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Medications

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Medications for postmenopausal osteoporosis prevention

Risk of osteoporosis increases after menopause, when levels of estrogen — which helps preserve bone density — drop. Until recently, most doctors recommended long-term hormone replacement therapy (HRT) to treat postmenopausal women who need medication to prevent bone loss. But things changed after results from a large trial on a common HRT drug showed that estrogen plus progestin (as the medication Prempro) did more harm than good. An increased risk for breast cancer and cardiovascular events outweighed the benefits of less colorectal cancer and fewer fractures. (See the Update from July 2002 for more information on the trial.)

Health experts now encourage most women who have been taking long-term HRT for osteoporosis prevention to consider an alternative. Fortunately there are several options. Each of the FDA-approved treatments (see chart) has potential benefits and risks that women and their doctors should weigh before making a decision. Even with HRT’s proven risks, it may still be a good choice for certain women — especially in lower doses, which recent data have shown to have bone benefits comparable to higher, standard doses.

Approved medications for osteoporosis prevention

Medication

How to take it

Bone benefits

Side effects

Comments

Alendronate (Fosamax)

Orally, once daily in the morning or as a larger dose once a week; take with 6–8 ounces of water and stay upright for 30 minutes.

Increases bone density at the spine and hip; reduces spinal and hip fracture risk. Side effects uncommon.

Heartburn, nausea, inflammation of the esophagus, muscle pain.

Interferes with cells that break down bone. Well-tolerated when taken properly.

Risedronate (Actonel)

Orally, once daily in the morning or as a larger dose once a week; take with 6–8 ounces of water and stay upright for 30 minutes.

Increases bone density at the spine and hip; reduces spinal and hip fracture risk. Side effects uncommon.

Abdominal pain, nausea, constipation, joint pain.

Interferes with cells that break down bone. Well-tolerated when taken properly.

Raloxifene (Evista)

Orally, once daily, any time.

Increases bone density (but less so than alendronate or risedronate); reduces spinal fracture risk. Side effects uncommon.

Hot flashes, leg cramps, deep-vein blood clots.

Acts like estrogen in bone but is an anti-estrogen in breast tissue; may reduce breast cancer risk.

Estrogen (Premarin, Estrace, other brands)

Orally, once daily, any time; or weekly by skin patch.

Increases bone density; some evidence for fracture reduction.

Increases the risk for breast cancer (after 4–5 years) and cardiovascular events when combined with a progestin (as Prempro) and taken orally.

May be recommended if other medications are not tolerable or menopausal symptoms persist.

Sources: Boosting Bone Strength: A Guide to Preventing and Treating Osteoporosis, Harvard Health Publications, Boston, 2000; Managing Osteoporosis, Part 3: Prevention and Treatment of Postmenopausal Osteoporosis, American Medical Association, 2000; Osteoporosis: Guide to Prevention, Diagnosis, and Treatment, Brigham and Women’s Hospital, Boston, 2002

December 2002 Update

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Botox injections

With the recent nod of approval from the Food and Drug Administration (FDA), the popularity of Botox injections has surged. Spas, shopping malls, walk-in clinics and even parties advertise the availability of this age-defying treatment. Even before FDA approval, the use of Botox was on the rise, increasing 61% between 2000 and 2001, according to the American Society of Plastic Surgeons.

Botox, the trade name for botulinum toxin type A, is used to lessen the telltale signs of aging by softening frown lines on the forehead and brow, crow’s feet at the corners of the eye, and other wrinkles. But what is this toxin, how does it work, and who should be administering the procedure?

Botulinum toxin type A is one of several proteins secreted by the bacterium Clostridium botulinum. These proteins are neurotoxins; they attack nerve cells and paralyze the affected muscles. Ingestion of botulinum toxins causes the infamous food poisoning botulism. But when the purified form of botulinum toxin type A is injected into the muscles below the skin in very low doses, the result is a reduction in wrinkling.

As we age, our skin becomes less elastic and wrinkles remain even when the muscles controlling the skin are relaxed. Botulinum toxin lessens wrinkles by attaching itself to nerve endings in the muscle and preventing the release of the neurotransmitter acetylcholine. This blocks the nerve signals transmitted from the brain to the muscles and paralyzes or weakens the muscle controlling the wrinkled skin. The result is the smoothing out of the skin from disuse — if it can’t move, it can’t wrinkle.

Botox injections are done in a quick and easy procedure lasting less than 30 minutes. The toxin takes effect within a week. The results are temporary, however, so retreatment is necessary within three to six months. Botox may be used in conjunction with or as an alternative to other facial skin rejuvenation procedures such as chemical peels or laser skin resurfacing. When performed by an experienced physician, the most common adverse side effects of the procedure include headache, respiratory infection, flu syndrome, and nausea.

With the potential results and relative ease, it is easy to forget Botox is a prescription drug and not just an injection. However, the results of the procedure largely depend on the injector’s knowledge of the complex muscular anatomy of the face, the effects of the drug, and the principles of aesthetics. Each face must be treated differently. An inexperienced or careless injector may introduce the toxin into parts of the face that result in droopy eyelids or brows. Injections in several parts of the face at the same time can result in excessive paralysis, leading to a "frozen" or unexpressive look that may take a few months to disappear.

For the best results, anyone considering this procedure should find a dermatologist or dermatologic surgeon with training and experience in the technique. The physician should also spend adequate time with the patient discussing the desired results and the patient’s medical history. A patient must understand the risks, benefits, alternatives, and reasoning for the procedure. The injections should be performed in an appropriate setting such as a medical office with medical personnel and equipment ready to deal with potential complications.

The injections are on the pricey side, though, costing an average of $400.

December 2002 Update

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Erythromycin and Pyloric Stenosis

A study published in the July 2002 issue of the Archives of Pediatrics and Adolescent Medicine confirms suspicions that a common antibiotic can cause a serious condition in very young infants.

Infantile hypertrophic pyloric stenosis (IHPS) occurs when the muscle surrounding the outlet from the stomach becomes overgrown and obstructs the passage of food into the intestines. The condition, which usually arises in the first three to five weeks of life, causes projectile vomiting. This can lead to dehydration, weight loss, and electrolyte imbalances that affect kidney function. Physicians have long believed that exposure to the antibiotic erythromycin is related to the condition.

To investigate the link, researchers tracked the antibiotic use and IHPS occurrence in over 314,000 infants between 1985 and 1997. Of the 7,138 infants given prescriptions for erythromycin within the first 90 days of life, 804 were diagnosed with pyloric stenosis. Further analysis showed that while infants younger than two weeks old were rarely given erythromycin, those who were exposed within the first two weeks of life were eight times as likely to develop IHPS as an infant who had not received the drug during this time. Babies who received erythromycin after the first two weeks did not appear to have an increased risk for the condition.

Physicians commonly use erythromycin to treat infants with illnesses such as respiratory and ear infections, whooping cough, and conjunctivitis. The results of this study suggest the risks and benefits of erythromycin need to be carefully weighed — and perhaps other antibiotics tried — before it is prescribed for use in infants younger than two weeks.

October 2002 Update

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Chemotherapy not needed for all breast cancers

Chemotherapy may not be necessary for all breast cancer patients. A study published in the July 17, 2002, issue of the Journal of the National Cancer Institute indicated that postmenopausal women whose breast cancer is sensitive to estrogen may not benefit from adding chemotherapy to the estrogen-blocking drug tamoxifen.

The International Breast Cancer Study Group’s Trial IX looked at 1,669 women whose breast cancer had not spread to their lymph nodes. After being grouped according to their cancer’s estrogen sensitivity — estrogen receptor-positive or -negative — half of the women received chemotherapy followed by five years of tamoxifen, while the other half received only tamoxifen.

Those with ER-negative breast cancer enjoyed a statistically significant benefit in terms of disease-free survival (time before relapse; appearance of another cancer; or death) and overall survival when treated with chemotherapy followed by tamoxifen. But for those in the ER-positive group there was no difference in disease-free survival or overall survival when treated with the combined therapy.

Chemotherapy, in addition to tamoxifen, is regularly prescribed for the majority of postmenopausal patients with lymph-node negative, ER-positive breast cancer. The researchers hope that results from this and similar studies will encourage clinicians to treat postmenopausal women with a more individualized program, one that takes the estrogen sensitivity of their cancers into account.

September 2002 Update

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Aspirin and heart disease

Should you take aspirin to prevent a heart attack? According to a new study, aspirin helps lower cardiovascular risk, but whether or not you should take it depends on a bevy of factors.

The study, published in the May 9, 2002, issue of the New England Journal of Medicine, analyzes the major trials on the subject. Four out of five of the randomized trials show a reduction in cardiovascular events (especially heart attacks) with aspirin use. (In randomized trials, researchers randomly assign patients to one of the treatments being tested.) But the studies' statistics vary wildly. For example, risk reduction ranged from 4%–44%, depending on the study. All but one trial showed that aspirin use increased the risk of bleeding, most commonly in the stomach.

Two large observational studies also showed that aspirin use decreased coronary events in both people with and without heart disease. (In observational studies, researchers simply monitor subjects' behaviors and health, they do not test a specific treatment on them.) Subjects' ages had an impact in both studies, with aspirin's benefit on the heart kicking in when subjects hit 50 years old in one, 60 years old in the other. Other trials have found that aspirin has the greatest effect on patients with high risk for heart disease.

So what should you do? That depends a lot on your heart disease risk. To calculate your risk go to this downloadable scoring system on the National Institutes of Health Web site.

Then, if you answer yes to any of these questions, talk to your doctor about starting aspirin therapy:

  • Is your risk for heart disease 1.5% or higher per year?
  • Is your risk between 0.7% and 1.4% per year? If so, and you answer yes to one or more of the following questions, ask your doctor about treatment:
    • Are you in poor physical shape?
    • Do you have diabetes or high blood pressure and damage to your organs?
    • Do you strongly want to start aspirin therapy?

But if your risk is 0.6% or lower per year, you're probably not a good candidate for aspirin therapy. You should also avoid the therapy if you're allergic to aspirin, prone to bleeding, or suffer from platelet disorders or ulcers. Your own preference is another important factor in making this decision.

Keep in mind that if you have high blood pressure, you'll need to take extra care to control it in order to get the most benefits from aspirin. Also, besides stomach bleeding, aspirin use may cause hemorrhagic stroke.

July 2002 Update

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Lifestyle and Drug Therapies Effectively Prevent Type 2 Diabetes

Type 2 diabetes affects approximately 8% of adults in the United States. An additional 10 million Americans are at high risk for the disease. This type of diabetes begins gradually, later in life. Most people with type 2 diabetes produce plenty of insulin, but their tissues resist the action of the hormone, so their blood sugar levels rise; some people develop the disease as their insulin production gradually slows down.

Although treatment may prevent some complications of type 2 diabetes, which can include atherosclerosis, vision impairment, and nerve damage, it cannot eliminate the condition altogether. As a result, prevention of type 2 diabetes remains preferable. In a recent study in the New England Journal of Medicine (NEJM), researchers from the Diabetes Prevention Program Research Group sought to determine whether lifestyle intervention or drug treatment could be used to prevent or delay the onset of type 2 diabetes.

The researchers gathered 3,234 subjects who they determined to be at high risk for diabetes based on elevated blood sugar levels. They assigned the subjects to one of three interventions: twice-daily treatment with 850 mg of metformin (a drug commonly used to lower blood sugar in people with type 2 diabetes), lifestyle intervention, or placebo. The goal of the lifestyle intervention was to achieve a weight reduction of at least 7% of initial body weight through a low-fat, low-calorie diet, and to complete at least 150 minutes of moderate-intensity physical activity per week. As measured by the researchers, the lifestyle intervention group achieved much greater weight loss and increased their physical activity level more than the metformin or placebo groups.

After almost 3 years of follow-up, the scientists found that the incidence of type 2 diabetes was 58% lower in the lifestyle intervention group and 31% lower in the metformin group than in the placebo group. In addition, the incidence of type 2 diabetes was 39% lower in the lifestyle intervention group than in the metformin group.

The NEJM study showed that lifestyle intervention and treatment with metformin effectively prevents type 2 diabetes in people at high risk for the condition, regardless of race, ethnicity, gender, or age. The combination of increased physical activity, dietary changes, and weight loss produces particularly effective results.

June 2002 Update

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Healthy Diet Eradicates Need for Trendy Supplements in Elderly

Magazine ads and television commercials tout dietary supplements that claim to be a veritable fountain of youth for seniors. Images of grandparents able to keep up with their grandkids convince older adults that shakes, energy bars, and special vitamins will help boost energy and decrease signs of aging.

Health experts, however, stress that a well-balanced diet rich in fruit and vegetables is just as effective and probably safer. But many older adults skip meals and eat small amounts of fruits and vegetables, citing reasons ranging from rotten teeth to unhappiness with eating alone.

While doctors acknowledge that nutritional shakes and energy bars are helpful for seniors who need to gain weight or have trouble chewing or swallowing, those who eat a balanced diet or stay active do not need them.

In spite of what the experts have said, the savvy advertisements are convincing millions of seniors that they need these expensive supplements, some of which have not even been proven safe.

Herbs are also a source of concern. Saw palmetto, an extracts made from the fruit of the saw palmetto plant, is promoted as a treatment for an enlarged prostate. Many people believe that herbs are natural and therefore safe but this is not the case. In fact, as with most nonprescription herbal products, the composition of the extract and the dosage have not been standardized and the supplement is not regulated by the FDA. If you decide to use saw palmetto, tell your doctor in order to alert him or her to possible interactions between it and other medications you may be taking.

People who are on strict diets — like those prescribed for kidney disease, heart disease, or diabetes — must be especially wary of adding any special supplements to their diet. Regardless of whether health problems are present, you should always consult a physician before starting any dietary regimen.

May 2002 Update

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New Guidelines for Rheumatoid Arthritis Treatment

Rheumatoid arthritis (RA) is a chronic autoimmune disease affecting more than 2 million people in the United States. It causes pain, stiffness, and swelling in the joints, as well as inflammation in organs. Guidelines for the management of the disease were first created in 1996, but significant developments since then prompted the American College of Rheumatology to publish an updated version in the February 2002 issue of its journal, Arthritis & Rheumatism.

A key addition to the new guidelines is the emphasis on early diagnosis and treatment. Recent studies have confirmed that if RA is treated early and aggressively, the course can be altered and the onset of joint destruction can be delayed. The report advises patients to consider nonsteroidal antiinflammatory drugs (aspirin, ibuprofen), glucocorticoid injections, or prednisone to control symptoms once diagnosed. But the new guidelines recommend most people begin treatment with the more potent disease-modifying antirheumatic drugs (DMARDs) within three months of diagnosis. If prognosis is poor, however, DMARDs should be initiated as soon as the diagnosis is confirmed.

The guidelines give information on the efficacy, potential side effects, cost, and administration methods of several new drugs being used in the treatment of RA. These new therapies include three genetically engineered biologic response modifiers (entanercept, infliximab, and anakinra) which target chemicals that cause inflammation. The use of entanercept and infliximab, which work by blocking important inflammation messenger proteins, represent a major advancement in RA treatment. Also presented is a new DMARD, Leflunomide, which slows the structural damage brought on by RA. The guidelines recommend using the aggressive drugs in combination — for example, a biological agent plus a DMARD or two DMARDs.

These new therapeutic options are already being used in the treatment of RA. But for physicians who treat the disorder, the primary value of the new guidelines is the parameters they set for RA therapy and medications.
April 2002 Update

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New Diabetes Guidelines from the ADA

In the January 2002 supplemental issue of Diabetes Care, the American Diabetes Association (ADA) released a compilation of all its position statements on diabetes care, including three new ones. It includes the first update of the ADA's nutrition guidelines since 1994.

One of the reports, Evidence-Based Nutrition Principles for the Treatment and Prevention of Diabetes, outlines changes as to how diabetics should approach carbohydrate intake, giving them more dietary freedom. Previously, diabetics were advised to avoid eating simple sugars and fast-acting carbohydrates like table sugar because these were believed to be more rapidly absorbed than complex starches found in such foods as potatoes, thus aggravating hyperglycemia. But there is little scientific evidence to support this theory. In fact, the simple sugar sucrose is no worse for a diabetic than starch, so the ADA now recommends simply using the carbohydrate terms sugar, starch, and fiber instead.

The new guidelines also advise that it's more important for people with diabetes to monitor and adjust their insulin requirements according to the total amount of carbohydrates in food rather than the source or type. They therefore dismiss the practical value of the glycemic index, which calculates how quickly the carbohydrate content of a person's overall diet raises blood sugar levels. Nevertheless, some carbohydrate sources are healthier than others, so the ADA recommends diabetics get their carbohydrates from whole grains, fruits, and vegetables because they are also rich in fiber, vitamins, and minerals.

Diets rich in carbohydrates and low in fats used to be recommended for all patients with diabetes but this has changed since the discovery that diets rich in monounsaturated fatty acids lead to improvements in HDL ("good") cholesterol levels, triglyceride levels, and overall diabetes control.

The use of fructose as an added sweetener is not recommended, but natural fructose in fruits and other sweeteners like saccharin and aspartame appear to be safe. The guidelines address many other important nutrition issues, but specifically they recommend that diabetics get 60%–70% of their caloric intake from carbohydrates and monounstaturated fats, 15%–20% from protein, and less than 10% from saturated fats. Overall, these new options afford diabetics more choices in their diets-choices that will provide a diet more people can adhere to.

Another of the reports, Treatment of Hypertension in Adults with Diabetes, addresses hypertension, which occurs in up to 60% of diabetics and substantially increases the risk of vascular problems, such as coronary heart disease and other serious complications. The most recent evidence supports the use of aggressive hypertension treatment to avoid these complications. The ADA recommends people with diabetes aim for a blood pressure (BP) of less than 130/80 mm Hg. If a diabetic's BP is 130–139/80–89, the report suggests adopting behavioral changes such as reducing salt intake, losing weight, and becoming more physically active. However, if his or her BP is greater than 140/90, drug treatment should be started. Angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), diuretics, and beta blockers are recommended as first-line treatments. In many cases, patients will need three or more drugs to control their BP.

The third report, Standards of Medical Care for Patients with Diabetes Mellitus, is a comprehensive guide intended to provide an overview of the components of diabetes care, treatment goals, and tools to evaluate the quality of care. It also goes over strategies for successful guideline implementation. For instance, successful programs give patients access to nurses for case management services, diabetes educators, and group visits.

For the complete reports, go to http://care.diabetesjournals.org/content/vol25/suppl_1/.
April 2002 Update

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New Drugs Have Had Impact on Glaucoma Therapy

Glaucoma strikes nearly 4 million people in the United States, and is a major cause of blindness. It is characterized by excessive fluid pressure in the eye, which can damage the optic nerve. The good news is that when caught and treated early, vision can usually be spared.

Glaucoma can be treated either with medications or with surgery. Until recently, physicians primarily treated glaucoma with topical ß blockers, which reduced the amount of fluid, called aqueous humor, produced in the eye. When drugs were not effective, a surgical procedure would be used to improve drainage of the fluid. Over the past five years, however, three new classes of glaucoma medications have come into use: prostaglandin analogues (latanoprost), which remove aqueous humor through the uveal tissues; topical carbonic anhydrase inhibitors (dorzolamide), which reduce the amount of aqueous humor produced in the eye; and α-2 agonists (brimonidine), which decrease production of aqueous humor and increase fluid outflow.

Investigators in Scotland set out to determine the impact that these new classes of drugs have had on the treatment of glaucoma. They reviewed a national registry that recorded the prescription and surgery statistics for Scotland from 1989 through 1999. The researchers found that the number of surgical procedures performed per 1,000 glaucoma patients increased between the years 1989 and 1994, then decreased by 45.9% from 1994 through 1999. During the same period (1994–1999), the number of medications prescribed per 1,000 glaucoma patients increased by 24.9%, mostly due to a rise in the prescription of the new drug classes.

Although the new drugs have altered the medical and surgical treatment of glaucoma, the researchers note that it is still too early to tell whether the new medications will prevent the need for surgery, or only delay it.
March 2002 Update

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Birth Control Patch

The first skin patch approved for birth control by the U.S. Food and Drug Administration will be available by prescription in 2002. Ortho Evra works by slowly releasing progestin and estrogen, the same hormones used in birth control pills, into the bloodstream. Its efficacy lies in the prevention of ovulation and the thickening of the cervical mucus, which makes it harder for sperm to enter the uterus.

Ortho Evra is 99% effective in preventing pregnancy. However, the side effects include an increased risk of blood clots, heart attack, and stroke. This risk is even higher for cigarette smokers. In three clinical trials involving over 3,000 women taking Ortho Evra, 5% of participants had at least one patch that detached from their skin and 2% withdrew from the trial due to skin irritation. Also, the patch appeared to be less effective in women weighing more than 198 pounds.

The regimen is similar to that of birth control pills. The patch is changed once a week for three weeks. The patch-free fourth week allows for a menstrual period. The small (less than two square inches) and paper-thin design makes Ortho Evra easy to hide beneath clothing. It can be applied to the buttocks, abdomen, upper torso (front or back), and the upper outer arm, and be worn in a different place each week.
February 2002 Update

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Simvastatin and Niacin, But Not Antioxidants, Reduce Risk of Coronary Heart Disease

High levels of low-density lipoprotein (LDL) cholesterol and low levels of high-density lipoprotein (HDL) cholesterol both increase risk of coronary heart disease (CHD). Studies have shown that simvastatin, one of the statin medications, can lower levels LDL cholesterol and that niacin, a B vitamin, can raise levels of HDL cholesterol. Less consistent evidence indicates that antioxidant vitamins, such as vitamin E or vitamin C, may also help reduce the risk of CHD. In a study published in the New England Journal of Medicine, researchers sought to determine whether combining lipid-altering therapy with antioxidant vitamin therapy would have benefits that exceeded those of either therapy alone.

One hundred and sixty patients, all of whom had coronary heart disease, low HDL levels, and normal LDL levels, participated in the study. The average age of the study participants was 53 years. The researchers assigned the subjects to one of four treatment regimens: simvastatin plus niacin, antioxidants alone, simvastatin and niacin plus antioxidants, or placebo. The antioxidant therapy was comprised of vitamin E, vitamin C, beta carotene, and selenium.

After three years of treatment, the researchers used an imaging technique called coronary angiography to measure the amount of atherosclerotic plaque in the patient's arteries and compared it to angiographic measurements taken prior to the initiation of treatment. They found plaque formation increased by 3.9% in the placebo group, by 1.8% in patients taking antioxidants alone, and by 0.7% in the simvastatin and niacin plus antioxidant group. The amount of plaque decreased by 0.4% in the group that was assigned to simvastatin plus niacin therapy.

The laboratory results correlated with actual coronary events. In this study, the primary endpoint was defined as death from coronary causes, heart attack, stroke, or revascularization. The frequency of that endpoint was 24% in the placebo group, 21% in the antioxidant only group, 14% in the group taking simvastatin, niacin, and antioxidants, and 3% in the simvastatin plus niacin group. Only the simvastatin plus niacin group had a statistically significant decrease in clinical events.

These findings were somewhat surprising because not only did the addition of antioxidant therapy to lipid-altering therapy not improve the clinical outcome, it actually worsened the risk of a coronary event. One explanation proposed by the authors suggested that antioxidants might limit the increase of HDL2, a subtype of HDL believed to be the most protective HDL constituent. Additional study is needed to determine whether therapy with individual antioxidants would have a different result than the harmful effect of the combination antioxidant therapy tested in this analysis.

Side effects from niacin therapy led to the withdrawal of two participants from the study, while another two remained in the study but stopped taking niacin.
January 2002 Update

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Pregnancy and Anticonvulsant Drugs

"Do you have epilepsy or take any anticonvulsant drugs?" This is a common question asked of pregnant women and women who are planning to become pregnant. The cause for the concern is the risk of birth defects associated with the disease. But whether birth defects are related to the mother's epilepsy or caused by the drugs used to treat it remained unknown until recently.

A study published in the New England Journal of Medicine examined newborns for birth defects related to anticonvulsant drugs. Each newborn belonged to one of three groups: newborns exposed to anticonvulsant drugs in the womb; newborns of mothers with epilepsy who did not take anticonvulsant drugs; and newborns of mothers without epilepsy or a history of seizures. Results showed birth defects were more frequent in infants exposed to anticonvulsant drugs (20% of infants exposed to one drug had birth defects and 28% of infants exposed to two or more drugs had birth defects). However, the infants of mothers with epilepsy who were not treated with anticonvulsant drugs were at no greater risk of birth defects then infants of mothers without epilepsy.

This study suggests birth defects are caused by anticonvulsant drugs and not by epilepsy itself. A separate, earlier study based on data from a number of different countries identified the types of birth defects associated with common anticonvulsant drugs. Some of these findings are summarized below:

Birth Defect Related Anticonvulsant Drug
Spina bifida Valproic acid
Oral clefts Phenobarbital or methylphenobarbital
Heart defects Phenobarbital, methylphenobarbital, valproic acid, or carbamazepine
Brain and face abnormalities, shortened limbs Valproic acid

If you take anticonvulsant drugs and are pregnant, or are thinking of becoming pregnant, consult your physician about the risks to your baby.
November 2001 Update

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Side Effect Warning for New Rheumatoid Arthritis Drug, Remicade (Infliximab)

All drugs have side effects, but some of them don't become apparent until after the drugs have been approved and in use for some time.

Remicade (infliximab), a powerful new drug for rheumatoid arthritis, has been found to worsen congestive heart failure. The drug was actually being tested to see if it would help patients with congestive heart failure. Instead, the opposite was seen in a trial involving 150 people with moderate to severe congestive heart failure. Of the 101 subjects treated with Remicade, 7 died. In contrast, no fatalities occurred in the 49 patients being treated with the sugar pill placebo.

Some 2 million Americans suffer from rheumatoid arthritis, while 5 million have congestive heart failure. So an undetermined number must have both illnesses. As a result, Centocor, the company making Remicade, after consultation with the U.S. Food and Drug Administration, has sent letters to doctors urging that patients with both rheumatoid arthritis and congestive heart failure not be treated with their drug.
November 2001 Update

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Angiotensin-II-receptor Antagonists for Diabetic Nephropathy

Anyone with type 2 diabetes knows about the host of complications that can result if blood sugar is not kept under tight control. One complication is diabetic nephropathy, or kidney damage. When functioning normally, our kidneys keep proteins and other beneficial substances in the blood and filter out waste products, which the body excretes as urine. Diabetes can interfere with this process. As a result, waste products remain in the blood and protein is excreted into the urine (proteinuria).

Angiotensin-converting-enzyme (ACE) inhibitors have been shown to slow the progression of renal, or kidney, disease in patients with type 1 diabetes. ACE inhibitors are widely given to patients with type 2 diabetes for the same purpose, even though there's less evidence they are effective. A set of studies published in the September 20, 2001 New England Journal of Medicine examined the effects of a different class of drugs, called angiotensin-II-receptor antagonists on nephropathy caused by type 2 diabetes.

The first study involved 1,715 patients with type 2 diabetes, above-normal blood pressure, urinary protein excretion of at least 900 mg per day, and serum creatinine levels (a marker of kidney damage) between 1-3 mg/dL. Each day, the patients took either 300 mg of the angiotensin-II-receptor antagonist irbesartan, 10 mg of the calcium-channel blocker amlodipine, or a placebo. After an average of 2.6 years, significantly fewer patients receiving irbesartan experienced a doubling of serum creatinine, end-stage renal disease, or death than patients taking either amlodipine or placebo (33% vs. 41% vs. 39%).

In another study, which involved a similar patient group, investigators studied the effects of the angiotensin II-receptor antagonist losartan versus the effects of a placebo. At the end of 3.4 years, patients taking losartan had a 25% risk reduction in the incidence of serum creatinine doubling and a 28% risk reduction of end-stage renal disease compared to patients taking a placebo. However, losartan did not have any effect on the rate of death.

An editorial accompanying the NEJM articles suggests that although angiotensin-II-receptor antagonists performed well in these trials, they are still far from effective in all patients. In addition, this study did not compare the performance of angiotension-II-receptor antagonists to that of the widely used ACE inhibitors.
October 2001 Update

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Inhalers Lead to Hip Bone Loss

Medications commonly used for the long-term treatment of asthma may lead to hipbone loss in premenopausal women.

Researchers at Brigham and Women's Hospital in Boston found bone mass in the hip and trochanter decreased in women taking inhaled glucocorticoids, a type of steroid used for treating asthma. The rate of bone loss also increased with the rate of dosage. The three-year prospective study involved 109 women aged 18 to 45. Bone density was measured at the beginning of the study, after six months of treatment and at one, two, and three years.

Bone density was found to decline 0.00044 grams per square centimeter per puff of medicine per year of treatment. Although that's a small amount, it can be significant in the long run. If a woman with asthma is treated with six puffs of triamcinolone acetonide (the glucocorticoid studied) twice a day for 20 years, she could expect to have 0.106 grams per square centimeter less bone in her hip than she would have had without the treatment, according to this study. That degree of bone loss has been associated with a risk of hip fractures more than double that of normal women 65 and older.

Besides the hip, measurements were also taken at the spine and femoral neck, but no changes were found there. The rate of decline also varied between patients in the same dosage group and no reason for that could be found.

Though osteoporosis is a major health problem for women, the study's authors admit that inhaled glucocorticoids are among the most effective and safest medicines for asthma. They suggest doctors prescribe the lowest effective dose and patients using high doses should ask their doctors to periodically assess their bone density.
The results of previous, less extensive studies on inhaled steroids and bone density have been mixed.
October 2001 Update

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Statins Associated With Lower Dementia Risk

Most people who develop dementia - poor memory and intellectual functioning that often accompanies old age - have Alzheimer's disease. But a small, yet sizable group of people appear to develop dementia from a narrowing of the arteries supplying the brain. The lack of blood can lead to many small areas of damage to the brain; each too small to be noticeable as a "stroke," but collectively devastating in their effect. This syndrome is called "vascular dementia" to differentiate it from Alzheimer's disease and other types of dementia.

Presumably because high cholesterol levels contribute to the damage of brain's blood vessels, researchers have looked for evidence that people who use statins might have a lower rate of dementia. Statins are the most widely used cholesterol-lowering drugs. In addition to protecting the brain's arteries from atherosclerosis, some scientists believe statins may also help protect the brain against non-vascular forms of dementia, including Alzheimer's disease.

A recent study examined the relationship between statin use and types of dementia among people living in the United Kingdom. The researchers identified 284 people with dementia, and matched them with 1,080 "control" subjects of similar age and sex, but without dementia. After adjusting statistically for a wide range of clinical information, the researchers found statin use was associated with a 71% reduction in dementia risk.

Could statins really cut the risk for dementia by two-thirds or more? It seems unlikely, since other studies haven't suggested protective effects of this size. On the other hand, this study adds to several other laboratory and epidemiological investigations that suggest statins might provide some benefit in the protecting the brain - if for no other reason than lower cholesterol levels lead to healthier brain arteries. No one should start taking statins as a strategy for preventing dementia, but these data do provide another reason for people with elevated cholesterol levels who are on these medications to be sure they take them as prescribed.
October 2001 Update

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Diet and Exercise Dramatically Delay Type 2 Diabetes

Americans at high risk for type 2 diabetes can sharply lower their chances of getting the disease with diet and exercise, according to the results of a major clinical trial. The same study also found the oral diabetes drug metformin (Glucophage) reduces diabetes risk, though less dramatically.

The findings came from the Diabetes Prevention Program (DPP), a major clinical trial comparing diet and exercise to metformin in 3,234 people with impaired glucose tolerance, a condition that often precedes diabetes. Smaller studies in China and Finland had previously shown diet and exercise can delay type 2 diabetes in at-risk people. But the DPP, conducted at 27 centers nationwide, is the first major trial to show diet and exercise can effectively delay diabetes in a diverse American population of overweight people with impaired glucose tolerance (IGT). IGT is a condition in which blood glucose levels are higher than normal but not yet diabetic.

Of the 3,234 participants enrolled in the DPP, 45 percent are from groups that suffer disproportionately from type 2 diabetes: African Americans, Hispanic Americans, Asian Americans and Pacific Islanders, and American Indians. The trial also recruited others known to be at higher risk for type 2 diabetes, including people age 60 and older, women with a history of gestational diabetes, and people with a first-degree relative with type 2 diabetes.

Participants ranged from age 25 to 85, with an average age of 51. All had impaired glucose tolerance as measured by an oral glucose tolerance test, and all were overweight, with an average body mass index (BMI) of 34. They were randomly assigned to one of the following groups: intensive lifestyle changes with the aim of reducing weight by 7 percent through a low-fat diet and exercising for 150 minutes a week; treatment with the drug metformin (850 mg twice a day), approved in 1995 to treat type 2 diabetes; and a standard group taking placebo pills in place of metformin.The latter two groups also received information on diet and exercise.

During an average follow up of about 3 years, about 29 percent of the group receiving standard treatment developed diabetes. In contrast, 14 percent of the diet and exercise, and 22 percent of the metformin arms developed diabetes. Volunteers in the diet and exercise arm achieved the study goal, on average a 7 percent — or 15-pound — weight loss, in the first year and generally sustained a 5 percent total loss for the study's duration. Participants in the lifestyle intervention arm received training in diet, exercise (most chose walking), and behavior modification skills.

In all, participants in the random intensive lifestyle intervention reduced their risk of type 2 diabetes by 58 percent, and those who received metformin reduced their risk of getting type 2 diabetes by 31 percent.
September 2001 Update

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FDA Issues Guidance on Levothyroxine Sodium, a Popular Thyroid Hormone

For decades, Levothyroxine sodium, the most popular thyroid hormone for replacement therapy, had not been required to go through the Food and Drug Administration's approval process. But in 1997, the FDA reclassified all oral levothyroxine products as "new drugs," obligating the manufacturers to meet approved New Drug Applications (NDAs) before August 14, 2001. A history of potency and stability problems with orally administered levothyroxine sodium products resulted in the agency's decision.

Two levothyroxine sodium products, Unithroid and Levoxyl, have recently been approved by the FDA to treat hypothyroidism. And now the FDA is issuing guidance regarding the transition of patients from unapproved to these approved products, and the handling of those products being marketed without an approved application. The FDA will gradually do away with the unapproved products to allow manufacturers of approved products to expand to meet demand and to give patients and health care providers enough time for a clean transition.

Two of the most common formulations that are being phased out are Synthroid and Levothroid. Manufacturers of unapproved oral levothyroxine sodium drug products without an NDA pending with the FDA must cease distribution by August 14, 2001.
August 2001 Update

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High Blood Pressure Drug Performs No Better Than Standard Treatment

An FDA advisory panel has decided to inform doctors about the results of a government study that found Cardura (doxazosin), a popular blood pressure medication sold by Pfizer, was less effective than a generic diuretic (chlorthalidone) in reducing some forms of cardiovascular disease. But the panel also concluded the agency didn't need to extend this warning to patients.

Cardura, which has been on the market for 10 years, is an alpha-adrenergic receptor blocker that relaxes smooth muscle throughout the peripheral parts of the body, including the blood vessels. It's often used for the management of hypertension, a condition involving persistently high arterial blood pressure. Hypertension is a major risk factor for the development of coronary heart disease, heart attacks and strokes.
Cardura's role in managing hypertension was investigated as part of the National Institute of Health's Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), the first large-scale blood pressure treatment study to compare several newer drug treatments with a cheaper generic diuretic.

The first part of ALLHAT was stopped early because users of Cardura had 25% more cardiovascular events and were twice as likely to be hospitalized for congestive heart failure as users of the diuretic. But the study didn't find Cardura users were any more likely to die than those using the diuretic. As a result, the NIH advised high blood pressure patients who now take Cardura consult with their doctors about a possible alternative. They also suggested the drug may not be the best choice for new patients. The American College of Cardiology followed with a clinical alert that advised physicians to stop prescribing Cardura and reassess its treatment value.

Last year, a group of patients filed a lawsuit with a U.S. District court claiming Pfizer did little to inform doctors and patients about the results of ALLHAT, but the petition was handed over to the FDA. The FDA advisory panel concluded that while it appeared the diuretic was more effective than Cardura in preventing congestive heart failure, there was not enough data to prove Cardura was harmful. The FDA often follows the recommendations of its advisory panels. Pfizer continues to maintain that Cardura is safe.
July 2001 Update

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Statins Reduce C-reactive Protein

Half of all heart attack victims have normal cholesterol levels. Consequently, doctors are looking for new methods to improve heart disease prevention. One promising new approach involves testing for high levels of the inflammation marker C-reactive protein to identify people who might benefit from drug therapy.

C-reactive protein (CRP) is secreted from the liver in response to inflammation in the body. Because atherosclerosis is partly an inflammatory process, high levels of CRP have been shown to predict the risk of heart disease. A new study has found that statins can reduce the risk of coronary events in people who have high levels CRP. These drugs are already used to lower LDL cholesterol, but the researchers found its anti-inflammatory effect was independent of its cholesterol-lowering abilities.

The five-year randomized trial done at Brigham and Women's Hospital and Harvard Medical School involved 5,742 participants. The researchers found that Lovastatin decreased both CRP levels by an average of 14.8% and the rates of coronary events. Other statins has also previously been shown to reduce CRP levels.

This study suggests statins may be an effective preventive therapy for people with high CRP levels — even if they have low or normal LDL cholesterol. Though everyone is encouraged to make healthy lifestyle changes to reduce their heart disease risk, only those at high-risk are candidates for these costly drugs. And measuring CRP levels in conjunction with cholesterol testing should better identify these high-risk individuals.
July 2001 Update

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TNF Inhibitors Effective for Treatment of Rheumatoid Arthritis

Two members of a new class of drugs have been found to reduce the joint damage associated with rheumatoid arthritis. Rheumatoid arthritis (RA) is an inflammatory disease that causes pain, swelling, stiffness, and progressive loss of function in the joints.

Two studies published in the New England Journal of Medicine evaluated the effectiveness of TNF inhibitors, drugs that neutralize the inflammatory protein known as tumor necrosis factor (TNF). TNF is overproduced in the joints of patients with rheumatoid arthritis and is believed to be responsible for much of the joint damage in RA.

In one study, conducted at the Johns Hopkins University in Baltimore, etanercept (Enbrel) was compared to methotrexate in 632 patients with early-stage rheumatoid arthritis. Etanercept acted more rapidly to decrease symptoms than methotrexate. In addition, etanercept was more effective at slowing the progress of joint erosion; the rate of joint damage, as measured by x-rays, was significantly reduced in the etanercept group compared to the methotrexate group. After one year of treatment, 72% of the etanercept patients had no progression in joint erosion compared to 60% of the methotrexate-treated patients.

The second study, conducted at the University of Texas Southwestern Medical Center in Dallas, followed 428 patients with chronic, active rheumatoid arthritis for 12 months. The researchers found that a combination of the TNF inhibitor infliximab (Remicade) and methotrexate significantly reduced the symptoms of RA and halted progression of joint damage compared to treatment with methotrexate alone. Nearly 52 percent of the patients taking the infliximab and methotrexate combination showed symptom reductions, compared with 17 percent of methotrexate-only patients. X-ray examination showed that joint damage came to a halt in patients given the drug combination. In addition, joint damage decreased in 40-55 percent of patients on the combination therapy, implying that some damage had been repaired. Meanwhile, joint damage progressed in the group given only methotrexate. The combination therapy, which was well tolerated, also significantly improved quality of life.

Methotrexate, the standard rheumatoid arthritis medication, was approved more than a decade ago for treating certain types of arthritis and skin conditions. However, it can cause serious side effects including liver damage. In contrast, both TNF inhibitors were well tolerated.

An estimated 1%of the adult U.S. population has rheumatoid arthritis, and it is about two to three times more common in women than men.
May 2001 Update

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FDA Approves Gleevec to Treat Leukemia

Chronic myelogenous leukemia (CML), one of four main types of leukemia, strikes about 5,000 people every year. On average, patients live 3-4 years after receiving a diagnosis of CML. Last week, the FDA approved Gleevec (imatinib mesylate, also known as STI 571) as an oral treatment for CML.

Gleevec has been shown to substantially reduce the level of cancerous cells in the bone marrow and blood of treated patients. In clinical trials, 90 percent of patients in the first phase of CML went into remission within the first six months of taking Gleevec. Of patients in the second phase of CML, 63 percent went into remission with Gleevec. The drug produced few side effects.

Additional studies need to be done to determine how long the effects of this drug last, whether patients become resistant to the drug, and, most importantly, whether Gleevec can actually extend a patient's life.

Still, the results are promising. Currently, the only cure for CML is a bone marrow transplant. Even if a patient is lucky enough to find a marrow donor match, the procedure is successful less than 2/3 of the time. Interferon, a widely used treatment for CML, can extend a patient's life for up to two years, but it has several serious side effects and does not cure the disease. Gleevec may be used in patients in the early stage of CML who do not respond to interferon therapy, and in patients in the later stages of CML.

Most people with CML have a chromosomal abnormality, known as the Philadelphia chromosome, in which portions of two different chromosomes are switched. The result is the creation of an abnormal protein that allows the uncontrolled production of white blood cells, which can interfere with the function of other organs in the body. Gleevec blocks a signal sent out by the abnormal protein, thus blocking the rapid growth of white blood cells.

The FDA's approval of the drug came after a surprisingly short 2½ months. Most drugs that, like Gleevec, are granted a priority review, take six months to approve. The approval was based on three separate studies that involved about 1,000 patients with CML. The drug has generated enthusiasm in the medical community because it targets a specific, cancer-causing protein, without damaging other cells.

Scientists at an American Society of Clinical Oncology meeting announced earlier this month that Gleevec had also produced remission in 180 patients with advanced cases of an intestinal cancer known as gastrointestinal stromal tumor (GIST). Until now, GIST cancers have been incurable; GIST patients normally die within one year of receiving their diagnosis.
May 2001 Update

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Hormonal Therapy Recommended for All Hormone-Receptor-Positive Breast Cancers

In a statement issued late last year, the National Institutes of Health recommended that all women who have hormone-receptor-positive breast cancer receive hormonal therapy in addition to their primary treatment (surgery alone or surgery plus chemotherapy). This recommendation holds regardless of a woman's age, menopausal status, tumor size, or whether the cancer has spread to the lymph nodes.

Hormone-receptor-positive cancers grow in response to the hormone estrogen, which is produced by the ovaries. Tamoxifen (Nolvadex, Tamoplex), the most widely used hormonal therapy, works by blocking estrogen receptors on breast cancer cells. It is used to halt, slow, or prevent tumor growth. Studies have shown that women who take tamoxifen for five years reduce their annual risk of a recurrence of breast cancer by 40%. Taking the drug for more than five years offers no additional advantage, and it increases the risk of toxic effects.

Premenopausal breast cancer patients under the age of 50 reap a significant benefit from adjuvant tamoxifen therapy. Results from a small study show that women under 50 who received tamoxifen in addition to chemotherapy had a 40% reduction in recurrence and a 39% reduction in death compared with women who had chemotherapy alone. These results are not conclusive, however, because of the small trial size. A study currently underway in Canada may provide more reliable results.

Postmenopausal women with very small, low-grade tumors, however, may experience only a small overall benefit from tamoxifen. After menopause, women have lower levels of estrogen in their bodies. Studies have shown that women in this group who undergo chemotherapy but do not take tamoxifen may live as long as women of the same age with no history of breast cancer. Because tamoxifen can cause rare, serious side effects such as blood clotting and endometrial cancer, postmenopausal women and their physicians should weigh the benefits of taking the drug against the risks.
May 2001 Update

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Killing H. Pylori Helps Prevent Gastrointestinal Bleeding in Patients Taking Low-Dose Aspirin

Many people take low-dose aspirin on a daily basis to help prevent heart attacks. Others take larger doses of stronger nonsteroidal antiinflammatory drugs (NSAIDs), such as naproxen (Anaprox, Aleve, others), to relieve musculoskeletal pain such as that caused by arthritis. When taken on a regular basis, however, NSAIDs often cause ulcers and gastrointestinal (GI) bleeding. Ulcers, which are raw, crater-like breaks in the mucosal lining of the digestive tract, may also be caused by excess acid production and a bacterium known as Helicobacter pylori (H. pylori).

In a study published in the New England Journal of Medicine, researchers enrolled 400 patients with a history of GI bleeding who were taking aspirin or other NSAIDs to prevent heart disease or to control musculoskeletal pain. They set out to find whether eradicating H. pylori infection reduces the risk of recurrent GI bleeding in these patients. For six months, 250 patients were given an 80 mg "baby" aspirin once per day, while the remaining 150 patients received 500 mg of naproxen twice per day. Within each of the two groups, patients were randomly assigned to take either a daily dose of omeprazole (Prilosec), an acid-suppressing medication, or a one-week antibiotic treatment to eradicate H. pylori infection, followed by placebo for the remainder of the trial.

The researchers found that in patients taking aspirin, those who were treated for H. pylori had a 1.9% risk of GI bleeding while the risk for those taking omeprazole was 0.9%. In other words, for patients on low-dose aspirin, the treatments were almost equal.

The results were very different for patients taking naproxen. 19% of the naproxen patients who had H. pylori treatment suffered from recurrent bleeding. In contrast, only 4% of the omeprazole group did.

The study suggests that patients with a history of GI bleeding who take low-dose aspirin to prevent heart attacks should be tested for H. pylori infection and treated if the infection is found to be present. Patients taking non-aspirin NSAIDs and who have experienced GI bleeding are more likely to benefit from acid-suppressing therapy.
April 2001 Update

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Ipriflavone Not Effective for Osteoporosis

For years, estrogen replacement therapy was the drug of choice for treatment of osteoporosis in postmenopausal women. But the potential risks of HRT sent women searching for alternatives. One option was phytoestrogens — plant-based compounds that bind to estrogen receptors in the body, presumably mimicking the beneficial effects of estrogen without its potential risks. Of the phytoestrogens, the most promising was ipriflavone, a synthetic version of a naturally occurring isoflavone, a type of phytoestrogen.

But a well-designed study published in the March 21, 2001, Journal of the American Medical Association refutes the positive results of previous studies, demonstrating that ipriflavone does not prevent bone loss or reduce the risk of fracture in postmenopausal women. It also cautions that ipriflavone lowers levels of lymphocytes, an effect that could make women more vulnerable to infection.

In the JAMA study, members of the Ipriflavone Multicenter European Fracture Study Group assigned 474 postmenopausal white women with low bone mass aged 45 to 75 to either 200 mg of ipriflavone taken three times per day or a placebo for the three-year duration of the trial.

At the end of the trial, the researchers found no significant difference between the treatment groups in regard to bone mineral density measured at the lumbar spine, total hip, and distal radius; in biochemical markers of bone formation or bone resorption; or in the number of vertebral fractures suffered by the women.

The major difference was that women treated with ipriflavone experienced significant drops in their lymphocyte concentration. 13.2% of the ipriflavone-treated women developed lymphocytopenia, a condition defined as a total lymphocyte concentration below 500/µL. Of these women, 52% returned to normal lymphocyte values within one year of discontinuation of the drug; 81% returned to normal within two years.

In reviewing their findings, the researchers cautioned against the use of ipriflavone to treat osteoporosis.

Women throughout much of the world have used ipriflavone since 1969 to treat osteoporosis. More recently it has been sold over-the-counter in the United States as Ostovone.
April 2001 Update

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Sertraline Effectively Treats Depression in Alzheimer's Patients

A large portion of the 4 million Americans with Alzheimer's disease (AD) — a progressive degenerative disease of the brain that results in memory loss, impaired thinking, and personality change — also suffer from major depression. This can make the already devastating condition even more difficult, not only for patients, but also for their caregivers. Until recently, the efficacy of antidepressants in such patients was uncertain. Now, a study from The American Journal of Psychiatry shows that sertraline (Zoloft) a type of antidepressant known as a selective serotonin reuptake inhibitor (SSRI) is more effective than placebo in reducing depression in patients with AD. This study is the first to show both the efficacy and safety of an SSRI in treating depression in patients with AD.

A team of researchers from the Johns Hopkins University School of Medicine and the Copper Ridge Institute in Maryland selected 22 patients with Alzheimer's disease who also met the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for having had a major depressive episode. Over the course of the 12-week double-blind trial, the scientists gave the patients, whose average age was 77, either a placebo or up to 150 milligrams of sertraline per day. All patients and caregivers received illness education, encouragement, and emotional support every three weeks over the course of treatment.

The scientists found that AD patients who had been given sertraline experienced significantly greater improvements in mood than patients who received a placebo. In addition, the sertraline patients experienced less decline than placebo patients in participation in daily activities.

Side effects of the drug included tremor, restlessness, and gastrointestinal complaints. But all were mild, and there was no significant difference in side effects between the sertraline group and the placebo group.
April 2001 Update

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Warfarin and Vaginal Cream Drug Interaction Warning

The Food and Drug Administration (FDA) has issued a warning stating that women taking the prescription blood thinner warfarin (Coumadin) should consult their doctor or pharmacist before using over-the-counter vaginal creams containing the antifungal drug miconazole because of an increased risk of bleeding or bruising. Miconazole is an active ingredient in many over-the-counter creams and suppositories used to treat vaginal yeast infections.

Doctors were already aware of adverse reactions between warfarin and systemically administered miconazole. This warning urges women to beware of creams and suppositories as well.

The warning was issued in response to two reports of abnormal blood clotting tests in women taking the anticoagulant warfarin who used vaginal miconazole. In addition to the abnormal blood-clotting test, one of the two women also developed bruises, bleeding gums, and a nosebleed. Two journal articles also warned of a possible interaction between warfarin and vaginal miconazole.

The FDA warning will appear on miconazole-containing product labels and consumer brochures.
April 2001 Update

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New Medication Approved to Treat Eczema

Atopic dermatitis is a chronic, hereditary skin condition that causes redness, itching, and oozing lesions. It mainly affects children but can persist into adulthood. Doctors often prescribe oral or topical corticosteroids for serious cases. But while steroids are very effective at quieting inflammation, they can have adverse side effects. Steroid creams may cause thinning of the skin and decreased collagen production, while oral corticosteroids can have more serious adverse effects.

Now, dermatologists have high hopes for a new ointment, tacrolimus (Protopic), which was recently approved by the FDA to treat moderate to severe eczema in patients who cannot tolerate or are not adequately helped by standard therapies. The FDA approved tacrolimus on the basis of three 12-week studies that found 90% improvement in about one-third of the patients who used the medication. Two additional one-year studies, also considered by the FDA, found that adults who used the drug intermittently over the course of the year had no adverse effects except temporary burning and stinging. Because tacrolimus can increase sensitivity to ultraviolet (UV) light, users should avoid sunlight, tanning beds, and treatment with UVA or UVB light.
March 2001 Update

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Does Aspirin Prevent Preeclampsia?

Preeclampsia, also known as toxemia, is a condition that affects pregnant women and their unborn baby. It is characterized by high blood pressure, water retention, and protein in the urine. The condition, which usually occurs after the 5th month of pregnancy, can lead to seizures, kidney and liver damage, slow fetal growth, and even fetal or maternal death. Preeclampsia affects up to 8% of pregnancies, and is responsible for 10-15% of maternal deaths. In the past decade, several studies have looked at the effectiveness of aspirin in preventing preeclampsia.

Early studies showed promising results. But larger, more recent studies failed to show any benefit.

In an effort to reconcile these conflicting results, British researchers reviewed several studies involving over 30,000 women who were at increased risk for preeclampsia. (Risk factors include preexisting high blood pressure, diabetes, a first pregnancy, pregnancy as a teenager or over the age of 40, and pregnancy involving multiple fetuses.) The women had been randomized to receive an antiplatelet drug (usually low-dose aspirin), a placebo, or no antiplatelet medication.

The researchers concluded that aspirin reduced the risk of preeclampsia by 15%. Their review also showed that aspirin decreased the risk of premature births by 8% and the risk of stillbirths or newborn deaths by 14%. Based on these results — acknowledged by the researchers as showing only small to moderate benefits — the researchers recommended the use of aspirin. Several issues including the optimal dosage, the proper time to start treatment, and which women are most likely to benefit, remain unresolved.

Despite the results of this review, some leading experts are unconvinced that aspirin is effective at preventing preeclampsia. However, even physicians who doubt aspirin's efficacy agree that at doses of less than 80 milligrams per day, aspirin is not harmful. If your physician prescribes aspirin to prevent preeclampsia, it may or may not be effective — but in any case, it won't be harmful.
March 2001 Update

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FDA Approves Weekly Dose of Fosamax (alendronate) for Osteoporosis Treatment and Prevention

The FDA recently approved once-a-week doses of Fosamax (alendronate) for the prevention and treatment of osteoporosis. The weekly dose for prevention is 35 mg while the weekly dose for treatment is 70 mg. Fosamax, which was already approved for once-a-day use, works by slowing bone loss.

The main advantage of the once-a-week version is convenience. Doctors recommend that Fosamax be taken first thing in the morning, on an empty stomach, approximately 30 minutes before breakfast, and that patients not lie down for at least 30 minutes after taking the medication. Patients may find that they prefer to adhere to this routine only once a week, rather than every day.

FDA approval was based largely on a two-year clinical trial that showed that for postmenopausal women, a weekly 70 mg dose of alendronate was just as effective at increasing bone mineral density as a 10 mg daily dose. The study included 1,258 postmenopausal women with a mean age of 67. The once-weekly alendronate dose was effective regardless of the women’s underlying condition, age, bone mineral density (BMD), or pre-existing fractures.

Compared with the daily dose, 70 mg of alendronate once a week was better tolerated and produced fewer serious upper gastrointestinal and esophageal problems. The weekly dose also produced similar gains in bone mineral density at the lumbar spine, total hip, femoral neck, hip, and total body sites.
February 2001 Update

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Treating Chronic Hepatitis C

An estimated 3.9 million people in the United States are infected with the hepatitis C virus (HCV). Hepatitis C affects the liver. In many — but not all — cases, hepatitis C progresses from mild to moderate inflammation (hepatitis), to scarring (fibrosis), to severe fibrosis with loss of liver function (cirrhosis), and finally liver failure. It is the leading cause of chronic liver disease and liver transplantation. But not all cases of hepatitis C progress to cirrhosis and the rate of progression of the disease is often unpredictable.

The standard of care for treating hepatitis C is a combination of the antiviral drugs interferon-alpha and ribavirin. However, these drugs are not completely effective, they cause side effects, and they are expensive. Given the drugs' limitations and the unpredictable nature of disease progression, doctors remain in disagreement about whether treatment should begin at the onset of mild inflammation, or whether it should be delayed until a moderate amount of inflammation or cirrhosis exists.

Using information from recent studies about the natural progression of HCV, researchers created a computer model that would help determine the optimal time to start combination antiviral drug therapy with interferon-alpha and ribavirin. The simulation projected that 18 percent of patients who had a liver biopsy every three years and started treatment at the onset of moderate inflammation would progress to cirrhosis after 20 years. This strategy avoided the need for treatment in 50 percent of patients, and increased life expectancy by 1.2 years. In patients who began treatment at the onset of mild inflammation, only 16 percent would progress to cirrhosis after 20 years, increasing life expectancy by another 0.4 years. In comparison, the computer model predicted that 27 percent of patients in the control group, which was left untreated, would have cirrhosis after 20 years.

This study illustrated that beginning antiviral treatment at the onset of mild inflammation is the most effective treatment strategy. However, for patients with HCV and mild inflammation of the liver who do not wish to receive drug treatment or hope to delay it, biopsy management is also a reasonably effective option that could avoid treatment altogether.

A Promising New Drug: Peginterferon
In January 2001, the FDA approved Peg-Intron (peginterferon) to treat hepatitis C. Peginterferon is a form of interferon-alpha that stays active in the immune system longer than interferon-alpha. As a result, it can be taken once a week, as opposed to three times a week.

Two recent studies published in the New England Journal of Medicine compared the effects of another brand of peginterferon, called Pegasys, with interferon-alpha on patients with chronic hepatitis C. Both studies revealed that peginterferon is significantly more effective in managing the virus. It was also better tolerated and had fewer side effects.

In the clinic, interferon-alpha is usually given in combination with ribavirin, which has been shown to double the effectiveness of interferon-alpha. Researchers regard testing a combination of peginterferon and ribavirin the next logical step in determining how to treat this disease more successfully.
February 2001 Update

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Products Containing Phenylpropanolamine (PPA) Pulled From Shelves

Responding to concerns that phenylpropanolamine (PPA), an ingredient found in many over-the-counter medications, may increase risk of hemorrhagic stroke (see the Family Health Guide online update on phenylpropanolamine), the U.S. Food and Drug Administration has asked manufacturers to remove drugs containing PPA from the market. The following list may not be complete and does not include drug store and supermarket brands, so please check the label or ask your pharmacist. You should also discard any items in your medicine cabinet that contain PPA.

Drugs Pulled From the Market:
Acutrim Diet Gum Appetite Suppressant Plus Dietary Supplements
Acutrim Maximum Strength Appetite Control
Alka-Seltzer Plus Children's Cold Medicine Effervescent
Alka-Seltzer Plus Cold Medicine (cherry or orange flavor)
Alka-Seltzer Plus Cold Medicine Original
Alka-Seltzer Plus Cold & Cough Medicine Effervescent
Alka-Seltzer Plus Cold & Flu Medicine Effervescent
Alka-Seltzer Plus Cold & Sinus Effervescent
Alka-Seltzer Plus Night Time Cold Medicine Effervescent
BC Allergy Sinus Cold Powder
BC Sinus Cold Powder
Comtrex Deep Chest Cold & Congestion Relief
Comtrex Flu Therapy & Fever Relief Day & Night
Contac 12 Hour Cold Capsules
Contac 12 Hour Cold Caplets
Coricidin D Cold, Flu & Sinus
Dexatrim Caffeine Free
Dexatrim Extended Duration
Dexatrim Gelcaps, Dexatrim Vitamin C / Caffeine Free
Dimetapp Cold & Allergy Chewable Tablets
Dimetapp Cold & Cough Liqui-Gels
Dimetapp DM Cold & Cough Elixir
Dimetapp Elixir
Dimetapp 4-Hour Liqui-Gels
Dimetapp 4-Hour Tablets
Dimetapp 12-Hour Extentabs Tablets
Naldecon DX Pediatric Drops
Permathene Mega-16
Robitussin CF
Tavist-D 12 Hour Relief of Sinus & Nasal Congestion
Triaminic DM Cough Relief
Triaminic Expectorant Chest & Head Congestion
Triaminic Syrup Cold & Allergy
Triaminic Triaminicol Cold & Cough
January 2001 Update

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Zinc Lozenges Have No Beneficial Effect on the Common Cold

Over the past few years, more and more people have begun to reach for zinc lozenges at the first sign of a cold. But a study published in the journal Clinical Infectious Diseases suggests that there is little scientific evidence of zinc's effectiveness to support the treatment's popularity.

In a study funded by Warner Lambert Consumer Healthcare, a company that manufactures zinc lozenges, researchers conducted two clinical trials to test zinc's efficacy. One trial involved 273 people who were exposed to a specific cold virus, called rhinovirus, to induce a cold. The other trial involved 281 subjects with natural colds. Both groups were broken up into four subgroups that received one of the following treatments: 13.3 milligrams (mg) of zinc gluconate, 11.5 mg of zinc acetate, 5 mg of zinc acetate, or a placebo. Zinc gluconate and zinc acetate are different formulations of zinc; zinc gluconate is more commonly found in lozenges. Treatment was started within a day of the onset of cold symptoms and continued every 2-3 hours (up to 6 lozenges per day) until the cold symptoms disappeared, or up to 14 days.

The researchers measured the effects of the treatments on both the duration and severity of the colds. Patients self-scored the severity of seven cold symptoms: sneezing, runny nose, nasal obstruction, sore throat, cough, headache, and hoarseness.

At the end of the study, researchers found that zinc gluconate had a small but significant effect on the duration of induced cold symptoms. People who had taken zinc gluconate had cold symptoms for about 2.5 days as opposed to 3.25 for high-dose zinc acetate and 3.5 days for low-dose zinc acetate and placebo. None of the treatments, including zinc gluconate, reduced the severity of cold symptoms for the first three days of the cold. And none of the zinc preparations or placebo had a significant effect on the duration or severity of symptoms in people with natural colds.

Overall, the study suggests that zinc lozenges have little, if any, beneficial effect on the treatment of the common cold.
January 2001 update

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FDA Approves Femara as First-Line Breast Cancer Treatment

On January 10, 2001, the U.S. Food and Drug Administration (FDA) approved Femara (letrozole) as a first-line treatment for postmenopausal women with advanced breast cancer. Femara was originally approved in 1997 to treat advanced breast cancer in women who did not respond to standard antiestrogen drugs such as tamoxifen.

The hormone estrogen stimulates the growth of about half of all breast cancers, known as hormone-receptor-positive breast cancers. Femara, which works by blocking the production of estrogen, can now be used as a principal therapy for these and hormone-receptor-unknown advanced breast cancers. For 20 years, tamoxifen, which blocks estrogen from binding to an estrogen receptor on cancer cells, has been used as a first-line treatment in early and advanced breast cancer patients with hormone-receptor-positive or hormone-receptor-unknown cancer. It has also been used to slow the progress of tumor growth of breast cancers that have metastasized, or spread to other parts of the body.

The recent FDA approval of Femara was based on the results of a randomized, double-blinded, multinational clinical trial comparing Femara and tamoxifen. It involved more than 900 postmenopausal women with locally advanced breast cancer, breast cancer that had spread to other parts of the body, or recurring breast cancer that could not be treated with surgery or radiation. The trial showed that Femara increased time to progression of the disease to 9.4 months, compared to 6 months for tamoxifen. The gain is considerable for late-stage cancer, and it allows women to delay more toxic chemotherapy. The side effects for both drugs were comparable and included back, joint, and bone pain, nausea, and hot flashes.

What is not known at this point is whether Femara will have any role in the prevention of breast cancer. Tamoxifen is often given to hormone-receptor-positive breast cancer patients after surgery, to prevent tumors from recurring and to women with a strong family history of breast cancer to prevent the disease from developing in the first place. Femara has not yet been approved for either of these purposes.
January 2001 Update

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Manufacturer Voluntarily Withdraws Lotronex

Lotronex (alosetron) is a prescription medication used to treat diarrhea-predominant irritable bowel syndrome in women. Last month, the Food and Drug Administration issued important safety warnings for the use of this drug based upon reports of intestinal damage due to impaired blood flow to the intestine (ischemic colitis) and complications of severe constipation (bowel obstruction and rupture) in patients on Lotronex.

On November 30, the manufacturer (Galaxo Wellcome) informed the FDA that it will voluntarily remove this drug from the market. Any patient currently taking Lotronex should contact her physician to discuss other treatment options. For more information, please visit the Center for Drug Evaluation and Research Web page on Lotronex or call 888-INFO-FDA (888-463-6332).

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Cholesterol-Lowing Drugs for . . . Osteoporosis?

As we age, our bones tend to become less dense (that is, more porous and prone to fracture) — a condition known as osteoporosis. Typically thought of as a problem for post-menopausal women, men also suffer fractures due to osteoporosis. As a result, roughly 1.5 million Americans each year will have to endure the pain and inconvenience of a broken bone — often the hip, the wrist, or vertebra. It is hopeful news then, that the class of cholesterol-lowering drugs called "statins" may also provide some protection against the weakening of bones.

By analyzing data on 6,110 women in New Jersey, most of whom were over age 75, researchers discovered that those patients who had used a statin were 50% less likely to experience a hip fracture — even when investigators adjusted for the presence of other diseases or conditions (including diabetes, cancer, high blood pressure, and congestive heart failure). The chances of breaking a hip were lower still when statin use was current. Use of non-statin drugs to lower cholesterol was not associated with a similar protective effect on the bones. Another study, conducted in Britain, showed that statins seem to help the body increase bone mineral density at the hip, which in turn lowers a person's risk for hip fracture, and that this benefit accrues even after only a few weeks or months of statin use.

The likely reason that statins benefit bones as well as cholesterol levels is that these drugs act upon a series of chemical reactions called the "mevalonate pathway." Mevalonate is necessary for the body to produce cholesterol, but it is also involved in bone formation and resorption. Right now researchers think that this discovery may lead the way to additional (and possibly better) medications to treat or prevent osteoporosis. While people who do not need to take medication for high cholesterol should not rush to the doctor to ask for a statin, those who already take these medications should take comfort in knowing that they may be getting double benefits from their daily dose.

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Benefits of COX-2 Inhibitors for Familial Adenomatous Polyposis

Familial adenomatous polyposis (FAP) is a condition in which an inherited mutation in the APC (adenomatous polyposis coli) gene results in the formation of multiple polyps in the mucous membrane of the large intestine. As early as puberty, hundreds of polyps may be evident in people with FAP, and the presence of these growths practically ensures that these individuals will develop colon cancer. The risk is so close to 100% that many FAP patients have their large intestines removed (colectomy) to protect them from this very serious diagnosis.

The enzyme cyclooxygenase-2 appears to play a role in the growth of polyps. It makes sense then, that researchers would be interested in seeing whether COX-2 inhibitors — a new class of nonsteroidal antiiflammatory medication that suppresses cyclooxygenase-2 — might provide some protection against colon cancer. In fact, data from a study conducted at the M.D. Anderson Cancer Center (Houston, TX) and St. Mark's Hospital (London) suggest that 400 mg of the COX-2 inhibitor celecoxib (Celebrex), taken twice daily can suppress colorectal adenomas in people with familial adenomatous polyposis.

Researchers studied 77 FAP patients between the ages of 18 and 65 years old. At the start of the trial, these volunteers were tested for the APC gene mutation and also underwent endoscopy. During the procedure, physicians identified areas of the rectum and/or colon with a high density of polyps so they could compare the degree of polyposis before and after treatment with celecoxib. Investigators then randomly assigned the study subjects to one of three protocols: 1) 400 mg of celecoxib twice daily, 2) 100 mg of celecoxib twice daily, or 3) placebo. The three groups were followed for six months. Fifty-three percent of the individuals taking 400 mg of celecoxib experienced a 25% or more reduction of the average number of colorectal polyps. Only 31% of patients taking the 100 mg dose (and a mere 7% of the placebo group) showed a comparable benefit. In addition, the 400 mg group experienced significant improvement in polyposis throughout the large intestine (including the rectum, ascending colon, and cecum, and in the transverse descending, and sigmoid colon). The patients in the 100 mg group and placebo group did not show similar improvement.

Right now it is unclear whether prolonged treatment with celecoxib, or a medication like it, could limit the extent of polyps, replace or delay the need for colectomy, or perhaps keep polyps from becoming cancerous. However, this data suggest that celecoxib could be used along with current treatments to suppress the formation of polyps in patients who are waiting to undergo surgical removal of the intestine and in cases where the rectum is not removed along with the colon.

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Purchasing Prescriptions Online

Your mother always warned you about taking candy from strangers. Now a new study cautions consumers about buying prescription drugs from electronic strangers. The Internet offers unparalleled access to health care information and increasingly unparalleled shopping for prescription pharmaceuticals. However, a survey conducted by researchers at the University of Pennsylvania found these online pharmacies are, at best, expensive alternatives to traditional pharmacies and at worst, potentially dangerous substitutes for your doctor's advice.

The study reviewed Internet sites offering prescription drugs directly to the public. Information examined included the procedures for obtaining medication, prescription and shipping costs, cost of physician consultations, and physician qualifications. Study investigators then compared the prices of consultations and two popular medications — Viagra (for impotence) and Propecia (for hair loss) — with prices at the clinics and pharmacies in their area.

Thirty-seven of the 45 sites required a prescription or online physician approval before purchase. Nine sites, all based overseas, required no physician consent. Most consultations consisted of online medical history forms and limited interaction through e-mail. The resulting medication was 10% more expensive on the Web before adding shipping costs. Consultation costs, too, were higher, averaging 15% above clinic rates.

While the additional costs might not worry those consumers more interested in convenience or privacy, the potential risks should. The dangers associated with sites that do no require any form of physician approval are obvious. However, none of the sites, even those requiring a doctor's approval, revealed the names, specialties, or qualifications of their physicians. The lack of a physical exam likely increases the risk of misdiagnosis, and only five sites listed their business' physical address, should a problem occur.

In June of 1999, the American Medical Association issued a statement condemning doctors who diagnose patients without access to the patient's medical records, a reasonable likelihood of follow-up, or, at least, a physical exam. More regulations will certainly follow. Until then, consumers should think twice before surfing to the online pharmacy. For more information on managing your medications, see page 1,156 of the Family Health Guide.

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Aspirin for Preventing Stroke and Other Vascular Problems

An aspirin a day keeps a stroke away in patients with a history of heart disease, but a recent review in Archives of Neurology reveals the drug’s stroke-preventing properties may not extend to healthy people.

Researchers from the University of Texas Health Science Center and three other institutions have concluded aspirin does not reduce the risk of stroke in people without heart disease. Indeed, their results suggest regular aspirin use might even slightly increase the risk in people at low risk for vascular problems. These conclusions were reached after the investigators performed a meta-analysis on five existing studies examining the preventive effects of aspirin. (A meta-analysis is a mathematical method used to compare the results of similar studies.) The researchers also reviewed four large observational studies that looked at regular aspirin use and stroke risk in low-risk individuals.

The five trials used in the meta-analysis involved a total of 52,251 participants with a mean age of 57 years. Three of the studies excluded women, though women accounted for roughly 20% of the total number of patients. Three studies used people at high risk for vascular disease, such as those with high blood pressure or diabetes, while the other two used healthy males at low risk. Dosage varied from 75 mg to 650 mg per day. The mean rate of stroke was 0.3% per year during an average study period of five years.

The meta-analysis found no significant risk reduction for patients taking aspirin compared with those taking a placebo. In contrast, the participants still enjoyed a 26% decrease in heart attack risk.

The researchers' review of four observational studies found aspirin modestly increases the risk of bleeding into the brain in low-risk patients — such bleeding can cause hemorrhagic stroke. However, hemorrhagic stroke accounts for only 10-15% of all strokes. Most strokes are ischemic, meaning they are caused by a temporary interruption in the blood flow to brain. When the four studies were pooled, no significant increase in risk of ischemic stroke was apparent.

The researchers stress that more information is needed before guidelines regarding stroke risk and aspirin use can be generalized. Certainly, people with a history of heart disease or whose risk of a heart attack eclipses their risk of stroke can benefit from aspirin. However, the majority of the subjects in the reviewed studies were middle-aged males. Men in this age group are more likely to suffer heart attacks, not strokes. Women and the healthy elderly were underrepresented, yet they are more prone to strokes rather than heart attacks. As a result, it’s still unclear whether anyone with a low risk of heart problems should be regularly taking aspirin.

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Caution Always Key in Using Herbal Medicines

A recent study published in the New England Journal of Medicine offers another important reminder on careful use of herbal remedies. This caution is rooted in the absence of strict pharmaceutical controls in the manufacture of such products and how the lack of these requirements can leave room for tragic errors.

In the mid-1990s, doctors at a clinic in Belgium treated 43 patients with end-stage kidney failure, requiring dialysis or transplant. Not surprisingly, these individuals had something in common in their medical histories. Between 1990 and 1992, each had used a Chinese herbal remedy in combination with two other drugs for weight loss. The herbal preparation supposedly contained Stephania tetrandra and Magnolia officinalis. But the sudden appearance of kidney failure in these patients, caused their doctors to suspect that the herb Aristolochia fangchi, which is poisonous to the kidneys, had unintentionally been substituted for S. tetrandra. The Chinese names for A. fangchi and S. tetrandra sound similar and the two are often confused. Analysis showed that the herbal remedy did, in fact, contain aristolochic acids, which are derived from A. fangchi. Aristolochic acids cause cancer in rats and mutations in bacteria and mammals.

Reports of patients who had developed urothelial carcinoma (cancer of the tissues lining the bladder, ureter, and part of the kidney), as well as kidney failure related to the Chinese herbs, drew concern among the Belgian doctors. When one of their patients also developed this cancer, the doctors decided that all patients with end-stage kidney failure related to the use of Chinese herbs should be checked for cancer of these organs. By removing these organs, the doctors hoped to prevent cancer from developing in their patients. Thirty-nine of the 43 patients agreed to undergo the preventive surgery. Of these patients, 46% of them already had cancerous growths in the removed tissues. In addition, 19 of the remaining 21 patients had abnormal growths in the urinary system. The investigators also analyzed DNA samples taken from the kidneys and ureters of each patient. The DNA samples for every patient showed changes typically found after exposure to aristolochic acid. The researchers compared these results to analysis of DNA samples taken from eight patients with end-stage kidney failure unrelated to Chinese herbs. None of these control samples showed DNA changes formed by aristolochic acid.

The doctors calculated the cumulative dose of the implicated herb and other treatments for each patient. They found that the risk of cancer was related to the cumulative dose of A. fangchi. Because many of the patients had also taken appetite suppressants as well as a diuretic, the doctors noted that these drugs might enhance the toxicity of aristolochic acid.

This case study provides strong evidence suggesting a relationship between the Chinese herb A. fangchi and urothelial carcinoma. While a manufacturing mistake led to the introduction of this herb into an herbal preparation for weight loss, this study highlights the risks involved in taking herbal remedies. There is little control over the quality of herbal medicines. This means that the label on an herbal medicine may not accurately represent what is actually in the container, as was the case with S. tetrandra. Several countries have banned the use of herbs that contain aristolochic acid, yet Aristolochia is readily available in the United States in capsule form.

In the United States, the FDA does not have the authority to assess the safety and efficacy of a dietary supplement before it reaches the shelves of stores. The agency is allowed to restrict a supplement only after it proves the substance is harmful as commonly consumed, but there is no adequate system for reporting serious side effects associated with these products. Furthermore, the FDA does not have any way of knowing which herbal remedies contain harmful substances such as aristolochic acid. The case of the Chinese herbal diet pill and its association with urothelial cancer is just one of a number of cases that demonstrate the need for greater oversight of dietary supplements and caution in the use of supplements on the part of consumers.

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Important Notice: Nationwide Recall of Etodolac Capsules

ESI Lederle, the manufacturer of Etodolac, has recalled one lot number (9991052) of its generic Etodolac (Lodine (R )) Capsules 300 mg. ESI Lederle advises patients taking Etodolac Capsules 300 mg to stop using them immediately until it is clear that their supply of this drug did not come from the recalled lot. Patients should call their pharmacist immediately in order to determine whether or not their Etodolac Capsules 300 mg came from lot number 9991052. If the lot number cannot be determined, patients should assume that their Etodolac Capsules 300 mg came from the recalled lot and should stop taking them immediately and call their physician without delay.

Etodolac Capsules 300 mg are used by arthritis patients. All Etodolac Capsules mg in every lot produced can be identified by their white color and a red "300" at one end and a red "59911" over a red "3607." The recalled lot of Etodolac Capsules 300 mg may contain acebutolol hydrochlorine, a beta blocker, and can cause serious side effects, and even death, in some patients. Capsules from the lot being recalled were first distributed on October 18, 1999. Patients who have already discontinued taking Etodolac Capsules 300 mg and who have not experienced any side effects should not be concerned.

To return affected Etodolac Capsules 300 mg to ESI Lederle, call 800-747-7016. Pharmacies and wholesalers have been told to return all Etodolac Capsules 300 mg as well. Healthcare providers and pharmacists have also been informed of the recall.
October 2000 Update

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Calcium Carbonate's Effect on the Absorption of Levothyroxine

A recent study has revealed that calcium carbonate may reduce the body's ability to absorb the thyroid medication levothyroxine. The people who are probably most affected by this discovery are postmenopausal women, since they often end up taking both levothyroxine and calcium carbonate. However, anyone taking levothyroxine and calcium carbonate concurrently can experience the same effect.

Patients participating in the study ranged in age from 27 to 78 years old and were almost evenly divided between men and women. They all had hypothyroidism (low thyroid function) and were taking levothyroxine. During the study, they were asked to take 1,200 mg of calcium carbonate daily over a three-month period. The majority of patients had significantly lower levels of thyroxine by the end of this period. They were then asked to discontinue taking the calcium carbonate, and their thyroxine levels were measured again after two months. At the end of the two-month period, their thyroxine levels were found to have returned to normal range.

In light of the fact that patients participating in the study were instructed to take the calcium carbonate daily with the levothyroxine on an empty stomach, researchers believe that the acidity level in the stomach may be a factor in how much levothyroxine is absorbed by the body. Researchers have suggested that one way to curb calcium carbonate's effect on levothyroxine is to take the calcium carbonate after a meal in order to optimize the body’s absorption of levothyroxine. They add that if while taking calcium carbonate and levothyroxine concurrently, a patient's thyrotropin level rises, it would be advisable to separate the times at which he or she takes calcium carbonate and levothyroxine on a given day. In some cases, physicians might want to increase the dosage of levothyroxine, to compensate for the effects of calcium carbonate.
October 2000 Update

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Inhaled Corticosteroids Affect Bone-Mineral Density

While inhaled corticosteroids are effective in controlling asthma, a recent study suggests that long-term use of higher doses of inhaled steroids may predispose both men and women to osteoporosis.

Researchers studied a group of men and women between the ages of 20 and 40 years old. All had mild asthma and had been using a steroid inhaler for an average of six years. Because the study did not include patients with severe asthma, decreased growth and physical activity in childhood would most likely not be a contributing factor to patients' decrease in bone-mineral density. In addition, fewer than 10% of the participants had used a steroid inhaler before the age of 15. Most participants (80%) had been using beclometasone dipropionate, though the results for participants using budesonide and fluticasone propionate were the same.

What researchers found was that long-term exposure to high doses of an inhaled corticosteroid produces a significant decrease in bone-mineral density at the spine and femur. Such a decrease in bone-mineral density is associated with a doubling of the risk for fracture. Researchers also discovered that the length of time a patient used a steroid inhaler was similar to the patient's cumulative dose in its effect on the patient's bone-mineral density. Researchers also concluded that participants who had taken inhaled steroids long term and in high doses would enter their 50s and 60s with lower bone-mineral densities than those participants who had taken an inhaled corticosteroid in low doses.

People with asthma who need to use a high-dose steroid inhaler over an extended period of time should consult their doctor about the best measures they can take to prevent osteoporosis.
October 2000 Update

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Side Effect Warnings for New Arthritis Drug Enbrel

Individuals taking Enbrel, a new rheumatoid arthritis medication, should be advised of the following. Among patients taking Enbrel, there have been 10 cases of low blood-cell counts, including reductions in red and white blood cells and platelets — which leave patients vulnerable to infection. Five of the individuals who developed this serious side effect died. Patients taking Enbrel are advised to seek medical care if they experience any of the following symptoms: persistent fever, bruising, bleeding, or paleness. If blood tests show significant abnormalities, they should consider discontinuing the drug. It should be noted that the Food and Drug Administration has stated that there is no proof that Enbrel causes dangerous anemia.

In patients with multiple sclerosis (MS) who also take Enbrel for their rheumatoid arthritis, the drug may increase MS symptoms. Among people who do not have MS, but have been taking Enbrel, there have been 11 cases of patients acquiring certain demyelinating diseases, a specific type of nerve disorder that includes MS. New cases of MS in Enbrel users are rare, however, and, in fact, there is no evidence that MS strikes Enbrel users more often than it strikes the general population. However, since Enbrel might increase MS symptoms in users who already have this condition, individuals with MS should consider these reports when evaluating treatment options for rheumatoid arthritis.
October 2000 Update

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Phenylpropanolamine Safety Concerns

A recently released study reports that use of phenylpropanolamine (PPA) — an ingredient in many over-the-counter medications — is associated with an increased risk of hemorrhagic stroke (stroke caused by bleeding into the brain). Phenylpropanolamine causes blood vessels to contract, which can help relieve nasal congestion. It also stimulates the central nervous system, thereby acting as an appetite suppressant. Many cold and allergy products (for example, Contac, Sudafed, and Robitussin-CF) and diet aids (Acutrim, Dexatrim) contain PPA.

Over the past 20 years, more than 30 published case reports have linked PPA intake with bleeding in the brain. One of the earliest reports concerned a diet pill (which is no longer available) that contained both PPA and caffeine. The report’s authors concluded that PPA might cause brain bleeding more often than believed and may trigger episodes of high blood pressure. Later reports implicated products that contained only PPA. Most of these were related to PPA in diet pills, although at least five involved PPA found in cold remedies.

An epidemiological study of PPA and stroke was published in 1984. This research looked at the number of cerebral hemorrhages that occurred among HMO patients who had filled a prescription for phenylpropanolamine between 1977 and 1981. This analysis concluded that PPA users were no more likely to experience bleeding in the brain than people who hadn’t used PPA. Yet, the FDA and the manufacturers of products containing PPA agreed that more study was needed. In 1992, they commissioned the Hemorrhagic Stroke Project (HSP) in which investigators compared 702 individuals who had experienced a brain hemorrhage with 1,376 control subjects. The study volunteers included men and women ages 18-49 years old.

After researchers adjusted for the impact of race, history of high blood pressure, cigarette smoking, and educational level, they found users of cold-remedies or diet pills containing PPA were 49% more likely to have a hemorrhagic stroke when compared to individuals who had not taken PPA. Users of PPA in cold medicines (but not diet pills) had a 23% higher risk of hemorrhagic stroke when compared to non-users.

PPA consumed in diet pills increased that risk substantially, however, being 15 times greater for users than nonusers — even after statistical adjustments. For women, the association between PPA in appetite suppressants and hemorrhagic stroke was 17 times higher (after statistical adjustment) for users versus nonusers. For first dose PPA users, the statistically adjusted risk for brain bleeding was three times greater than for controls.

Study investigators also observed that bleeding in the brain was more likely to occur in people who took greater than the median dose (75 mg). Interestingly, when compared to control subjects, case subjects were significantly more likely to have other risk factors for hemorrhagic stroke. For example, they were nearly twice as likely to have a history of high blood pressure, a family history of hemorrhagic stroke, heavy alcohol use, and were also more likely to report cocaine use. The PPA users were more likely to have taken aspirin (which may raise hemorrhagic stroke risk) and more than twice as likely than controls to have consumed caffeine and more than 10 times as likely to have had recent nicotine exposure. Like PPA, caffeine and nicotine also constrict blood vessels, perhaps exaggerating this effect and contributing to bleeding risk.

Certainly, this research strongly suggests that taking PPA in diet pills might increase hemorrhagic stroke risk. Because weight loss achieved through the use of these drugs is not apt to be healthy or long lasting, there is little to justify the apparent increased risk of using PPA-containing diet pills. The associated risk for stroke with PPA use in cold medicines is not as dramatic, yet these data are a sobering reminder to take seriously the directions and warnings on products containing PPA. Specifically, people with heart disease and high blood pressure should not take PPA without consulting their doctors. Individuals who take monoamine oxidase inhibitors (used for depression, psychiatric or emotional conditions, and Parkinson’s disease) — or who have stopped taking them only within the last two weeks — also should not take products containing PPA until they clear it with their physicians. Finally, these data bring home the message that over-the-counter drugs are drugs, and like prescription medications, they come with potential risks and side effects.

Right now it is uncertain whether the FDA will vote to restrict medications with PPA to prescription-only status, but it is taking these results under advisement.

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