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7 August 2006

I.  WHAT'S NEW?
   TARGET DOCUMENT™
II.  QUIZ (Fill  In The Blanks)
   New Blood Test Detects Early Stage Breast Cancer
III.  HISTORY OF MEDICINE
   Early Origins of Aspirin
IV. PUBLIC HEALTH
   In 2005, Measles Came Back to the US From Romania
V. RHEUMATOLOGY
   Anti-CCL2 Monoclonal Antibody  - More Work Needed
VI. ORTHOPEDICS
Biphosphonate Treatment  in Osteogenesis Imperfecta
VII. INFECTIOUS DISEASE
   Smallpox Vaccine Can Be Diluted
VIII. FDA
   This Year's Flu Vaccine - 4 Manufacturers Cleared
IX. Target Health Inc.

I. WHAT'S NEW

TARGET DOCUMENT™

Target Health will be releasing an Internet-based document system for clinical trials, by the end of August. Target Document™ will allow for document uploads anywhere in the world, document ownership, multiple roles and responsibilities, full archiving, signature routing and electronic signatures. We can host the application, or we can do a technology transfer. Training of users takes about 2 hours and the administrator, just a little longer. Target Document™ is reasonably priced. For more information, please contact  Dr. Jules T. Mitchel.

II. QUIZ (Fill  In The Blanks)

New Blood Test Detects Early Stage Breast Cancer 

A new blood test that detects breast cancer at its earliest stage could become a vital weapon in fighting the disease. The test could pinpoint 1) ___ long before it would show up using other methods like 2) ___. This blood test, could be adapted to identify ovarian and prostate cancers as well. Trial results showed it was up to 1,000 times more 3) ___ than existing tests. The results could have far-reaching implications for diagnosis of the disease, which claims up to 400,000 lives a year worldwide. Breast cancer is the most common female cancer, with 1.1million new cases each year. Currently a combination of breast examination, imaging with mammography and 4) ___, and biopsy are used to diagnose the condition. The new diagnostic test works by detecting subtle changes in 5) ___ in the bloodstream, caused when the 6) ___ system starts to fight a cancer. The test may also help identify whether a tumor is 7) ___, ensuring that the best treatment can be quickly selected. Early detection of cancer gives the best chance of effective treatment. The five-year survival rate can be as high as 97% if the disease has not spread. The findings of the new blood test are reported in the Journal of Proteome Research, August 4th, 2006. The pilot studies show that using blood samples, breast cancer and several other types of epithelial cancers (ovarian, prostate, melanoma) can be detected with much better sensitivity and specificity. This may allow new, less 8) ___, safer and much less expensive approaches for the early diagnoses. It would also help in distinguishing malignant and benign 9) ___ and in monitoring cancer therapy.

ANSWERS: 1) cancer; 2) mammography; 3) sensitive; 4) ultrasonography; 5) proteins; 6) immune; 7) malignant; 8) invasive; 9) tumors

III. HISTORY OF MEDICINE

Early Origins of Aspirin  

Hippocrates, the father of modern medicine, lived sometime between 460 B.C.E. and 377 B.C.E. Hippocrates left historical records of pain relief treatments, including the use of powder made from the bark and leaves of the willow tree to help heal headaches, pains and fevers. In 1828, Johann Buchner, professor of pharmacy at the University of Munich, isolated a tiny amount of bitter tasting yellow, needle-like crystals from the willow bark, which he called salicin. Two Italians, Brugnatelli and Fontana, had in fact already obtained salicin in 1826, but in a highly impure form. However, not until 1829, did scientists discover, that it was the compound called salicin from willow bark, which was responsible for the pain relief. By 1829, Henri Leroux had improved the extraction procedure to obtain about 30 g from 1.5 kg of bark. In 1838, Raffaele Piria, then working at the Sorbonne in Paris, split salicin into a sugar and an aromatic component (salicylaldehyde) and converted the latter, by hydrolysis and oxidation, to an acid of crystallized colorless needles, which he named salicylic acid.

IV. PUBLIC HEALTH

In 2005, Measles Came Back to the US From Romania

Measles was declared eliminated from the United States in 2000 but remains endemic worldwide. However In 2005, a 17-year-old unvaccinated girl who was incubating measles, returned from Romania, creating the largest documented outbreak of measles in the United States since 1996. The following report, published in the New England Journal of Medicine (2006;355:447-455), describes the events around this potential public health crisis. The study was a case-series investigation, involving molecular typing of viral isolates, surveys of rates of vaccination coverage, interviews regarding attitudes toward vaccination, and cost surveys. What happened is as follows: one day after her return home, approximately 500 persons attended a gathering with the index patient. Approximately 50 of these persons lacked evidence of measles immunity, of whom 16 (32%) acquired measles at the gathering. During the six weeks after the gathering, a total of 34 cases of measles were confirmed. Of the patients with confirmed measles, 94% were unvaccinated, 88% were less than 20 years of age, and 9% were eventually hospitalized. Of the 28 patients who were 5 to 19 years of age, 71% were home-schooled. Vaccine failure occurred in two persons. The virus strain was genotype D4, which is endemic in Romania. Although containment measures began after 20 persons were already infectious, measles remained confined mostly to children whose parents had refused to have them vaccinated, primarily out of concern for adverse events from the vaccine. Seventy-one percent of patients were from four households. Estimated costs of containing the disease were at least $167,685, including $113,647 at a hospital with an infected employee. Prior to the epidemic, levels of measles-vaccination coverage in Indiana were 92% for preschoolers and 98% for sixth graders. According to the authors, this outbreak was caused by the importation of measles into a population of children whose parents had refused to have them vaccinated because of safety concerns about the vaccine. Fortunately, high vaccination levels in the surrounding community and low rates of vaccine failure averted an epidemic. Maintenance of high rates of vaccination coverage, including improved strategies of communication with persons who refuse vaccination, is necessary to prevent future outbreaks and sustain the elimination of measles in the United States.

V. RHEUMATOLOGY

Anti-CCL2 Monoclonal Antibody  - More Work Needed     

Chemokines such as CCL2/monocyte chemotactic protein 1 (MCP-1) play a key role in leukocyte migration and are potential targets in the treatment of chronic inflammatory disorders. As a result, a study published in Arthritis & Rheumatism (2006;54:2387-2392), was performed to evaluate the effects of human anti-CCL2/MCP-1 monoclonal antibody (ABN912) treatment in patients with rheumatoid arthritis (RA). For the investigation, patients with active RA were enrolled in a randomized, placebo-controlled, dose-escalation study of ABN912. Infusions were administered on day 1 and day 15. In the dose-escalation phase, 4 cohorts of 8 patients each underwent serial arthroscopic biopsy of synovial tissue. Immunohistochemistry and digital image analysis were used to characterize biomarkers in synovial tissue. Laboratory evaluation included pharmacokinetic analysis and immunotypic studies of peripheral blood mononuclear cells. To assess the clinical effects of treatment with ABN912, an additional 21 patients were treated with the highest tolerated dose. The total study population comprised 45 patients: 33 patients received ABN912, and 12 patients received placebo. ABN912 treatment was well tolerated. There was no detectable clinical benefit of ABN912 compared with placebo, nor did treatment with the study drug result in a significant change in the levels of biomarkers in synovial tissue and peripheral blood. Unexpectedly, there was a dose-related increase in ABN912-complexed total CCL2/MCP-1 levels in peripheral blood, up to 2,000-fold. According to the authors, ABN912 treatment did not result in clinical or immunohistologic improvement and may have been associated with worsening of RA in patients treated with the highest dose. The results might have been related to the greatly increased level of total CCL2/MCP-1 in serum that was observed following treatment with ABN912. This observation may be relevant for a variety of antibody-based therapies.

VI. ORTHOPEDICS

Biphosphonate Treatment  in Osteogenesis Imperfecta

Osteogenesis Imperfecta (OI) - commonly known as the "brittle bone" disease is a genetic disorder characterized by bones that break easily, often from little or no apparent cause. A person with OI may break a rib while coughing, or a leg by rolling over in their sleep. OI has been documented in all ethnic groups, and affects a person throughout his/her lifetime. Recently, a study published in the The Journal of Pediatrics (2006;149:174-179), was performed to evaluate prospectively the efficacy of bisphosphonate treatment in infants with severe forms of OI (Type III). For the study, just after diagnosis at birth, 5 newborns (group A) started treatment (2 mg/kg neridronate administered intravenously for 2 consecutive days, every 3 months) and 5 (group B) started treatment after 6 months. Ten untreated children, matched for gender, age, and clinical severity of OI, constituted a historical control group (group C). Weight, length, and number of fractures were measured every 3 months. Every 6 months, serum and urinary levels of calcium, phosphorus, creatinine, serum alkaline phosphatase, 25-hydroxyvitamin D, insulin-like growth factor I, parathyroid hormone, and osteocalcin, urinary type I collagen N-terminal telopeptide, and lateral radiography of vertebral column were measured. Results showed that Group A had better growth and a lower incidence of fractures than groups B and C in the first 6 months of treatment. In the second 6 months, both groups A and B had lower fracture rates than group C. After 12 months of therapy, osteocalcin and insulin-like growth factor I levels significantly increased only in group A. The urinary Ca/Cr ratio and N-terminal telopeptide/Cr ratio significantly declined only in treated patients. Vertebral body area and the structure of vertebral bodies improved in all treated patients, but especially in group A. It was concluded that cyclical neridronate treatment, started just after diagnosis at birth, had positive effects on growth and fracture rate.

VII. INFECTIOUS DISEASE

Smallpox Vaccine Can Be Diluted

Recent primary vaccine trials of diluted Aventis Pasteur smallpox vaccine (APSV) demonstrated that immunization "take" rates, defined by the presence of a vesicle or pustule ("take") at the inoculation site 6–11 days after immunization, did not differ between the dilution groups. However, there have been no studies that examine the cellular immune response or that distinguish CD4+ T cell responses from CD8+ T cell responses after primary immunization with varying dilutions of APSV.  As a result, a study published in The Journal of Infectious Diseases (2006;194:435-443), was performed to examine the cellular immune response,in vaccinia-naive healthy adults (n = 91) receiving inoculations with an undiluted or diluted (1:5 and 1:10) suspension of the APSV, using an intracellular cytokine staining assay. Results showed that the diluted vaccine induced vaccinia virus (VV)–specific CD4+ and CD8+ T cell responses 1 month after primary immunization that were comparable to those induced by undiluted vaccine. The cellular immune responses were correlated with the reactogenicity profile of subjects and did not differ between dilution groups. Furthermore, expression of the interleukin-7 receptor  chain, which has been proposed to distinguish antigen-specific T cells that differentiate into long-lived memory T cells, did not differ among groups, suggesting that dilution of the vaccine does not affect the quantity of VV-specific memory T cells. It was concluded that  APSV is an effective smallpox vaccine inducing strong humoral and cellular immune responses after a primary immunization even at diluted doses.

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.

This Year's Flu Vaccine - 4 Manufacturers Cleared

Influenza or "the flu" is a contagious respiratory illness caused by influenza viruses. It can cause mild to severe illness, and at times can lead to death. The best way to prevent this illness is by getting vaccinated. Although it is best to be immunized in the fall, getting the vaccine in the winter months when flu season often peaks is also recommended. According to the Centers for Disease Control and Prevention, every year in the United States, on average 5-20% of the population gets the flu, more than 200,000 people are hospitalized and approximately 36,000 people die from it. Some individuals are at high risk for serious complications from influenza, such as the elderly, children, and people with certain chronic medical conditions. Each year, influenza vaccine manufacturers submit information and samples of their virus strains being manufactured for the upcoming seasonal flu season, for review and testing in FDA laboratories. Because different influenza virus strains may appear each year, one or more of the strains in the vaccine may need to be changed to protect against what public health experts think are the strains most likely to be infectious that year. The FDA announced that it has approved this year's seasonal flu vaccines that include the new strains of virus judged likely to cause flu in the Northern Hemisphere in 2006-2007. This season's approved formulation is identical to that recommended by both the World Health Organization and FDA's Advisory Committee. The formulation includes one strain that was used in last year's vaccine and two new strains. Seasonal flu vaccines do not protect against avian flu, which is caused by different viral strains. There are four vaccine manufacturers approved to market their vaccines in the United States: Chiron Vaccines, Ltd.; GlaxoSmithKline Biologicals; MedImmune Vaccines, Inc.; and Sanofi Pasteur, Inc. The manufacturers have projected making a total of about 100 million doses of influenza vaccine for the 2006–2007 season, but these projections could change as manufacturing continues.

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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