Tag: Pharmacology

An avian influenza virus isolated from an infected Vietnamese girl has been determined to be resistant to the drug oseltamivir, the compound better known by its trade name Tamiflu, and the drug officials hope will serve as the front line of defense for a feared influenza pandemic. Scientists from the University of Wisconsin-Madison, working with colleagues in Vietnam and Japan, report in a brief communication in next week’s edition (Oct. 20, 2005) of the journal Nature that a young girl, provided with a prophylactic dose of the drug after experiencing mild influenza symptoms, developed a strain of the virus that was highly resistant to the drug. The finding suggests that health officials – now stockpiling millions of doses of the drug to forestall a global outbreak of influenza and buy time to develop and mass produce a vaccine – should also consider other options, according to Yoshihiro Kawaoka, an international authority on influenza and the senior author of the Nature paper.

Recent reports indicate the federal government may spend billions of dollars to stockpile as much as 81 million courses of Tamiflu to forestall a possible influenza pandemic. The government has already stockpiled an estimated 12 to 13 million courses. “This is the first line of defense,” says Kawaoka, a professor in the UW-Madison School of Veterinary Medicine who holds a joint appointment at the University of Tokyo. “It is the drug many countries are stockpiling, and the plan is to rely heavily on it.” The drug would be used to slow the spread of influenza until a vaccine is developed, which may take up to six months.

Tamiflu is delivered orally and works to impede the spread of the virus by binding to and inhibiting one of the surface enzymes the virus uses to exit infected cells of a host. Once inside a host cell, the virus commandeers the cell’s reproductive machinery to make new infectious particles that go on to take over other cells. When the drug is at work, Kawaoka explains, “the virus is still able to replicate inside a cell, but is unable to get out and infect other cells.” Oseltamivir, which Kawaoka describes as an “amazing drug,” is one of three compounds proven to be effective against influenza. One class, derivatives of the compound adamantine, would be less effective, as some flu viruses have already evolved resistance to it. The other drug, zanamivir, which was developed prior to oseltamivir, is effective, but is formulated as a powder and requires that a clinician provide instructions for use. Thus, it is more cumbersome to administer than the orally delivered Tamiflu.

These flu-fighting drugs, says Kawaoka, are by no means a replacement or alternative to a vaccine. Effective vaccines can confer immunity, preventing the virus from gaining a toehold in the body. But it is unlikely sufficient quantities of a vaccine can be produced and stockpiled prior to the emergence of a new virus in human populations. If avian influenza does emerge and becomes infectious from human to human – and nearly all experts agree that will happen at some point in the future – an outbreak similar to the 1918 influenza pandemic could occur. That pandemic killed as many as 50 million people, more than died on all the battlefields of World War I. Scientists and vaccine manufacturers would be in a race against time to produce enough doses to forestall disaster. Drugs like Tamiflu, used in combination with quarantine, would be intended to slow the spread of the disease until a vaccine is produced.

Kawaoka says there may not be enough Tamiflu to go around even though countries are stockpiling it. The Wisconsin scientist says that will create a risk of patients sharing the drug and using smaller doses, which could accelerate the emergence of virus resistant to the drug and hamper efforts to contain the spread of the disease. He says health officials should consider stockpiling zanamivir and recommending that only the therapeutic dosages of Tamiflu be administered to patients. “We’ve been watching for this change (in the virus),” Kawaoka says. “This is the first, but we will see others. There’s no question about it.”

Science Daily
November 8, 2005

Original web page at Science Daily

Nearly one third of the world’s adult population suffers with the pain of arthritis. While NSAIDs and COX-2 inhibitors offer the promise of relief, these drugs also bring the risk of adverse effects, from stomach ulcers to heart attack. Recent studies have suggested the potential of tapping into the body’s supply of painkilling peptides as a safe, natural approach to arthritis pain management. Extraneous substances such as morphine can be disadvantageous in arthritis pain therapy due to a large number of adverse side-effects associated with these compounds. In addition, the lack of selectivity of morphine means that precise targeting of μ-opioid receptors to control chronic pain has proven to be problematic. What’s more, several clinical and experimental studies of μ-opioid therapy have shown ambiguous results.

The recent discovery of a natural morphine-like compound in joints called endomorphin 1 could circumvent these therapeutic drawbacks due to its greater selectivity for the μ-opioid receptor. Endomorphin 1 has the potential, therefore, to be a major painkilling agent in the body with less chance of risk. Researchers at the University of Calgary set out to determine the effectiveness of endomorphin 1, with a painkilling capacity equal to or greater than morphine – on knee joint pain. Their subjects were male rats with induced arthritis, both acute and chronic. Their findings, featured in the October 2005 issue of Arthritis & Rheumatism , shed light on why u-opioid therapy may not work to control long-term arthritis pain.

Previous research into μ-opioid therapy for arthritis has primarily focused on changes occurring in the hours immediately following tissue inflammation. This study is the first to examine the impact on chronic inflammation. The rat models were randomly assigned to the different treatment groups: acute (48-hour) inflammation, chronic (1-week and 3-week) inflammation, and normal controls. Under anesthesia, endomorphin 1 was injected into the arthritic knee joints of all affected rats. Therapeutic effectiveness was assessed by measures of joint edema formation and sensory nerve activity associated with pain.

In rats with acute arthritis, endomorphin 1 worked to significantly reduce the hypersensitivity of joint nerves by as much as 75 percent. In the rats with chronic arthritis, however, endomorphin 1 had no observable effect on the telltale triggers of pain. On the strength of these findings, researchers concluded that chronic inflammation negates the pain-relieving benefits of the body’s μ-opioid receptors. “These observations highlight a possible inadequacy of the endogenous opioid system to alleviate chronic arthritis pain,” notes study author Dr. Jason McDougall. By offering clear insights into the disappointment of μ-opioid therapy, this study suggests the need for rethinking the best use of endomorphin 1 and redirecting pain management research toward more promising alternatives for long-term arthritis sufferers.

Science Daily
October 25, 2005

Original web page at Science Daily

By examining how proteins have evolved, UT Southwestern Medical Center researchers have discovered a set of simple “rules” that nature appears to use to design proteins, rules the scientists have now employed to create artificial proteins that look and function just like their natural counterparts. By examining how proteins have evolved, UT Southwestern researchers have discovered a set of simple “rules” that nature appears to use to design proteins. In two papers appearing in the Sept. 22 issue of the journal Nature, Dr. Rama Ranganathan, associate professor of pharmacology, and his colleagues detail a new method for creating artificial proteins based only on information they derived from analyzing certain characteristics that individual natural proteins have in common with each other. “The goal of our research was not to find another way to make artificial proteins in the lab, but to discover the rules that nature and evolution have used to design proteins,” Dr. Ranganathan said. “The rules we have extracted from the evolutionary record of proteins contain a substantial fraction of the information required to rebuild modern-day proteins. We’re building solutions so close that, at least in a test tube, we can’t tell them apart from natural proteins.”

Dr. Ranganathan said there could still be many small differences between the artificial proteins and the natural ones, and further testing would need to be done to determine whether they work within an actual organism. “Our work suggests that modern-day proteins have likely inherited much of the information specifying their structure and basic aspects of function from their ancestors, but it is also possible that they have been fine-tuned over time to have their own idiosyncratic features in specific cells,” said Dr. Ranganathan, who also is a Howard Hughes Medical Institute (HHMI) investigator. “We are suggesting that the functions proteins have today are the result of fine-tuning a basic ancestral template that we have now figured out.”

Proteins, which carry out the body’s life functions, are composed of molecules called amino acids, which are strung together in long chains. These chains loop about each other, or fold, in a variety of ways. Their specific three-dimensional shapes help proteins to perform their biological functions. For decades, scientists have known that the sequence of amino acids that make up a protein determines the protein’s structure and its function. What has not been known is what information contained within that sequence produces the proper structure. All proteins are made up of 20 specific amino acids. Even for a small protein made up of 100 amino acids, the number of possible combinations of amino acids is staggering, many times more than the number of atoms in the known universe.

“How did nature devise the right sequences that resulted in functioning proteins? Somehow, it found a way,” Dr. Ranganathan said. “One implication of our work is that the evolutionary protein-design process may not be as complex as was previously thought.” Earlier research has shown that for a given group of related proteins, or protein family, all family members share common structures and functions. By examining more than 100 members of one protein family, the UT Southwestern group found that the proteins share a specific pattern of amino acid selection rules that are unique to that family. “What we have found is the body of information that is fundamentally ancient within each protein family, and that information is enough to specify the structure of modern-day proteins,” Dr. Ranganathan said.

He and his team tested their newly discovered “rules” gleaned from the evolutionary record by feeding them into a computer program they developed. The program generated sequences of amino acids, which the researchers then “back-translated” to create artificial genes. Once inserted into laboratory bacteria, the genes produced artificial proteins as predicted. “We found that when isolated, our artificial proteins exhibit the same range of structure and function that is exhibited by the starting set of natural proteins,” Dr. Ranganathan said. “The real test will be to put them back into a living organism such as yeast or fruit flies and see how they compete with natural proteins in an evolutionary sense.”

Science Daily
October 25, 2005

Original web page at Science Daily

In a study published in The American Journal of Gastroenterology, researchers found that budesonide capsules are an effective treatment to prolong and maintain the period of remission of Crohn’s Disease. Previous studies have demonstrated that budesonide is effective for inducing remission of Crohn’s disease. Four double-blind, placebo-controlled trials were conducted with identical protocols in which patients with Crohn’s Disease, and medically induced remission, received a treatment of oral budesonide for 12 months. Results showed that budesonide taken at 6 mg/day is effective for prolonging time to relapse and for significantly reducing rates of relapse. “Long-term treatment with budesonide is well-tolerated and the frequency and types of adverse events are similar to placebo,” states lead researcher,William J. Sandborn, MD. “Safety of a long-term medication is obviously important, but how well a patient tolerates their medication is also important and can affect patient adherence to therapy.”

Crohn’s disease is a long-term disease that results from inflammation of the digestive tract. It is a debilitating sickness, even for patients who are classified as having mild to moderate disease. Currently, there are no treatment options available that prevents recurrence of symptoms. “As stated, this disease is recurring in nature, so extending the time a patient can be symptom-free or with diminished symptoms is an important feature of treatment. Budesonide capsules are a treatment option for Crohn’s disease that has been shown in studies not only to be very effective in relieving symptoms, but also in extending the time before patients experience a recurrence.”

Science Daily
October 11, 2005

Original web page at Science Daily

Researchers at Yale School of Medicine provide direct evidence that two parts of a neuronal system, one that promotes eating and another that suppresses eating, are critical for the acute regulation of eating and body weight, according to a study published online in the September 11 issue of Nature Neuroscience. The paper makes it clear that the agouti-related peptide-expressing (AgRP) neurons are mandatory for eating. “Previous studies showed that the brain, particularly the hypothalamus, is responsible for the regulation of eating,” said co-senior author Tamas Horvath, chair and associate professor in the Section of Comparative Medicine, and associate professor in neurobiology and the Department of Obstetrics, Gynecology & Reproductive Sciences. “But until now, no experimental evidence was available to prove that AgRP neurons are critical for acute regulation of eating.”

Horvath’s collaborator Jens Bruening of the University of Cologne in Germany introduced the avian diphtheria toxin receptor into neurons in the feeding support system of transgenic mice. When the animals were adults, two injections of toxin caused the specific cell population to die within 48 hours, impairing the mouse’s ability to eat and resulting in acute anorexia. These mice also showed marked reduction in blood glucose, plasma insulin and Leptin concentrations. “Our results confirm the hypothesis that these two systems are critical for eating and the cessation of eating,” said Horvath. “Previous transgenic approaches failed to provide this proof because of compensatory mechanisms that could operate during development. None of those actually knocked out neuronal function. In this case, however, neurons are gone and there is no time to replace their function.” In explaining the significance of the finding, Horvath said, “It is important to ensure that the multibillion dollar academic and pharmaceutical approach against metabolic disorders is leaning in the right direction. The approach in general could also eventually lead to specific destruction of cells in other kinds of diseases.”

Yale University
September 27, 2005

Original web page at Yale University

It seems that placebos have a real physical, not imagined, effect – activating the production of chemicals in the brain that relieve pain. Placebos are treatments that use substances which have no active ingredient. But if people are told that what they are being given contains an active painkiller, for example, they often feel less pain – an effect that has normally been considered psychological. Recent studies, though, suggest otherwise. For example, when a placebo was secretly mixed with a drug that blocks endorphins – the body’s natural painkillers – there was no placebo effect, showing that endorphins are involved in the placebo painkiller process (New Scientist print edition, 26 May 2001, p 34). Now Jon-Kar Zubieta’s team at the University of Michigan at Ann Arbor, US, has confirmed that placebos relieve pain by boosting the release of endorphins.

Fourteen healthy males in their twenties volunteered to try what they were told was “a medication that may or may not relieve pain”. To induce pain, the researchers gave the young men infusions into the jaw that made them ache. During the experiment, the volunteers had to rate the intensity of pain every 15 seconds on a scale of 1 to 100; most judged it to be about 30. Unbeknown to them, the measure was used to keep pain constant by increasing or decreasing the infusion of the pain-inducer. This pain management was necessary because the body’s own opioids – the endorphins – tend to alleviate pain slightly over time, and the researchers wanted to separate this effect from that caused by the placebo.

All the volunteers, who were given a placebo of salt solution, reported feeling less pain. But the researchers did not simply take their word for it: instead, they scanned the volunteers’ brains using positron emission tomography (PET). They had injected the volunteers with a radioactive tracer that binds to the same mu-opioid receptors as endorphins do, which allowed them to figure out the level of endorphins produced in each volunteer’s brain.

The young men, who acted as their own controls, were scanned three times: before the experiment began, when they were in pain but had not yet been given the placebo, and after they had been given the placebo. Half the volunteers experienced the pain-only condition first, while the other half got the benefit of the placebo first. The scans revealed that after the volunteers took the placebo, their brains released more pain-relieving endorphins than normal. Zubieta thinks the placebo effect is piggybacking on the body’s innate painkilling system. “[The system] is there to ensure the survival of the organism,” he says. “The placebo effect is acting through these mechanisms.” But exactly how it does this remains a mystery.

Journal reference: The Journal of Neuroscience (vol 25, p 7754)

New Scientist
September 13, 2005

Original web page at New Scientist

The natural world has been medicine’s most effective arsenal, providing life-saving antibiotics and our most potent anti-cancer drugs. Now, with help from the National Cancer Institute (NCI), a consortium of UW-Madison scientists will embark on a five-year program of drug discovery by copying and improving nature’s designs to develop new medicines to treat colon, breast, cervical and pancreatic cancer. The new effort will involve faculty and staff scientists from the UW-Madison School of Pharmacy, the McArdle Laboratory for Cancer Research, and the UW Comprehensive Cancer Center.

“Natural products, especially those from microorganisms, have been a valuable source of new cancer drugs for many decades,” says Ben Shen, a UW-Madison professor of pharmaceutical sciences and chemistry and the leader of the new National Cooperative Drug Discovery Group. Shen, working with Michael Hoffmann, Richard Hutchinson, Paul Lambert, Jon Thorson, Lynn Van Campen and other faculty and staff, will direct the $5.6 million multidisciplinary program to produce and test analogs of natural compounds that have potential as anti-cancer drugs.

The new program will help fill a drug-discovery void as pharmaceutical companies have largely abandoned natural products research. Identifying and synthesizing the very complex molecules that make up the biologically active compounds found in microbes, marine organisms and plants is a difficult process, Shen says. New drugs are needed desperately to replace and improve existing medicines, and to provide new avenues for treating cancers that resist treatment with current drugs. “Some people believe the tank of natural products for drug use has run dry,” says Shen. “But we don’t think that’s true at all.” He notes that 60-75 percent of drugs approved to treat infectious disease and cancer over the past 25 years are of natural origin.

New technologies, together with existing libraries of previously discovered natural compounds, will help the UW-Madison group identify and evaluate molecules that may have value in the fight against cancer. Techniques to genetically manipulate microbes and synthesize their biologically active products, plus novel mouse models of cancer and real-time tumor imaging methods, will underpin much of work in the new NCI-funded program.

In nature, biologically active compounds produced by plants and animals almost always have potential as medicines because they are effective at killing microbes or, in the context of runaway cell growth that is cancer, can inhibit the ability of cells to multiply and grow. But the molecules that make up those natural compounds are very complex and, frequently, generate problematic side effects. The task of the new UW-Madison group will be to construct molecules that mimic natural anti-cancer agents, but that have been altered to reduce side effects and improve their efficacy. “Mother Nature made these products, but not for us to use as a cancer drug,” Shen explains. “The goal is to build molecules that maintain their biological activity but whose side effects have been limited.”

With new compounds in hand, the group of researchers will first test them in drug screens in the lab and, for promising candidates, in new mouse models for the cancers the group is targeting. “No one has been putting these compounds into the tests for use as cancer drugs in the way we plan,” says Shen. With traditional UW-Madison strengths in chemistry and biology, Shen believes the new program will flourish on campus. “We have a set of new technologies that will help us take some of these natural products to the next level of cancer drug discovery.” The ultimate goal, he says, is to establish a pipeline of natural-product analogs that will appeal to the pharmaceutical industry as ripe for development for the next generation of anti-cancer compounds.

Wisconsin University
August 30, 2005

Original web page at Wisconsin University

Scientists have used a glowing protein from fireflies to observe the activity of a molecule that is an important target for new drugs to treat cancer, autoimmune diseases and several other disorders. The target molecule, known as IKK (for IKappa kinase), regulates processes that can trigger dramatic changes in cellular physiology. Scientists have linked these changes to many different disorders. “Our new system allows researchers to monitor whether drugs for these conditions are hitting this exact molecular target in cell culture and laboratory animals,” says senior investigator David Piwnica-Worms, M.D., Ph.D., professor of molecular biology and pharmacology and of radiology.

Piwnica-Worms and lead author Shimon Gross, Ph.D., a postdoctoral fellow, measured light from the firefly protein, luciferase, to monitor IKK activity in tumor cells and inflamed liver cells in live mice. They also showed that the technique can greatly reduce the costs of tests that establish the best dosages for drugs that target IKK. Their results appear in the August 2005 issue of Nature Methods.IKK stands at a pivot point in the middle of an important set of linked chain reactions known as the NF-KappaB pathway. The pathway can start at many different receptors on cell surfaces; its finish changes the activity levels of varying genes. The result, according to Piwnica-Worms, is that the potential reaction patterns in the NF-KappaB pathway form an hourglass-like shape, fanning out among many options at the start, narrowing in the middle, and again fanning out among many options at the end.

“At the waist of that hourglass is IKK,” he explains. “This appears to put it in a position to be the key regulator of the pathway, and that has made it a subject of great interest both from the perspective of understanding how this pathway works and from that of developing new drugs for conditions that involve this pathway”. Piwnica-Worms’ laboratory has previously developed techniques that use luciferase to monitor protein-protein interactions. Researchers can employ an instrument known as an in-vivo bioluminescence camera to take real-time measurements of light from luciferase in cell cultures and in cells within live animals.

To use the firefly protein to monitor IKK, Gross altered cell lines to genetically fuse the luciferase protein to IKB (IKappaB), the protein that comes immediately after IKK in the NF-KappaB pathway. When the pathway is enabled, IKK triggers reactions that lead to the degradation of IKB. In cells with genetically altered IKB, the attached luciferase is broken down too, meaning scientists can detect increased IKK activity via decreased light from the cells. “This is like doing in-vivo pharmacodynamics and pharmacokinetics,” says Piwnica-Worms in reference to the sciences that study the effects, distribution and dissipation of drugs. “Traditionally the only ways we could do those kinds of studies were either to test for levels of the drug in the blood or to label the drug with a radioactive tracer. “In the case of NF-KappaB, there were also methods that monitored IKK activity via changes in the levels of gene activation at the end of the pathway,” he notes. “But those took hours to days to deliver results, and our approach works continuously and in real time.”

In their study, Gross and Piwnica-Worms tested the technique in live mice by transplanting genetically altered tumor cells and by using a technique that inserted the fused IKB/luciferase protein into liver cells only. They are currently working to develop a line of mice with the IKB/luciferase fusion built into its genetic code. In addition, they showed that the system is not only helpful for learning if a drug is having the desired effect, it can also be used to fine-tune drug dosage for maximum benefit. “One of the reviewers of our paper suggested that we should use the system to produce a full dose-response curve, which helps establish how to best use a drug,” Piwnica-Worms says. “Establishing that normally takes 6 months and 300 mice. With our monitoring technique, Shimon did it in a 5-day period using 30 mice. That’s going to lead to tremendous cost savings.” Because the luciferase-based monitoring system allows monitoring in live animals, Gross could perform multiple tests on the same mouse over time. He was also able to monitor the mice for individual variances that could inappropriately bias the results.

Washington University
August 3, 2005

Original web page at Washington University

Sufferers of muscular dystrophy may soon be able to protect their hearts with a chemical that acts as ‘sticking plaster’ for muscle cells. The drug could help avoid the heart problems that many with the condition suffer from. Heart failures are the second most common cause of death among patients of Duchenne muscular dystrophy, an inherited disease. The condition’s main symptoms involve deterioration of muscles used for movement, but the heart is often also affected, leading many sufferers to die in their twenties. The muscle wasting is caused by the lack of a protein called dystrophin, although researchers did not know why this weakens heart muscle cells. The answer seems to be that cells lacking this protein are less resistant to stretching, say Joseph Metzger of the University of Michigan in Ann Arbor, and his colleagues.

Metzger and his colleagues took individual heart muscle cells from healthy mice and from mice genetically engineered to lack dystrophin, and stretched the cells by 20%. Cells lacking dystrophin were more likely to break, the researchers report in a study published online by Nature. This is because the cell membranes become torn as they are stretched. Calcium ions, which are crucial to muscle-cell contraction, flood in through the holes, causing the cell to hypercontract. “The cell rolls into a little ball and dies,” says Metzger.

When the researchers treated the cells with a chemical called poloxamer 188, a drug used to plug holes in membranes, cell death was averted. The chemical acts like a ‘finger in a dike’, Metzger’s team reports, by preventing calcium influx. All the dystrophin-lacking mice given drugs that stress the heart by causing it to beat faster were also saved from death when treated with poloxamer 188, the researchers add. “During the stress test, 40% of untreated muscular dystrophy mice progressed to cardiac failure,” says Metzger’s colleague DeWayne Townsend. “The poloxamer had an instant corrective effect, which surprised us.”

The researchers warn, however, that it will be a long time before the drug can be declared safe to use on humans. Poloxamer 188 has been used to treat sickle-cell anaemia, but in short bursts; muscular dystrophy patients might have to take the drug for life. “If issues of dosing and long-term safety can be resolved, our research suggests that poloxamer 188 could be a new therapeutic agent for preventing or limiting progressive damage to the hearts of patients,” Metzger says. He and his team also want to test the drug on mice with other types of muscular dystrophy. The Duchenne form is one of nine different versions that affect humans.

Nature
April 2, 2005

Original web page at Nature

“Journals have devolved into information laundering operations for the pharmaceutical industry”, wrote Richard Horton, editor of the Lancet, in March 2004. In the same year, Marcia Angell, former editor of the New England Journal of Medicine, lambasted the industry for becoming “primarily a marketing machine” and co-opting “every institution that might stand in its way” . Medical journals were conspicuously absent from her list of co-opted institutions, but she and Horton are not the only editors who have become increasingly queasy about the power and influence of the industry. Jerry Kassirer, another former editor of the New England Journal of Medicine, argues that the industry has deflected the moral compasses of many physicians, and the editors of PLoS Medicine have declared that they will not become “part of the cycle of dependency…between journals and the pharmaceutical industry”. Something is clearly up.

The most conspicuous example of medical journals’ dependence on the pharmaceutical industry is the substantial income from advertising, but this is, I suggest, the least corrupting form of dependence. The advertisements may often be misleading and the profits worth millions, but the advertisements are there for all to see and criticise. Doctors may not be as uninfluenced by the advertisements as they would like to believe, but in every sphere, the public is used to discounting the claims of advertisers.

The much bigger problem lies with the original studies, particularly the clinical trials, published by journals. Far from discounting these, readers see randomised controlled trials as one of the highest forms of evidence. A large trial published in a major journal has the journal’s stamp of approval (unlike the advertising), will be distributed around the world, and may well receive global media coverage, particularly if promoted simultaneously by press releases from both the journal and the expensive public-relations firm hired by the pharmaceutical company that sponsored the trial. For a drug company, a favourable trial is worth thousands of pages of advertising, which is why a company will sometimes spend upwards of a million dollars on reprints of the trial for worldwide distribution. The doctors receiving the reprints may not read them, but they will be impressed by the name of the journal from which they come. The quality of the journal will bless the quality of the drug.

Fortunately from the point of view of the companies funding these trials—but unfortunately for the credibility of the journals who publish them—these trials rarely produce results that are unfavourable to the companies’ products.
Paula Rochon and others examined in 1994 all the trials funded by manufacturers of nonsteroidal anti-inflammatory drugs for arthritis that they could find. They found 56 trials, and not one of the published trials presented results that were unfavourable to the company that sponsored the trial. Every trial showed the company’s drug to be as good as or better than the comparison treatment.

By 2003 it was possible to do a systematic review of 30 studies comparing the outcomes of studies funded by the pharmaceutical industry with those of studies funded from other sources. Some 16 of the studies looked at clinical trials or meta-analyses, and 13 had outcomes favourable to the sponsoring companies. Overall, studies funded by a company were four times more likely to have results favourable to the company than studies funded from other sources. In the case of the five studies that looked at economic evaluations, the results were favourable to the sponsoring company in every case.

The evidence is strong that companies are getting the results they want, and this is especially worrisome because between two-thirds and three-quarters of the trials published in the major journals—Annals of Internal Medicine, JAMA, Lancet, and New England Journal of Medicine—are funded by the industry. For the BMJ, it’s only one-third—partly, perhaps, because the journal has less influence than the others in North America, which is responsible for half of all the revenue of drug companies, and partly because the journal publishes more cluster-randomised trials (which are usually not drug trials).

Why are pharmaceutical companies getting the results they want? Why are the peer-review systems of journals not noticing what seem to be biased results? The systematic review of 2003 looked at the technical quality of the studies funded by the industry and found that it was as good—and often better—than that of studies funded by others. This is not surprising as the companies have huge resources and are very familiar with conducting trials to the highest standards.

The companies seem to get the results they want not by fiddling the results, which would be far too crude and possibly detectable by peer review, but rather by asking the “right” questions—and there are many ways to do this. Some of the methods for achieving favourable results are listed in the Sidebar, but there are many ways to hugely increase the chance of producing favourable results, and there are many hired guns who will think up new ways and stay one jump ahead of peer reviewers.

Then, various publishing strategies are available to ensure maximum exposure of positive results. Companies have resorted to trying to suppress negative studies, but this is a crude strategy—and one that should rarely be necessary if the company is asking the “right” questions. A much better strategy is to publish positive results more than once, often in supplements to journals, which are highly profitable to the publishers and shown to be of dubious quality. Companies will usually conduct multicentre trials, and there is huge scope for publishing different results from different centres at different times in different journals. It’s also possible to combine the results from different centres in multiple combinations.

These strategies have been exposed in the cases of risperidone and odansetron, but it’s a huge amount of work to discover how many trials are truly independent and how many are simply the same results being published more than once. And usually it’s impossible to tell from the published studies: it’s necessary to go back to the authors and get data on individual patients.

Journal editors are becoming increasingly aware of how they are being manipulated and are fighting back, but I must confess that it took me almost a quarter of a century editing for the BMJ to wake up to what was happening.
Editors work by considering the studies submitted to them. They ask the authors to send them any related studies, but editors have no other mechanism to know what other unpublished studies exist. It’s hard even to know about related studies that are published, and it may be impossible to tell that studies are describing results from some of the same patients. Editors may thus be peer reviewing one piece of a gigantic and clever marketing jigsaw—and the piece they have is likely to be of high technical quality. It will probably pass peer review, a process that research has anyway shown to be an ineffective lottery prone to bias and abuse.

Furthermore, the editors are likely to favour randomised trials. Many journals publish few such trials and would like to publish more: they are, as I’ve said, a superior form of evidence. The trials are also likely to be clinically interesting. Other reasons for publishing are less worthy. Publishers know that pharmaceutical companies will often purchase thousands of dollars’ worth of reprints, and the profit margin on reprints is likely to be 70%. Editors, too, know that publishing such studies is highly profitable, and editors are increasingly responsible for the budgets of their journals and for producing a profit for the owners. Many owners—including academic societies—depend on profits from their journals. An editor may thus face a frighteningly stark conflict of interest: publish a trial that will bring US$100 000 of profit or meet the end-of-year budget by firing an editor.

How might we prevent journals from being an extension of the marketing arm of pharmaceutical companies in publishing trials that favour their products? Editors can review protocols, insist on trials being registered, demand that the role of sponsors be made transparent, and decline to publish trials unless researchers control the decision to publish. I doubt, however, that these steps will make much difference. Something more fundamental is needed. Firstly, we need more public funding of trials, particularly of large head-to-head trials of all the treatments available for treating a condition. Secondly, journals should perhaps stop publishing trials. Instead, the protocols and results should be made available on regulated Web sites. Only such a radical step, I think, will stop journals from being beholden to companies. Instead of publishing trials, journals could concentrate on critically describing them.

PloS Medicine
June 7, 2005

Original web page at Plos Medicine

Ever since the United States government passed laws governing the prescription of opioid drugs early in the 20th century, doctors and regulators have been engaged in a balancing act, trying to use the drugs to treat pain appropriately while preventing their abuse. But growing use of opiate medications by patients with chronic, non-terminal pain–which carries a small, but real, risk of addiction–has made achieving balance even more difficult. A climb in prescription drug abuse has paralleled the rise in legitimate use, and law enforcement and regulatory crackdown efforts have made many physicians afraid to prescribe pain medication to patients who really need it. “The person who suffers the worst is the patient,” says Howard Heit, a physician and chronic pain specialist, certified in addiction medicine and practicing in Virginia.

Heit and others in the pain treatment field say the relationship between law enforcement and physicians has taken a turn for the worse, a reversal from 2002, when the Drug Enforcement Administration (DEA) voiced intentions to act with “balance” in regulating prescription narcotics. Around that time, Heit says, the DEA approached a group of pain experts to develop a document that would help clarify legal and clinical issues. They came up with Prescription Pain Medications: Frequently Asked Questions and Answers for Health Care Professionals and Law Enforcement Personnel. The DEA released the document in August 2004, complete with a press conference at the Washington Press Club. The Journal of the American Medical Association reviewed it favorably.

Two weeks later, the administration pulled the document from its Web site, disavowing it “because it contained misstatements.” In November, the DEA published an interim policy statement that some say is more an effort to intimidate than to illustrate. For example, while the original FAQ document stated that the amount of opiate medication a physician prescribed or the number of patients in his or her practice taking the drugs could not be used as the “sole basis for investigation by regulators or law enforcement,” the new DEA statement said such factors “may indeed be indicative of diversion,” and that investigation is warranted “merely on suspicion that this law is being violated, or even just because it wants assurances that it is not.”

“The word flip-flop comes to mind,” says David Joranson, senior scientist and director of the Pain and Policy Studies Group at the University of Wisconsin Comprehensive Cancer Center and a member of the principal working group that wrote the FAQ. William Grant, a spokesman for the DEA, says, “The withdrawal of the document doesn’t represent a change in our investigative emphasis or approach.” Some speculate that the DEA withdrew the document after learning it was going to be used in the defense of William Hurwitz, the Virginia physician convicted in December of 50 counts, including illegal prescription of narcotic pain relievers to patients.

Hurwitz was prescribing opiate drugs to treat chronic, non-terminal pain. While this is not why he was prosecuted, the practice remains controversial in some medical circles, says Russell Portenoy, chairman of pain medicine and palliative care at Beth Israel Medical Center in New York City. Such treatments may mean relief for “thousands, if not hundreds of thousands, of patients,” but a shortage of safety data is cause for concern. Regardless, wider application of opiates has led to “very rapid growth” in opioid consumption in the United States and in other parts of the world, Portenoy says. The Automation of Reports and Consolidated Orders System (ARCOS) has shown a steady climb in medical use of morphine, fentanyl, oxycodone, and hydromorphone in the US from 1990 to 2001. The amount of morphine, as measured in grams distributed, grew by 59% from 1990 to 1996, and by another 49% from 1997 to 2001.
While European countries have seen a similar increase in legitimate opiate use, cultural forces, including a generally less punitive attitude toward drug addiction, have meant the medical community and drug regulators are not at odds to the extent seen in the United States.

Portenoy and others in the field say there is no evidence that a contemporaneous rise in prescription drug abuse–with 2 million people using prescription pain relievers for non-medical reasons in 2001 for the first time, compared to 600,000 in 1990, according to the National Survey on Drug Use and Health–has anything to do with growing medical use of opiates. Research shows that between 3% and 19% of individuals receiving opiate treatment for pain will become addicted, according to Deborah Haller, director of research in the Department of Psychiatry at St. Luke’s-Roosevelt Hospital in New York City. “Most experts in this field would agree that if a person doesn’t have a personal history of an addiction problem, it’s not a big risk,” she says.

Much of the confusion, then and now, lies in the distinction between dependence, which is associated with physical withdrawal symptoms, and addiction. The definitions of the two phenomena have been tangled, with physical dependence equated with addiction, rather than understood as an expected consequence of regular opiate use. In 2001, the American Pain Society, the American Academy of Pain Medicine, and the American Society of Addiction Medicine published definitions of tolerance, dependence, and addiction intended to clear up the confusion. According to the document, addiction is characterized by one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving.

A problem remains, says Portenoy: There is no external validation of an addiction diagnosis. It remains a matter of clinical judgment. And abuse, or so-called aberrant drug-related behavior, is even more difficult to define and appears more common. “When you look at these kinds of issues from a diagnostic perspective, you can see it’s something of a morass right now,” he says. Meanwhile, regulators have sought to crack down on the growing problem of prescription drug abuse by targeting individual physicians and pharmacists, making legitimate practitioners afraid even to deal with patients in pain, Joranson says.
Joranson argues for a more systematic, “public health” approach to drug abuse and diversion, involving a thorough investigation into the sources of diverted drugs–whether they are criminals stealing pain pills from drugstores and warehouses or fraudulent doctors. But the war on drugs doesn’t lend itself to such an approach, Joranson says; headline-grabbing SWAT raids on physicians’ offices and pharmacies tend to be more popular.

Michael Weaver, a physician certified in addiction medicine who runs pain clinics through Virginia Commonwealth University Medical Center and has published extensively on treating individuals with addiction problems, says the best way to cope with the issue of pain treatment and addiction is to carefully assess patients before prescribing opioids to determine if they may be at risk for abusing them. “I think if you’re going to treat chronic pain in a doctor’s office, you need to be more structured than people have been,” says Jane Ballantyne, chief of the Division of Pain Medicine at Massachusetts General Hospital. “We’re beginning to see that we physicians have to take on board the treatment of addiction as well as the treatment of pain,” Ballantyne adds. “To ignore it is just to make matters worse.”

E-mail address The Scientist Daily
May 24, 2005

Original web page at The Scientist

Whe fallout from Vioxx’s withdrawal has left some researchers asking where to go from here. When Merck pulled its blockbuster painkiller, Vioxx, from the market on Sept. 30, 2004, after a large clinical trial provided evidence that the drug increased the risk of heart attack and stroke, the move cast doubts on the safety of similar Cox-2-specific inhibitors, including Pfizer’s Celebrex and Bextra, Prexige, which is manufactured by Novartis, and another Merck drug, Arcoxia. In February, a panel of experts advising the US Food and Drug Administration aired those doubts, but voted against banning Celebrex, Bextra, or Vioxx. Regardless, some scientists worry that the shadow of risk could hamper future research on the entire class. “In light of the Vioxx withdrawal and the public outcry, I expect there will be fewer dollars available to do the research that we need to do to find out how these–and other–drugs work,” says Matt Breyer, professor of medicine at Vanderbilt University, adding that Vioxx’s cancer-prevention and disease-fighting benefits should continue to be researched.

Clinical results of the aborted Adenomatous Polyp Prevention of Vioxx (APPROVe) trial have not yet been published. But many are still interested in discovering whether Vioxx does fight cancer, something seen as overwhelmingly positive. Many researchers worry that other studies looking for beneficial side effects from Cox-2 inhibitors might get shut down as well. Some already have. In late December of 2004, the National Cancer Institute (NCI) halted a 2000-patient test of Celebrex’s efficacy in stopping the growth of colon polyps. NCI said it had reviewed the pattern of cardiovascular events in the trial, after hearing of the Vioxx withdrawal, and determined a 2.5-fold rise in heart attacks and strokes for patients taking 400 mg daily and a 3.5-fold increase in those taking 800 mg daily.

Another trial, testing Celebrex and naproxen on Alzheimer patients, was also halted. Some other trials are still going forward, albeit with heightened oversight and more stringent patient consent forms. Janet Woodcock, acting deputy commissioner of the FDA, says that the agency will need to be more careful about approving drugs like Arcoxia and Prexige, which are currently approved in parts of Europe. But she echoed the February panel’s assertion that some risk is acceptable. “As far as we’re concerned, we understand there are trade-offs with any given drug,” she says.

Eric Topol, chairman of cardiovascular medicine at the Cleveland Clinic and a vehement critic of Merck’s and the FDA’s handling of Vioxx, says that more prudent use of the painkillers could become standardized. “The future I foresee is one where you do a one-time screen of the patient, to determine likelihood of particular diseases… and then plan a treatment taking into account those predispositions. If you have risk for colon cancer, say, but low risk for heart disease, a Cox-2 inhibitor might still be a good drug for you.”

That future appears a long way off, however. “There’s been very little research into linking drug therapy and genomics,” says Tony Yaksh, vice chairman for research in the Department of Anesthesiology at the University of California, San Diego. “And as for Vioxx and Celebrex, there have been no studies at all.” Yaksh says one study should be undertaken immediately: Find all the patients who have taken Vioxx or another Cox-2 drug for a long period of time and compare the gene sequences of those who had thrombotic events with those who did not. “That’s how you come up with the chromosomal maps we need to take this to the next stage,” he says.

Victor Schuster, chairman of medicine at Montefiore Medical Center and Albert Einstein College of Medicine, agrees. “Merck’s got the blood samples. The tests are do-able, and the results would give us insights into the mechanisms. You could do SNP [single nucleotide polymorphism] analysis and find the correlations. That would be a good entry point to investigating the higher incidence of cardiovascular events and deciding what to do about it.”

E-mail address The Scientist Daily
May 24, 2005

Original web page at The Scientist

Researchers struggle to place a cyclooxygenase splice variant in context. Acetaminophen poses a pain-relief puzzle. Despite sharing some properties with conventional nonsteroidal anti-inflammatory drugs, such as aspirin, it doesn’t inhibit cyclooxygenase (Cox) -1 or -2. Three years ago, researchers postulated that acetaminophen might inhibit Cox-3–a Cox-1 splice variant. Since then, however, research into Cox-3 failed to generate much consensus. “The scientific community was very enthusiastic at the beginning,” says Bela Kis of Wake Forest University. But that excitement has faded. Some continue to probe Cox-3, however, hoping the molecule may provide clues for conditions including Alzheimer disease and some cancers as well as offer some new physiological insights.

Even the name is controversial. Several researchers believe that Cox-3 should be reserved for the product of a third independent COX gene. Kis prefers the term Cox-1b, even though, he says, it doesn’t seem to show Cox activity. Indeed, Kis’ group found that Cox-1b shows an entirely different amino acid sequence to other Coxs. More recently, Kis’ group found that prostaglandin production in cerebral endothelial cells, a crucial step in fever development, is very sensitive to inhibition by acetaminophen and suggested that the drug inhibits Cox-2. “The evidence seems to indicate, at least in humans and rodents, that [Cox-1b] has no relevance to prostaglandin production or the effect of acetaminophen,” he says. Regardless, Cox-1b’s physiological role isn’t clear. Other groups question whether humans express Cox-3. But Francis Berenbaum, from the Saint-Antoine Hospital, Paris, comments that last December researchers reported during the Osteoarthritis Research Society International Congress that human chondrocytes express Cox-3. Berenbaum recently confirmed this suggestion and plans to present his research later this year.

The research’s implications go beyond nociception. Neal Davies, from Washington State University, says that Cox-3 might also be involved in Alzheimer disease and some cancers. More fundamentally, Kis says that studies of Cox variants may illuminate the regulation of gene transcription and splicing. “It is an interesting question–why and how an organism sometimes transcribes Cox-1 and synthesizes a protein with Cox activity and sometimes transcribes a Cox-1b and produces a completely different protein with a completely different function.”

Resolving the outstanding issues requires research on several fronts. Berenbaum, for example, called for investigations into Cox-3 expression and function compared with Cox-1 and Cox-2 in different organs and characterizations of the prostaglandins produced by the enzymes in different situations. Davies adds that researchers need specific inhibitors and inducers. “There are many unanswered pharmaceutical hypotheses. Many laboratories and companies, including my own, are answering these questions,” he says. Nevertheless, he notes, our “understanding of Cox splice variants is still in its infancy.”

E-mail address The Scientist Daily
May 24, 2005

Original web page at The Scientist

Pharmaceutical chemists try constantly to modify the structures of antibiotic compounds as bacteria develop resistance to the drugs currently in use. In the case of tetracycline, which treats a broad range of infections including pneumonia, efficient synthetic routes to derivatives have proven hard to develop. The scientists have now found a strategy to access a broad range of structural variants (all of them 6-deoxytetracyclines) in sufficient quantity for bacterial testing in culture. Tetracyclines consist of four consecutively fused carbon rings, labeled A through D, and D-ring variations have shown particular promise against resistant bacteria. The authors prepared the AB fragment first, and then use the same reaction sequence to attach any of six distinctly modified D rings, forming the C ring in the process. The overall routes proceed in 5 to 7% net yield in 14 steps from benzoic acid.

E-mail address Science Mailer
May 10, 2005

Original web page at Science Magazine

Don’t try this at home. Several times a day, for several days, you induce pain in someone. You control the pain with morphine until the final day of the experiment, when you replace the morphine with saline solution. Guess what? The saline takes the pain away.

This is the placebo effect: somehow, sometimes, a whole lot of nothing can be very powerful. Except it’s not quite nothing. When Fabrizio Benedetti of the University of Turin in Italy carried out the above experiment, he added a final twist by adding naloxone, a drug that blocks the effects of morphine, to the saline. The shocking result? The pain-relieving power of saline solution disappeared.

So what is going on? Doctors have known about the placebo effect for decades, and the naloxone result seems to show that the placebo effect is somehow biochemical. But apart from that, we simply don’t know.

Benedetti has since shown that a saline placebo can also reduce tremors and muscle stiffness in people with Parkinson’s disease (Nature Neuroscience, vol 7, p 587). He and his team measured the activity of neurons in the patients’ brains as they administered the saline. They found that individual neurons in the subthalamic nucleus (a common target for surgical attempts to relieve Parkinson’s symptoms) began to fire less often when the saline was given, and with fewer “bursts” of firing – another feature associated with Parkinson’s. The neuron activity decreased at the same time as the symptoms improved: the saline was definitely doing something.

We have a lot to learn about what is happening here, Benedetti says, but one thing is clear: the mind can affect the body’s biochemistry. “The relationship between expectation and therapeutic outcome is a wonderful model to understand mind-body interaction,” he says. Researchers now need to identify when and where placebo works. There may be diseases in which it has no effect. There may be a common mechanism in different illnesses. As yet, we just don’t know.

Source: 13 things that do not make sense

New Scientist
March 29, 2005

Original web page at New Scientist

There have been concerns that low blood cholesterol concentrations may cause non-vascular mortality and morbidity. Randomisation of large numbers of people to receive a large, and prolonged, reduction in cholesterol concentrations provides an opportunity to address such concerns reliably.

20,536 UK adults (aged 40-80 years) with vascular disease or diabetes were randomly allocated to receive 40mg simvastatin daily or matching placebo. Prespecified safety analyses were of cause-specific mortality, and of total and site-specific cancer incidence. Comparisons between all simvastatin-allocated versus all placebo-allocated participants (ie, “intention-to-treat”) involved an average difference in blood total cholesterol concentration of 1.2 mmol/L (46 mg/dL) during the scheduled 5-year treatment period.

There was a highly significant 17% (95% CI 9-25) proportional reduction in vascular deaths, along with a non-significant reduction in all non-vascular deaths, which translated into a significant reduction in all-cause mortality (p=0.0003). The proportional reduction in the vascular mortality rate was about one-sixth in each subcategory of participant studied, including: men and women; under and over 70 years at entry; and total cholesterol below 5.0 mmol/L or LDL cholesterol below 3.0 mmol/L. No significant excess of non-vascular mortality was observed in any subcategory of participant (including the elderly and those with pretreatment total cholesterol below 5.0 mmol/L), and there was no significant excess in any particular cause of non-vascular mortality. Cancer incidence rates were similar in the two groups, both overall and in particular subcategories of participant, as well as at particular primary sites. There was no suggestion that any adverse trends in non-vascular mortality or morbidity were beginning to emerge with more prolonged treatment.

These findings, which are based on large numbers of deaths and non-fatal cancers, provide considerable reassurance that lowering total cholesterol concentrations by more than 1 mmol/L for an average of 5 years does not produce adverse effects on non-vascular mortality or cancer incidence. Moreover, among the many different types of high-risk individual studied, simvastatin 40 mg daily consistently produced substantial reductions in vascular (and, hence, all-cause) mortality, as well as in the rates of non-fatal heart attacks, strokes and revascularisation procedures.

BioMed Central
March 29, 2005

Original web page at BioMed Central