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Research Notes - Drug Safety(08/28/07 - MSNBC) Docs often write off patient side-effect concerns When patients feel they might be having an adverse drug effect, doctors will very often dismiss their concerns, a new study shows. In a survey of 650 patients, taking cholesterol-lowering drugs called statins, who reported having adverse drug reactions, many said their physicians denied that the drug could be connected to their symptoms, Dr. Beatrice A. Golomb of the University of California at San Diego and her colleagues found. "Physicians seem to commonly dismiss the possibility of a connection," Golomb told Reuters Health. "This seems to occur even for the best-supported adverse effects of the most widely prescribed class of drugs... Clearly there is a need for better physician education about adverse effects, and there is a strong need for patient involvement in adverse event reporting." The best-known side effects of statins, which include widely prescribed drugs such as Lipitor and Zocor, are liver damage and muscle problems, although statins have also been tied to changes in memory, concentration and mood, among other problems. Physician reaction to a potential side effect is crucial because the muscle problems can progress to a rare but potentially fatal condition called rhabdomyolysis if the drug isn’t discontinued. The researchers investigated the response of doctors to statin patients who believed they were having adverse drug reactions. In the great majority of cases, the patient, not the doctor, initiated the discussion. Forty-seven percent of patients with muscle problems or cognitive problems said their doctors dismissed the possibility that their symptoms were statin-related, while 51 percent of patients with peripheral neuropathy, a type of nerve pain affecting the extremities, said their doctors denied a possible connection with statins. Overall, 32 percent of patients reported that their doctors told them there was no link between their symptoms and statin use, 39 percent said their physicians said such a connection was possible, and 29 percent said their doctors “neither endorsed nor dismissed the possibility of symptom link to statins.” The investigators were "surprised" at how frequently patients reported that their doctors dismissed their concerns, Golomb said. While her study wasn’t designed to find out why, the researcher notes that while the pharmaceutical industry is sure to get the word out about a drug’s benefits, there is "really no corresponding interest group to make sure that physicians learn about adverse effects." Patients should be aware of the potential adverse effects of any medication they’re taking, she said. And those who find their doctors dismiss their concerns should probably look elsewhere for medical care, she added. "In general patients should always have physicians that they feel are hearing them." (08/16/07 - ABC News) Government Warns Parents About Giving Kids Over-the-Counter Cold Remedies Every parent in the country is likely familiar with over-the-counter cold medicines - and even comfortable reaching for them when their children are ill. But a public health advisory issued by federal health officials Wednesday may change the way many parents view cough and cold preparations intended for their children's relief. The FDA said that children under 2 shouldn't be given these remedies without a doctor's order because of serious adverse effects, including death. Dr. Janet Serwint, associate professor of pediatrics at Johns Hopkins Children's Center in Baltimore, Md., said her past experiences certainly raise a red flag - especially considering the dosing errors that send many children each year to hospitals for medical treatment. "I've been involved with cases in which the parent and the grandparent both gave the child the preparation without knowing it, and were not worried because it is over-the-counter," she said. "I have been in situations where parents gave more and more doses because they assumed it was safe." The advisory comes two months ahead of a scheduled FDA Nonprescription Drugs Advisory Committee meeting on Oct. 18-19 to discuss the use of the drugs by children - a meeting spurred by a petition in March by a group of doctors, including Serwint. Concern may well be warranted. In January, a study conducted by the Centers for Disease Control and Prevention (CDC) showed that in 2004 and 2005, more than 1,500 children under the age of 2 had to be taken to an emergency department due to serious health problems after taking these common remedies. Three of these children died. Other reports have suggested that young children up to the age of 6 may be at risk of life-threatening adverse effects from the medications. The findings have prompted some doctors to worry that parents who give these products to their children may be putting them at risk for hallucinations, seizures and potentially fatal heart problems - all in exchange for little, if any, real benefit. The medicines have since come under harsh scrutiny from at least one professional organization; last year, the American College of Chest Physicians recommended that parents avoid giving cough and cold medicines to their children, particularly younger children. Industry representatives continue to stand by the safety and efficacy of the products, however. In a statement issued Thursday, Linda Suydam, president of the trade association Consumer Healthcare Products Association (CHPA), which represents U.S. manufacturers and distributors of over-the-counter medicines and nutritional supplement products, defended the remedies. "Millions of Americans safely and effectively use OTC cough and cold medicines every year, both for themselves and for their families," according to the statement. "These medicines have been found safe and effective by the U.S. Food and Drug Administration (FDA) and are the same medications families have trusted for decades to help relieve cough and cold symptoms and make their children feel better." But Dr. Joshua Sharfstein, commissioner of the Baltimore City Health Department, called this assertion "completely untrue." "There products have not been evaluated for safety in children," he said. "They kind of snuck in through an evaluatory back door." Cough medicines are one of a number of products whose safety profiles have been tested on adults, but not on children - a concern reiterated in March by Dr. Charles Ganley, director of the FDA's office of nonprescription drug products. Sharfstein was also part of the group of doctors that petitioned the FDA to review the products on the grounds that they haven't been specifically evaluated for safety and effectiveness in this age group. "What we're asking is for these products to be held to a reasonable standard of safety and efficacy [for children]," he said. "To the extent that there is evidence in kids, the evidence is that they don't work." Pediatricians Urge Caution The warnings about cough and cold remedies are being echoed by many pediatricians, who note that parents may not be aware of possible adverse effects. "In proper doses it is not dangerous, but some parents don't know what proper doses are," Dr. Lisa Thornton, a pediatrician at Children's Hospital in Chicago told ABC News medical editor Dr. Tim Johnson on ABC News Now's "Healthy Life" program Thursday. Part of the confusion over dosing, she said, has to do with the fact that the amount of the drugs taken by the child should be measured according to the child's weight rather than their age, since children of the same age can vary drastically in terms of weight. "What we discuss with parents is that these medicines do have dangerous side effects, even though they are sold over-the-counter," Thornton said. "Pediatricians need to stress to parents that these are medicines that are not without side effects." Thornton noted that there are several drug-free ways to sooth a child's cough. Parents may want to place a vaporizer in the child's room, or have the child take a hot shower, as the steam may soothe their throats and sinuses. Even spending time with a child as they fall asleep can often help relax children when they are uncomfortable. And as for the medicines, it is still unclear whether the Oct. 18-19 meeting will yield new regulations. However, Sharfstein said he is optimistic. "I think it is very encouraging that this is going before an advisory committee," he said. "It's a mechanism for the FDA to really shift tracks on how it's treated these products." From a Baltimore Sun article - Drug industry representatives contend that cold and cough medications are clearly labeled with instructions concerning use in children and that adverse reactions are most likely the result of directions not being followed. But Sharfstein said current warnings are not enough. The group's petition asks the FDA to go a step beyond previous label warnings by restricting the marketing of them for use in children under 6. Sharfstein said the fact that the FDA is going to hold hearings is more important than reiterating warnings: "I think what the FDA is saying is a step on the way to re-evaluating what currently exists. But if this remains the FDA's position, it would be disappointing." In their petition, Sharfstein and other physicians cited the deaths of four Baltimore children under age 4 in the past six years linked to cough and cold medications. The culprit in the deaths appeared to be a cough suppressant, dextromethorphan, an ingredient in many of the preparations, said Ancona, who was not involved in the petition. The parents apparently overdosed their children when the youngsters didn't respond to a more appropriate dose, he said. In a follow-up letter to the FDA in May, the physicians said the absence of dosing information on labels for children under 2 constitutes a "safety hazard in an age range highly vulnerable to overdose." Because labeling instructions direct parents to consult doctors before giving the medicine to children under 2, it creates an impression that medical evidence exists for appropriate dosing levels for them. "But no such evidence exists," the letter said. The letter also cited a study that found the medications either caused or were contributing factors in the deaths of 13 children under age 16 months in Philadelphia between 1999 and 2005. When these drugs are taken in higher-than-normal doses, they can affect the heart's electrical system, leading to arrhythmias, which are irregular heartbeats. Some medicines affect the blood vessels and, in high doses, have been associated with high blood pressure and stroke. In rare cases, children have been injured even when given recommended doses, The New York Times reported. From a New York Times article - If, despite label warnings, parents continue to use the drugs inappropriately in young children, the agency could take more serious action, like restricting the drugs’ wide availability. Most drugs that have been withdrawn in the past 15 years were taken off the market because doctors and patients failed to heed prominent warnings. Some prominent pediatricians and public health experts said that the drug agency’s advisory did not go far enough. One group petitioned the agency to ban the marketing of the drugs for children under the age of 6, and some said that the medicines should no longer be sold over-the-counter for use in children at all. “Unless convincing evidence shows that these medications are effective for children, their easy availability to families should be re-examined,” said Dr. Ian M. Paul, a pediatrician at Penn State Children’s Hospital in Hershey, Pa. ... Some of the drugs have drawings or pictures of infants in diapers on their labels. The debate results because the standards for drug approvals have changed sharply in the decades since many of the medicines in children’s cough and cold products were approved. If those drugs were currently up for review, they would not be approved for use in children because the manufacturers never tested them thoroughly in children. Instead, the drugs' makers performed studies in adults and then simply assumed that they would work in children. Such assumptions, once common, are no longer acceptable. Indeed, a growing number of studies in children suggest that cough and cold medicines work no better than placebos. Among the ingredients that have caused concern are anticough medicines including dextromethorphan, which is the DM in many preparations. They can cause neurological problems, including abnormal movements and hallucinations, even in standard doses. Another is pseudoephedrine [Sudafed], which is a decongestant that has been associated with infant deaths, increased blood pressure and arrhythmias. Some of the injuries and deaths associated with these products have resulted when parents gave two different products to their child, not realizing that both contained identical medicines, resulting in an overdose. In rare cases, children have been injured when given recommended doses. Everyone agrees that more studies in children are needed, but companies have little incentive to undertake new trials because the medicines’ patents long ago expired. So the F.D.A. must decide how to regulate drugs that it knows very little about — a position in which it frequently finds itself. In such circumstances, it often turns to advisory boards. Despite the growing worries, sales of the drugs are booming. Most major pharmacies carry a dozen or more brands. The medicines are popular largely because children have an average of 6 to 10 colds each year, far more than adults. Even those who petitioned the agency to raise the age limit on the drugs said that dramatic regulatory action against the drugs was unlikely. ... Cold medications for children have been criticized in the past. Last year, the American College of Chest Physicians released clinical practice guidelines advising caregivers not to recommend cough suppressants and other over-the-counter medications for young children because of their ineffectiveness and the increased risk of complications and death. From a Washington Post article: In March, the FDA said it was reviewing the safety of children's over-the-counter cold and cough remedies. Dr. Charles Ganley, the FDA's director of the Office of Nonprescription Products, said at the time that the agency has been "looking into the issue of safety of children's cough medicine since the middle of last year." He noted that when these medicines were originally approved, in some cases several decades ago, there was no mandate that the effectiveness, safety or dose be determined for children; rather, the guidelines were extrapolated from studies done with adults. "We have not established a dose that is safe for children 2 and under," Ganley said during a teleconference. "We hope to have our review done in several months and then make recommendations." Reference: FDA Public Health Advisory: Nonprescription Cough and Cold Medicine Use in Children Comment: The pseudoephedrine contained in infant OTC cold remedies is the (1S,2S)- diastereomer of ephedrine (which has an 1R,2S- configuration). Ephedrine and pseudoephedrine are the two main active ingredients in the Chinese herb, Ma Huang (Ephedra sinica). On April 12, 2004, the FDA banned the sale of ephedra-containing supplements because of reports of adverse effects including death, yet it has continued to allow the large-scale marketing of pseudoephedrine-containing OTC cold remedies for infants (as the NY Times article cited above mentioned, some of the boxes are decorated with diaper-clad infants). In other words, there seems to be something of a double standard in operation here. (08/13/07 - London Telegraph) Pill can delay a baby far longer than you want Every day millions of women pop a tiny pill giving it as much thought as they would swallowing an aspirin. After all, the benefits of oral contraception - easy-to-use, reliable and protective against ovarian and endometrial cancer - are well documented. But for an increasing number of women there is a lesser known and distressing side-effect - amenorrhea, or lack of ovulation - that materialises only when they stop taking it. When Dal Bamford came off the Pill, the last thing she imagined was that she wouldn't ovulate for eight months. "It was an emotional roller-coaster," she says. "I started researching possible causes on the net. There were some frightening stories of women with ovarian dysfunction and even premature menopause. I had to stop searching as it was sending my imagination haywire. All the while I was beating myself up for not taking more responsibility for my own health. I just believed my doctor and trusted the Pill without questioning." Dal, a 31-year-old Oxford graduate and manager in a telecoms company in London, had stopped taking Microgynon 30 in April 2006. "My husband and I weren't planning a family straight away but I thought I should come off the Pill for a while beforehand," she says. "I had started taking it at university when I did a lot of rowing; my periods could be heavy and got in the way of my exercise regime. It was very convenient and gave me no problems." Once she had gone without a period for six months, she visited her GP. Thyroid and blood tests were taken but, as the results came back normal, her GP told her to "wait a while", recommending a course of Clomid to induce ovulation if her cycle had not returned after a year. "I did not want to take more drugs," says Dal, "as I felt that was the problem in the first place." Amenorrhea is a distressing condition, not least because women usually discover it exists only when they are trying to conceive. While the difficulties faced by women in their forties trying to start a family are familiar, it seems that healthy, younger women are increasingly experiencing problems. "I have seen cases where women in their thirties have not ovulated for two or three years after taking the contraceptive pill," says Dr Marilyn Glenville, author of Natural Solutions to Infertility. "The Pill artificially suppresses your hormones, effectively making your ovaries dormant. Sometimes it can make the reproductive system go into hibernation." For the majority of women, it is still the most effective method of contraception and, once off the Pill, regular menstruation usually resumes within a few weeks. Other women, however, are not so fortunate. "Women are taking the Pill without a break for many years and are waiting until later in life to start a family, so their natural fertility is also in decline," says Dr Glenville. Her sentiments are shared by Dr Margaret Cook, former consultant haematologist at St John's Hospital, Livingston, West Lothian. "I would tell any woman beyond the age of 34 still on the Pill to consider alternative contraception if she wants to have a family in the near future," she says. Dr Cook believes that many GPs have a "cavalier attitude" when it comes to prescribing the Pill. "It is all too often billed as some kind of magic pill, but it is a powerful drug that has serious side-effects which need to be highlighted. Many doctors have the tendency to highlight the good points and shove all the bad points under the carpet." The contraceptive pill works primarily by preventing ovulation through the suppression of hormones, thereby stopping an egg being released. The monthly bleed while on the contraceptive pill is therefore essentially a "fake period". Most GPs state that it can take two or three months for a normal cycle to return but some women experience amenorrhea for considerably longer. "I see about six new cases every month," says Dr Gerard Conway, consultant in reproductive endocrinology at University College London Hospital. "Often blood tests will come back as normal, so it can be harder to pinpoint the actual cause. Some women may have a more sensitive reproductive system where the hypothalamus [the hormone-regulating gland in the brain] is triggered to close down more easily than those of others." Two otherwise healthy women who have also suffered amenorrhea following the contraceptive pill are Karen Inglis and Louise Lennon. When Karen, a 26-year-old special needs teacher from Aberdeen, stopped taking Microgynon 30, she only had one period during the first six months. "I could handle not getting pregnant," she says, "but the fact that my body was not working was frustrating and worrying. My GP told me that women who got their period back immediately were 'lucky'. If I had known, I would have stopped taking the Pill earlier." Louise, a 30-year-old IT consultant from London, agrees. "I had sleepless nights, worried that I may have missed my chance of having a family," she says. Having taken Loestrin 30 for six years, it was nine months before her periods returned. "I tried to stay calm, but after six months I began to worry. I dreaded seeing friends as they would casually ask when I might be starting a family - they didn't know that I was crying myself to sleep with fear that I might be infertile." Louise visited her GP and after a series of blood tests and scans was told that everything was normal. She, too, was told that if her menstrual cycle had not returned within a year she would be prescribed Clomid. But Dr Sammy Lee, an embryologist at University College London, says that Clomid is prescribed all too often as the "cheap and cheerful option". "It can have harmful effects," he says. "It can further disrupt the hormones and lead to poor-quality eggs." Reluctant to take Clomid, Dal, Karen and Louise decided to try a combination of acupuncture, Chinese herbs and reflexology as alternative treatment. Dr Lily Hua Yu, who specialises in women's fertility problems at the Acumedic centre in north London, the largest established Chinese medical organisation in Europe, sees an increasing number of women in their thirties with fertility problems. "I see at least five women every week with fertility problems who have a history of taking the contraceptive pill, stress, and an imbalanced diet, and I've seen some patients who've not had a period for up to two years. These women are very distressed and it is something that could have been corrected earlier if they had stopped taking the Pill sooner." Within six weeks of treatment, both Dal and Karen became pregnant. "I felt incredibly blessed that through sheer luck I had stumbled across the therapy that allowed it all to happen," says Dal. Five weeks into Louise's treatment with Dr Hua Yu her periods returned. "I was so relieved. It is so good to know that we can now start trying for a family." Although Dr Lee acknowledges that much of the evidence is anecdotal, he believes there are too many success stories from alternative therapies for them to be completely ignored. "Studies conducted at Göteborg University in Sweden have also shown increased rates of ovarian blood flow as a direct result of acupuncture," he says. The benefits of the Pill may be legion but its side-effects should not be ignored. As Dr Glenville says: "The problem with the Pill is that no woman really knows what the repercussions will be when she stops taking it." (07/19/07 - BBC) Weight loss pill warning issued. A weight-loss drug used by thousands is unsafe for those also taking antidepressants, health watchdogs warn. The European Medicines Agency advises patients with ongoing major depression or those on antidepressants against taking rimonabant. About 41,000 UK patients have been treated with rimonabant since it was launched in the UK in June 2006. Last month US safety officials voted to ban the pill amid concerns about increased suicide risk. Rimonabant, brand name Acomplia, is currently recommended for obese patients with a risk of developing diabetes or cardiovascular disease. It works by blocking receptors in the part of the brain that regulates food intake and the body's ability to break down sugars and fats in the blood. The UK's National Institute of Clinical and Health Excellence is currently appraising the drug for use on the NHS. The EMEA said doctors in the EU had been warned "of the risk of psychiatric side effects" since June 2006 but it was now upgrading this warning. Evidence suggests that one in 10 people who take rimonabant may develop psychiatric side effects. The commonest psychiatric side effects are low mood and depression. Anxiety, irritability, nervousness and sleep disorders may also occur. Approximately one patient in every 100 may experience suicidal thoughts. Up to the end of June 2007, the UK's drug safety regulator, the Medicines and Healthcare products Regulatory Agency, had received a total of 318 cases, from UK sources, of adverse drug reactions which were suspected to have been caused by rimonabant. This included 364 psychiatric reactions. Amongst these, there were 48 reports of depression, 16 reports of suicidal thoughts and one report of self-injury. The MHRA advised: "If you start to experience symptoms of depression while taking Acomplia, or if you are currently being treated with antidepressants, consult your doctor. If you have had depression in the past but feel well on Acomplia, you should continue treatment with Acomplia and discuss your treatment with your doctor at your next routine appointment." Sanofi-aventis, the drug company that makes Acomplia, said the product's labelling had been updated accordingly. "Acomplia is now contraindicated in patients with ongoing major depressive illness and/or ongoing anti-depressive treatment. "'Special Warnings and Precautions' of the Summary of Product Characteristics (SmPC) have been updated as well to include information on depressive disorders," a statement from the company said. (07/13/07 - Washington Post) Diabetes Drug Side Effect Reports Triple In the month after a surprising analysis revealed possible heart risks from the blockbuster diabetes drug Avandia, reports of side effects to federal regulators tripled. The sudden spike is a sign that doctors probably were unaware of the drug's possible role in their patients' heart problems and therefore may not have reported many such cases in the past, several experts said. It also shows the flaws of the safety tracking system and suggests that a better one might have detected a potential problem before the drug had been on the market for eight years. Avandia is used to control blood sugar, helping more than 6 million people worldwide manage Type 2 diabetes, the kind that is linked to obesity. These people already are at higher risk for heart attacks, so news that the drug might raise this risk by 43 percent was especially disturbing. In the 35 days after May 21, when the New England Journal of Medicine published the analysis on the Internet, reports of heart attacks, deaths and hospitalizations leaped. The sharp rise in reports of heart problems appears in data obtained by The Associated Press through a Freedom of Information Act request to the federal Food and Drug Administration. Only five heart attacks were reported in the 35 days before the study, compared with 90 in the same period afterward. Heart-related hospitalizations went from 11 to 126. The reports involve rosiglitazone, sold as Avandia and Avandamet. Reporting a drug's side effects is voluntary, and only a crude indication rather than a scientific measure of how many problems patients are actually having. The FDA relies on this unenforced system once a drug is on the market. Critics say it leads to haphazard oversight in which problems can be missed because doctors don't connect the dots between a drug and symptoms they see in an individual patient. With Avandia, the published analysis likely led to more cases being reported, said Vanderbilt University diabetes specialist Dr. Alvin C. Powers. "Now, patients and their doctors are much more aware of the possible link between Avandia and cardiovascular disease. This is good - this is going to help us going forward to determine whether or not this drug is safe," he said. The drug's manufacturer, British-based GlaxoSmithKline PLC, insists that the drug is safe and effective. "This is a very well-known phenomenon," where news reports lead to increased reporting, said company spokeswoman Mary Anne Rhyne. "It's good that there's awareness of the reporting system, but drawing conclusions on such data is inappropriate." The FDA plans hearings on safety concerns about the drug on July 30. In the meantime, diabetes experts have advised users of the medication to talk to their doctors and not to immediately discontinue it. The side effects reported range from as minor as a blister to as serious as sudden cardiac death. Most of the reports the AP reviewed seemed to involve serious side effects, and rosiglitazone was listed by the FDA as the "primary suspect" rather than other medicines the patient may have been taking. There was a total of only 50 adverse event reports in January and 73 in February. From April 16 to May 21, when the study was published, 121 events were reported, including 11 deaths. In the 35 days after the study, 357 events were reported, including 38 deaths. "You really can't infer anything about incidence rates from that," because the spike in reports is likely due to the "publicity effect" of the study, said Dr. David Graham, an FDA drug safety expert. Dr. David Nathan, chief of diabetes care at Massachusetts General Hospital, agreed, saying it was "not conceivable" that only five people among the 1 million Americans taking Avandia had heart attacks in the month preceding the May 21 study, as the FDA reports suggest. "It just heightens the concern about the poor reporting we have," said Nathan, who has received speaker fees from Glaxo and other drug companies. Powers and Graham have no financial ties to any diabetes drug makers. The issue has roiled the medical community and sparked congressional probes into whether the FDA is properly investigating safety issues. The FDA issued a "safety alert" about the drug only after the May 21 study came out, even though Glaxo had informed the agency of its own analysis of heart risks nearly a year beforehand and possibly as early as 2005. Avandia's label warns about possible heart failure and other heart problems when taken with insulin. The drug also raises LDL, or bad cholesterol, and can cause fluid retention and weight gain. BMJ. 2007 Jun 9. Questions have emerged in the United States and Australia about the effectiveness and possibly dangerous side effects of Gardasil, Merck's newly licensed vaccine for human papillomavirus. In the US, three deaths closely time related to immunisation with the vaccine were among 1637 adverse reactions reported by Judicial Watch, a public interest watchdog. Judicial Watch obtained the reports from the Food and Drug Administration using the Freedom of Information Act. The reports were filed through the FDA's vaccine adverse event reporting system. (06/24/07 - U.K. Independent) Huge weight gains reported by patients on prescription drugs Thousands of people who take prescription medicines for everyday conditions are gaining large amounts of weight as an unexpected side effect, scientists have warned. Researchers, who found that some patients were putting on up to 22lbs in a year, say that the drugs may even be contributing to the nation's rocketing obesity epidemic. All of the patients they studied, on medication for conditions as diverse as diabetes, epilepsy, depression, high blood pressure and schizophrenia, showed evidence of weight increase. "Given the common and long-term use of many of these drugs," said the researchers, "it is likely that they play a significant contributory role in the increasing prevalence of obesity." A team from Glasgow University and Glasgow Royal Infirmary reviewed and analysed data on drug use by more than 25,000 people to quantify the effects of prescription drugs. All of the drugs included in the review are used to treat chronic diseases by large numbers of people. In the UK, it is estimated that around 2.6 million people have been diagnosed with coronary heart disease, for which beta-blockers are widely prescribed. More than 400,000 people have epilepsy, and around 1.3 million people have type 1 or type 2 diabetes. "In the light of these figures, the number of individuals in the population receiving treatment with an obesogenic drug is potentially quite high. In Scotland alone, the number of prescriptions dispensed for beta-blockers and tricyclic antidepressants between 2004 and 2005 exceeded one million and two million respectively," says the report. With many of the drugs, weight gain was significant and rapid, according to the researchers. Just how they lead to weight gain varies, and is in some cases unknown. Some, like corticosteroids, increase appetite, while beta-adrenoceptor blockers reduce metabolic rate. Olanzapine and clozapine, drugs used for psychiatric conditions, resulted in the most weight gain - up to 22lbs in 52 weeks. Insulin for type 2 diabetes was found to increase weight by up to 13.2lbs, while some drugs for depression added up to 8lbs, and some for high blood pressure led to gains of up to 3lbs. A heart drug added 5lbs, while some treatments for epilepsy added more than 12lbs, and some bipolar drugs led to weight gains of around 8lbs. The researchers say that many other drugs which are being prescribed and have not been investigated may also have an effect on weight. They also suggest that unexpected weight gain may be a reason why some people stop taking prescribed drugs: "Non-compliance with any drug therapy is a widespread problem, and around half of patients prescribed long-term medication for the management of chronic diseases do not comply fully with treatment. Non-compliance is reported as an issue with many of the drugs included in this review, and the weight gain associated with them may contribute to this." In future, the scientists suggest, doctors should discuss with patients the risk of weight gain before they start treatment: "This review provides evidence of the weight gain potential of some common drugs. It is perhaps only now, in light of the present epidemic of obesity, that the negative effect on body weight is a pertinent issue. The potential of weight gain should be discussed with patients prior to the institution of therapy." (06/18/07 - Huffington Post) David Kirby: Tired of Autism Yet? So many people are fighting so bitterly over the alleged link between vaccines and autism right now: On this website, in federal court, and even within prominent American families - as poignantly reported in today's New York Times. But the grueling debate has actually united the fighting factions in at least one way: Most people (save for a handful of fringe parents who believe that autism is some altered state of being, worthy of celebration) are probably just plain tired of autism and the fight over its cause. They really want to settle this debate and move on. I know I do. The irony is that the multi-million-dollar court battles, the melodramatic headlines and the alarm over parents retreating from vaccinations are all so terribly unnecessary. All we need do is conduct a thorough study of vaccinated and unvaccinated children, and see if there is any difference in their rates of autism spectrum disorders. It could be a year or more before we get a decision on the first autism "test case" being heard in federal vaccine court right now, and years more before all 4,800 pending cases are settled. Meanwhile, the Gonzales Justice Department has earmarked millions in taxpayer dollars to fight the autism parents and their attorneys tooth-and-nail in these supposedly "non-adversarial" administrative proceedings. And regardless of the court rulings, neither side is going to back down, period. But one good study by a respected team of investigators could probably settle this mess by Christmas. Last year, Rep. Carolyn Maloney (D-NY) introduced the "Comprehensive Comparative Study of Vaccinated and Unvaccinated Populations Act," to spend federal money on looking closely at the two groups of children. The CDC, which has the conflicted task of boosting vaccination rates while also monitoring vaccine safety, dismissed the Maloney bill, saying it would be impossible to locate large enough numbers of unvaccinated American children needed for an accurate comparison. But that simply isn't true. Dan Olmsted, author of the "Age of Autism" column at UPI, wrote last year about a large medical group in the Chicago suburbs called Homefirst Health Services, which is largely geared toward parents who home birth their kids, and who tend not to vaccinate. Dr. Mayer Eisenstien, who founded the practice in 1973, told Olmsted that, of the 35,000 children given care at Homefirst, very few have autism, and those who do were all vaccinated. "I don't think we have a single case of autism in children delivered by us who never received vaccines," he said. (Cases of childhood diabetes and asthma were also reportedly very low.) Other possible unvaccinated populations include children of chiropractors, Scientologists Christian Scientists and the Amish - though some protest that this last group might be protected by insular genes or a pre-industrial lifestyle, without noting the obvious benefit that such a groundbreaking discovery would confer. Critics of the study idea, who insist that vaccines have been 100 percent exonerated, ridicule the Maloney bill as a redundant, monumental waste of time and money. Even so, their position is a bit hard to understand. No matter what happens in Vaccine Court, (which many say is the wrong venue for such a fight, anyway), this tired old debate will drag on for years, God help us. (For an excellent explanation of why, please read last Friday's blog [see below] by CBS News Capitol Hill Correspondent Sharyl Attkisson). But a study of vaccinated-vs.-unvaccinated kids would, in its powerful, elegant simplicity, compel at least one side to finally fold up shop and go away. When doing autism surveillance studies, The CDC usually looks at eight-year-olds, to ensure that all late-diagnosed kids are counted. It seems reasonable, then, to randomly select 1,000 (or 5,000, or whatever number is needed for statistical significance) unvaccinated eight-year-olds, and compare them to vaccinated children of the same age (born in 1999, by the way, at the height of mercury exposures from vaccines). Will autism rates be exactly the same between the two groups, as the CDC and others would predict (especially among boys, who are four times more likely than girls to have the disorder)? It's perfectly reasonable to assume that they will (thus disproving Olmsted's intriguing, but admittedly layperson's, report out of Chicago). And just think what a joyous moment that would be. I, for one, would be shouting from the rooftops. I take no joy in pointing to vaccines as a possible contributor to autism, and I would be only too happy to declare the hypothesis dead in the water, and move on with my (admittedly autism-free) life with friends and family. Many scientists will say that other large population studies of vaccines failed to show a link to autism, but none of those studies were the same as this proposed investigation, which would look at all vaccines given to children who were all born in the United States, in the same year, and even maybe in the same region. Such a massive work of epidemiology could run a million dollars or more. But that is just a fraction of what is being spent, by us via our government, right now defending vaccines in federal court. If the drug companies, and the Bush Administration, and Congress, and the public health establishment, are so very confident in the total safety of all childhood vaccines (and their components, including mercury), then why would they reasonably object to such a study? If the results showed that vaccinated children were, all around, more healthy and robust than unvaccinated kids - that would pretty much kill all lawsuits right there, send waves of reassurance to billions of parents around the world, and make people like me shut up and go away. I would, blissfully, not write about autism and vaccines again. (I have a new book deal to occupy me, about corporate vs. environmental health, which my publisher St. Martin's Press will announce shortly. I am not an autism activist, and this is not my crusade). And if the federal government or the drug companies simply won't cough up the finances needed to fund such a feud-settling study, then maybe when Bob Wright begins speaking with his daughter Katie again, she can convince him to propose that the mega-charity write a mega-check. Neuroendocrinology. 2007 Jun 15. Context: Atypical antipsychotics (SGA) have the propensity to induce weight gain. Objective: The aim was to evaluateearly changes in hormones involved in neuroendocrine regulations (serum cortisol, growth hormone and prolactin) and positive energy balance (serum insulin, leptin and ghrelin) during SGA treatment in normal-weight patients with schizophrenia with the purpose of exploring the possibility to combat weight gain early through manipulation of circulating hormone levels. Design: We conducted a randomized, partly cross-sectional and partly longitudinal, prospective study. Setting and Patients: Eighteen normal-weight in-patients with schizophrenia treated with FGA (first-generation antipsychotics) were referred to the Institute of Psychiatry. Twenty age-, gender- and BMI-matched healthy subjects were investigated at the Neuroendocrine Unit, Belgrade University. Intervention: Oral glucose tolerance test (OGTT) was performed at baseline in all and then 13 patients were assigned to receive SGA (risperidone or clozapine) and OGTT was repeated after 1 and 3 months. Results: At baseline, patients with schizophrenia had higher peak glucose levels (p < 0.05), glucose area under the curve (AUC; p < 0.05), peak insulin levels (p < 0.05), insulin AUC values during OGTT (p < 0.01) and the calculated homeostasis model assessment (HOMA-IR) value than control subjects (p < 0.05). Patients with schizophrenia showed higher morning cortisol (p < 0.05) levels than control subjects. After 1 and 3 months of SGA therapy patients with schizophrenia gained bodyweight by 3.5 and 8.6%, respectively. Leptin levels steadily increased while cortisol levels decreased in the first month and remained so. Serum glucose, insulin and ghrelin levels on SGA were similar as at baseline. Circulating ghrelin levels decreased after OGTT during SGA which is consistent with a role for ghrelin in the initiation of meals. Conclusions: Treatment with SGA was associated with continuous weight gain, with an early increase in serum leptin levels and decrease in cortisol levels. Elevated circulating leptin was ineffective in the control of fat deposition. Similar plasma ghrelin levels and similar decrease pattern of ghrelin after OGTT compared to healthy subjects signify intact meal-promoting effects of ghrelin during SGA therapy, which at the same time renders anorexigenic pathways ineffective. This may lead to weight gain and further studies with a ghrelin antagonist may provide support for this hypothesis. (06/15/07 - CBS News) Autism: Why The Debate Rages With the first autism case now being heard in federal vaccine court in Washington D.C., it makes sense to ask: Why is anyone even still debating the possibility of a link between vaccines and autism? After all, for years, many government health officials, advisors and vaccine manufacturers have said there's no association. Here are a number of reasons why the question remains open: 1. While government scientists, advisors and pharmaceutical companies have been responsible for infinite lifesaving and life improving medical advances, they are not infallible.
2. Government scientists, advisors and vaccine manufacturers often take an all-or-nothing approach to vaccinations.
3. Government officials and mainstream scientists who dispel any vaccine/autism/ADD link have ties to vaccine makers.
4. Non-profits which dispel any vaccine/autism/ADD link have ties to vaccine makers.
5. The dual role of the CDC undermines the appearance of fairness.
6. There is no definitive research proving a link between vaccines and autism or ADD, but there is also no definitive research ruling it out.
7. Those who say autism and ADD are not linked to vaccines do not know what is causing the epidemics.
Vaccinations have provided lifesaving miracles in public health. However, it's undisputed that they are also responsible for many serious adverse events including brain disorders and, rarely, deaths. Trying to maximize the potential benefits of vaccines and minimize the harm shouldn't be seen as a threat to the nation's inoculation program, it's merely a logical step forward. One scientist who testified for the plaintiff this week in The Vaccine Court said there's a way to test children for a hidden hole in their immune make-up that makes them susceptible to bad immune reactions from vaccinations. He said that, ideally, every child should undergo such a test before their first vaccinations. But he also said the test is very expensive and so "not worth it." Many parents might disagree. If they knew such a test was available, they'd find a way to pay for it. But such information has to be disseminated to the public before a first step can even be considered. Mainstream medicine initially said that autism was caused by mothers who weren't affectionate enough with their children. If that doesn't teach us that we should always seek further knowledge and not necessarily accept what's spoon-fed to us by certain experts ... then nothing will. (05/15/2007 - Daily Mail) Popular diet pill is a 'suicide risk' A weight loss pill used by thousands of Britons has been branded a suicide risk by drug safety officials. More than 10,000 Britons are believed to be using the prescription-only drug Acomplia, which can help dieters lose up to ten per cent of their body weight. Hailed as an important weapon in the war against obesity, it interferes with the part of the brain involved with cravings. But on Thursday, a committee advising the U.S. Food and Drug Administration voted to ban the pill after concerns about its psychiatric side-effects. The 14-member-panel heard testimony that Acomplia increases the risk of suicidal thoughts even in patients without a history of depression. Its maker, the French pharmaceutical company Sanofi-Aventis, had failed to demonstrate the drug was safe, the panel concluded. The FDA is not bound to follow the committee's advice, but the unanimous verdict makes it unlikely that the drug will be approved in the U.S. Sanofi-Aventis had planned to launch Acomplia – chemically known as rimonabant – last year in America, the world's biggest drug market. It forecast annual world sales of more than £1.5billion. But yesterday shares in the company nosedived, wiping around £4billion off its market value at one stage. The European Medicines Agency, which licensed the drug and has the power to order its withdrawal from European shelves, will review the pill's safety at a meeting next week. Acomplia was launched in Britain last June, at a cost of £55 a month. Since then, there have been 310 adverse reactions, including 152 psychiatric disorders. UK doctors have previously ruled the drug is safe, even when used by obese patients with heart problems and other complications. Professor Anthony Barnett, professor of medicine at Birmingham University, said warnings about possible psychiatric side-effects are already available on the drug’s packets. He said it is 'of concern' that U.S. authorities had rejected the drug, but added: 'They are being supercautious. I would expect the European agency to look at their decision. The drug is recommended for obese patients at risk from cardiovascular conditions and diabetes and it helps them lose five to ten per cent of their body weight. But this decision reinforces the fact that there is a risk-benefit ratio with the drug that means it should not be used in patients without other problems. It's not something for patients who are a little bit overweight.' Professor Barnett said more than 10,000 patients have been prescribed the drug by consultants or GPs since last June. The FDA panel reached its decision after examining 49 different Acomplia studies involving more than 13,000 volunteers in Canada, France and the U.S. Those taking the drug were asked to describe their feelings and 1,200 reports then picked at random for analysis. Of those taking the drug, two committed suicide, one said they were considering suicide and one was diagnosed as suffering from depression that could lead to suicide. Others users reported suffering from delusions. There were six reports of psychotic behaviour, including a man who tried to strangle his daughter. In the placebo group – those taking a dummy pill – two people attempted suicide and five talked about it. ... (05/21/2007 - CBS/AP) Diabetes Drug Tied To Heart Risk In Study Avandia, the biggest-selling diabetes drug in the world, is linked to a greater risk of heart attack and possibly death, says a new scientific analysis published online Monday. More than 6 million people worldwide have taken the drug sold by London-based GlaxoSmithKline PLC since it came on the market eight years ago. Pooled results of dozens of studies revealed a 43 percent higher risk of heart attack and a 64 percent greater risk of cardiovascular death, according to the review published by the New England Journal of Medicine. ... "There are more heart attacks, more strokes, deaths, et cetera," one of the study's researchers, Dr. Steven Nissen, said. "It is most urgent that both the FDA and the company look at the original source data and do careful analysis." ... GlaxoSmithKline earns $3 billion a year from the drug, the biggest-selling diabetes drug in the world, according to Forbes magazine. The government will take no immediate action on a label change or other measures regarding the drug, said Dr. Robert J. Meyer of the U.S. Food and Drug Administration's Center for Drug Evaluation and Research. FDA officials acknowledged that Glaxo submitted information last August indicating some increased risk from the drug but that other studies were contradictory. CBS News correspondent Wyatt Andrews reports the FDA said it has studied the same data as Nissen, but that "unpublished data" suggests "contradictory evidence about (Avandia's) risks" — which essentially means the FDA doesn't have enough evidence to pull the drug off the market. However, several members of Congress expressed alarm at the report and said they would hold hearings on the safety issues. Avandia is used to treat Type 2 diabetes, the most common form of the disease, which is linked to obesity and afflicts 18 million Americans and 200 million people worldwide. This form of diabetes occurs when the body does not make enough insulin or cannot effectively use what it manages to produce. Avandia helps sensitize the body to insulin and was considered a breakthrough medication for blood-sugar control. In a strongly worded editorial accompanying the study, patients were warned not to quit Avandia on their own without discussing their concerns with their doctors, wrote Drs. Bruce Psaty and Curt Furberg. To the extent that the new analysis shows valid risks, the drug "represents a major failure of the drug-use and drug-approval processes in the United States," they said. Psaty, a researcher at the University of Washington, said the Nissen study means there's no good reason for most patients to take Avandia. "There is little evidence for using this drug," Psaty told WebMD. "The purpose of reducing blood sugar is to prevent cardiovascular events. Now the possibility of cardiovascular benefit associated with Avandia appears remote — indeed, it appears linked to harm. So the rationale for prescribing it at this time is just not clear." When the drug was approved, "evidence was at best mixed" on its benefit, wrote the two doctors. Both have been frequent critics of the FDA's failure to spot dangers in the drug approval process and its conduct in the case involving Vioxx. The popular arthritis medicine sold by Merck & Co. was taken off the market in 2004 when heart problems came to light after it had been taken by millions of people Several experts said Avandia was another example of the FDA failing to detect a safety problem early enough. "This study is sure to increase criticism of the U.S. Food and Drug Administration for approving Avandia in the first place," said CBS News correspondent Barry Bagnato. The report on the diabetes drug's risks follow Glaxo's $2.5 million settlement of a lawsuit filed by former New York Attorney General Eliot Spitzer over the release of data on the safety and effectiveness of its drugs. Spitzer, now New York governor, accused Glaxo of fraudulently withholding some results of studies that had examined the safety of prescribing the antidepressant Paxil to children. GlaxoSmithKline disputed that it attempted to mislead anyone, and said it has always been in favor of widespread disclosure of clinical trial results. The company's clinical trials registry (http://ctr.gsk.co.uk) is available to the public, although the reports within it are highly technical and may appear incomprehensible to an untrained reader. ... See also: (06/06/2007 - CBS/AP) Top Diabetes Doc: Drugmaker Threatened Me The controversy surrounding GlaxoSmithKline's diabetes drug Avandia [rosiglitazone] grew Wednesday as a medical expert told Congress that executives threatened to sue when he first raised questions in 1999 about the treatment's safety. ... Dr. John Buse told lawmakers that after he drew attention in 1999 to heart problems among some patients using Avandia, SmithKline Beecham, which later combined with GlaxoWellcome, warned him that some executives wanted to hold him accountable for a $4 billion drop in the company's stock. In a letter to SmithKline distributed at the hearing, Buse wrote: "Please call off the dogs. I cannot remain civilized much longer under this kind of heat." Buse, who is head of endocrinology at the University of North Carolina and is set to become president of the American Diabetes Association, said he eventually signed a clarifying statement with the company that was used to ease concerns from investors. But one year later, Buse sent a letter to the FDA raising the same concerns. FDA Commissioner Andrew von Eschenbach ... revealed that FDA is ordering Glaxo and rival Eli Lilly to add black box warnings to their diabetes drugs Avandia and Actos, strengthening existing warnings about heart failure, a condition where the heart does not adequately pump blood. The issue is separate from the trend toward heart attacks highlighted in the New England Journal of Medicine. ... More than 6 million people worldwide have taken Avandia or a related drug, Avandamet, since it came on the market in 1999. Glaxo reported total U.S. sales of $2.2 billion for the drug last year. Avandia's label (.pdf) already warns about possible heart failure and other heart problems when taken with insulin. The drug also raises LDL, or bad cholesterol, and can cause fluid retention and weight gain. J Pharmacol Exp Ther. 2007 May. Although tamoxifen can trigger steatohepatitis, the mechanism of steatosis is unclear. We hypothesized that this DNA-intercalating, cationic amphiphilic drug could accumulate within mitochondria to impair fatty acid oxidation, respiration, and mitochondrial DNA relaxation and synthesis. We studied the in vitro effects of tamoxifen on topoisomerases and mouse liver mitochondria and its in vivo hepatic effects in mice treated for 1 to 28 days with a daily dose of tamoxifen reproducing the plasma concentrations observed in humans. In vitro, tamoxifen inhibited topoisomerase-mediated plasmid DNA relaxation. It accumulated 40-fold inside mitochondria and inhibited both respiration and fatty acid oxidation. In vivo, a single dose of tamoxifen inhibited palmitic acid oxidation and hepatic lipoprotein secretion. Tamoxifen administration also decreased mitochondrial DNA synthesis and progressively depleted hepatic mitochondrial DNA, down to 40% of control values at 28 days. The decrease in mitochondrial DNA-encoded respiratory complexes sensitized mitochondria to the inhibitory effects of tamoxifen on mitochondrial respiration. Hepatic steatosis was absent at 5 days, mild at 12 days, and moderate at 28 days. The fatty acid synthase protein was normally expressed at 12 days but was decreased by 52% at 28 days. In conclusion, tamoxifen decreases hepatic triglyceride secretion, and it accumulates electrophoretically in mitochondria, where it impairs beta-oxidation and respiration. Tamoxifen also inhibits topoisomerases and mitochondrial DNA synthesis and progressively depletes hepatic mitochondrial DNA in vivo. These combined effects could decrease fat removal from the liver, thus causing hepatic steatosis despite a secondary down-regulation of hepatic fatty acid synthase expression. (03/02/07 - ABC News) Cough and Cold Remedies for Young Children For many parents, it can seem like an easy fix for a young children crying out during the night - give them a dropper full of cold medicine. But now doctors worry that cold and cough medicines for children under age 6 may be ineffective and life threatening, as they have been found to lead to hallucinations, seizures and heart problems, according to a 2005 study from the Centers for Disease Control and Prevention. A group of doctors has petitioned the Food and Drug Administration, which has begun a review of these products, which were not specifically evaluated for safety and effectiveness in young children. The FDA frequently uses adult data for children, who are given different dosage guidelines. The doctors will tell you there are no safe cold medicines for young children. Motrin is safe, but not products that include antihistamine, expectorant, cough suppressant, decongestant or a mix of those ingredients. However, the industry says the cold and cough medicines are safe when used according to the proper recommended dosage. The Consumer HealthCare Products Association issued a statement saying, "These medicines have been found safe and effective by the U.S. Food and Drug Administration and are the same medicines that families have safely relied upon for decades to help relieve cough and cold symptoms and make their children feel better." It added it welcomed the opportunity to work with the FDA to ensure consumers have safe and effective medicines. Guidance for Parents Children typically catch eight to 10 colds in their first two years of life, according to the American Pediatrics Association. For those under 3 months old, they advise calling a pediatrician at the first sign of illness, as colds at that age can lead to more serious ailments. When kids under the age of 6 come down with a cold or cough, the CDC and APA offering the following guidance:
J Pediatr. 1992 Oct. A 16-year-old boy with short stature and mild primary hypothyroidism received subcutaneous injections of either recombinant human growth hormone or placebo in diluent that contained glycerol and m-cresol as a preservative. While he was receiving the study drug, myalgia developed and serum creatine kinase values were elevated. Both resolved when injections were stopped and recurred when injections of diluent alone were given. The myalgia and elevated creatine kinase activity were apparently caused by a component of the diluent. J Pharmacol Exp Ther. 1991 Nov. Administration of either aspirin or salicylic acid (3 mmol.kg-1 b.wt. i.p.) decreased by 50 and 65%, respectively, the in vivo oxidation of [U-14C]palmitic acid to [14C]CO2 in mice; after salicylic acid administration, exhalation of [14C]CO2 from [1-14C]palmitic acid, [1-14C]octanoic acid or [1-14C]butyric acid was decreased by 87, 33 and 38%, respectively. Inhibition lasted 9 hr. It was associated with markedly decreased blood glucose concentrations and increased plasma ketone bodies. Repeated administration of salicylic acid (2 mmol.kg-1 i.p. every 8 hr) tripled hepatic triglycerides and produced mild microvesicular steatosis of the liver at 22 hr in fasted mice. In vitro, salicylic acid (1.5 mM) had no or little effect on the formation of beta-oxidation products from [1-14C]octanoic or [1-14C]palmitoyl-L-carnitine, in the presence of ATP, carnitine (40 microM) and coenzyme A (40 microM), but decreased by 51% that from [1-14C]palmitic acid. In the latter system, increasing the concentrations of coenzyme A and carnitine to 200 microM suppressed the inhibitory effect of salicylic acid. Salicylic acid (1.5 mM) decreased by 80% the in vitro mitochondrial formation of palmitoyl-coenzyme A from [1-14C]palmitic acid and 10 microM coenzyme A; again, increasing the concentration of coenzyme A prevented inhibition. We conclude that salicylic acid decreases the mitochondrial activation and thus beta-oxidation of long chain fatty acids, presumably by sequestering extramitochondrial coenzyme A and possibly carnitine. Diabetes Care. 1990 Jan. m-Cresol and methyl p-hydroxybenzoate are preservatives in insulin preparations. As previously reported, in diabetic patients on continuous subcutaneous insulin infusion, users of insulin-containing m-cresol had significantly more inflamed infusion sites than users of insulin with methyl p-hydroxybenzoate. This study assessed the influence of insulin with and without these preservatives on leukocyte function. Leukocyte function was investigated in a killing experiment, expressed as the percentage of bacteria killed after 60 min incubation of bacteria (Staphylococcus aureus), polymorphonuclear leukocytes, serum, and insulin preparations. Because preservative is retained by the infusion device, insulin with preservative was tested before and after 1 and 4 days perfusion with a PVC pump catheter. After perfusion, the amount of preservative was reduced (percentage of original concentration after 1 and 4 days 8 and 30% m-cresol and 42 and 72% methyl p-hydroxybenzoate, respectively). The killing percentage in insulin with m-cresol reduced compared with insulin without preservative (mean +/- SE 95.4 +/- 0.8%) and the control without insulin (95.8 +/- 0.8%), both before and after 1 and 4 days perfusion (74.8 +/- 0.7, 80.2 +/- 2.8, and 80.6 +/- 1.6%, respectively; P less than 0.01). The same occurred in insulin with methyl p-hydroxybenzoate (85.0 +/- 0.9% before and 88.4 +/- 0.9 and 86.2 +/- 0.8% after 1 and 4 days perfusion; P less than 0.05). All insulin preparations with m-cresol caused lower killing percentages than corresponding insulin preparations with methyl p-hydroxybenzoate (P less than 0.05). These results demonstrate that both preservatives impaired leukocyte function, but m-cresol was the most noxious in this respect. Hepatology. 1988 Sep-Oct. Intravenous administration of high doses of tetracycline may produce severe microvesicular steatosis of the liver in man. A similar disease is observed after ingestion of drugs which inhibit hepatic mitochondrial fatty acid beta-oxidation and in subjects with various inborn defects in this metabolic pathway. We therefore determined the effects of tetracycline on the mitochondrial oxidation of fatty acids in mice and in man. In vitro, addition of tetracycline 0.25, 0.5, 1 or 2 mM inhibited by 15, 38, 56 and 65%, respectively, the formation of beta-oxidation products during incubation of palmitic acid with mouse liver mitochondria and the various cofactors necessary for beta-oxidation. Inhibition was reversible. Inhibition appeared even greater with human liver mitochondria. Tricarboxylic acid cycle activity, assessed by the in vitro formation of [14C]CO2 from [1-14C]acetylcoenzyme A by mouse liver mitochondria, was inhibited by 25, 32 and 43%, respectively, in the presence of 0.5, 1 or 2 mM of tetracycline. In vivo, administration of tetracycline, 0.25 or 1 mmole per kg, inhibited by 53 and 84%, respectively, the exhalation of [14C]CO2 during the first 3 hours following the administration of a tracer dose of [U-14C]palmitic acid. Administration of tetracycline, 0.0625, 0.25 or 1 mmole per kg, 6 hr before the measurement, increased hepatic triglycerides by 100, 170 and 250%, respectively. After 1 mmole per kg, accumulation of hepatic triglycerides was maximum at 24 hr, reaching 9-fold the control value; liver histology showed microvesicular steatosis at 6 and 24 hr. We conclude that tetracycline inhibits the mitochondrial oxidation of fatty acids in mice and in man. |