NIH Interactions

Target Health Inc. is pleased to announce that Dr. Jules T. Mitchel will again be providing consultations to NIH in the area of clinical trials. Other government activities include 1) EDC services using Target e*CRF® for a critical treatment protocol in Juvenile Rheumatoid Arthritis, 2) participation in two Stimulus Grant Proposals, and 3) Regulatory Consultant for the CounterAct Program.

For more information about Target Health and any of our software tools for paperless clinical trials, please contact Dr. Jules T. Mitchel (212-681-2100 ext 0) or Ms. Joyce Hays (212-876-5000). Target Health’s software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website at:

Genetic Factors Hold Promise for Treatment of Vascular Diseases

Researchers have discovered a key switch that makes stem cells turn into the type of muscle cells that reside in the wall of blood 1) ___. The same switch might be used in the future to limit growth of vascular muscle cells that a) cause narrowing of arteries leading to heart attacks and strokes, b) limit formation of blood vessels that feed cancers, or 3) make new blood vessels for organs that are not getting enough 2) ___ flow. In a study published in the current issue of the journal Nature, the researchers found that a tiny RNA molecule, called microRNA-145 (miR-145), not only had all the information necessary to turn a stem cell into a vascular smooth 3) ___ cell (VSMC), but could also affect VSMCs in the adult artery. VSMCs have the unique property that they can start dividing when an artery is injured or during atherosclerosis, ultimately causing narrowing of the vessel. miR-145 and its sister microRNA, miR-143, work together to stop the pathologic division of VSMCs. In the setting of vessel disease, their activity is reduced, thus allowing the VSMCs to divide and clog up the 4) ___. microRNAs are small RNA molecules that do not make protein, but instead affect that amount of protein synthesized by the cell from their target mRNAs. miR-145 and miR-143 together control the synthesis of a network of “master regulators” that control VSMCs, and thereby are able to function as a central “switch” for the behavior of these cells. The ability of miR-145 to efficiently direct the cell fate of vascular smooth muscle cells from stem cells represents the power of these tiny microRNAs to exert major effects on cells. miR-143 is highly enriched when embryonic stem cells turned into cardiac stem cells, and miR-143 and miR-145 are both present as the heart forms in mice. miR-143 and miR-145 are directly controlled by a protein called myocardin, which itself is sufficient to “reprogram” an adult non-muscle cell into a 5) ___. Furthermore, the activation of these microRNAs by myocardin is necessary for myocardin to induce the VSMC fate. In one type of stem cell, miR-145 by itself was enough to completely push the stem cell into a functioning VSMC. These findings suggested that miR-143 and miR-145 are involved in the switch between the differentiation and proliferation of VSMCs – and thus contribute to vessel 6) ___ in heart disease. Interestingly, miR-145 mRNA is reduced to almost undetectable levels in atherosclerotic blood vessels with thickened walls. Since miR-145 is necessary and sufficient for differentiation of VSMCs, it is possible that restoring its activity could prevent the vessel narrowing in 7) ___. The targets that miR-145 and miR-143 regulate are not only major regulators of VSMCs, but also control whether cells divide excessively in conditions such as cancer. The down regulation of miR-145 in numerous cancers and the findings in this study, raise the possibility that miR-145 could function as a pro-differentiation factor in cancers and could be a new therapeutic target. The findings have fundamental implications for the treatment of vessel diseases like atherosclerosis and also may be important for 8) ___. The research was supported the National Institutes of Health, the California Institute for Regenerative Medicine (CIRM) and the American Heart Association. 


vessels; 2) blood; 3) muscle; 4) artery; 5) VSMC; 6) narrowing; 7) atherosclerosis; 8) cancer

Jamestown, VA – Historic Medical News

Forensic analysis of a small piece of human skull discovered by archaeologists in a 400-year-old trash pit at Historic Jamestown has confirmed that it is the earliest known evidence of surgery and autopsy in early 17th-century English America. It also tells a painful story about the final moments of one settler’s life. The bone was a piece of occipital bone from the back of the skull. This individual received a traumatic blow to the back of his head with an ax-like object made of stone, that fractured his skull. Circular cut marks in the bone show that a surgeon attempted to drill two holes in the skull using a trepan to relieve pressure. The procedure was not completed, probably because the patient died. Saw marks on the top edge of the bone indicated that an autopsy was subsequently performed. It was determined that the victim was an adult male because of the shape of the occipital bone and the pronounced muscle markings on the skull. The victim apparently died soon after he was injured, since the fractures do not show any sign of healing. The hand-size fragment of bone, about 4″ x 4 3/4″, was found in a bulwark trench surrounding the west corner of the James Fort site and was discarded there with other trash no later than about 1610, based on other artifacts found in the same area. No other bones or skull pieces belonging to the individual have been found. The skull is believed to be that of a European male because testing revealed that the bone contains traces of lead. This could be a result of eating and drinking from lead-glazed pottery or pewter, which was a common practice in Europe. Archaeologists have also unearthed medical tools and objects at the James Fort site including a Spatula mundani, part of a bullet extractor (terrabellum) and numerous pieces of pottery from apothecary jars, which were typically used to contain herbs and medicines. The Spatula mundani, devised and named by 17th-century surgeon John Woodall, was used to treat severe constipation. The spoon end of the instrument was to withdraw “hard excrements,” while the spatula was probably for stirring preparations and applying ointments and plasters. The bullet extractor was used for grabbing and removing a bullet from a wound. It is likely that the tools were sent to Jamestown in a surgeon’s chest that Woodall outfitted for the expedition. The gift is recorded in a list of instructions to Sir Thomas Gates from the Virginia Council in May 1609, and probably included the surgical instruments illustrated in the 1617 edition of Woodall’s book, “The Surgeon’s Mate.” The skull fragment and the medical objects substantiate historical documents that indicate the presence of barbers, surgeons (chirurgeons), doctors and apothecaries in Jamestown as early as 1607-1610.


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Sequential Treatment of Drug-Resistant Tumors with Targeted Minicells

According to an article published online in Nature Biotechnology (28 June 2009), a new method of attacking cancer cells has proved surprisingly effective in animal tests. The method is intended to avoid two major drawbacks of standard chemotherapy which is the lack of treatment specificity and the fact that cancer cells often develop resistance. For the study, mice were implanted with a human uterine tumor that was highly aggressive and resistant to many drugs. All of the treated animals were free of tumor cells after 70 days of treatment, while  the untreated mice were dead after a month. According to the authors, who work for EnGeneIC of suburban Sydney, Australia, similar outcomes have been achieved in more than 20 dogs with advanced brain cancer. The company has conducted successful safety tests in a large number of monkeys and will start safety trials in patients with all kinds of solid tumors in three Melbourne hospitals next month. The EnGeneIC method uses minicells to deliver a variety of agents to tumor cells, including both anticancer toxins and mechanisms for suppressing the genes that make tumors resistant to toxins. The minicells are generated from mutant bacteria which, each time they divide, pinch off small bubbles of cell membrane. The minicells can be loaded with chemicals and coated with antibodies that direct them toward tumor cells. No tumor cell, so far as is known, produces a specific surface molecule for toxins to act on. But 80% of solid tumors have their cell surfaces studded with extra-large amounts of the receptor for a particular hormone, known as epidermal growth factor. The minicells can be coated with an antibody that recognizes this receptor, so they are more likely to attach themselves to tumors than to the normal cells of the body. The tumor cells engulf and destroy the minicells, a standard defense against bacteria, and in doing so are exposed to whatever chemicals the minicells carry. What also helps direct the minicells toward tumors is that the blood vessels around tumors tend to be leaky, and the minicells are small enough to leave the circulation at the leak sites. The minicells do not seem to stimulate the immune system, even though they are made of bacterial cell membrane. The reason may be that the provocative parts of the membrane are masked by antibodies with which the minicells are coated. For the study, cancer-ridden mice were treated with two waves of minicells. The first wave contained an agent that suppressed an important gene for toxin resistance. That gene makes a protein that pumps toxin out of cells, and is a major cause of the resistance that tumors often develop toward chemotherapeutic agents. After the toxin-expelling gene had been knocked down in the tumor cells, a second wave of minicells were injected, each loaded with half a million molecules of doxorubicin, a toxin used in chemotherapy. The two-wave treatment arrested tumor growth in mice implanted with either human colon or human breast tumors, and enabled mice with drug-resistant human uterine tumors to eliminate the tumors altogether. The idea of treating cancer with bacteria goes back to the 19th century, when physicians noticed that cancer patients who became infected sometimes enjoyed a remission.


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Influenza Virus in 1918 and Today

Influenza viruses have eight genes, two of which code for virus surface proteins-hemagglutinin (H) and neuraminidase (N)-that allow the virus to enter a host cell and spread from cell to cell. There are 16 H subtypes and 9 N subtypes, and, therefore, 144 possible HN combinations. However, only three (H1N1, H2N2 and H3N2) have ever been found in influenza viruses that are fully adapted to infect humans. Other combinations, such as avian influenza H5N1, occasionally infect people, but they are bird viruses, not human viruses. The eight influenza genes can be thought of as players on a team: certain combinations of players may arise through chance and endow the virus with new abilities, such as the ability to infect a new type of host; that is likely what happened to spark the 1918 H1N1 pandemic.


It has been shown that the founding virus was an avian-like virus. The virus had a novel set of eight genes and-through still-unknown mechanisms-gained the ability to infect people and spread readily from person to person. The influenza virus that wreaked worldwide havoc in 1918-1919 founded a viral dynasty that persists to this day. In an article published online on June 29 by the New England Journal of Medicine, the authors argue that we have lived in an influenza pandemic era since 1918, and they describe how the novel 2009 H1N1 virus now circling the globe is yet another manifestation of this enduring viral family. According to Dr. Anthony Fauci, one of the authors “The 1918-1919 influenza pandemic was a defining event in the history of public health,” and that the legacy of that pandemic lives on in many ways, including the fact that the descendents of the 1918 virus have continued to circulate for nine decades.” Not only did the 1918 H1N1 virus set off an explosive pandemic in which tens of millions died, during the pandemic the virus was transmitted from humans to pigs, where-as it does in people-it continues to evolve to this day. All human-adapted influenza A viruses of today-both seasonal variations and those that caused more dramatic pandemics-are descendents, direct or indirect, of that founding virus, and thus we can be said to be living in a pandemic era that began in 1918. How exactly do new influenza gene teams make the leap from aquatic birds to a new host, such as people or other mammals? What factors determine whether infection in a new host yields a dead-end infection or sustained, human-to-human transmission, as happened in 1918? Research on such topics is intense, but at this time definitive answers remain elusive. It is known that the human immune system mounts a defense against the influenza virus’s H and N proteins, primarily in the form of antibodies. But as population-wide immunity to any new variant of flu arises, the virus reacts by changing in large and small ways that make it more difficult for antibodies to recognize it. For nearly a century, then, the immune system has been engaged in a complicated pas de deux with the 1918 influenza virus and its progeny. The partners in this dance are linked in an endless effort to take the lead from the other. While the dynasty founded by the virus of 1918 shows little evidence of being overthrown, the authors note that there may be some cause for optimism. When viewed through a long lens of many decades, it does appear that successive pandemics and outbreaks caused by later generations of the 1918 influenza dynasty are decreasing in severity. This is due in part to advances in medicine and public health measures, but this trend also may reflect viral evolutionary pathways that favor increases in the virus’s ability to spread from host to host, combined with decreases in its tendency to kill those hosts. According to the authors, although we must be prepared to deal with the possibility of a new and clinically severe influenza pandemic caused by an entirely new virus, we must also understand in greater depth, and continue to explore, the determinants and dynamics of the pandemic era in which we live.

Migraine Frequency and Risk of Cardiovascular Disease in Women 

While migraine has been associated with risk of cardiovascular disease (CVD), data on the association between migraine frequency and CVD are sparse. As a result, a study published on line in Neurology on 24 June 2009), was performed with 27,798 US women aged 45 years, who were free of CVD, and for whom information was available on their lipids and migraine frequency. For each subject, migraine frequency was categorized as < monthly, monthly, and weekly. Incident CVD was confirmed after medical record review. Results showed that of the 3,568 women with active migraine at baseline, 75.3% reported a migraine frequency of < monthly, 19.7% monthly, and 5.0% weekly. During 11.9 years of follow-up, 706 CVD events occurred. Compared with women without migraine, the multivariable-adjusted hazard ratios (HRs and CI) among active migraineurs for CVD were 1.55 (1.22-1.97), 0.65 (0.31-1.38; ns), and 1.93 (0.86-4.33; ns) for an attack frequency of < monthly, monthly, and weekly, respectively. The association between migraine frequency and CVD was only apparent among with migraine with associated aura. Among those, the multivariable-adjusted hazard ratios (HRs) for women with a migraine frequency < monthly ranged from 1.81 for coronary revascularizations to 2.43 for myocardial infarction. For women with active migraine with aura and migraine frequencies of weekly, had a significant increased risk of ischemic stroke (HR = 4.25). According to the authors, the association between migraine and cardiovascular disease varies by migraine frequency and that significant associations were only found among women with migraine with aura. Ischemic stroke was the only outcome associated with a high-attack frequency while a low-attack frequency was associated with any vascular event.

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 Multaq to Treat Heart Rhythm Disorder

Atrial fibrillation and atrial flutter cause the heart to beat abnormally fast and sometimes prevent blood from being properly pumped out of the heart. The FDA has approved Multaq tablets (dronedarone) to help maintain normal heart rhythms in patients with a history of atrial fibrillation or atrial flutter (heart rhythm disorders). The drug is approved to be used in patients whose hearts have returned to normal rhythm or who will undergo drug or electric-shock treatment to restore a normal heart beat. Multaq may cause critical adverse reactions, including death, in patients with recent severe heart failure. The drug’s label will contain a boxed warning, the FDA’s strongest warning, cautioning that the drug should not be used in severe heart failure patients. According to the FDA, Multaq represents a therapeutic innovation for treatment of the heart rhythm disorder of atrial fibrillation. In a multinational clinical trial with more than 4,600 patients, Multaq reduced cardiovascular hospitalization or death from any cause by 24%, when compared with an inactive pill (placebo). Most of that effect represents reduced hospitalizations, especially hospitalizations related to atrial fibrillation. The most common adverse reactions reported by patients in clinical trials were diarrhea, nausea, vomiting, fatigue and loss of strength. Multaq is manufactured by Paris-based Sanofi-Aventis.

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