic; 6) unfertilized; 7) nucleus; 8) harvested; 9) DNA; 10) transfer

III. HISTORY OF MEDICINE

Early Hospitals

The greatest contribution of Rome to battlefield medicine was the establishment of the hospital system. By the time of Hadrian (CE 98-138) each legion of 6,000 to 6,500 troops, had a legionary physician (medicus legionis) with medici cohortis assigned to each cohort of approximately 600 men. These military-establishment physicians were regarded as, exempt from guard and combat duty and ranked as non-commissioned officers. In the elite Praetorian and city cohorts, the physicians were required to be Roman citizens, while the physicians of the vigiles and auxiliary troops serving in Italy and the Roman provinces could be freedmen or foreigners. For this reason, the staff surgeons of the Roman army outside Rome were called medici ordinarii. Legionary physicians were considered all to be of equal rank, had no immediate medical superiors and were subordinate only to their camp commander; and in his absence, the tribunes of the legion. It was their task to supervise the food, clothing, encampment and general hygiene of the troops and to run the camp hospital. Each military camp had its own traveling valetudinarium to accommodate the sick and the wounded. According to the writer Vegetius, hospital personnel consisted of hospital superintendents, physicians, and sanitary personnel, who carried dressing materials in a pouch and were attended by pupil understudies.. A turn of the century excavation of a static Roman hospital at Köln, Germany revealed a well-laid out structure with design features that indicated awareness of infection and ways of preventing its spread. This hospital could accommodate up to 220 patients comfortably with 38 small wards, a dining room, two exercise quadrangles, sewers, water-piping, a heating plant and a kitchen. When the Romans withdrew from Britain in the 4th century, most of their customs and medical organization were stamped out by the invaders who followed. The army surgeon of Roman times did survive in Wales - there is a mention of medeci attached to the forces of Welsh kings - but in England and the rest of Europe, it is not until the Norman conquest and the Crusades that we again find a rudimentary form of medical attention on the battlefield.

IV. HEMATOLOGY

Not All Aspirins Are The Same

Aspirin resistance may be relatively common and associated with adverse clinical outcomes. Meta-analyses have clearly shown that 75 mg plain aspirin is the lowest effective dose. However, it is not known whether the recent increased use of enteric-coated aspirin could account for aspirin resistance. As a result, a study published in the journal Stroke (2006;37:2153-2158), was performed to determine whether enteric-coated aspirin is as effective as plain aspirin in healthy volunteers. For the study, 71 healthy volunteers were enrolled in 3 separate bioequivalence studies. Using a crossover design, each volunteer took 2 different aspirin preparations. Five aspirin preparations were evaluated, 3 different enteric-coated 75 mg aspirins, dispersible aspirin 75 mg and asasantin (25 mg standard release aspirin plus 200-mg modified-release dipyridamole given twice daily). Serum thromboxane (TX) B2 levels and arachidonic acid–induced platelet aggregation were measured before and after 14 days of treatment. Results showed that all other aspirin preparations tested were inferior to dispersible aspirin (P<0.001) in their effect on serum TXB2 level. Treatment failure (<95% inhibition serum TXB2 formation) occurred in 14 subjects, none of whom were taking dispersible aspirin. Mean weight for those demonstrating treatment failure was greater than those with complete TXB2 (>99%) inhibition (P<0.001). Using logistic regression analysis an 80-kg subject had a 20% probability of treatment failure. Asasantin was the most potent preparation in terms of inhibition of platelet aggregation. According to the authors, equivalent doses of the enteric-coated aspirin were not as effective as plain aspirin, and that lower bioavailability of these preparations and poor absorption from the higher pH environment of the small intestine may result in inadequate platelet inhibition, particularly in heavier subjects.

V. OPHTHALMOLOGY

AMD Risk Factors - Smoking Yes, Fish Oils No

A study, recently published in Archives of Ophthalmology (2006;124:995-1001), was designed to evaluate modifiable risk and protective factors for age-related macular degeneration (AMD) among elderly twins. The study was based on data derived from the US Twin Study of Age-Related Macular Degeneration. The study is composed of elderly male twins from the National Academy of Sciences, National Research Council World War II Veteran Twin Registry. For the study, in order to determine genetic and environmental risk factors for AMD, twins were first surveyed for a prior diagnosis of AMD, and then underwent 1) an eye examination, 2) fundus photography, and 3) food frequency and 4) risk factor questionnaires. This latter environmental component of the study included 681 twins: 222 twins with AMD (intermediate or late stages) and 459 twins with no maculopathy or early signs. Risk for AMD according to cigarette smoking and dietary fat intake was estimated using logistic regression analyses. Results showed that current smokers had a 1.9-fold increased risk (P = .06) of AMD while past smokers had about a 1.7-fold increased risk (P = .009). Increased intake of fish reduced risk of AMD, particularly for 2 or more servings per week (P trend = .04). Dietary omega-3 fatty intake was inversely associated with AMD (odds ratio, 0.55) comparing the highest vs lowest quartile. Reduction in risk of AMD with higher intake of omega-3 fatty acids was seen primarily among subjects with low levels (below median) of linoleic acid intake, an omega-6 fatty acid (P trend<.001). The attributable risk percentage was 32% for smoking and the preventive fraction was 22% for higher omega-3 intake. According to the authors, this study of twins provides further evidence that cigarette smoking increases risk while fish consumption and omega-3 fatty acid intake reduce risk of AMD.

VI. CARDIOLOGY

High Carbohydrate, Low Glycemic Index Seems To Work?

Despite the popularity of low-glycemic index (GI) and high-protein diets, there have been no randomized, controlled clinical trials which have systematically compared their relative effects on weight loss and cardiovascular risk. As a result, a study published in the Archives of Internal Medicine (2006;166:1466-1475), was performed to specifically address these issues. For the study, a total of 129 overweight or obese young adults (body mass index, > 25 [calculated as weight in kilograms divided by the square of height in meters]) were assigned to 1 of 4 reduced-fat, high-fiber diets for 12 weeks. Diets 1 and 2 were high carbohydrate (55% of total energy intake), with high and low GIs, respectively; diets 3 and 4 were high protein (25% of total energy intake), with high and low GIs, respectively. The glycemic load was highest in diet 1 and lowest in diet 4. The main outcome measures were changes in weight, body composition, and blood chemistry profile. Results showed that while all groups lost a similar percentage of weight (diet 1, -4.2%; diet 2, –5.5%; diet 3, –6.2%; and diet 4, –4.8%; P = .09), the proportion of subjects in each group who lost 5% or more of body weight varied significantly by diet (diet 1, 31%; diet 2, 56%; diet 3, 66%; and diet 4, 33%; P = .01). Women on diets 2 and 3 lost approximately 80% more fat mass (–4.5 kg and –4.6 kg) than those on diet 1 (–2.5 kg; P = .007). Mean low-density-lipoprotein cholesterol levels declined significantly in the diet 2 group (–6.6 but increased in the diet 3 group (+10.0, P = .02). Goals for energy distribution were not achieved exactly: both carbohydrate groups ate less fat, and the diet 2 group ate more fiber. According to the authors, both high-protein and low-GI regimens increase body fat loss, but cardiovascular risk reduction is optimized by a high-carbohydrate, low-GI diet.

VII. NEONATOLOGY

Diabetes, Perinatal Mortality and Congenital Abnormalities

According to an article published in the British Medical Journal (2006;333:177-180), a study was performed to determine information about the risk of perinatal mortality and congenital anomaly rates for babies born to women with type 1 or type 2 diabetes. The study included 231 maternity units in England, Wales, and Northern Ireland. The study population included 2,359 pregnancies to women with type 1 or type 2 diabetes who delivered between 1 March 2002 and 28 February 2003. The main outcome measures were 1) stillbirth rates; 2) perinatal and 3) neonatal mortality, and ; 4) prevalence of congenital anomalies. Of the 2,359 women with diabetes, 652 had type 2 diabetes and 1,707 had type 1 diabetes. Women with type 2 diabetes were more likely to come from a Black, Asian, or other ethnic minority group (type 2, 48.8%; type 1, 9.1%) and from a deprived area (type 2, 46.3% in most deprived fifth; type 1, 22.8%). Perinatal mortality in babies of women with diabetes was 31.8/1000 births. Perinatal mortality was comparable in babies of women with type 1 (31.7/1000 births) and type 2 diabetes (32.3/1000) and was nearly four times higher than that in the general maternity population. One hundred forty one major congenital anomalies were confirmed in 109 offspring. The prevalence of major congenital anomaly was 46/1000 births in women with diabetes (48/1000 births for type 1 diabetes; 43/1000 for type 2 diabetes), more than double that expected. This increase was driven by anomalies of the nervous system, notably neural tube defects (4.2-fold), and congenital heart disease (3.4-fold). Congenital heart disease was diagnosed antenatally in 23/42 (54.8%) offspring; anomalies other than congenital heart disease were diagnosed antenatally in 48/67 (71.6%) offspring. It was concluded that perinatal mortality and prevalence of congenital anomalies are high in the babies of women with type 1 or type 2 diabetes, but that the rates do not seem to differ between the two types of diabetes.

VIII. FDA

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.

Drug For Hunter Syndrome Approved - Orphan Drug

Hunter Syndrome, which usually becomes apparent in children one to three years of age, is a disease in which the person's body is defective in producing the chemical iduronate-2-sulfatase, which is needed to adequately breakdown complex sugars produced in the body. Symptoms include growth delay, joint stiffness, and coarsening of facial features. In severe cases, patients experience respiratory and cardiac problems, enlargement of the liver and spleen, neurological deficits, and death. The FDA has approved Elaprase (idursulfase), the first product for the treatment of Hunter syndrome (Mucopolysaccharidosis II, or MPS II). Elaprase is a new molecular entity, which is an active ingredient never before marketed in the United States. Elaprase was designated as an orphan product by FDA. Orphan products, such as Elaprase, are generally developed to treat rare diseases or conditions that affect fewer than 200,000 people in the U.S. The Orphan Drug Act provides a seven-year period of exclusive marketing to the first sponsor who obtains marketing approval for a designated orphan product. Hunter syndrome is diagnosed in approximately one out of 65,000 to 132,000 births. Elaprase was approved after a randomized, double-blind, placebo-controlled study of 96 patients with Hunter syndrome showed that the treated participants had an improved capacity to walk. At the end of the 53-week trial, patients who received Elaprase infusions experienced on average a 38-yard greater increase in the distance walked in six minutes compared to the patients on placebo. The most serious adverse events reported during the trial were hypersensitivity reactions to Elaprase that could be life-threatening. They included respiratory distress, drop in blood pressure, and seizure. Other frequent, but less serious adverse events included fever, headache and joint pain. Because of the potential for severe hypersensitivity reactions, appropriate medical support should be readily available when Elaprase is administered. Patients and their physicians are encouraged to participate in a voluntary Hunter Outcome Survey which has been established to monitor and evaluate the safety and effects of long-term treatment with Elaprase. Elaprase is manufactured by Shire Human Genetic Therapies, Inc., in Cambridge, MA.

For more information about our expertise in Regulatory Affairs, please contact Dr. Jules T. Mitchel or Dr. Glen Park.

IX. TARGET HEALTH

TARGET HEALTH INC. (www.targethealth.com) is a full service e*CRO 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 (PADT) assists companies in strategic planning from Discovery to Market Launch. Let us help you on your next project.

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