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August 1999

Bruce H. Woolley, Pharm.D., Editor

Vol. 6, No.8

Kenneth J. Hunt, Associate Editor


The latter half of this decade has observed the advent of a number of new and improved atypical antipsychotic agents (e.g., olanzapine (Zyprexa®/ Lilly). This agent which was launched in the U.K. in 1996, primarily affects the dopaminergic and the serotonergic systems by blocking specific receptors. It has also demonstrated efficacy in the muscarinic and in the adrenergic systems. The therapeutic advantage of these atypical antipsychotics been attributed to the serotonergic effects.

According to studies, the primary uses for olanzapine are adult schizophrenia and other related psychoses. Adolescent schizophrenia and related illnesses such as bipolar affective disorder, mania, affective psychoses, and symptom control in dementia are secondary indications. Olanzapine’s efficacy is reported to be similar to resperidone and haloperidol, two older antipsychotic drugs. Yet, this drug has been clinically suggested as superior to the older antipsychotic agents in terms of efficacy and side-effect profiles.(1) Olanzapine has also demonstrated superior to these drugs according to the Brief Psychiatric Rating Scale (BPRS) with fewer extra-pyramidal side effects.(2)

Evidence for the use of olanzapine in treatment-resistant schizophrenia and for the use of a conventional antipsychotic-induced tardive dyskinesia, suggests some indication for switching therapy from existing antipsychotics, especially when problems do occur. The side effects reported with the drug include dizziness, drowsiness, constipation, and a dry mouth. About 40% of olanzapine patients gain weight – especially if they were underweight prior to treatment. Any drug, including alcohol, which may cause drowsiness or dizziness, will increase these side effects in users of olanzapine.

With good clinical rationale, olanzapine has been proposed as a first-line treatment for schizophrenic and psychotic disorders. The drug has few extra-pyramidal side effects and has a potential to reduce positive and negative symptoms over most conventional antipsychotics as well as some other atypical antipsychotics. The drug is tolerated well in humans. Reported evidence suggests that olanzapine is relatively less likely to produce sexual dysfunctions. The general efficacy and side-effect profile suggests that olanzapine is effective in the initial management of psychotic disorders.

1. Current Medical Research and Opinion 15(2):79-85, 1999. © 1999 LibraPharm Limited
2. Beasley, C. M., Tollefson, G., Tran, P., et al. (1996). Olanzapine versus placebo and haloperidol: acute phase results of the North American double-blind olanzapine trial. Neuropsychopharmacol., 14(2), 111-123.


Nonsteroidal anti-inflammatory agents are a major factor in the pathogenesis of gastric and duodenal ulcers, upper gastrointestinal bleeding, and death. According to estimations, the COX-2 inhibitor celecoxib (Celebrex®/ Searle & Pfizer) is associated with a substantially lower rate of untoward events such as the frequency of ulcer, hemorrhage, and other complications. In addition, the rates of dyspepsia in patients were found to be diminished after taking the specific COX-2 inhibitors.

The COX-2 inhibitors, celecoxib and recently approved rofecoxib (Vioxx®/Merck), spare COX-1 the major cyclo-oxygenase isoform involved with prostaglandin production in the GI tract and normal platelet function. Health professionals now hope that the inhibitors will result in a lower incidence of gastroduodenal ulcerations and in a lower incidence of significant complications such as perforations and bleeding.

A possible future combination of NSAIDs in combination with Nitric Oxide (NO) is being investigated in animal studies. Nitric Oxide increases gastric mucosal blood flow, bicarbonate, and mucus secretion. Thus, the beneficial effects to the upper gastrointestinal tract are similar to those seen with prostaglandins.

Two prominent physicians have developed agents, which combined NO with NSAIDs. These agents may have obviated the detrimental effects of the NSAIDs, and may have created similar benefits to those demonstrated by COX-2-type agents. According to the developers, a substantial amount of evidence in experimental animals indicates that the NO-NSAIDs do not produce the degree of gastrointestinal injury and gastrointestinal inflammation observed with conventional NSAIDs.

The COX-2 NSAIDs offer relief from the pain and from the suffering of arthritis while significantly reducing the risk of gastrointestinal injury associated with older NSAIDS. Although NO-NSAIDs is an investigational compound, it appears to be as effective as the COX-2 NSAIDs in animal studies. Human studies on these compounds are anxiously awaited.

Thanks to Medline summary of Wallace J, Bjorkman D: NO-NSAIDs versus COX-2 specific agents, in, Bjorkman D (chair): Presented at Digestive Disease Week, Orlando, Fla., 1999.


This month’s feature in our ongoing review of herbal remedies has been a compound used since early Greek medicine. The name "Feverfew," from the Latin word for "fever reducer," was given to the plant Tanacetum parthenium by the Greek physician Dioscorides, who prescribed the herb for "all hot inflammations." In the modern day, feverfew is developing a reputation as an alternative remedy in the treatment of migraine headaches. Medical interest in feverfew was renewed in Great Britain after a story was published in Prevention magazine in 1978. This story related the anecdotal success that a certain woman had in using feverfew for her migraines. Since then, medical studies have been conducted and research is underway on various components of feverfew.

According to laboratory studies, parthenolide, a lactone considered the active compound in feverfew, causes vasodilation of blood vessels, and reduces inflammation at the sub-cellular level by inhibiting the over aggregating of platelets in the bloodstream. Other constituents of the herb are reported to inhibit phagocytosis, platelet aggregation, and secretion of inflammatory mediators such as arachidonic acid and serotonin.(1) Feverfew is thought to down regulate the brain’s response to biogenic amines which appears to be consistent with feverfew’s ability to prevent headaches but not cure them, and is consistent with the months of use needed for clinical efficacy.

Proper concentration of parthenolide in feverfew extracts is critical for effective prevention of migraines. A critical consideration in commercial Feverfew products has been the consistency in parthenolide content. "Standardized extracts", developed in the last few years are suggested to insure a minimum parthenolide content of at least 0.2 percent. Patients purchasing feverfew products should purchase only those extracts with a guaranteed parthenolide content of at least 0.2%.

Since some promising results exist, feverfew is considered inexpensive, safe, and helpful in some major studies. Further high-quality research is required, but funding may be difficult, since herbs are not patentable in the United States. Herbal manufacturers are not required to sink large investments into researching the herbs they sell.

Heptinstall S, White A, Willimson L, Mitchell J. Extracts of Feverfew inhibit granule secretion in blood platelets and polymorphonuclear leukocytes. Lancet. 1985;1:1071-1074.


In June of 1999 the FDA issued a public health advisory to physicians concerning the risks of liver toxicity associated with the use of the oral antibiotic trovafloxacin and alatrofloxacin (Trovan®/Pfizer)). Trovafloxacin, a fluoroquinoline antibiotic has been used to treat many different types of infections. It was approved for marketing in December of 1997, and became available on the market in February of 1998. Based on new safety data related to serious liver injury, the FDA is advising physicians that trovafloxacin should be reserved for use only in patients who meet ALL of the following specific criteria:

Have at least one of the following infections that is judged by the treating physician to be serious and life- or limb-threatening:

  1. nosocomial pneumonia
  2. community acquired pneumonia
  3. complicated intra-abdominal infections (including post-surgical infections)
  4. gynecologic and pelvic infections
  5. complicated skin and skin structure infections, including diabetic foot infections
  6. receive their initial therapy in an in-patient health care facility (i.e., hospital or long- term nursing care facility)
  7. the treating physician believes that, even given the new safety information, the benefit of the product for the patient outweighs the potential risk.

From FDA Health Advisory: Lumpkin, Murray M. Deputy Center Director (Review Management)
Center for Drug Evaluation and Research, June 9, 1999


Much to the chagrin of the American Medical Association, a 253-page package of "patients’ rights" legislation was passed in mid-July by the U.S. Senate. According to the AMA, the bill had not even been seen or reviewed by some of those who voted on it, which, they said, contained last-minute special protections for the insurance industry.

The AMA president, Thomas Reardon, held a press conference and expressed disappointment in the Senate, accusing them of bowing to the insurance industry as well as denying the American public the fundamental right to health care when they need it. "This is really an HMO Bill of Rights that rewards the insurance industry and betrays patients," said D. Ted Lewers, MD, chair of the AMA. "They were in such a hurry to take care of the HMOs, they completely forgot about our patients."

The President vowed to veto this bill if it passes through the House of Representatives. Even so, the state of American health care has taken the center stage in American politics. This bill will undoubtedly be a key issue in the upcoming presidential campaign. In the meantime, the AMA will continue to urge Congress to develop a bill that will protect patients and physicians. Hopefully, allowing them to make decisions based on the best interests of the patient rather than basing treatment decisions solely on cost.

The AMA is insisting that any package of patients’ rights must include the right to an independent and fair external appeal of health plan decisions, the right to hold health plans accountable when their decisions harm patients, and the right to have physicians decide what treatment is medically necessary. They also want a guarantee that these rights will apply to all Americans.

Thanks to AMA News Release: In the Light of Day: "HMO Protection Act" Looks Even Worse: AMA July 19, 1999


A recent study suggests that aggressive cholesterol-lowering therapy with atorvastatin (Lipitor®/Parke-Davis & Pfizer) is at least as effective as angioplasty in reducing epidsodes of low blood flow to the heart of low-risk patients. In addition, the authors reported that patients treated with atorvastatin had fewer hospitalization over 18 months than those who received angioplasty.

Pitt D. et al: N Engl J Med 1999; 341: 2

The information and opinions expressed in the Therapeutics Letter do not necessarily reflect the official policy of the sponsoring organizations.