Science Weekly: Why we should learn to love the meteorite

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The benefits of Earth being hit by a meteorite; the secret world of turtles; and the effect of women’s tears on men

Goodbye 2010 and Welcome 2011

We want to wish our over 3,700 readers of ON TARGET a healthy and prosperous New Year. ON TARGET, published continuously since 1995, is now sent directly to countries in every continent except Antarctica; if you happen to be there right now, or know someone who is there or will be there, please let us know.

Since 1993, Target Health has been directly involved with 27 unique new drug, biologic and device products approvals in markets all over the world. In 2010, Target e*CRF was used in the pivotal trials for HRA’s NDA for emergency contraception which was one of the 24 FDA drug approvals. Target Health also monitored the study, performed the very complex statistical analyses, wrote the study reports and represented HRA at FDA. This approval represents 4% of the drug approvals this year at CDER. Pretty good for a company with 47 employees.

In addition, Target e*CRF was used for the PMA approval of the Abbott RealTime HBV assay for measuring the blood’s viral load of hepatitis B virus (HBV). This assay is the first and only approved test capable of automating HBV viral load testing from sample extraction to final results.

2011 milestones will include: 1) At least 2 more FDA approvals, 2) A major publication the DIA Journal, 3) Release of Target e*Studio™ which will allow for the configuration of Target e*CRF® applications by developers outside of Target Health; our first contract has been signed by LSK Global Pharmaceutical Services out of Korea, 4) Initiation of at least 2 studies with Target e*CTR® (eClinical Trial Record), our direct data entry software, thus bypassing paper source records. One IND has already been cleared by FDA.

Target Health also gives back to society by contributing The Corporate Special Projects Program of the Metropolitan Opera in NYC. This program provides vital financial support for outreach programs at the Met and broadens the Met’s audience to include a cross-section of Americans of all ages, ethnic backgrounds and economic levels. Programs benefiting from this program include: 1) Revivals, 2) Metropolitan Opera Free Parks Concerts, 3) Radio Broadcasts, 4) Metropolitan Opera Early Notes Project, 5) Special Constituencies Ticket Program, 6) The Lindemann Young Artist Development Program, and 7) the Metropolitan Opera telecasts on PBS. Other contributing pharmaceutical companies are Roche and Pfizer.

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, and if you like the weekly newsletter, ON TARGET, you’ll love the Blog.

More Evidence That Malaria Drug Could Help Combat Cancer, and That Breaks from Treatment Could Improve Results



Scientists investigating the cancer-fighting properties of artesunate – a drug commonly used to treat 1) ___ – have found early evidence that combining it with an existing cancer drug has the potential to make each drug more effective than when used alone. They also found that regular treatment 2) ___ could improve success levels. The findings, recently published in the International Journal of Cancer, are the result of tests on human 3) ___ cells studied outside the body (in vitro studies) by Dr Wai Liu and Professor Angus Dalgleish at St George’s, University of London.

Artesunate is well-known for combating malaria by reducing the amount of malaria-infected 4) ___ in the body that cause the disease – and a number of scientific studies have already found that it may have the same effect on cancerous cells, consequently reducing the size of the cancer. This latest study adds further evidence to this theory. It also suggests that, in addition to actively killing infected cells to reduce the 5) ___ of the cancer, artesunate may have the ability to prevent the disease from developing further by stunting the growth of the individual cancerous cells that cause the disease. They found that which effect it takes to combat the disease varies depending on the type of cancer.

The researchers analyzed how four different types of human cancer cells – two of which represented cancer of the colon, and the others breast and lung – reacted to artesunate when it was used both alone and in 6) ___ with other anti-cancer drugs. They found that artesunate prevented the cancer from growing in all four types of cell lines tested, in addition to reducing the size of the cancer in those cell lines derived from breast and lung cancer. The researchers then combined artesunate with other common anti-cancer drugs in an attempt to boost activity, and this showed favorable responses with a drug called lenalidomide. When used together, these two drugs increased the effectiveness of the treatment in all four types of cancer cells tested, and had the largest effect on the lung cancer cells. When used separately, artesunate reduced the amount of lung cancer cells, or the size of the cancer, by 20 per cent, whilst lenalidomide reduced its size by 10 per cent. However, by using the two 7) ___, at the same concentrations, the cancer was reduced by around 60%.

The research also indicates that artesunate could be made more effective at reducing the size of the cancer if used in shorter bursts, separated by drug-free periods. The researchers showed that with this treatment pattern, the cancer’s size was reduced where artesunate had previously only been preventing the cancer from growing. The introduction of drug-free periods was also shown to further reduce the size of the cancerous mass where it was already being reduced without the drug-free periods. For example, in the breast cancer cell lines, a continuous exposure to artesunate achieved just a 10% reduction in the size of the cancer, but the reduction with 8) ___ period was increased to over 50%. Dr Liu says: “Whilst stunting cell growth is a useful effect, destroying the cells to reduce their numbers is the preferred effect. These two processes are actually linked together, to the extent that if a drug inhibits cell growth it will inadvertently inhibit the ability of the cells to be destroyed. We have shown that by using short bursts of artesunate, the cancer cells regain the ability to be 9) ___.”

He concludes that: “Whilst these studies are conducted on cells outside the body and reactions can vary in the human body, this research provides new insight into how 10) ___ interacts with cancer drugs and different treatment patterns to combat cancer, and provides a starting point from which studies can be based.”

ANSWERS: 1) malaria; 2) breaks; 3) cancer; 4) cells; 5) size; 6) combination; 7) together; 8) drug-free; 9) destroyed; 10) artesunate

Alexander Shulgin (1925 – to present)

Alexander Shulgin at 85

Dr. Alexander Shulgin began studying organic chemistry at Harvard University in 1943, at the age of 19, but dropped out of school and joined the U.S. Navy, where he eventually became interested in pharmacology. Shugin earned his Ph.D. in biochemistry from the University of California, Berkeley followed by post-doctoral work in the fields of psychiatry and pharmacology at University of California, San Francisco. After working at Bio-Rad Laboratories as a research director for a brief period, he began work at Dow Chemical Company as a senior research chemist.

Shulgin’s opportunity for further research came with his development of Zectran, the first biodegradable pesticide, a highly profitable product for the Dow Chemical Company. In 1965, Shulgin left Dow to pursue his own interests, and became a private consultant, also frequently teaching classes in the local universities and at the San Francisco General Hospital. Through his friend Bob Sager, head of the U.S. Drug Enforcement Agency’s (DEA) Western Laboratories, Shulgin formed a relationship with the DEA and began holding pharmacology seminars for the agents, supplying the DEA with samples of various compounds, and occasionally serving as an expert witness in court.

In 1967, Shulgin was introduced to MDMA (ecstasy) by Merrie Kleinman, a graduate student in the medicinal chemistry group he advised at San Francisco State University. MDMA had been synthesized in 1912 by Merck and patented in 1912 as a byproduct of another synthesis. Ecstasy may be a recreational drug these days, but it was initially designed to treat depression and post-traumatic stress disorder. Shulgin went on to develop a new synthesis method, and in 1976, introduced the chemical to Leo Zeff, a psychologist from Oakland, California. Zeff used the substance in his practice in small doses as an aid to talk therapy.

After judicious self-experiments, Shulgin enlisted a small group of friends with whom he regularly tested his creations. They developed a systematic way of ranking the effects of the various drugs, known as the Shulgin Rating Scale, with a vocabulary to describe the visual, auditory and physical sensations. He personally tested hundreds of drugs, mainly analogues of various phenethylamines (family containing MDMA and mescaline), and tryptamines (family containing DMT and psilocybin). There are a seemingly infinite number of slight chemical variations, all of which produce variations in effect – some pleasant and some unpleasant, depending on the person, substance and situation.

Since his work on MDMA in the 1970s, Alexander Shulgin discovered and self-tested more than 230 psychoactive compounds, some of which have induced uncontrollable vomiting, paralysis and “the feeling that his bones were melting,” according to a Scientific American report from 2008.

2009 H1N1 Vaccine Induces Safe and Robust Immune Response in Asthma Patients

People with asthma are at risk for developing severe disease when infected with the influenza virus. In addition, there is concern that the long term use of corticosteroids, which are used to control asthma symptoms and known to suppress the immune system, might affect the ability to mount a healthy immune response to the vaccine.

Results from a government-sponsored clinical trial of inactivated 2009 H1N1 influenza vaccine in people with asthma (published online in the Journal of Allergy and Clinical Immunology; December 2009), indicate that a single dose of vaccine was able to induce a strong immune response predictive of protection. The findings also suggest that individuals over the age of 60 who have severe asthma may require a larger dose of vaccine.

In late 2009, NIH rapidly designed and sponsored a clinical study to determine the dose and number of doses of the 2009 H1N1 influenza vaccine needed to safely produce a protective immune response in people with asthma. The design of the trial was similar to that of other NIAID-sponsored clinical trials of 2009 H1N1 influenza vaccines in healthy adults. In these trials, a single dose of the vaccine containing 15 micrograms of the influenza hemagglutinin molecule – the main target of the protective antibody response – was found to be well tolerated and induced a strong immune response in most participants.

The study enrolled 390 people aged 12 to 79 years with asthma. Participants were divided into two groups based on the severity of their disease. The first group exhibited mild or moderate asthma, and the second group exhibited severe asthma. For the purposes of the study, people with mild or moderate asthma were characterized as needing no or low to moderate doses of inhaled corticosteriods to control their disease symptoms. Those with severe asthma needed high doses of inhaled corticosteriods and frequently required oral corticosteriods to control their symptoms.

Half of the participants in each group received a 15-microgram dose of vaccine, and the other half received a 30-microgram dose. Three weeks later, each participant received a second dose in the same amount as the first dose. The vaccine, manufactured by Novartis by methods used to prepare each year’s seasonal vaccine, contained inactivated 2009 H1N1 influenza virus and therefore could not cause influenza infection.

The study measured the level of antibodies against the 2009 H1N1 influenza virus three weeks after each injection. Results showed the vaccine to be safe and effective in producing an immune response. In participants with mild to moderate asthma, and in most participants with severe asthma, a single 15-microgram dose was sufficient to induce a protective immune response. The immune response after the first dose was not further improved after a second dose, indicating that a single dose was adequate. Participants older than age 60 with severe asthma had diminished immune responses to the 15-microgram dose of vaccine, but the 30-microgram dose gave an adequate response.

Safety data were collected and examined throughout the course of the study by the investigators and by an independent safety monitoring committee. Participants were followed for any side effects they may have experienced from the vaccine, as well as for asthma attacks that occurred during the study. The vaccine did not exacerbate participants’ asthma. In addition, the vaccine was well-tolerated, and its safety profile was found to be the same as that obtained in other studies in which the vaccine was given to the general public.

Study Identifies Genetic Variant That Can Lead To Severe Impulsivity

According to a study published online in Nature (DOI: 10.1038/nature09629; 23 December 2010), a genetic variant of a brain receptor molecule has been identified that may contribute to violently impulsive behavior when people who carry it and are under the influence of alcohol. The report includes both human genetic analyses and gene knockout studies in animals.

The study evaluated a sample of violent criminal offenders in Finland whose violent crimes where categorized as spontaneous and purposeless. The reason Finland was studied was due to its unique population history and medical genetics. Modern Finns are descended from a relatively small number of original settlers, thus reducing the genetic complexity of diseases in that country. Thus according to the authors, by studying the genetics of violent criminal offenders within Finland increased the chances of finding genes that influence impulsive behavior.

For the study, DNA was sequenced from the impulsive subjects and compared with those sequences with DNA from an equal number of non-impulsive Finnish control subjects. Results showed that a single DNA change that blocks a gene known as HTR2B was predictive of highly impulsive behavior. HTR2B encodes one type of serotonin receptor in the brain. Serotonin is a neurotransmitter known to influence many behaviors, including impulsivity.

Interestingly, the genetic variant alone was insufficient to cause people to act impulsively. Carriers of the HTR2B variant who had committed impulsive crimes were male, and all had become violent only while drunk from alcohol.

The authors then conducted studies in mice and found that when the equivalent HTR2B gene is knocked out or turned off, mice also become more impulsive. Studies of any alcohol interaction in the knockout mice are ongoing.

According to the authors, the findings could lead to a better understanding of some aspects of impulsivity and ultimately may lead to strategies for diagnosing and treating some clinically important manifestations of impulsive behavior. The researchers caution, however, that impulsivity is a complex trait with multiple genetic and environmental causes.


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Rare Cancer Linked to Cell Oxygen Deficiency

Gastrointestinal stromal tumors (GIST) are tumors of the esophagus, stomach, and intestines. They occur in cells of the nervous system, which control the muscles of the digestive tract. Within the last 10 years, researchers have found that the majority of adults who develop GIST have mutations in two genes, known as KIT and PDGFRA. The drug imatinib (Gleevec) is effective in treating many GIST having mutations in these genes. Unfortunately, most GIST tumors that occur in children do not have KIT or PDGFRA mutations, and imatinib is not effective for treating them. Pediatric GIST is very rare, occurring in less than 1 in a million individuals each year.

According to an article published in the Proceedings of the National Academy of Sciences (2011; 108:314-318), GIST has been shown to be linked to a shutdown in an enzyme that helps supply oxygen to cells. In some cases, the enzyme’s failure to function resulted from errors in genes containing the information needed to make the enzyme. In others, the cause could not be identified, but was believed to be genetic.

For the study, the research team set out to find genetic causes of GIST among individuals who do not have mutations in the genes for KIT or PDGFRA. The study examined tissue from 34 GIST patients for mutations in the genes for succinate dehydrogenase, an enzyme that processes oxygen to obtain energy for cells. The study narrowed the search to genes for succinate dehydrogenase because earlier research has shown that mutations in this enzyme are a hallmark of Carney Stratakis syndrome, a rare disorder in which individuals develop GIST and paraganglioma, a tumor that also affects cells of the nervous system.

The study found that 12% of the GIST patients had mutations in genes containing the information needed to make the up the parts, or subunits, of succinate dehydrogenase. Specifically, the patients had defects in the B and C subunits of the enzyme. Although the remaining patients did not have any of these mutations, succinate dehydrogenase in tissue from their tumors did not appear to be functioning and cellular respiration was disrupted. The authors believe that undiscovered mutations account for the enzyme’s failure to function.

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

Predicting the Healthcare Future… (with proper caveats)

This being the season of predictions (and resolutions–but that’s for another venue) On-Target thought it timely and appropriate to “take up the challenge” and weigh in on the 2011 prospects for healthcare reform generally and the Affordable Care Act (ACA) in particular.

So, acknowledging the inherent hazards of making predictions that can actually be checked and taking note of the warnings of wiser folks who have commented on the difficulty of making predictions, “especially about the future”, here goes…

Conventional wisdom holds that the November elections profoundly changed the dynamics around the implementation of the ACA. However, the practical consequences of this new reality are unclear. On the key issues of outright repeal and court challenges to the individual mandate, expect considerable rhetoric but likely less action during 2011. While the reconfigured House may well attempt (and succeed) in repealing the ACA, there is little chance the Senate will agree and additionally the virtual certainty of a Presidential veto. Thus outright repeal would be a political strategy rather than a policy initiative.

The outcome of court challenges to the individual mandate, an integral component of the ACA, are less easily predicted since the opinions of individual judges in disparate jurisdictions are involved. Lower Court disagreements will likely persist, and the overall impact of these challenges during 2011 will depend upon the willingness of the Supreme Court to grant expedited review and resolve the matter with finality. This seems highly unlikely (during 2011), so expect to see much written on the issue and enjoy the chance to learn some constitutional law from the array of distinguished legal scholars likely to “weigh-in” on the matter; however, don’t expect resolution.

In sum, the ACA is very likely to survive 2011, largely intact, but the new House may well decide to make a “statement” by passing repeal.

Finally, we examine biosimilar/interchangeable products, areas of great interest to Target Health’s clients and subjects of a “grand bargain” in the ACA. The bargain was an attempt to balance the need to support innovation by conferring sufficient product exclusivity, now promised for 12 years post licensing (not approval), with the societal benefits of competition (by offering an expedited pathway for biosimilar approval following innovator patent expiry). Ultimately, the FDA will need to “fill in” the regulatory blanks, and that process has begun with a stakeholder meeting held in late 2010. Look for this process to advance, cautiously, in 2011 with the Agency providing additional specificity around the requirements for biosimilar approval. We at Target Health shall monitor this process.

Altogether, there will be much rhetoric and a modicum of activity and the implementation of the ACA will move, perhaps a bit unsteadily, forward. We shall try and keep readers updated on the status of relevant elements of the ACA, especially those that impact the approval, marketing and reimbursement of pharmaceuticals and devices, as the negotiations progress. (Mark L. Horn, MD, MPH; CMO Target Health Inc.)

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