Providing information or promoting drugs?

On 12 September, US Food and Drug Administration (FDA) officials released finalized recommendations for drug makers that wish to provide medical literature to doctors about unapproved uses of their products. It's no small matter, since over 20% of US prescriptions are written for ‘off-label uses’.

Earlier guidelines required companies to commit to submitting an application to the FDA for the unapproved use before sharing peer-reviewed journal articles or reference publications about it. However, the new recommendations permit sales representatives to share data about uses that companies don't plan to submit for FDA review.

Additionally, the finalized version of the new guidelines does not require that drug companies provide peer-reviewed materials that reach different conclusions about the unapproved use.

The revised policy recommends that that peer-reviewed materials given to doctors are not “marked, highlighted, summarized, or characterized by the [company] in any way”. Such actions could be considered ‘off-label promotion’ of drugs, which is what US pharmaceutical giant Eli Lilly did when it used catchy slogans to persuade doctors to prescribe the antipsychotic Zyprexa for unauthorized use in elderly patients (Lilly pleaded guilty to violating US law on 15 January). This practice is still illegal. However, I doubt the relaxed guidelines will help companies provide an unbiased view of their drug’s safety and clinical effectiveness—something that certain companies apparently need help with.

Photo by zimpenfish

Pediatric placebos

When I was a small child, I had an earache, so I asked my dad for a Band Aid. The source of my discomfort was an inner ear infection, so antibiotics would have been more on the mark—but a Band Aid seemed better than nothing. The placebo effect is powerful.

As reported in the New York Times this week, there is now a placebo pill designed for children that you can buy. The product is called Obecalp (placebo spelled backwards) and available online for $5.95 a bottle. Each cherry-flavored chewable Obecalp tablet is essentially a lump of sugar in a medicinal disguise. “Invented by a mommy,” says the website advertisement, featuring a headshot of the product’s inventor, a mother of three from Severna Park, Maryland. The implication is that, if a mom came up with the idea, then it must be okay to give fake meds to your children.

But how will mom (or dad) explain the situation when their children discover that the magical tablets they received for headaches, stomachaches and sore throats were always a hoax? The use of placebos sends an uncertain message to children. They will eventually know that their parents deceived them. Moreover, there is something unnerving about looking to pills for the answer to every ailment. There are other ways to comfort children. In some cases they simply need a dose of attention to feel better. Perceived physical ailments may also be a sign of emotional or mental distress that a sugar tablet cannot fix.

Doctors admit to prescribing placebos, according to a study published earlier this year in the Journal of General Internal Medicine. Researchers at the University of Chicago surveyed 466 physicians from three Chicago-area medical schools and found that nearly half of all respondents had used placebos in their clinical practice. One of their most common reasons for doing so: “to calm patients.” Something is wrong with a medical system in which patients need pills and injections to feel tranquil and reassured that they have received adequate care. It’s hard to imagine that adding more pills to the market, even if they are fakes, will help change this culture.

Posted on behalf of Coco Ballantyne

Image by Fillmore Photography via Flickr

Gene mutation may reveal clues for treating lung diseases

Oct. 15, 2009 -- A genetic mutation found in four children born with multiple abnormalities may provide insight into potential treatments for newborn lung distress and chronic obstructive pulmonary disease (COPD).

The children were born with abnormally developed lungs, gastrointestinal and urinary systems, skin, skull, bones and muscles. In addition, all had cutis laxa, an inherited connective tissue disorder that causes skin to hang loosely from the body. Three of the patients died from respiratory failure before age 2.

Details about the discovery of the mutation, found by researchers from Washington University School of Medicine in St. Louis, McGill University, New York University Langone Medical Center and collaborating institutions, are published in the Oct. 15 online edition of the American Journal of Human Genetics.

Elaine C. Davis, Ph.D., senior author and associate professor of anatomy and cell biology at McGill University in Montreal, Canada, compared various tissues from a mouse genetically engineered to be missing a form of the LTBP4 gene with skin tissue samples from one of the children. She found remarkable similarities. The mouse, provided by Daniel Rifkin, M.D., the Charles Aden Poindexter Professor of Medicine and professor of cell biology at NYU Langone Medical Center, showed similar connective tissue alterations by electron microscopy as the patient. The child had cutis laxa, lethal pulmonary complications and gastrointestinal and urinary disease.

Based on these observations, researchers in the laboratory of Zsolt Urban, Ph.D., a pediatric geneticist at Washington University School of Medicine, sequenced the LTBP4 gene in the four children and confirmed they had mutations. He determined that the patients were the first described to show severe symptoms of a novel syndrome, which the researchers have named Urban-Rifkin-Davis Syndrome.

The findings have potential implications for newborns with underdeveloped lungs as well as older patients with severe lung diseases, including COPD, says Urban, first author of the paper.

"Many newborns commonly have breathing difficulties," Urban says. "Part of the problem is that the lung is not developed properly, especially the alveoli, the tiny sacs at the end of the smallest airways that serve as a place for oxygen uptake and gas exchange. This finding helped us identify a gene essential for the development of alveoli and potentially provide a target for intervention in premature babies."

Urban says potential treatments could include introducing the protein product of the LTBP4 gene to the newborn or using existing drugs that can moderate transforming growth factor beta (TGFß), which is overactivated in the tissues of these children. The drug losartan, now in trials for treating Marfan syndrome, another connective tissue disorder, has been shown to limit TGFß and merits further research as a possible treatment.

The researchers now are broadening their research into the new syndrome among other patients with cutis laxa. Urban, assistant professor of pediatrics, of medicine and of genetics at Washington University School of Medicine, heads the International Center for the Study of Cutis Laxa at St. Louis Children's Hospital.

"We are finding that about 70 percent of cutis laxa patients with pulmonary, gastrointestinal and urinary problems have Urban-Rifkin-Davis Syndrome," Urban says. "Now we will look at what percentage of cutis laxa patients with only pulmonary problems have the mutation."

Early developmental problems that are not detectable in childhood may predispose a person to age-related disease such as COPD, Urban says. Urban and colleagues are also testing samples collected from patients with COPD for LTBP4 mutations. When lungs are damaged with COPD, alveoli lose their elastic quality, and the walls between them are destroyed as they become thick and inflamed.

"Patients who may have a slightly reduced activity of LTBP4 might be more susceptible to chronic lung diseases later in life," Urban says. "Identifying genes that are central for the formation of alveoli may help us devise ways to regenerate alveoli in patients with COPD."

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Urban Z, Hucthagowder V, Schürmann N, Todorovic V, Zilberberg L, Chio J, Sens C, Brown C, Clark R, Holland K, Marble M, Sakai L, Dabovic B, Rifkin D, Davis EC. Mutations in LTBP4 cause a syndrome of impaired pulmonary, gastrointestinal, genitourinary, musculoskeletal and dermal development. American Journal of Human Genetics. Advance online publication Oct. 15, 2009.

This study was funded in part by the National Institutes of Health, March of Dimes, Phillip Morris USA Inc. and the Canadian Institutes of Health Research.

Washington University School of Medicine's 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked third in the nation byU.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.

Scientists identify roots of diabetic tissue damage

Oct. 21, 2009 -- Results from comprehensive assessments of diabetes' effects on cell metabolism may aid efforts to reduce diabetic damage to nerves, blood vessels and other tissues, according to researchers at Washington University School of Medicine in St. Louis and elsewhere.

The scientists found that by blocking the sorbitol pathway, one of several pathways cells employ to use the sugar glucose, they could prevent diabetic damage to nerves and blood vessels in a rat model. Prior clinical trials of blockers for this pathway have been disappointing, according to the researchers, but they and others now think that may be because the sorbitol pathway was inadequately blocked.

"What we've found should help fine-tune efforts to slow or prevent diabetes-associated complications such as hardening of the arteries, damage to vision and loss of nerve function," says senior author Joe Williamson, M.D., retired professor of pathology and immunology. "Evidence suggests that such complications are caused by increased levels of superoxide, and our results point to the sorbitol pathway as the main source of this chemically reactive compound."

The paper appeared online in the journal Antioxidants and Redox Signaling and will appear in print in the future.

Normally, cells use glucose mostly to make energy through a process called glycolysis. However, as glucose levels rise, cells begin to use glucose in a process called the sorbitol pathway. The high glucose levels associated with diabetes increase cells' use of glucose via glycolysis and the sorbitol pathway.

Both processes alter a molecule known as NAD (nicotinamide adenine dinucleotide), changing it to NADH, or NAD plus a hydrogen atom. To keep glycolysis possible, cells have to convert NADH back to NAD. If NADH levels increase relative to NAD, a metabolic imbalance occurs that can limit energy production essential for normal cell function and survival.

Pyruvate, an antioxidant produced by glycolysis, normally helps facilitate conversion of NADH into NAD. However, the sorbitol pathway does not produce pyruvate. Williamson and his colleagues theorized that when diabetes increases sorbitol pathway use, it places an increased burden on the cell by creating more NADH but leaving it with relatively less pyruvate to help change it back into NAD. They noted that a cell faced with too much NADH and too little pyruvate can turn to other enzymes to achieve the conversion, and that these enzymes produce superoxide as a product, making them an important source of diabetic tissue damage.

For the new paper, they tested the first component of this theory in a rat model of diabetes. Among other results, they found inhibiting either of two specific steps in the sorbitol pathway improved vascular function in the rats and reversed impaired motor nerve conduction velocity, or the speed at which nerves transmit electrical signals to stimulate muscles.

"It's already been established in other studies that pyruvate supplementation normalizes vascular dysfunction caused by high glucose levels and slows cataract formation in diabetic animals," Williamson says. "These results support our theories of why this happens, and others may be able to build upon this to create new and improved treatments for diabetes."

Sorbitol pathway inhibitors similar to those used by the researchers have been tested previously with disappointing results in clinical trials, but Williamson says recent studies in animals suggest those inhibitors may not have blocked the sorbitol pathway sufficiently.

"We've assembled what appears to be the most coherent explanation to date on how high glucose levels affect several different aspects of cell metabolism, and all the indicators point to the sorbitol pathway as the primary source of increased superoxide," he says. "More effective inhibitors of the sorbitol pathway are still being explored and may be able to prevent diabetic complications in the future."

For now, though, Williamson emphasizes that the best way for diabetics to prevent complications is to keep glucose levels as close to normal as possible.

Williamson also suggests that pyruvate, as a treatment for patients with poorly controlled diabetes, merits further study, but cautions that the body metabolizes pyruvate very quickly. He suggests that pyruvate may be most immediately useful in preventing diabetic damage to the eye, where it can be applied directly as eye drops and quickly reach its targets, the retina and lens.

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Yasuo I, Nyengaard J, Chang K, Tilton R, Kilo C, Mylari B, Oates P, Williamson J. Early neural and vascular dysfunction in diabetic rats are largely sequelae of increased sorbitol oxidation. Antioxidants and Redox Signaling, published online ahead of print.

Funding from the National Institutes of Health, Fonden til Laegevidenskabens Fremme (Copenhagen), the Lundbeck Foundation (Copenhagen) and the Kilo Research Foundation (St. Louis, MO) supported this research.

Washington University School of Medicine's 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked third in the nation byU.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.

Total Ankle Replacement with No Metal

Newswise — Patients suffering from severe arthritis now have an option for total ankle replacement that offers increased mobility and pain relief without permanent metal implants. Pioneered by Daniel K. Lee, D.P.M., F.A.C.F.A.S., at UC San Diego Medical Center, this technique is the first in the U.S to offer arthritis sufferers a non-metal, biological ankle replacement.

"Up until now, patients have had two options for replacing their ankle joints: metal implants or fusion of the joints," said Lee, director of foot and ankle surgery at UCSD Medical Center. "Now there is an option that actually restores the ankle with an FDA-approved biologic material that is similar to the collagen found in cartilage."

During a two hour minimally-invasive surgical procedure, Lee, a podiatric foot and ankle surgeon, removes the damaged cartilage around the ankle joint through a four centimeter incision. The collagen material is then molded into the joint where it adapts to the contour of the patient's ankle.

"Unlike a metal device, the advantage to this material is that the implant can be customized in size and contour for every patient's individual need," said Lee. "No matter how the patient's ankle is shaped, the collagen is a perfect fit."

The biologic material, processed from either human or animal collagen sources, has been used for more than 10 years in plastic and abdominal surgery and heart valve replacement. Since it is non-allergenic and sterile in nature, there is no risk of rejection or need for the patient to take immunosupressors.

To allow the material to integrate fully with the ankle joint, a temporary external device is used to stabilize the joint area while keeping it "distracted" or open for a period of 4-6 weeks. Attached by small pins, the cylinder-shaped device serves as a shock system to keep the joint free from friction and movement until healing is complete. The device is then removed entirely, which keeps the patient's ankle free from any metal parts.

"Within 3 weeks after surgery, we see an incorporation of tissue onto the damaged cartilage," said Lee. "The idea here is to avoid fusion of the ankle and to add longevity to the joint. We want to give patients as much mobility as possible so they can get back to the activities they love the most."

Lee's patient's range in age from 30-85. Robert Adams, 82, a retired professor, received the ankle replacement after repeated attempts at physical therapy.

"My ankle collapsed on me," said Adams. "I didn't like the idea of a fusion with no motion or opening up my ankle for a metal device. Following this surgery, I no longer have sharp or stabbing pains. I am continuing to improve and can get around better."

For years, patients have had the option of total joint replacement in the hips, knees, and ankle with titanium and other metal devices. While the implants are well suited for hips and knees, metal replacements for the ankle show a high level of failure and unwanted complications such as metal collapse and breakage. Once an ankle is replaced with metal, options for revision surgery are little to none.

According to the Centers for Disease Control, an estimated 46 million U.S. adults, approximately 1 in 5, report doctor-diagnosed arthritis. As the U.S. population ages, these numbers are likely to increase sharply. The number of adults with arthritis is projected to increase to 67 million by 2030, and a good proportion of U.S. adults will have limited activity as a result. Nearly two-thirds of people with arthritis are younger than 65.

Description

Patients suffering from severe arthritis now have an option for total ankle replacement that offers increased mobility and pain relief without permanent metal implants. Pioneered by Daniel K. Lee, D.P.M., F.A.C.F.A.S., at UC San Diego Medical Center, this technique is the first in the U.S to offer arthritis sufferers a non-metal, biological ankle replacement.