On Target

ON TARGET
COMPLIMENTARY NEWS LETTER OF TARGET HEALTH® INC.

25 November 2007

I. WHAT'S NEW?
Regulatory Meeting at Health Canada
II. QUIZ - (Fill In The Blanks)
Bacterial Conversation
III. HISTORY OF MEDICINE
Civil War Medicine
IV. PUBLIC HEALTH
Iraqi Veterans Suffering Long-Term Mental Health Problems
V. CARDIOLOGY
Dark Chocolate is Good For the Heart
VI. IMMUNOLOGY
There is No Relationship Between Childhood Vaccinations and Asthma
VII. REGULATORY AFFAIRS
FDA Approves Zyrtec (Cetirizine) for Nonprescription Use
VIII. TARGET HEALTH

I. WHAT'S NEW?

Regulatory Meeting at Health Canada

This past week, Dr. Glen Park, Sr. Director, Clinical and Regulatory Affairs presided at a very successful, highly interactive Pre-CTA meeting in Ottawa. The weather was beautiful and the view of the Ottawa River from the meeting room was breathtaking. The project is already ongoing in Israel, South Africa, and the US and will be shortly starting in Europe. Target Health is monitoring in the US and Canada, and performing 1) the global EDC trial, 2) data management, 3) biostatistics and 4) medical writing. We will also submit the NDA at the completion of the program.

For more information, please contact Dr. Jules T. Mitchel or Joyce Hays. For new business opportunities, contact Adrian Pencak, (Vice President, Business Development). Please visit our Website and Blog.

II. QUIZ (Fill In The Blanks)

Bacterial Conversation

Bacteria can 1) ___ between species, and have evolved mechanisms to interfere with the communication. Probably this is but one of many cunning strategies bacteria have for manipulating chemical communication. Certain snippets of their chemical conversation are almost universally understood. Howard Hughes Medical Institute researchers have found that bacteria of different 2) ___ can talk to each other using a common language, and that some species can manipulate the conversation to confuse other bacteria. The interspecies crosstalk and misdirection could have important consequences for 3) ___ health. The ability of cells to communicate with one another and the ability to interfere with the communication process could have consequences in niches containing competing species of bacteria or in niches where bacteria associate with humans. In the gut, the normal 4) ___ might interfere with cell-cell communication to thwart bacterial invaders. Using a chemical communication process called 5) ___ ___, bacteria converse among themselves to count their numbers and to get the population to act in unison. A synchronized group of bacteria can mimic the power of a multi-cellular 6) ___, ready to face challenges too daunting for an individual microbe going it alone. Swelling populations trigger their quorum-sensing apparatuses, which have different effects in different types of bacteria. One species might respond by releasing a 7) ___, while another might cut loose from a biofilm and move on to another environment. Each species of bacteria has a private 8) ___, but most also share a molecular vernacular, discovered about 10 years ago. A chemical signal called autoinducer-2 (AI-2), originating from the same gene in all bacteria, is released outside the cell to announce the cell’s 9) ___. Nearby bacteria take a local census by monitoring AI-2 levels and conduct themselves as the circumstances warrant. Researchers have speculated that AI-2 is a universal language, and the new studies from Princeton are the first to show those conversations taking place - and producing consequences — between co-mingling species. But this common language does not guarantee that the correct 10) ___ gets through. In an earlier study, it was found, that E. coli both produce and consume AI-2. This study set up an experiment where multitudes of E. coli first produced then devoured enough AI-2 to confuse marine bacteria, essentially fooling the thriving oceanic group into thinking its members were few, thereby terminating its quorum-sensing behaviors. In a more realistic encounter, E. coli was mixed with V. cholerae , the cholera-causing bacteria that mixes with E. coli in human guts. When cholera bacteria sense a quorum, they turn off their toxins and excrete an enzyme to cut themselves loose from the intestine in order move out of the body where they can infect another person. Here, E. coli squelched much of the quorum-sensing response of the cholera bacteria, although the effect was not as dramatic as with the marine bacteria. Consumption of the signal could be a mechanism that allows one kind of bacteria to block another kind of bacteria from counting how many neighbors they have and, in turn, properly controlling its behavior. This study moves us closer to really understanding how these 11) ___ interactions happen in nature.

ANSWERS: 1) communicate; 2) species; 3) human; 4) microflora; 5) quorum sensing; 6) organism; 7) toxin; 8) language; 9) presence; 10) message; 11) chemical

III. HISTORY OF MEDICINE

Civil War Medicine

The Civil War was fought, claimed the Union army surgeon general, "at the end of the medical Middle Ages." Little was known about what caused disease, how to stop it from spreading, or how to cure it. An injured Civil War soldier's chances of dying was about one in four. Working against incredible odds, however, the medical corps increased in size, improved its techniques, and gained a greater understanding of medicine and disease every year the war was fought. During the period just before the Civil War, a physician received minimal training. Nearly all the older doctors served as apprentices in lieu of formal education. Even those who had attended one of the few medical schools were poorly trained. In Europe, four-year medical schools were common, laboratory training was widespread, and a greater understanding of disease and infection existed. In contrast, the average medical student in the US trained for two years or less, received practically no clinical experience, and was given virtually no laboratory instruction. Harvard University, for instance, did not own a single stethoscope or microscope until after the war. When the war began, the Federal army had a total of about 98 medical officers, the Confederacy just 24. By 1865, some 13,000 Union doctors had served in the field and in the hospitals; in the Confederacy, about 4,000 medical officers and an unknown number of volunteers treated war casualties. It is estimated that more than 4,000 women served as nurses in Union hospitals. Civil War doctors managed to treat more than 10 million cases of injury and illness in just 48 months. Poet Walt Whitman, served as a volunteer in Union army hospitals, and claimed that "All but a few are excellent men...” Contrary to popular belief, anesthesia was available for injured soldiers. Surgeons would apply a cloth soaked in chloroform and knew enough to remove the rag often so that the patient would not get chloroform poisoning. Almost 3 out of every four operations was an amputation. Some doctors of that day had no real medical knowledge. For instance, one doctor suggested that each man should soap his socks in water each day, to avoid sores to the feet. Not only did this remedy not work, but also the soaps of that day were made of lye which would have made the sores even worse. One of the improvements during the Civil War was Hospital design. Before the War, hospitals were just one building, with no separation by illness. As a result, many died not of what they were in the hospital for, but of what someone else was suffering from. This changed during the War as hospitals were divided into wards for certain illnesses. This helped stop the spread of disease within the hospitals themselves. The Civil War brought US medicne out of the Middle Ages and became a catalyst towards the development of our current medical system.

IV. PUBLIC HEALTH

Iraqi Veterans Suffering Long-Term Mental Health Problems

In order to promote early identification of mental health problems among combat veterans returning from Iraq, the Department of Defense initiated population-wide screening at 2 time points, immediately on return from deployment and 3 to 6 months later. It appears that a previous article, which focused only on the initial screening, most likely underestimated the mental health burden. As a result, according to a article published in the Journal of the American Medical Association (2007;298:2141-2148), a study was performed to measure the mental health needs among soldiers returning from Iraq and the association of screening with mental health care utilization. The investigation was a population-based, longitudinal descriptive study of the initial large cohort of 88,235 US soldiers returning from Iraq who completed both a Post-Deployment Health Assessment (PDHA) and a Post-Deployment Health Re-Assessment (PDHRA) with a median of 6 months between the 2 assessments. The main outcome measures were the presence of posttraumatic stress disorder (PTSD), major depression, alcohol misuse, or other mental health problems, and referral and use of mental health services. Results showed that soldiers reported more mental health concerns and were referred at significantly higher rates 6 months after return from deployment when compared to after immediately returning from deployment. Based on the combined screening, clinicians identified 20.3% of active and 42.4% of reserve component soldiers as requiring mental health treatment. Concerns about interpersonal conflict increased 4-fold. Soldiers frequently reported alcohol concerns, yet very few were referred to alcohol treatment. Most soldiers who used mental health services had not been referred, even though the majority accessed care within 30 days following the screening. Although soldiers were much more likely to report PTSD symptoms on the PDHRA than on the PDHA, 49% to 59% of those who had PTSD symptoms identified on the PDHA improved by the time they took the PDHRA. There was no direct relationship of referral or treatment with symptom improvement. According to the authors, rescreening soldiers several months after their return from Iraq identified a large cohort missed on initial screening, and that the large clinical burden recently reported among veterans presenting to Veterans Affairs facilities seems to exist within months of returning home. Increased relationship problems underscore shortcomings in services for family members. Reserve component soldiers who had returned to civilian status were referred at higher rates on the PDHRA, which could reflect their concerns about their ongoing health coverage. Lack of confidentiality may deter soldiers with alcohol problems from accessing treatment.

V. CARDIOLOGY

Dark Chocolate is Good For the Heart

Coronary atherosclerosis is promoted by impaired endothelial function and increased platelet activation. Traditional risk factors, high oxidative stress, and reduced antioxidant defenses play a crucial role in the pathogenesis of atherosclerosis, particularly in transplanted hearts. It is well known that dark chocolate is rich with flavonoids with potent antioxidant properties. Thus, dark chocolate holds the potential to have a beneficial impact on graft atherosclerosis. As a result, a study published in the journal Circulation (2007;116:2376-2382) was performed to assess the effect of dark chocolate compared with cocoa-free control chocolate on coronary vascular and platelet function in 22 heart transplant recipients in a double-blind, randomized study. Coronary vasomotion was assessed with quantitative coronary angiography and cold pressor testing before and 2 hours after ingestion of 40 g of dark (70% cocoa) chocolate or cocoa-free (control), respectively. Two hours after ingestion of flavonoid-rich dark chocolate, coronary artery diameter was increased significantly (from 2.36 to 2.51 mm, P<0.01), whereas it remained unchanged in the control chocolate group. Endothelium-dependent coronary vasomotion improved significantly after dark chocolate (4.5%) versus -4.3% in the placebo group, (P=0.01). Platelet adhesion decreased from 4.9±% to 3.8% (P=0.04) in the dark chocolate group but remained unchanged in the control group. According to the authors, dark chocolate induces coronary vasodilation, improves coronary vascular function, and decreases platelet adhesion 2 hours after consumption, and that these immediate beneficial effects were paralleled by a significant reduction of serum oxidative stress and changes in serum flavonoid concentration.

VI. IMMUNOLOGY

There is No Relationship Between Childhood Vaccinations and Asthma

Atopy is the the genetic tendency to develop the classic allergic diseases -- atopic dermatitis, allergic rhinitis (hay fever), and asthma. Atopy involves the capacity to produce IgE in response to common environmental proteins such as house dustmite, grass pollen, and food allergens. Atopy comes from the Greek atopos, meaning out of place. The possible link between immunization and atopic diseases has been under intense debate in the last decade. As a result, a study was performed to systematically review the available evidence on the association of whole-cell pertussis and BCG vaccination with the risk of asthma in childhood and adolescence. For the study, the major medical electronic databases (Medline, National Library of Medicine Gateway, and Cochrane Library) were searched, and reference lists of the relevant publications were reviewed for relevant birth-cohort studies and randomized, controlled trials from 1966 to March 2006. Only studies that directly compared vaccinated and unvaccinated children, validated vaccination status by medical charts, and used preset criteria to define asthma were included. Data were abstracted by using a standardized protocol and computerized report form. Results were analyzed by applying a fixed-effect or random-effect model, according to the heterogeneity of the studies. Sensitivity analyses by scoring criteria were performed. For the analysis, seven studies of pertussis (whooping cough) vaccination with a total of 186,663 patients, and 5 studies of BCG vaccination (a preparation consisting of attenuated human tubercle bacilli that is used for immunization against tuberculosis), with a total of 41,479 patients met the inclusion criteria. Results showed no statistically significant association was detected between either whole-cell pertussis or BCG vaccination and incidence rates of asthma during childhood and adolescence. This lack of a significant association proved to be robust on sensitivity analyses for BCG but not for pertussis vaccine. According to the authors, currently available data, based on observational studies, do not support an association, provocative or protective, between receipt of the BCG or whole-cell pertussis vaccine and risk of asthma in childhood and adolescence.

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 Zyrtec (Cetirizine) for Nonprescription Use

After Dr. Mitchel left Consumer Health at Pfizer in the early 1990’s and prior to the establishment of Target Health, he ran the entire program to convert the ingredients now in Visine A (naphazoline hydrochloride and pheniramine maleate) from prescription to nonprescription use.

On November 9, 2007, the FDA announced that it had approved Zyrtec-D, a product which contains cetirizine HCl and pseudoephedrine HCl, for nonprescription use. Zyrtec, a drug developed by Pfizer, is marketed and distributed by McNeil Consumer Healthcare which bought Pfizer’s Consumer Health division. As a line extension, FDA has just approved tablet, chewable tablet, and syrup formulations of Zyrtec for nonprescription use. The nonprescription drug is approved for the temporary relief of symptoms due to hay fever or other respiratory allergies (sneezing; runny nose; itchy, watery eyes; itchy throat or nose) in adults and children 2 years of age and older. The tablets and chewable tablets are approved for the treatment of the symptoms of hay fever and other respiratory allergies, and to relieve the itching due to hives. The company will market two distinct Zyrtec products for each dosage form. One will provide directions for treating the symptoms of hay fever and other respiratory allergies. The other will contain directions for use to relieve the itching due to hives. Zyrtec may cause drowsiness in some people at recommended doses. Other common side effects include fatigue and dry mouth.

Sales to consumers of the Zyrtec-D are subject to restrictions in the Combat Methamphetamine Epidemic Act. This act places restrictions on the sale of products containing pseudoephedrine, such as limiting the amount that an individual can purchase, imposing record keeping requirements on the retail establishments that sell the product and that it be located with the pharmacist ("behind the counter").

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

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 HEALTH INC.
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Phone: (212) 681-2100; Fax (212) 681-2105

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Dr. Jules T. Mitchel, President
Ms Joyce Hays, CEO