A Lighter Look at the Health Care Debate – Courtesy of Dr. Tibor Sipos

The American Medical Association has weighed in on Obama’s new health care package. The Allergists were in favor of scratching it, but the Dermatologists advised not to make any rash moves. The Gastroenterologists had sort a gut feeling about it, but the Neurologists thought the Administration had a lot of nerve.  Meanwhile, Obstetricians felt certain everyone was laboring under a misconception;  while the Ophthalmologists considered the idea shortsighted. Pathologists yelled, “Over my dead body,” while the Pediatricians said, “Oh, grow up!” The Psychiatrists thought the whole idea was madness, while the Radiologists could see right through it. Surgeons decided to wash their hands of the whole thing and the Internists claimed it would indeed be a bitter pill to swallow. The Plastic Surgeons opined that this proposal would “put a whole new face on the matter”. The Podiatrists thought it was a step forward, but the Urologists were pissed off at the whole idea. Anesthesiologists thought the whole idea was a gas, and those lofty Cardiologists didn’t have the heart to say no. In the end, the Proctologists won out, leaving the entire decision up to the XXXs in Washington.

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

Alzheimer’s Clue Found

This week in the journal Nature, researchers report a step forward in understanding the pathology of Alzheimer’s disease. Two 1) ___ that are commonly mutated in the early-onset form of Alzheimer’s may cause the disorder by altering how presynaptic neurons release neurotransmitters. The mechanism may apply to other neurodegenerative disorders as well. More than 100 different mutations in two genes coding for the proteins presenilin 1 and 2 are associated with early-onset Alzheimer’s disease, but the exact effects of these 2) ___ on neural function is still unclear. This is the first study suggesting that presenilins play a presynaptic role. In 2007, when knockout mice were created that lacked both presenilin genes, the mice ended up with both memory deficits and neurodegeneration in the 3) ___ which are two key features of Alzheimer’s disease. In the current study, an attempt was made to determine on which side of the synapse the presenilins exert their effect. This was done by creating two strains of knockouts: one that lacked both presinilin genes only in the presynaptic neurons of a synapse in the hippocampus – a brain region that plays an important role in 4) ___ – and another where the genes were knocked out just post-synaptically. Measuring neural activity in dissected brain sections, the researchers were able to compare the effects of presenilins on pre- and post-synatpic activity. In presynaptic presenilin knockout mice, the researchers found drastically reduced long-term potentiation (LTP) – a physiological measure of memory formation. In postsynaptic presenilin knockouts, however, LTP was normal. Knocking out presynaptic 5) ___ also altered other aspects of neuronal function and reduced the probability of neurotransmitter release which depends on increases in calcium levels within the 6) ___. By blocking the release of calcium from the endoplasmic reticulum – an intracellular source of calcium – the researchers mimicked the effects of the presynaptic presenilin knockouts in control mice. This result points to intracellular calcium release as a possible mechanism by which presenilins regulate neuronal function. The main take home message is that there is a difference in the way neurons process 7) ___ levels in absence of presenilins, and that has an effect on synaptic function. Researchers studying neurodegenerative diseases have long debated whether knocking out these genes is a good model for 8) ___ because the exact role of the many presenilin mutations associated with the disease is unclear. Some argue that these mutations result in a “loss of function, in which case a knockout model would appropriately represent the changes that occur in Alzheimer’s patients. Others argue that these mutations result in a “gain of function,” or a change that cannot be replicated by knocking out the genes entirely. If patients with Alzheimer’s disease do indeed have non-functioning presenilin genes, the results of this study may suggest that presynaptic neurotransmitter release is a more general mechanism of 9) ___ diseases. For example, Shen and her colleagues found a presynaptic effect in a mouse model of Parkinson’s disease. These changes “might be a precursor to neurodegeneration,” and might therefore provide new targets for disease 10) ___.

ANSWERS: 1) genes; 2) mutations; 3) brain; 4) memory; 5) presenilins; 6) neuron; 7) calcium; 8) Alzheimer’s; 9) neurodegenerative; 10) therapies

1879 to 2009 Teething Medicine Poisons Babies

The following teething product has a had a long history of warnings. In a trial in 1879, a jury found that the death of a 1-year-old “had been caused by congestion of the brain caused by the administration of Monell’s Teething Cordial.” One hundred thirty years later, on July 29, 2009, a 22 day old baby was rushed to the ER of a NYC hospital for potassium bromide poisoning, caused by the same, very well known, teething product from the 1879s. Earlier this year, there was another case of infant poisoning, after using this same illegally sold product, from the Dominican Republic, which is banned in the US. Historically, potassium bromide was used as an anesthetic in surgery, but no longer. This Cordial is one of a number of folk remedies that immigrants use in their underground medical system. Enough so that doctors in largely immigrant neighborhoods have put together guides to the medicines for residents. Cordial De Monell – which contains potassium bromide, betula oil, oil of anise and a clear syrup base – retails for about $5 and is often used to treat teething and colic. The products are brought in by distributors who may not realize it is banned. It goes on for sale until someone gets sick and it is recognized as illegal by an agency. The baby was treated, last week, for the potassium bromide poisoning after parents took her to a hospital emergency room because of excessive sleepiness and lack of drinking. Doctors found that the parents had bought the cordial and had been adding the liquid to each of her meals over 12 days. She recovered after five days. Symptoms of potassium bromide ingestion may include sedation, trouble breathing and low blood pressure. The health department also noted that chronic ingestion of bromides over time by older children and adults may cause “bromism,” marked by behavioral changes that develop after two to four weeks, like irritability, headache, confusion, anorexia, slurred speech and lethargy. Source: The New York Times

Sun Exposure May Trigger Certain Autoimmune Diseases in Women

Dermatomyositis and polymyositis are the two major forms of myositis and both are considered autoimmune diseases, in which the body’s immune system attacks muscle or skin and sometimes other tissues. Dermatomyositis is typically accompanied by a distinctive reddish-purple rash on the upper eyelids or over the knuckles and is often made worse with sun exposure. According to an article published online in Arthritis & Rheumatism (30 July 2009), ultraviolet (UV) radiation from sunlight may be associated with the development of certain autoimmune diseases. The study found that women who lived in areas with higher levels of UV exposure when they developed an autoimmune muscle disease called myositis were more likely to develop the form known as dermatomyositis, which weakens the muscles and causes distinctive rashes, instead of the form called polymyositis that does not have a rash. According to the authors, although no direct cause and effect link between UV exposure and this particular autoimmune disease has been shown, the study confirms the association between UV levels and the frequency of dermatomyositis that were found in a previous investigation. The study is also the first to evaluate and find a possible UV radiation association in autoimmune diseases in women. The goal of the study was to determine if there was a relationship between the level of UV exposure at the onset of the disease and the type of myositis and autoantibodies that people developed. To conduct the study, the investigators collaborated with myositis centers across the country. Antibody titres were determined from 380 patients who had been diagnosed with dermatomyositis or polymyositis. Patients with autoimmune diseases make a variety of autoantibodies that are unique to different conditions. One autoantibody specifically associated with dermatomyositis is called the anti-Mi-2 autoantibody which, under UV radiation, increases levels of the Mi-2 protein that this autoantibody binds to. In addition to finding an association between the level of UV radiation and the proportion of women who developed dermatomyositis compared to polymyositis, the study found an association between UV levels and the proportion of women with the anti-Mi-2 autoantibody. According to the authors, women are more likely than men to develop many autoimmune diseases, but the reasons for this have not been clear. “The study only found the association between UV exposure and dermatomyositis in women and not in men, and it could be that inherent differences in how women and men respond to UV radiation may play a role in the development of certain autoimmune diseases.

Intensive Glucose Control Halves Complications of Longstanding Type 1 Diabetes

In the US, nearly 24 million people have diabetes. In adults, type 1 diabetes accounts for 5 to 10% of all diagnosed cases of diabetes. Formerly called juvenile-onset diabetes or insulin-dependent diabetes, type 1 diabetes develops when the body’s immune system destroys pancreatic beta cells, the only cells in the body that make the hormone insulin that regulates blood glucose. This form of diabetes usually arises in children and young adults, but it can occur at any age. Management involves keeping blood glucose levels as close to normal as possible with three or more insulin injections a day or treatment with an insulin pump, careful monitoring of glucose, and close attention to diet and exercise. Type 2 diabetes, or adult-onset diabetes, accounts for about 90 to 95% of all diagnosed cases of diabetes in adults. It usually begins as insulin resistance, a disorder in which the cells do not use insulin properly. As the need for insulin rises, the pancreas gradually loses its ability to produce it. Type 2 diabetes is associated with older age, obesity, family history of diabetes, history of gestational diabetes, impaired glucose metabolism, physical inactivity, and race/ethnicity. African Americans, Hispanic/Latino Americans, American Indians, and some Asian Americans and Native Hawaiians or other Pacific Islanders are at particularly high risk for type 2 diabetes and its complications. According to a study published in the Archives of Internal Medicine (2009;169:1307-1316), near-normal control of glucose beginning as soon as possible after diagnosis would greatly improve the long-term prognosis of type 1 diabetes. The study also found that the outlook for people with longstanding type 1 diabetes has greatly improved in the past 20 years due to a better understanding of the importance of intensive glucose control as well as advances in insulin formulations, insulin delivery, glucose monitoring, and the treatment of cardiovascular risk factors. Data for the study was derived from the Diabetes Control and Complications Trial (DCCT) and its follow-up study, the Epidemiology of Diabetes Interventions and Complications (EDIC). The DCCT, conducted from 1983 to 1989, found that intensive glucose control was superior to conventional control in delaying or preventing the complications of type 1 diabetes. EDIC continues to follow DCCT participants to determine the long-term effects of prior intensive versus conventional blood glucose control. The study compared overall rates of eye, kidney, and cardiovascular complications in three groups of people diagnosed with type 1 diabetes an average of 30 years earlier. Two groups consisted of DCCT/EDIC participants–those randomly assigned to intensive glucose control or to conventional control. The third group was a subset of patients in the Pittsburgh Epidemiology of Diabetes Complications (EDC) study, who were matched to DCCT/EDIC participants by age, duration of diabetes, and degree of eye damage. The EDC, also funded by NIH, is a population-based study that has been following residents of Allegheny County, Pa., who were diagnosed with type 1 diabetes from 1950 to 1980. After 30 years of diabetes, compared to those receiving conventional glucose control, DCCT participants randomly assigned to intensive glucose control had about half the rate of eye damage (21% vs. 50%). They also had lower rates of kidney damage (9% vs. 25%) and cardiovascular disease events (9% vs. 14%). Eye damage ranged from significant damage without vision loss to blindness. Kidney damage ranged from mild kidney disease to kidney failure. Cardiovascular events encompassed heart attack, stroke, angina, and obstruction of the coronary arteries. The intensively treated DCCT group also had lower complication rates than EDC participants, whose rates were similar to DCCT’s conventional control group: eye damage (47%), kidney damage (17%), and cardiovascular disease events (14%). Not only did intensive glucose control halve the rates of eye and kidney damage, but the rates of vision loss and kidney failure were much lower than had been seen historically. After 30 years of diabetes, fewer than 1% of those receiving intensive glucose control in the DCCT had significantly impaired vision, kidney failure, or needed a limb amputation due to diabetes. The DCCT compared intensive management of blood glucose to conventional control in 1,441 people 13 to 39 years of age with type 1 diabetes. At the time, conventional treatment consisted of one or two insulin injections a day with daily urine or blood glucose testing. Participants randomly assigned to intensive treatment were asked to keep glucose levels as close to normal as possible. That meant trying to keep hemoglobin A1c (A1C) readings at 6% or less with at least three insulin injections a day or an insulin pump, guided by frequent self-monitoring of blood glucose. (A1C reflects average blood glucose over the previous two to three months.) Results showed that the rates of eye damage (30%) and kidney disease (12%) in all DCCT/EDIC participants who had type 1 diabetes for 25 years were also significantly lower than the rates of eye damage (40-53%) and kidney disease (35%) reported in the medical literature for comparable patients diagnosed in the 1950s to 1970s.

Genes Key to Staph Disease Found Together

One of the ways Staphylococcus bacteria become drug-resistant is through horizontal gene transfer, whereby resistance genes move from one bacterium to another. Staph bacteria also can exchange virulence genes using the same mechanism, but this was previously assumed to occur separately from the transfer of antibiotic resistance. According to an article published online in PLoS Pathogens (2009;5:e1000533), a study of Staphylococcus bacteria, including methicillin-resistant S. aureus (MRSA), has discovered a potent staph toxin responsible for disease severity. The study also found the gene for the toxin traveling with a genetic component of Staphylococcus that controls resistance to antibiotics. The study, now, shows for the first time that genetic factors that affect Staphylococcus virulence and drug resistance can be transferred from one strain to another in one exchange event. The research involved more than 100 strains of S. aureus and S. epidermidis, both bacteria found on the skin of most people. In recent decades, these bacteria have become increasingly virulent, often causing severe disease that can be resistant to traditional antibiotics such as methicillin. The study found that staphylococci secrete toxins of the phenol-soluble modulin (PSM) family that are primarily responsible for attracting and killing human white blood cells called neutrophils. This process is critical for the ability of S. aureus-including community-acquired MRSA-to cause disease. While screening S. aureus and S. epidermidis strains, the research team noticed that some strains produced one additional, previously unknown PSM toxin. The researchers hypothesized that the toxin was somehow connected to drug resistance. This idea surfaced because the toxin appeared in 10% of all MRSA strains and 68% of all methicillin-resistant S. epidermidis strains analyzed-whereas the researchers did not find it in strains of S. aureus or S. epidermidis that are sensitive to methicillin. The study confirmed its hypothesis by identifying the specific location that encodes the toxin, which was in gene clusters that control drug resistance, known as SCCmec. The group named the new toxin PSM-mec. According to the authors, this work represents a previously unknown example of a toxin hitchhiking on staphylococcal mobile genetic elements that are primarily in charge of transferring antibiotic resistance, and that the findings should alert the research community that aggressive, drug-resistant staph can evolve more quickly than previously assumed. The research group is continuing its study of PSM-mec in S. epidermidis, where the toxin is more prevalent. Ultimately, being able to neutralize PSM-mec and other toxins that attack human defenses could lead to new treatments for S. aureus and S. epidermidis disease.

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 New Drug Treatment for Type 2 Diabetes

The hormone insulin keeps blood sugar (glucose) levels within a narrow range in people who don’t have diabetes. People with Type 2 diabetes are either resistant to insulin or do not produce enough insulin to maintain normal blood sugar levels. The FDA has approved Onglyza (saxagliptin), a once-daily tablet to treat Type 2 diabetes in adults. Onglyza is in a class of drugs known as dipeptidyl peptidase-4 (DPP-4) inhibitors which stimulate the pancreas to make more insulin after eating a meal. The medication is intended to be used with diet and exercise to control high blood sugar levels. The most common side effects observed with Onglyza are upper respiratory tract infection, urinary tract infection, and headache. Other side effects include allergic-like reactions such as rash and hives. Approval of Onglyza was primarily based on the results of eight clinical trials. The application seeking FDA approval was submitted before December 2008 when the agency recommended that manufacturers of new diabetes drugs carefully design and evaluate their clinical trials for cardiovascular safety. Although Onglyza was not associated with an increased risk for cardiovascular events in patients who were mainly at low risk for these events, the FDA is requiring a postmarket study that will specifically evaluate cardiovascular safety in a higher risk population. Onglyza is manufactured by Bristol-Myers Squibb Co. of Princeton, N.J., and marketed by Bristol-Myers and AstraZeneca Pharmaceuticals LP, of Wilmington, Delaware.

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