Generics Blog|Medical-Care News

Stavudine (Zerit) may offer clinicians a new alternative for treatment of adults with advanced HIV infection.

Approved for marketing in June 1994, this nucleoside analogue is indicated for the treatment of patients who are intolerant to approved therapies for HIV infection, as well as for those who have experienced significant clinical or immunologic deterioration while receiving these therapies, or who have contraindications to their use.

“Clinical trial experience with stavudine indicates that it is an effective antiretroviral drug. It also appears to have some characteristics that may distinguish it from zidovudine, didanosine, and zalcitabine, although clearly more study is needed in an expanded patient population before any conclusive statements about relative safety and efficacy can be made,” commented Richard Pollard, MD, professor of internal medicine and microbiology, University of Texas Medical Branch at Galveston.

More than 800 patients are enrolled in an ongoing, phase III, multicenter, randomized, double-blind trial comparing stavudine and continued zidovudine in HIV-infected adults. These patients were able to tolerate zidovudine for at least 24 weeks prior to this treatment study. They also were required to have CD4 cell counts between 50 and 500 cells/mm3.

An interim analysis using the surrogate endpoint CD4 cell count was performed on data from 359 patients who had taken study medication for 12 weeks. The mean CD4 cell count among patients in the stavudine group increased 22 CD4 cells/mm3, while a decrease of 22 CD4 cells/mm3 was observed in the patients taking zidovudine. This blinded study is continuing, and complete evaluation of the data, including analysis of the incidences of opportunistic infections and death, is planned for December 1994.

“These results are very encouraging. While we have no head-to-head comparisons between stavudine and the other alternatives to zidovudine, the CD4 cell responses in stavudine-treated patients seem to be maintained for longer than those that have occurred when these other agents were introduced for treatment of advanced HIV infection, particularly in the early studies with didanosine,” noted Dr. Pollard.

Early experience with stavudine also suggests that the development of HIV-resistance may be less of a problem with this new agent compared with other antiretroviral drugs. “We must be very careful about drawing any conclusions at this point because stavudine hasn’t been used as long as zidovudine and the other agents. While resistance will no doubt increase as stavudine is used more widely, preliminary clinical findings and in vitro studies suggest that resistance may take longer to develop with stavudine use and may be of a lower level compared with the other antiretroviral drugs,” noted Dr. Pollard.

Prior to marketing, stavudine was used in a large number of HIV-infected patients as part of the Stavudine Parallel Track Program. During 20 months beginning October 1992, this study enrolled over 13,000 patients with CD4 cell counts below 300/mm3 who had not responded, were intolerant of, or had contraindications to therapy with zidovudine and didanosine. Patients were divided into three categories according to their weight and then randomized within each weight category to receive one of two different dosage regimens. Stavudine was provided to patients free of charge.

“The question often arises: ‘Why another nucleoside analogue?’ Looking at the high enrollment in the parallel track experience suggests that there are a lot of patients who need another therapeutic alternative and that there is definitely a role for an additional drug of this kind,” said Dr. Pollard.

Other studies evaluating the use of stavudine in patients with earlier HIV infection are expected to be underway soon. Two such studies will investigate stavudine in patients with CD4 cell counts of 300 to 600 cells/mm3 who have either no experience with antiretroviral treatment or have taken zidovudine for only a short duration. These studies will explore combinations of zidovudine and stavudine at currently recommended dosages.

Another study has been started to evaluate combined treatment with stavudine and didanosine.

The major clinical toxicity of stavudine has been peripheral neuropathy. In this respect it is similar to didanosine and zalcitabine. However, stavudine has not been associated with the hematologic toxicity that occurs with zidovudine, noted Dr. Pollard.
Self-limiting Side Effects

Peripheral neuropathy, characterized by numbness, tingling, or pain in the feet or hands, has occurred in 15 to 21% of patients who received stavudine in clinical trials. This side effect has generally been self-limiting if the treatment is withdrawn promptly. Therefore, patients should be cautioned to look for its potential signs. Stavudine can be reinitiated at a reduced dose of 20 mg bid if the symptoms resolve completely.

Due to its long intracellular half-life, stavudine is given only twice daily. Dr. Pollard pointed out that the stavudine dosage regimen makes it easier for patients to take than other drugs, which require either ingestion of more units per dose or more frequent administration.

Dr. Pollard is an investigator for clinical trials of stavudine funded by its manufacturer Bristol-Myers Squibb.

A common complaint about the otherwise highly praised new antidepressant fluoxetine (Prozac) is that it reduces sexual interest and capacity. A new study suggests that patients with this problem may see an improvement if they switch to another antidepressant, bupropion (Wellbutrin).

Largely by placing advertisements in newspapers, researchers found 39 patients, about equally divided between the sexes, who had been taking fluoxetine and were concerned about delayed or infrequent orgasm and loss of sexual desire. After two drug-free weeks, they were switched to bupropion. Eight dropped out during the first month on the new drug because of recurring depression or side effects (agitation, nausea, constipation, headache). Of the remaining 31, 29 recovered their capacity for orgasm at least partially; 25 said their libido had increased and were much or very much more satisfied with their sexual functioning. Men and women were affected similarly. During the next four weeks another six patients dropped out, but 21 of the 25 who took bupropion for eight weeks recovered their capacity for orgasm and felt greater sexual satisfaction without becoming depressed again.

The authors admit that since there was no control group, both patients and investigators could have been responding to their hopes rather than to the change in medication. But they suggest a neurochemical explanation for the difference between the two drugs. Fluoxetine enhances the transmission of serotonin, which may inhibit orgasm; bupropion may influence noradrenergic neurons that have the opposite effect.

WHAT’S NEW

For your elderly nursing home patients who are agitated, a recently approved antipsychotic agent may be an alternative to traditional antipsychotics, according to Ned H. Cassem, MD. Risperidone (Risperdal) has received FDA approval for the treatment of schizophrenia and other psychotic disorders.

“It’s a great help for us, because it helps people to settle down without the bad side effects that have troubled us up to now,” said Dr. Cassem.

He said risperidone’s main advantage, when given at low doses, is its relatively low incidence of parkinsonian side effects and tardive dyskinesia, common adverse effects of conventional antipsychotics. Until now, the only drug to offer this advantage was clozapine, which carried the risk of agranulocytosis, according to Dr. Cassem. Because this is not a significant risk with risperidone, weekly white blood cell monitoring is not required.

Risperidone is the first drug in a new chemical class called ben-zisoxazole derivatives. Although its exact mechanism for inducing fewer extrapyramidal side effects is unknown, the drug’s clinical benefits appear to derive from blockade of both serotonin and dopamine receptors.

For agitation, Dr. Cassem recommends a daily dose of 0.5 to 1 mg given at bedtime, not to exceed 10 mg/d.

Dr. Cassem is associate professor, Harvard Medical School, and chief of psychiatry, Massachusetts General Hospital, Boston.

Source: American College of Physicians 75th Annual Session, Miami Beach, FL

Eating more fiber-rich foods relieved abdominal pain and bloating for one out of four ISS sufferers in a recent University of Pittsburgh study. Even better: When the rest added the antidepressant paroxetine (Paxil), another two out of three reported that their discomfort faded away (Amer. Jour. of Gastroenterology, Sept 2002).

“Start by adding at least 25 g of fiber and six glasses of water a day. IBS is a problem that waxes and wanes. So bear with it for 6 weeks,” says researcher George L Arnold, MD. Still uncomfortable? Keep up the fiber, and ask your doctor about paroxetine.

This drug, which is gaining attention as a promising IBS treatment, boosts the levels of serotonin available to nerve cells throughout the body (not just in your brain). “Serotonin acts on the nerves in the gastrointestinal tract to cut some of the pain and spasms and restore more normal contractions,” Dr. Arnold says.

Today’s top medical news and feel-better tips

Antidepressant may restore life to tinnitus sufferers

As if severe ringing in the ears isn’t bad enough, the depression that usually tags along with it can act as an amplifier. The whole package can disrupt your sleep and your social life, not to mention your career.

Researchers used to think that those symptoms of depression wouldn’t go away until the noise did. But a new study suggests that tackling the depression first may give life back to sufferers of severe tinnitus. And in doing so, it may also make the ringing less loud.

Researchers gave the antidepressant drug nortriptyline to 49 patients suffering the dynamic duo of severe tinnitus and depression. After 12 weeks on the drug, the disabilities scientists thought were permanent began to lift significantly more than they did in the 43 people who received a dummy pill.

“On the drug, people were able to sleep, they were able to concentrate, they were able to do their jobs and enjoy their social activities more,” says Mark Sul-livan, M.D., Ph.D.,study author and assis-tant professor of psychiatry at the Univer-sity of Washington Medical School. The antidepressant group also reported greater decreases in the loudness of their tinnitus than the placebo group did (Archives of Internal Medicine, October 11, 1993).

“People used to assume that the disabilities were coming from the illness and that they would never go away,” says Dr. Sullivan. “But this is one of the first studies to show that if you reduce the depression, the disabilities that are associated with it go down, too, even though the medical illness remains.”

While the ringing seemed to diminish slightly, researchers aren’t sure whether the drug may have actually muffled it somehow or whether the drug simply allowed people to live with the noise better. It is known that antidepressants can also act as antipain medications, and that power may be behind their benefits against the oppressive loudness of tinnitus, says Dr. Sullivan.

Less severe cases of tinnitus and ones not accompanied by depression may respond to therapies like biofeedback or devices that mask tinnitus noise. But for the most severe cases, says Dr. Sullivan, “an antidepressant drug may be something to offer people where previously there was nothing.”

This approach may have implications for diseases such as heart disease, arthritis and diabetes, where the disabling symptoms of depression are believed to be a sidekick that won’t go away until the disease does. “This was a chance to prove that’s not necessarily so,” says Dr. Sullivan.

ANTIDEPRESSANT INTERACTIONS

The latest generation of antidepressants, the selective serotonin reuptake inhibitors — fluoxetine (Prozac), paroxetine (Paxil), fluvoxamine (Luvox), sertraline (Zoloft), and nefazodone (Serzone) –seem to have fewer side effects than their predecessors. However, as laboratory studies indicate, many of these newer agents have the potential to do more than elevate mood; they may also affect the metabolism of other drugs. The SSRIs do so by acting on the cytochrome P450 system — a family of approximately 30 closely related enzymes. These enzymes play a vital role in breaking down certain drugs in the liver so that they can be used by and eliminated from the body.

The cytochrome P450 system isn’t completely understood, but researchers have discovered that most of us don’t make all of the enzymes in the system and that our ability to make the enzymes diminishes with age. For that reason, each of us responds to drugs somewhat differently, and we often need to use a trial-and-error approach to find the right medication.

Taking an SSRI can further alter our individual response to other drugs. Each of the SSRIs inhibits one or more of the cytochrome P450 enzymes. As a result, medications that are metabolized by these enzymes — be they antihistamines, analgesics, or other antidepressants — may be absorbed less rapidly and remain in circulation for longer periods in people who are taking SSRIs. In some cases, an SSRI may increase the effectiveness of a second drug, allowing lower doses to be used; in others, an SSRI may cause toxic levels of the other drug to accumulate. For that reason, if you are taking one of the SSRIs it is important to let your clinician know the other medications — prescription and over-the-counter — that you are taking.

The chart below lists the SSRIs and the medications with which they might interact.

POSSIBLE INTERACTIONS AMONG COMMON DRUGS

Prozac, Zoloft: Elavil, Anafranil, Norpramin, Tofranil, Pamelor, Ludiomil, Valium, Xanax, Versed, Halcion, quinidine, Hismanal, Seldane, Lopressor, Inderol, Procardia, Adalat, Clozaril, Haldol, Moban, Triavil, Risperdal, Mellaril, codeine, Percodan, Talwin, Iidocaine, Mevacor, tamoxifen, testosterone, dextromethorphan

Paxil: Elavil, Anafranil, Norpramin, Tofranil, Pamelor, Ludiomil, Lopressor, Haldol, Moban, Triavil, Risperdal, Mellaril, codeine, Percodan, Talwin, dextromethorphan

Luvox: Elavil, Tofranil, Pamelor, Norpramin, Lopressor, Inderol, Clozaril, Haldol, Moban, Triavil, Risperdal, Mellaril, codeine, Percodan, methadone, Talwin, dextromethorphan, tacrine, caffeine, theophylline

Serzone: Norpramin, Xanax, Valium, Versed, Halcion, quinidine, Hismanal, Seldane, Cardizem, Procardia, Adalat, Iidocaine, hydrocortisone, dexamethasone

Although not a medically serious problem, enuresis (night time bedwetting) in older children is very frustrating for everyone. It adversely affects the child’s self-esteem and may lead to family discord. Drugs are often used to try to stop it.

Two drugs are commonly used to treat enuresis: imipramine (Tofranil), a drug commonly used to treat depression: and desmopressin (DDAVP), a drug similar to a natural hormone (anti-diuretic hormone) that is taken as a nasal spray.

Doctors usually prescribe one or the other drug. A recent report looked at the success of treating children with both drugs at the same time. The enuresis of all 15 children in the study wasn’t controlled with either drug when taken alone, so the doctors gave the children both drugs.

The combined therapy worked well. Eleven of the 15 children attained complete dryness, and another three children had a 50% reduction in wet nights. Side effects, always a concern, were very minimal. Two children complained of fatigue (not uncommon with antidepressants) and another two had headaches. None of the side effects were severe enough for the children to stop the medicines.