Health Research Report
59th Issue Date 23 JUN 2009
Compiled By Ralph Turchiano
Editors top five:
1. Eli Lilly and Zyprexa Under the Spotlight (criminal activity)
2. Dioxins in Food Chain Linked to Breastfeeding Ills
3. Children susceptible to pesticides longer than expected, study finds
4. ‘Cannabis alters human DNA’ — new study
5. Successful weight loss with dieting is linked to vitamin D levels
In this issue:
1. Dioxins in Food Chain Linked to Breastfeeding Ills
2. BPA may cause heart disease in women, research shows
3. Bisphenol A exposure in pregnant mice permanently changes DNA of offspring
4. A red-wine polyphenol called resveratrol demonstrates significant health benefits
5. Successful weight loss with dieting is linked to vitamin D levels
6. Newborn weights affected by environmental contaminants
7. ‘Cannabis alters human DNA’ — new study
8. Study finds autistics better at problem-solving
9. Powerful Nutrient Cocktail Can Put Kids with Crohn’s into Remission
10. Eli Lilly and Zyprexa Under the Spotlight
11. Antibiotics take toll on beneficial microbes in gut
12. Green tea may affect prostate cancer progression
13. Children susceptible to pesticides longer than expected, study finds
Public release date: 10-Jun-2009
Dioxins in Food Chain Linked to Breastfeeding Ills
Exposure to dioxins during pregnancy harms the cells in rapidly-changing breast tissue, which may explain why some women have trouble breastfeeding or don’t produce enough milk, according to a University of Rochester Medical Center study.
Researchers believe their findings, although only demonstrated in mice at this point, begin to address an area of health that impacts millions of women but has received little attention in the laboratory, said corresponding author B. Paige Lawrence, Ph.D., associate professor of Environmental Medicine and of Microbiology and Immunology at URMC.
“Estimates are that three to six million mothers worldwide are either unable to initiate breastfeeding or are unable to produce enough milk to nourish their infants,” Lawrence said. “But the cause of this problem is unclear, though it has been suggested that environmental contaminants might play a role. We showed definitively that a known and abundant pollutant has an adverse effect on the way mammary glands develop during pregnancy.”
Dioxins are generated mostly by the incineration of municipal and medical waste, especially certain plastics. Most people are exposed through diet. Dioxins get into the food supply when air emissions settle on farm fields and where livestock graze. Fish also ingest dioxins and related pollutants from contaminated waters. When humans take in dioxin – most often through meat, dairy products, fish and shellfish – the toxin settles in fatty tissues; natural elimination takes place very slowly. The typical human exposure is a daily low dose, which has been linked to possible impairment of the immune system and developing organs.
In 2004 Lawrence’s laboratory made the novel discovery that dioxin impairs the normal development of mammary glands during pregnancy. However, the underlying mechanisms were unclear, as was the extent of injury and whether exposure during certain stages of pregnancy had more or less of an impact on milk production.
This week, in an online report in Toxicological Sciences, researchers showed that dioxin has a profound effect on breast tissue by causing mammary cells to stop their natural cycle of proliferation as early as six days into pregnancy, and lasting through mid-pregnancy. In tissue samples from mice, exposure to dioxin caused a 50-percent decrease in new epithelial cells. This is important, Lawrence said, because mammary glands have a high rate of cell proliferation, especially during early to mid-pregnancy when the most rapid development of the mammary gland occurs.
Researchers also found that dioxin altered the induction of milk-producing genes, which occurs around the ninth day of pregnancy, and decreased the number of ductal branches and mature lobules in the mammary tissue.
The timing of dioxin exposure also seemed to be significant, the study noted. For example, when exposure occurs very early in pregnancy but not later, lab experiments showed that sometimes the mammary glands can partially recover from the cellular injury. However, although it is important to understand timing of exposure for research purposes, it is irrelevant for humans, who cannot really control their exposure to dioxins, Lawrence said.
“Our goal is not to find a safe window of exposure for humans, but to better understand how dioxins affect our health,” she said. “The best thing people who are concerned about this can do is think about what you eat and where your food comes from. We’re not suggesting that we all become vegans — but we hope this study raises awareness about how our food sources can increase the burden of pollutants in the body. Unfortunately, we have very little control over this, except perhaps through the legislative process.”
Much of Lawrence’s research focuses on a transcription factor known as aryl hydrocarbon receptor, or AhR.When pollutants enter the body they bind to AhR, which then turns on certain genes responsible for detoxification. By using dioxin to activate AhR, researchers have learned that dioxin impairs the ability to fight off infection. The link between dioxin and the immune system is still being studied, but meanwhile researchers looked further at the mammary tissue after observing coincidentally that cells involved in milk production were sustaining so much damage that rodents could not nourish their offspring.
The next step is to understand what controls the differentiation process. An important question to answer, Lawrence said, is whether the toxic harm is occurring directly in the breast, or if it occurs throughout the entire body but has a unique manifestation in the fatty mammary tissue.
The URMC research group is also studying a possible connection between dioxin and breast cancer.Their hypothesis is that dioxin exposure in some people might cancel the general protection that pregnancy has on breast tissue against breast cancer.
The research was supported by grants from the National Institutes of Health and the URMC Environmental Health Sciences Center, as well as the Art BeCAUSE Foundation of Boston, which funds breast-cancer related research.
Public release date: 10-Jun-2009
BPA may cause heart disease in women, research shows
CINCINNATI—New research by a team of scientists at the University of Cincinnati (UC) shows that bisphenol A (BPA) may be harmful for the heart, particularly in women.
Results of several studies are being presented in Washington, D.C., at ENDO 09, the Endocrine Society’s annual meeting, June 10-13.
A research team lead by Scott Belcher, PhD, Hong Sheng Wang, PhD, and Jo El Schultz, PhD, in the department of pharmacology and cell biophysics, found that exposure to BPA and/or estrogen causes abnormal activity in hearts of female rats and mice.
In addition, these researchers found that estrogen receptors are responsible for this affect in heart muscle cells.
“There is broad exposure to bisphenol A, despite recognition that BPA can have harmful effects,” Belcher says. “We had reason to believe that harmful cardiovascular affects can be added to the list.”
BPA, an environmental pollutant with estrogen activity, is used to make hard, clear plastic and is common in many food product containers. It has been linked to neurological defects, diabetes and breast and prostate cancer.
Using live cultures of cells isolated from rat or mouse hearts, researchers briefly exposed the cardiac cells to BPA and/or estrogen. Both compounds caused striking changes in the activity of cardiac muscle cells from females but not males. Additional studies revealed that these cellular changes in activity caused improperly controlled beating in the female heart.
“Low doses of BPA markedly increased the frequency of arrhythmic events,” Belcher says. “The effect of BPA on these cardiac arrhythmias was amplified when exposed to estradiol, the major estrogen hormone in humans.”
The mechanism underlying this harmful effect was investigated using cellular imaging techniques.
“BPA and/or estrogen rapidly stimulated contraction by altering control of the concentrations of free calcium inside the heart cell but only in heart muscle cells from females, showing that these effects were sex-specific,” Belcher says. “BPA’s presence increased the frequency of calcium ‘sparks’ from the sarcoplasmic reticulum—the part of the cardiac muscle that stores and releases calcium ions—indicating spontaneous release or ‘leak’ that’s likely causing the heart arrhythmias and may have other harmful actions, especially following heart attack.”
Belcher and colleagues also investigated the nature of the mechanisms that mediated the responses of the cardiac muscle cells to estrogen and BPA.
“Pharmacological studies using selective estrogen receptor drugs and animal models lacking estrogen receptors were used to investigate the role of each estrogen receptor in mediating the rapid sex-specific function effects of E2 and BPA in cells,” he says. “Our findings suggest that estrogen has opposing actions in cardiac cells.
“In female cardiac muscle cells, the blocking or genetic removal of estrogen receptor beta completely blocked the contractile effects of BPA and estrogen, while in males, blockade of the effects of estrogen receptor alpha caused the male heart to become more ‘female-like’ and become responsive to estrogen and BPA.
“These studies have identified new and important potential cardiac risks associated with BPA exposure that may be especially important for women’s heart health,” he says.
Public release date: 10-Jun-2009
Bisphenol A exposure in pregnant mice permanently changes DNA of offspring
Exposure during pregnancy to the chemical bisphenol A, or BPA, found in many common plastic household items, is known to cause a fertility defect in the mother’s offspring in animal studies, and now researchers have found how the defect occurs. The results of the new study will be presented Saturday at The Endocrine Society’s 91st Annual Meeting in Washington, D.C.
The study, funded partly by the National Institutes of Health, joins a growing body of animal research showing the toxic health effects of BPA, including reproductive and developmental problems. Last August the U.S. Food and Drug Administration found BPA to be safe as currently used but later said more research on its safety is needed. BPA is used to make hard polycarbonate plastic, such as for baby bottles, refillable water bottles and food containers, as well as to make the linings of metal food cans.
BPA has estrogen-like properties and in pregnant animals has been linked to female infertility.
“The big mystery is how does exposure to this estrogen-like substance during a brief period in pregnancy lead to a change in uterine function,” said study co-author Hugh Taylor, MD, professor and chief of the reproductive endocrinology section at Yale University School of Medicine.
To find the answer to that question, Taylor and his co-workers at Yale injected pregnant mice with a low dose of BPA on pregnancy days 9 to 16. After the mice gave birth, the scientists analyzed the uterus of female offspring and extracted DNA.
They found that BPA exposure during pregnancy had a lasting effect on one of the genes that is responsible for uterine development and subsequent fertility in both mice and humans (HOXA10). Furthermore, these changes in the offspring’s uterine DNA resulted in a permanent increase in estrogen sensitivity. The authors believe that this process causes the overexpression of the HOXA10 gene in adult mice that they found in previous studies.
The permanent DNA changes in the BPA-exposed offspring were not apparent in the offspring of mice that did not receive BPA injection (the controls). This finding demonstrates that the fetus is sensitive to BPA in mice and likely also in humans, Taylor said.
“We don’t know what a safe level of BPA is, so pregnant women should avoid BPA exposure,” Taylor said. “There is nothing to lose by avoiding items made with BPA—and maybe a lot to gain.”
Public release date: 11-Jun-2009
A red-wine polyphenol called resveratrol demonstrates significant health benefits
•Resveratrol shows therapeutic potential for cancer chemoprevention as well as cardioprotection.
•Resveratrol may aid in the prevention of age-related disorders, such as neurodegenerative diseases, inflammation, diabetes, and cardiovascular disease.
•Low doses of resveratrol improve cell survival as a component of cardio- and neuro-protection, while high doses increase cell death.
The benefits of alcohol are all about moderation. Low to moderate drinking – especially of red wine – appears to reduce all causes of mortality, while too much drinking causes multiple organ damage. A mini-review of recent findings on red wine’s polyphenols, particularly one called resveratrol, will be published in the September issue of Alcoholism: Clinical & Experimental Research; the review is also available at Early View.
“Reports on the benefits of red wine are almost two centuries old,” said Lindsay Brown, associate professor in the School of Biomedical Sciences at The University of Queensland and corresponding author for the study. “The media developed the more recent story of the French paradox in the early 1990s. However, studies on the actions of resveratrol, one of the active non-alcoholic ingredients, were uncommon until research around 1997 showed prevention of cancers. This led to a dramatic interest in this compound.” (See attached figure.)
Red wine contains a complex mixture of bioactive compounds, including flavonols, monomeric and polymeric flavan-3-ols, highly colored anthocyanins, as well as phenolic acids and the stilbene polyphenol, resveratrol. Brown said that some of these compounds, particularly resveratrol, appear to have health benefits.
“The breadth of benefits is remarkable – cancer prevention, protection of the heart and brain from damage, reducing age-related diseases such as inflammation, reversing diabetes and obesity, and many more,” said Brown. “It has long been a question as to how such a simple compound could have these effects but now the puzzle is becoming clearer with the discovery of the pathways, especially the sirtuins, a family of enzymes that regulate the production of cellular components by the nucleus. ‘Is resveratrol the only compound with these properties?’ This would seem unlikely, with similar effects reported for other components of wine and for other natural products such as curcumin. However, we know much more about resveratrol relative to these other compounds.”
Stephen Taylor, professor of pharmacology at the University of Queensland, agreed that resveratrol is the “compound du jour.”
“I think that red wine has both some mystique and some historical symbolism in the west,” said Taylor, “and of course, some various pleasures attached to its ingestion, all of which give it a psychological advantage edge, food-wise. Not many of us can or will eat a couple of cups of blueberries a day for years on end, but if we could do a population study for a decade or so on such a group, you might actually see similar results.”
Key points of the review include:
•Resveratrol exhibits therapeutic potential for cancer chemoprevention as well as cardioprotection.
“It sounds contradictory that a single compound can benefit the heart by preventing damage to cells, yet prevent cancer by causing cell death, said Brown. “The most likely explanation for this, still to be rigorously proved in many organs, is that low concentrations activate survival mechanisms of cells while high concentrations turn on the in-built death signals in these cells.”
•Resveratrol may aid in the prevention of age-related disorders, such as neurodegenerative diseases, inflammation, diabetes, and cardiovascular disease.
“The simplest explanation is that resveratrol turns on the cell’s own survival pathways, preventing damage to individual cells,” said Brown. “Further mechanisms help, including removing very reactive oxidants in the body and improving blood supply to cells.”
•Low doses of resveratrol improve cell survival as a mechanism of cardio- and neuro-protection, while high doses increase cell death.
“The key difference is probably the result of activation of the sirtuins in the nucleus,” said Brown. “Low activation reverses age-associated changes, while high activation increases the process of apoptosis or programmed cell death to remove cellular debris. Similar changes are seen with low-dose versus high-dose resveratrol: low-dose resveratrol produces cellular protection and reduces damage, while high-dose resveratrol prevents cancers.”
In summary, noted Brown, current scientific research is starting to explain reports from the last 200 years that drinking red wine improves health. “It is a cliché that ‘nature is a treasure trove of compounds,’ but studies with resveratrol show that this is correct! We need to understand better the vast array of compounds that exist in nature, and determine their potential benefits to health.”
“There is one particular point that deserves fleshing out,” added Taylor. “Resveratrol is largely inactivated by the gut or liver before it reaches the blood stream, where it exerts its effects – whatever they may be – good, bad, or indifferent. Thus, most of the reseveratrol in imbibed red wine does not reach the circulation. Interestingly, absorption via the mucous membanes in the mouth can result in up to around 100 times the blood levels, if done slowly rather than simply gulping it down. Of course, we don’t know if these things matter yet, but issues like this are real and generally ignored by all.”
Public release date: 11-Jun-2009
Successful weight loss with dieting is linked to vitamin D levels
Vitamin D levels in the body at the start of a low-calorie diet predict weight loss success, a new study found. The results, which suggest a possible role for vitamin D in weight loss, were presented at The Endocrine Society’s 91st Annual Meeting in Washington, D.C.
“Vitamin D deficiency is associated with obesity, but it is not clear if inadequate vitamin D causes obesity or the other way around,” said the study’s lead author, Shalamar Sibley, MD, MPH, an assistant professor of medicine at the University of Minnesota.
In this study, the authors attempted to determine whether baseline vitamin D levels before calorie restriction affect subsequent weight loss. They measured circulating blood levels of vitamin D in 38 overweight men and women before and after the subjects followed a diet plan for 11 weeks consisting of 750 calories a day fewer than their estimated total needs. Subjects also had their fat distribution measured with DXA (bone densitometry) scans.
On average, subjects had vitamin D levels that many experts would consider to be in the insufficient range, according to Sibley. However, the authors found that baseline, or pre-diet, vitamin D levels predicted weight loss in a linear relationship. For every increase of 1 ng/mL in level of 25-hydroxycholecalciferol—the precursor form of vitamin D and a commonly used indicator of vitamin D status—subjects ended up losing almost a half pound (0.196 kg) more on their calorie-restricted diet. For each 1-ng/mL increase in the active or “hormonal” form of vitamin D (1,25-dihydroxycholecalciferol), subjects lost nearly one-quarter pound (0.107 kg) more.
Additionally, higher baseline vitamin D levels (both the precursor and active forms) predicted greater loss of abdominal fat.
“Our results suggest the possibility that the addition of vitamin D to a reduced-calorie diet will lead to better weight loss,” Sibley said.
She cautioned, however, that more research is needed. “Our findings,” she said, “need to be followed up by the right kind of controlled clinical trial to determine if there is a role for vitamin D supplementation in helping people lose weight when they attempt to cut back on what they eat.”
Public release date: 15-Jun-2009
Newborn weights affected by environmental contaminants
New study from Sainte-Justine University Hospital Research Center, University of Montreal, McGill University and Public Health Agency of Canada
This release is available in French.
Montreal, June 15, 2009 – Recent epidemiological studies have revealed an increase in the frequency of genital malformations in male newborns (e.g., un-descended testes) and a decrease in male fertility.
The role played by the growing presence in our environment of contaminants that reduce male hormone action could explain this phenomenon.
It is known that the birth weight of males is higher than that of females due to the action of male hormones on the male fetus.If the exposure of pregnant women to environmental contaminants that diminish the action of male hormones has increased over the years, one would expect to see a decrease in the sex difference in birth weight.
This is exactly what a new study published in the July 2009 issue of Epidemiology shows. Investigators analyzed the Public Health Agency of Canada’s database on the birth weights of more than five million children born in Canada between 1981 and 2003.
Using statistical methods that control for changes over time of mother’s age and parity, the investigators effectively show a sustained decrease in birth weight differences between boys and girls, which supports the hypothesis of growing endocrine disruption related to environmental contaminants. Contaminants found in plastic materials represent plausible candidates, since they are known to diminish the action of male hormones.
“Our study underlines the importance of probing the impact of environmental contaminants on the health of mothers and fetuses and on the reproductive potential of future generations,” says lead researcher Dr. Guy Van Vliet, a pediatric endocrinologist and investigator at the Sainte-Justine University Hospital Research Center and a professor at the Department of Pediatrics of the Université de Montréal.
Public release date: 16-Jun-2009
‘Cannabis alters human DNA’ — new study
Research at University of Leicester highlights cancer risk from cannabis smoke
A new study published by University of Leicester researchers has found “convincing evidence” that cannabis smoke damages DNA in ways that could potentially increase the risk of cancer development in humans.
Using a newly developed highly sensitive liquid chromatography-tandem mass spectrometry method, the University of Leicester scientists found clear indication that cannabis smoke damages DNA, under laboratory conditions.
They have now published the findings in the journal Chemical Research in Toxicology1.
The research was carried out by Rajinder Singh, Jatinderpal Sandhu, Balvinder Kaur, Tina Juren, William P. Steward, Dan Segerback and Peter B. Farmer from the Cancer Biomarkers and Prevention Group, Department of Cancer Studies and Molecular Medicine and Karolinska Institute, Sweden.
Raj Singh said: “Parts of the plant Cannabis sativa, also known as marijuana, ganja, and various street names, are commonly smoked as a recreational drug, although its use for such purposes is illegal in many countries.
“There have been many studies on the toxicity of tobacco smoke. It is known that tobacco smoke contains 4000 chemicals of which 60 are classed as carcinogens. Cannabis in contrast has not been so well studied. It is less combustible than tobacco and is often mixed with tobacco in use. Cannabis smoke contains 400 compounds including 60 cannabinoids. However, because of its lower combustibility it contains 50% more carcinogenic polycyclic aromatic hydrocarbons including naphthalene, benzanthracene, and benzopyrene, than tobacco smoke.”
Writing in the journal Chemical Research in Toxicology, the scientists describe the development of a mass spectrometry method that provides a clear indication that cannabis smoke damages DNA, under laboratory conditions.
The authors added: “It is well known that toxic substances in tobacco smoke can damage DNA and increase the risk of lung and other cancers. Scientists were unsure though whether cannabis smoke would have the same effect. Our research has focused on the toxicity of acetaldehyde, which is present in both tobacco and cannabis.”
The researchers add that the ability of cannabis smoke to damage DNA has significant human health implications especially as users tend to inhale more deeply than cigarette smokers, which increases respiratory burden. “The smoking of 3-4 cannabis cigarettes a day is associated with the same degree of damage to bronchial mucus membranes as 20 or more tobacco cigarettes a day,” the team adds.
“These results provide evidence for the DNA damaging potential of cannabis smoke,” the researchers conclude, “implying that the consumption of cannabis cigarettes may be detrimental to human health with the possibility to initiate cancer development.”
Public release date: 16-Jun-2009
Study finds autistics better at problem-solving
University of Montreal and Harvard University research in Human Brain Mapping
Montreal, June 16, 2009 — Autistics are up to 40 percent faster at problem-solving than non-autistics, according to a new Université de Montréal and Harvard University study published in the journal Human Brain Mapping. As part of the investigation, participants were asked to complete patterns in the Raven’s Standard Progressive Matrices (RSPM) – test that measures hypothesis-testing, problem-solving and learning skills.
“While both groups performed RSPM test with equal accuracy, the autistic group responded more quickly and appeared to use perceptual regions of the brain to accelerate problem-solving,” says lead author Isabelle Soulières, a post-doctoral fellow at Harvard University who completed the experiment at the Université de Montréal. “Some critics agued that autistics would be unable to complete the RSPM because of its complexity, yet our study shows autistics complete it as efficiently and have a more highly developed perception than non-autistics.”
Fifteen autistics and 18 non-autistics were recruited for the study. Participants were 14 to 36 years old and matched according to their preliminary results on the Wechsler Adult Intelligence Scale. All subjects underwent magnetic resonance imaging to explore their neural activity during RSPM problem-solving. While autism is a common neurodevelopmental disability characterized by profound differences in information processing and analysis, this study showed that autistics have efficient reasoning abilities that build on their perceptual strengths.
“This study builds on our previous findings and should help educators capitalize on the intellectual abilities of autistics,” says senior researcher Laurent Mottron, the new Marcel & Rolande Gosselin Research Chair in Autism Cognitive Neuroscience of the Université de Montréal and psychiatry professor. “The limits of autistics should constantly be pushed and their educational materials should never be simplified.”
Adds Dr. Soulières: “The Raven’s Standard Progressive Matrices are among the most complex tests to provide insight on how a person understands and formulates rules, manages goal hierarchies and performs high-level abstractions. Our wager was that autistics could complete such a test and they surpassed our expectations.”
Public release date: 16-Jun-2009
Powerful Nutrient Cocktail Can Put Kids with Crohn’s into Remission
TAU researcher promotes liquid nutrition to combat inflammatory bowel disease
Treating children with inflammatory bowel disease (IBD) usually involves the same steroids-based medication prescribed to adults. But such treatments can have negative side effects for kids and teens dealing with IBD.
Dr. Raanan Shamir of Tel Aviv University’s Sackler School of Medicine and Schneider Children’s Medical Centre shows that there is another path to treating IBD in children: a nutritional formula that was first developed for astronauts. This supplement puts 60-70% of children with Crohn’s disease, a common IBD disorder, into remission — a success rate similar to that of traditional steroid-based drugs, but without side effects like malnutrition and growth retardation.
Dr. Shamir recently reported his research in the Journal of Pediatric Gastroenterology and Nutrition.
Eating Like an Astronaut
Dr. Shamir’s research was inspired by the problem of malnutrition and growth retardation in children battling IBD. Steroids and other biological agents, the most common treatment for IBD, were having an adverse affect on the children’s growth, despite their effectiveness in adult patients.
It was a problem first tackled by NASA: How could astronauts most efficiently get their daily nutrients? The answer was a specially-designed powder that contains all the daily nutrients a person needs. Aboard spacecrafts, astronauts dine on this nutritional powder mixed with water. Since then, these powders have become a common item on the pharmacy shelf.
A similar concept works wonders for children suffering from IBD. “Prepared powder, with liquids, gives you all the nutritional requirements you need for the day,” Dr. Shamir explains. “We don’t know why these formulas work, and nobody has shown that any one formula is preferable to another. People have to be committed and eat nothing else during the period of time they are on nutrition therapy, and it is difficult to do — but if they do it, they go into remission.”
To induce remission, children need to be on nutrition therapy for 6-8 weeks. And in order to maintain remission, 25-50% of their caloric intake must be supplied by nutrition therapy, sometimes for years. This is why children experiencing the treatment need the support of physicians, dieticians, psychologists, and of course their families.
Dr. Shamir’s quest to educate the international medical community about the benefits of nutrition therapy has been an uphill battle. “The acceptance of this is difficult,” he says. “You have to persuade the family. Not all physicians know it works, and it’s much easier to give someone a prescription than try to work with the child.”
A Replacement for Steroids
“In adults, studies have shown that steroids are more effective in the battle against IBD than nutrition-based therapies. I think it is easier to get compliance from children, especially when it involves their growth. For adults, growth is not a concern — they just want to feel better,” explains Dr. Shamir.
Dr. Shamir and his team of researchers have worked to show the international medical community that nutrition was equal to steroids in the treatment of children with IBD. “We published the most recent meta-analysis to show that nutrition is as good as steroids as a first-line therapy for Crohn’s disease,” he says.
The next step in his research, says Dr. Shamir, is to “define exactly the role of nutrition in inducing remission in these patients, and the role of nutrition in maintaining remission.
Public release date: 16-Jun-2009
Eli Lilly and Zyprexa Under the Spotlight
Reviewed by John M. Grohol, Psy.D. on June 14, 2009 Eli Lilly & Co.’s atypical antipsychotic medication, Zyprexa, was not only marketed to doctors for an unapproved, off-label use — the treatment of dementia in elderly patients — but it was done despite Lilly’s access and knowledge of at least seven studies that showed the drug was apparently ineffective for the treatment of dementia.
The studies also showed that the use of the drug resulted in “significantly” more deaths than patients taking placebo pills in the studies.
Eli Lilly plead guilty to federal charges in January 2009 for illegally marketing Zyprexa for off-label uses to older Americans from 1999 to 2001.
The latest Zyprexa revelation comes as Eli Lilly continues to fight in U.S. District Court in New York against claims brought against the company by pension plans and health care insurance companies seeking to get back money spent on purchasing Zyprexa for their customers. Lilly has settled numerous previous cases related to Zyprexa for approximately $2.62 billion, including a $615 million fine for the federal charge of marketing the drug for off-label uses.
Eli Lilly claims that the off-label marketing of Zyprexa for dementia in elderly patients ended in 2001. However, the groups suing Lilly claim that the drug manufacturer continued to promote Zyprexa to physicians treating elderly patients even the company claimed it had stopped, according to its own internal emails and documents.
According to the Bloomberg news agency, “The plaintiffs cite documents including a 2002 business plan calling for expanding prescriptions in off-label use. They also point to notes from Lilly sales representatives through 2003 recording efforts to press doctors to prescribe elderly patients Zyprexa for mood symptoms, irritability and insomnia.”
“Insurers and other so-called third-party payers contend Lilly should pay as much as $6.8 billion in damages for downplaying Zyprexa’s health risks, including excessive weight gain and the risk of contracting diabetes, and marketing the drug for unapproved uses to pump up profits,” Bloomberg further noted.
Notes written by Eli Lilly salespeople during their sales calls to doctors allegedly demonstrated their continued push to primary care physicians to prescribe Zyprexa for off-label, unapproved uses — something that is illegal for a drug company to do. As late as 2003, such notes indicated that salespeople were apparently still recommending Zyprexa for off-label uses such as helping elderly patients sleep, manage irritability, decrease hostility and improve unclear thinking — some of which are typical symptoms of dementia. Without using the word “dementia,” Lilly salespeople apparently continued to tout the benefits of Zyprexa for common dementia symptoms.
Side effects were, according to the latest unsealed documents, acknowledged, but minimized. According to Bloomberg, “‘Acknowledge weight gain but present it as a manageable side effect,” Lilly advised its sales force, according to the documents. “With most customers, we will continue to address the diabetes concern only when it arises,” the December 2001 document said. “Get back to selling!”’
The latest set of documents unsealed also showed that Lilly company employees wrote a number of the medical studies that demonstrated Zyprexa’s effectiveness. The studies were then submitted to medical journals and published under doctors’ names who agreed to put their names on the studies. The ghostwriting effort by Lilly was not publicly known before the unsealing of the court documents.
The seven studies that did not show Zyprexa’s effectiveness for dementia were not published in medical journals.
Zyprexa is Eli Lilly’s most profitable and lucrative drug, accounting for $4.7 billion in international sales in 2008 — accounting for over 30 percent of all atypical antipsychotics sales in the U.S.
Source: Bloomberg news agency and wire reports
Ralphs Note- Just a few days ago this drug was approved for use in children with Schizophrenia and Bi-Polar. If any of us knowingly poisoned someone, manslaughter and murder charges would be the first to come to mind.
Public release date: 16-Jun-2009
Antibiotics take toll on beneficial microbes in gut
ANN ARBOR, Mich. — It’s common knowledge that a protective navy of bacteria normally floats in our intestinal tracts. Antibiotics at least temporarily disturb the normal balance. But it’s unclear which antibiotics are the most disruptive, and if the full array of “good bacteria” return promptly or remain altered for some time.
In studies in mice, University of Michigan scientists have shown for the first time that two different types of antibiotics can cause moderate to wide-ranging changes in the ranks of these helpful guardians in the gut. In the case of one of the antibiotics, the armada of “good bacteria” did not recover its former diversity even many weeks after a course of antibiotics was over.
The findings could eventually lead to better choices of antibiotics to minimize side effects of diarrhea, especially in vulnerable patients. They could also aid in understanding and treating inflammatory bowel disease, which affects an estimated 500,000 to 1 million Americans, and Clostridium difficile, a growing and serious infection problem for hospitals.
Normally, a set of thousands of different kinds of microbes lives in the gut – a distinctive mix for each person, and thought to be passed on from mother to baby. The microbes, including many different bacteria, aid digestion and nutrition, appear to help maintain a healthy immune system, and keep order when harmful microbes invade.
“Biodiversity is a well-known concept in the health of the world’s continents and oceans. Diversity is probably important in the gut microsystem as well,” says Vincent B. Young, M.D., Ph.D., senior author of the study, which appears in the June issue of Infection and Immunity.
The study results suggest that unless medical research discovers how to protect or revitalize the gut microbial community, “we may be doing long-term damage to our close friends,” says Young, assistant professor in the departments of internal medicine and microbiology and immunology at the U-M Medical School.
Young and his colleagues used a culture-independent technique, using sequence analysis of 16S rRNA-encoding gene libraries, to profile the bacterial communities in the gut. It allows them to look for many more kinds of microbes than was possible with more limited methods. The result is a much more complete picture of the diversity of microbes in the gut.
Mice, which normally develop a diverse set of microbes after being born without one, then were given either cefoperazone, a broad-spectrum cephalosporin antibiotic, or a combination of three antibiotics (amoxicillin, bismuth and metronidazole). The scientists then observed what changes in the gut microbiota occurred immediately after the antibiotics were stopped or six weeks following the end of treatment.
“Both antibiotic treatments caused significant changes in the gut microbial community. However, in the mice given cefoperazone, there was no recovery of normal diversity. In other mice given the amoxicillin-containing combination, the microbiota largely recovered, but not completely,” says Young.
However, Young’s team found that a little socializing sparked recovery in even the most severely affected mice. Some of the mice given cefoperazone soon recovered normal microbes after an untreated mouse was placed in the same cage. That wasn’t a complete surprise, since mice have a habit of eating the feces of their cage mates and therefore picked up normal gut microbes quickly.
Not a lesson applicable to humans? In patients with refractory antibiotic-associated diarrhea due to C. difficile, there have been limited trials of treatments using “fecal transplants” to replace lost gut microbiota. Although this is a pretty unpalatable treatment at first glance, the clinical response was quite remarkable, Young says.
Although cefaperazone is not commonly used in the United States, related drugs such as cefoxitin are. The study findings suggest that it is really important to use antibiotics only when indicated, especially in people with health problems that might already compromise their gut microbe health, Young says. Multiple rounds of antibiotics may also deserve concern.
The findings will guide Young in related work in which he is using mouse models to examine how changes in the microbiota in the gut may influence how inflammatory bowel disease develops and progresses. The study will also inform ongoing research in his lab to gain insights into colitis associated with C. difficile infection. The Young laboratory recently published a study that demonstrates that long-term decreases in gut microbe diversity from repeated antibiotics are associated with recurring C. difficile infection in human patients.
Young cautions against concluding that popular probiotics supplements necessarily are safe and effective for everyone looking for a way to restore healthy gut microbes. An individual’s specific health needs and vulnerabilities have to be considered. “Probiotics may be part of the solution, but we don’t know that yet,” he says.
Other authors are: first author Dionysios A. Antonopoulos, Ph.D. Department of Internal Medicine, University of Michigan; Susan M. Huse, Ph.D., Mitchell L. Sogin,Ph.D., and Hilary G. Morrison, Ph.D., Marine Biological Laboratory, Woods Hole, Mass.; and Thomas M. Schmidt, Ph.D., Michigan State University.
Funding for the study came from the National Institutes of Health.
Public release date: 19-Jun-2009
Green tea may affect prostate cancer progression
PHILADELPHIA – According to results of a study published in Cancer Prevention Research, a journal of the American Association for Cancer Research, men with prostate cancer who consumed the active compounds in green tea demonstrated a significant reduction in serum markers predictive of prostate cancer progression.
“The investigational agent used in the trial, Polyphenon E (provided by Polyphenon Pharma) may have the potential to lower the incidence and slow the progression of prostate cancer,” said James A. Cardelli, Ph.D., professor and director of basic and translational research in the Feist-Weiller Cancer Center, LSU Health Sciences Center-Shreveport.
Green tea is the second most popular drink in the world, and some epidemiological studies have shown health benefits with green tea, including a reduced incidence of prostate cancer, according to Cardelli. However, some human trials have found contradictory results. The few trials conducted to date have evaluated the clinical efficacy of green tea consumption and few studies have evaluated the change in biomarkers, which might predict disease progression.
Cardelli and colleagues conducted this open-label, single-arm, phase II clinical trial to determine the effects of short-term supplementation with green tea’s active compounds on serum biomarkers in patients with prostate cancer. The biomarkers include hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF) and prostate specific antigen (PSA). HGF and VEGF are good prognostic indicators of metastatic disease.
The study included 26 men, aged 41 to 72 years, diagnosed with prostate cancer and scheduled for radical prostatectomy. Patients consumed four capsules containing Polyphenon E until the day before surgery — four capsules are equivalent to about 12 cups of normally brewed concentrated green tea, according to Cardelli. The time of study for 25 of the 26 patients ranged from 12 days to 73 days, with a median time of 34.5 days.
Findings showed a significant reduction in serum levels of HGF, VEGF and PSA after treatment, with some patients demonstrating reductions in levels of greater than 30 percent, according to the researchers.
Cardelli and colleagues found that other biomarkers were also positively affected. There were only a few reported side effects associated with this study, and liver function remained normal.
Results of a recent year-long clinical trial conduced by researchers in Italy demonstrated that consumption of green tea polyphenols reduced the risk of developing prostate cancer in men with high-grade prostate intraepithelial neoplasia (HGPIN).
“These studies are just the beginning and a lot of work remains to be done, however, we think that the use of tea polyphenols alone or in combination with other compounds currently used for cancer therapy should be explored as an approach to prevent cancer progression and recurrence,” Cardelli said.
William G. Nelson, V., M.D., Ph.D., professor of oncology, urology and pharmacology at the Johns Hopkins Kimmel Cancer Center, believes the reduced serum biomarkers of prostate cancer may be attributable to some sort of benefit relating to green tea components.
“Unfortunately, this trial was not a randomized trial, which would have been needed to be more sure that the observed changes were truly attributable to the green tea components and not to some other lifestyle change (better diet, taking vitamins, etc.) men undertook in preparation for surgery,” added Nelson, who is also a senior editor for Cancer Prevention Research. However, “this trial is provocative enough to consider a more substantial randomized trial.”
In collaboration with Columbia University in New York City, the researchers are currently conducting a comparable trial among patients with breast cancer. They also plan to conduct further studies to identify the factors that could explain why some patients responded more dramatically to Polyphenon E than others. Cardelli suggested that additional controlled clinical trials should be done to see if combinations of different plant polyphenols were more effective than Polyphenon E alone.
“There is reasonably good evidence that many cancers are preventable, and our studies using plant-derived substances support the idea that plant compounds found in a healthy diet can play a role in preventing cancer development and progression,” said Cardelli.
Public release date: 19-Jun-2009
Children susceptible to pesticides longer than expected, study finds
BERKELEY — Although it is known that infants are more susceptible than adults to the toxic effects of pesticides, this increased vulnerability may extend much longer into childhood than expected, according to a new study by researchers at the University of California, Berkeley.
Among newborns, levels of paraoxonase 1 (PON1), an enzyme critical to the detoxification of organophosphate pesticides, average one-third or less than those of the babies’ mothers. It was thought that PON1 enzyme activity in children approached adult levels by age 2, but instead, the UC Berkeley researchers found that the enzyme level remained low in some individuals through age 7.
Based upon the findings, reported this month in the journal Environmental Health Perspectives, the study authors recommend that the U.S. Environmental Protection Agency (EPA) re-evaluate the current standards for acceptable levels of pesticide exposure.
“Current EPA standards of exposure for some pesticides assume children are 3 to 5 times more susceptible than adults, and for other pesticides the standards assume no difference,” said Nina Holland, UC Berkeley adjunct professor of environmental health sciences and senior author of the paper. “Our study is the first to show quantitatively that young children may be more susceptible to certain organophosphate pesticides up to age 7. Our results suggest that the EPA standards need to be re-examined to determine if they are adequately protecting the most vulnerable members of the population.”
In 2001, the EPA began restricting organophosphate pesticides in products sold for use in homes, mainly because of risks to children. However, organophosphate pesticides, such as chlorpyrifos and diazinon, are still used in agriculture in the United States and elsewhere.
The study, conducted by UC Berkeley’s Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS), involves 458 children from an agricultural region who were followed from birth through age 7. Cord blood samples were collected from all children to determine their PON1 genotype and to obtain baseline measures of the enzyme’s activity level.
For more than 100 of the children in the study, researchers were able to obtain at least four additional measurements – at ages 1, 2, 5 and 7 – of PON1 activity. Almost all the children in the study had 2 to 3 time points assessed, for a total of 1,143 measurements of three types of PON1 enzyme activity.
One’s PON1 genotypic profile determines how effectively the enzyme can metabolize toxins. For example, people with two copies of the Q form of the gene – known as a QQ genotype – produce a PON1 enzyme that is less efficient at detoxifying chlorpyrifos oxon, a metabolite of chlorpyrifos, than the enzyme produced by people with two R forms of the gene. Similarly, individuals with two T forms of the PON1 gene on a different part of the chromosome generally have a lower quantity of the enzyme than do those with two C forms of the gene.
Previous research led by Holland found that some of the QQ newborns may be 50 times more susceptible to chlorpyrifos and chlorpyrifos oxon than RR newborns with high PON1 levels, and 130 to 164 times more susceptible than some of the RR adults.
Of the children in this latest study, 24 percent had the QQ genotype, and 18 percent had the TT genotype, both of which are associated with lower activity of the PON1 enzyme. Moreover, 7.5 percent of the children had both QQ and TT genotypes, which is considered an even more vulnerable profile.
On average, the quantity of enzyme quadrupled between birth and age 7. The greatest rise in enzyme activity was among children with the RR and CC variants of the PON1 gene, which quickly outpaced the increase in children with the QQ and TT genotypes.
The fact that enzyme activity remained low for certain kids with vulnerable genotypes well past age 2 was surprising for the study authors. The researchers are continuing to collect data for these children as they grow older to see if the pesticide susceptibility continues.
“In addition to its involvement in the metabolism of pesticides, many studies are now finding that PON1 may play an important role in protecting against oxidative stress, which is linked to diseases from asthma to obesity and cardiovascular disease,” said study lead author Karen Huen, a UC Berkeley Ph.D. student in environmental health sciences. “The children in our study whose genotypes are related to lower PON1 activity may not only be more susceptible to pesticides throughout much of their childhood, they may also be more vulnerable to other common diseases related to oxidative stress.”
Notably, other studies have found that PON1 genotypes vary by race and ethnicity, with the Q variants more common among Caucasians, less common among Latinos, and least common among African Americans. The majority of the subjects in this study were Mexican-American.
“What’s important about this study is that it shows that young children are potentially susceptible to certain organophosphates for a longer period of time than previously thought,” said Brenda Eskenazi, UC Berkeley professor of epidemiology and director of CHAMACOS and the Center for Children’s Environmental Health Research. “Policymakers need to consider these vulnerable populations when establishing acceptable levels of exposure to different pesticides.”
Funding from the National Institute of Environmental Health Sciences and the EPA helped support this research.