The 3rd Annual Skin Workshop, hosted by our friend and colleague, Dr. Bo Michniak-Kohn, will be held at the Rutgers Life Science Building, Busch Campus (Piscataway, NJ) on October 22, 9:30-3:30. This is a must for those interested in topical products. Let us know if you will be attending.

For the session on Alternatives to Animal Testing, three prominent scientists will present : Priya Batheja, Ph.D. of Capsugel/Pfizer in Boston, Nava Dayan, Ph.D. from Lipo Chemicals, Inc., and Richard Mendelsohn, Ph.D. of Rutgers-Newark.

For the Taking Innovations to Market session, the keynote speakers will be Dr. Neal Walker and Dr. Stuart Shanler of Vicept Therapeutics, who will share their experience in reformulating oxymetazoline hydrochloride (Afrin) to become a topical therapy for patients with Rosacea.

A panel on tech transfer and intellectual property issues in personal care products will complete the program.

For more information about Target Health contact Warren Pearlson (212-681-2100 ext 104). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel or Ms. Joyce Hays. Target Health’s software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website.

Mapping the Brain on a Massive Scale

Graphic: Christine Daniloff, MIT

A massive new project to scan the brains of 1,200 volunteers could finally give scientists a picture of the neural architecture of the human brain and help them understand the causes of certain neurological and psychological 1) ___. The National Institutes of Health announced $40 million in funding this month for the five-year effort, dubbed the Human Connectome Project, which will use new imaging technologies, some still under development, to create both structural and functional maps of the 2) ___ brain.

The project is novel in its size as most brain-imaging studies have looked at tens to hundreds of 3) ___. Scanning so many people will shed light on the normal variability within the brain structure of healthy adults, which will in turn provide a basis for examining how neural “wiring“ differs in such disorders as autism and schizophrenia. The project also plans to collect genetic and behavioral data, testing participants’ sensory and motor skills, memory, and other cognitive functions, and deposit this information along with brain scans in a public database without any of the patients’ personal information. Scientists around the world can then use the 4) ___ to search for the genetic and environmental factors that influence the structure of the brain.

“We want to learn as much as we can, not only about the typical patterns of brain connectivity, but also about the differences in 5) ___ that make each of us a unique individual,“ says David Van Essen, a neuroscientist at Washington University in St. Louis, who is one of the project leaders. “If you’re good at math, and I’m better at certain types of memory, can we identify some of the wiring characteristics that account for those differences?“

The most detailed studies to date of the neural 6) ___ that connect one brain cell to another have focused on animal brains, because scientists can examine the animals’ living tissue cells and their networks under a microscope. Because researchers will be scanning only identical and 7) ___ twins and their siblings, the scientists can get a sense of the role that genetics and environment play in shaping brain structure. Structures of the brain that are highly dictated by genes will be more similar in identical twins than in fraternal twins, for example.

Most human brain imaging studies have employed magnetic 8) ___ imaging (MRI) to examine the gross anatomy of the brain or functional MRI to detect which regions are active during specific tasks. But advances in brain imaging technologies in recent years, as well as growing computing power, have made it possible to look at the fine wiring connecting brain regions. “If we want to understand the brain, we need to know what individual areas are doing and how they talk to each other,“ says Russell Poldrack, director of the Imaging Research Center at the University of Texas at Austin.

Van Essen and his collaborators plan to scan participants using two relatively recent variations on MRI. Diffusion imaging, which detects the flow of water molecules down insulated neural wires, indirectly measures the location and direction of the fibers that connect one part of the brain to another. Functional connectivity, in contrast, examines whether activity in different parts of the brain fluctuates in synchrony. The regions that are highly correlated are most likely to be 9) ___, either directly or indirectly. Combining both approaches will give scientists a clearer picture. Collaborators at the University of Minnesota and Massachusetts General Hospital are optimizing existing scanners with new magnets and custom analysis programs so that they are better suited to detecting these circuits. This will be a landmark study, and may have the same kind of impact on neuroscience that the Human Genome Project had on human 10) ___.

ANSWERS: 1) diseases; 2) human; 3) brains; 4) database; 5) wiring; 6) circuits; 7) fraternal; 8) resonance; 9) connected; 10) genetics

Mental Illness in the 19th Century (not much different from the 21st Century cruelty of throwing mentally ill people into prison)

“Madness”1857 lithograph by Armand Gautier, showing personifications of dementia, megalomania, acute mania, melancholia, idiocy, hallucination, erotic mania and paralysis in the gardens of the Hospice de la Salpêtrière

Paul Eugen Bleuler (April 30, 1857 – July 15, 1939)

Dr. Paul Eugen Bleuler was a Swiss psychiatrist most notable for his contributions to the understanding of mental illness and coining the term schizophrenia. Bleuler was born in Zollikon, a small town near Zürich. He studied medicine in Zürich, and later studied in Paris, London and Munich after which he returned to Zürich to take a post as an intern at the Burghölzli, a university hospital.

In 1886 Bleuler became the director of a psychiatric clinic at Rheinau, a hospital located in an old monastery on an island in the Rhine. Rheinau was noted at the time for being backward, and Bleuler set about improving conditions for the patients resident there. Bleuler returned to the Burghölzli in 1898 where he was appointed director. In the 1890s, Bleuler became interested in Sigmund Freud’s work, favorably reviewing Josef Breuer and Sigmund Freud’s Studies on Hysteria. Like Freud, Bleuler believed that complex mental processes could be unconscious. He encouraged his staff at the Burghölzli to study unconscious and psychotic mental phenomena. Influenced by Bleuler, Carl Jung and Franz Riklin used word association tests to integrate Freud’s theory of repression with empirical psychological findings. For a time Bleuler even consulted Freud about his own self-analysis. As the leader of a major teaching and research hospital, Bleuler’s support for Freud was very important to the early growth of psychoanalysis.

Bleuler is particularly notable for naming schizophrenia, a disorder which was previously known as dementia praecox. Bleuler realized the condition was neither a dementia, nor did it always occur in young people (praecox meaning early) and so gave the condition the purportedly less stigmatizing but still controversial name from the Greek roots schizein (“to split”) and phren (“mind”). Bleuler treated celebrated Russian ballet dancer Vaslav Nijinsky after his breakdown in 1919.

Bleuler coined the New Latin word autismus (English translation autism) in 1910 as he was defining symptoms of schizophrenia, deriving it from the Greek word autos (meaning self). According to the Critical Dictionary of Psychoanalysis by Charles Rycroft, it was Bleuler who introduced the term ambivalence (in 1911). Bleuler is also recognized today for having a neurological condition called synesthesia, in which information from the sensory systems crosses over with the result that an individual experiences one sensation as another – tasting colors, hearing numbers or seeing music, for example.

Added Benefits To Starting HIV Treatment Early

According to an article published online in Blood (13 September 2010), HIV-infected individuals who begin antiretroviral therapy (ART) soon after acquiring the virus may have stronger immune responses to other pathogens than HIV-infected individuals who begin ART later. This finding suggests that early initiation of ART may prevent irreversible immune system damage and adds to the body of evidence showing significant health benefits from early ART. The study measured the quantity and qualities of B cells in blood samples taken from three groups of study volunteers: men who had been infected with HIV for fewer than 6 months; men who had been infected with HIV for 6 months or more (often for several years); and men who were not infected with HIV. The HIV-infected men began taking ART for the first time once they entered the study.

At the outset of the study, the number of B cells in the blood of both groups of HIV-infected men was significantly lower than the number of B cells in the blood of the uninfected men. B cells make proteins called antibodies that can flag pathogens for destruction by the immune system and prevent them from infecting cells. However, once the two groups of HIV-infected men began ART, however, the numbers of B cells in their blood increased significantly and to similar degrees. Qualitatively, however, the relative proportions of six different types of B cells differed both within and among each of the three groups at the study outset and one year after the HIV-infected men had started ART. Results showed that early treatment restored resting memory B cells to the same level as that in HIV-uninfected men, but late treatment did not. Resting memory B cells remember how to make antibodies to a pathogen and can last a lifetime. Also, early ART reduced the proportion of immature B cells to the same level as that in HIV-uninfected men, but late treatment did not. In addition, after one year, the late-treatment group had a significantly greater proportion of so-called exhausted B cells-those that have shut themselves off and resist doing their usual pathogen-fighting activities-compared with the other two groups of participants.

To learn how these differences affected immune system responses to new infections, the study examined how the two groups of HIV-infected men responded to influenza vaccination at the start of the study and one year after beginning treatment. At the one-year point, a significantly greater proportion of B cells made anti-influenza antibodies in the early treatment group compared with the late treatment group. This suggests that starting ART early in the course of HIV infection enables individuals to fight off other pathogens better than if they start ART later, when the infection has become chronic.

ONCOLOGY

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Outcome after Reduced Chemotherapy for Intermediate-Risk Neuroblastoma

Neuroblastoma is a cancer of the peripheral nervous system (found outside of the brain and spinal cord), and is responsible for 12% of all deaths due to cancer in children under 15 years of age. It is the most common non-brain solid tumor in children. Nearly 50% of patients with neuroblastoma have a high-risk form of the disease and have poor long-term survival despite very intensive treatment. The previously established standard treatment for neuroblastoma uses high doses of chemotherapy to destroy as many cancer cells as possible. But this form of chemotherapy (myleoablative therapy) also destroys some normal blood-forming cells, so it is followed by giving back previously collected blood-forming cells to restore immune system function and blood cell formation. Patients who respond to this therapy are then given the drug isotretinoin to further treat any remaining cancer cells. Isotretinoin is a derivative of vitamin A and is also used to treat severe acne. Moreover, it has been found to prevent the proliferation of neuroblastoma cells. More than half of the patients with high-risk neuroblastoma treated in this manner succumb to the disease.

According to a study published in the New England Journal of Medicine (2010;363:1313-132), administering a new form of immunotherapy to children with neuroblastoma increased the percentage of those who were alive and free of disease progression after two years. The percentage rose from 46% for children receiving a standard therapy to 66% for children receiving immunotherapy plus standard therapy.

A newer approach to cancer treatment is immunotherapy, which in this instance uses an antibody called ch14.18 to target a substance on the surface of tumor cells called GD2. The GD2 is expressed by cancers such as neuroblastoma but is also present on some normal nerve cells. Early-phase studies demonstrated the safety and activity of ch14.18 when it was given with other drugs that boost the immune system. Those drugs include a factor which stimulates white blood cell growth and a hormone that increases the number and activity of certain types of immune cells.

In this study, 226 children with high-risk neuroblastoma who had responded to myeloablative therapy were randomly assigned to receive standard therapy (isotretinoin), or isotretinoin, ch14.18, and the immune system boosting drugs. The median time these patients were followed in the study was approximately two years. Although the original plan had been to compare outcomes after three years, the study stopped early because of the strongly positive results, allowing those on standard therapy to switch to ch14.18 immunotherapy if they wished.

Toxicities, including pain, low blood pressure, capillary leak (leakage of blood from capillaries in the circulatory system to the surrounding tissue), and hypersensitivity reactions, were encountered with the immunotherapy treatment at a significantly greater rate than compared to those who just received the standard therapy. However, side effects in the immunotherapy group were temporary and primarily resolved when treatment was stopped.

Because there was no pharmaceutical company to make ch14.18 when the phase III trial started, The National Cancer Institute (NCI) manufactured the agent and provided it to COG for the clinical trial. NCI continues to manufacture ch14.18 and to make it available to children with high-risk neuroblastoma through ongoing Children’s Oncology Group clinical trials.

How The Salmonella Bacteria Spread In Humans

The Centers for Disease Control and Prevention estimate that salmonella infections sicken 40,000 people each year in the United States, though the actual number of infections is likely much higher because many cases are mild and not diagnosed or reported. Currently, salmonella is the focus of an ongoing U.S. public health investigation into contaminated chicken eggs.

While much is known about the human infectious cycle of salmonella, scientists have yet to understand how the bacteria escape the gut to spread infection. Epithelial cells line the outer and inner surfaces of the body, such as the skin and gut, and form a continuous protective tissue against infection. But salmonella have learned how to live inside epithelial cells and use them for their benefit. salmonella protect themselves within special membrane-bound compartments, called vacuoles, inside gut epithelial cells.

New findings published in the Proceedings of the National Academy of Sciences (DOI: 10.1073/pnas.1006098107 (2010) could explain how salmonella bacteria, a common cause of food poisoning, efficiently spread in people. In a study, researchers describe finding a reservoir of rapidly replicating salmonella inside epithelial cells (see video: http://videocast.nih.gov/wmv/salmonellaReplication.wmv). These bacteria are primed to infect other cells and are pushed from the epithelial layer by a new mechanism that frees the salmonella to infect other cells or be shed into the intestine.

Using special high-resolution microscopes to view laboratory-grown human intestinal epithelial cells and laboratory mice infected with salmonella, a secondary population of salmonella was discovered that was not confined within a vacuole, but instead moving freely inside the epithelial cells. This reservoir of salmonella is distinct from vacuolar salmonella. These bacteria multiply much faster; they have long tail-like projections, called flagella, used to move; and they exhibit a needle complex they use to pierce cells and inject their proteins. With these attributes, this population of salmonella is genetically programmed to invade new cells.

The study observed that epithelial cells containing the hyper-replicating, invasive salmonella are eventually pushed out of the intestinal tissue into the gut cavity, setting the salmonella free. The mechanism used to push these salmonella-infected cells into the body cavity resembles the natural mechanism humans use to shed dying or dead epithelial cells from their gut. The authors believe that salmonella have hijacked this mechanism to facilitate their own escape.

The human immune system, however, also senses that these are not normal, dying cells in the gut and triggers a response that includes release of interleukin-18, a small protein that sets off an inflammation cascade. Interleukin-18 also is prominent in chronic intestinal inflammation associated with autoimmune disorders, such as inflammatory bowel disease.  The effects of interleukin-18 release provide an explanation for the acute intestinal inflammation associated with salmonella infections.

TARGET HEALTH excels in Regulatory Affairs and Public Policy issues. Each week we highlight new information in these challenging areas.

FDA Issues Final Rule On Safety Information During Clinical Trials

Congratulations to FDA on this Guidance.

The FDA has issued a final rule that clarifies what safety information must be reported during clinical trials of investigational drugs and biologics. “This final rule will expedite FDA’s review of critical safety information and help the agency monitor the safety of investigational drugs and biologics,“ said Rachel Behrman, M.D, associate director for medical policy in the FDA’s Center for Drug Evaluation and Research. “These changes will better protect people who are enrolled in clinical trials.“

The new rule requires that certain safety information that previously had not been required to be reported to FDA be reported within 15 days of becoming aware of an occurrence. These reports include:

1.     findings from clinical or epidemiological studies that suggest a significant risk to study participants

2.     serious suspected adverse reactions that occur at a rate higher than expected

3.     serious adverse events from bioavailability studies which determine what percentage and at what rate drug is absorbed by the bloodstream and bioequivalence studies which determine whether a generic drug has the same bioavailability as the brand name drug

The rule also provides examples of evidence that would suggest that an investigational product may be the cause of a safety problem. Under current regulations, drug sponsors often report all serious adverse events, even if there is little reason to believe the product caused the event. Such reporting complicates and delays the FDA’s ability to detect a safety signal. The examples address when a single event should be reported or when there is need to wait for more than one occurrence.

In addition, the rule revises definitions and reporting standards so that they are more consistent with two international organizations, the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use and the World Health Organization’s Council for International Organizations of Medical Sciences. The changes are designed to help ensure harmonized reporting of globally conducted clinical trials.

Along with this final rule, the FDA also issued a draft guidance for industry and investigators that provides information and advice about the new requirements and other information.

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

Target Health (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 (eCTD), IDE, NDA (eCTD), BLA (eCTD), PMA (eCopy) and 510(k) submissions, execution of Clinical Trials, Project Management, Biostatistics and Data Management, EDC utilizing Target e*CRF®, and Medical Writing.

Target Health has developed a full suite of eClinical Trial software including:

1) Target e*CRF® (EDC plus randomization and batch edit checks)

2) Target e*CTMS™

3) Target Document®

4) Target Encoder®

5) Target Newsletter®

6) Target e*CTR™ (electronic medical record for clinical trials).

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