THERAPEUTICS REPORT
| July 1999 | Bruce H. Woolley, Pharm.D., Editor |
Vol. 6, No.7 |
Kenneth J. Hunt, Associate Editor |
MORE EFFECTIVE DRUG TREATMENT FOR ULCERATIVE COLITIS
Researchers have designed a drug that has the same activity and mechanism of action as sulfasalazine without the adverse effects. Balsalazide disodium (Colazide®/ Biorex) is a prodrug that is designed to release 5-aminosalicylic acid (5-ASA) into the colonic lumen following cleavage of the parent molecule in the body. The carrier molecule in balsalazide (4-aminobenzoyl-b-alanine) was selected because it is an inert compound and it allows for the delivery of a high concentration of 5-ASA to the colon mucosa without the severe intolerance associated with sulphasalazine.
Balsalazide is a "designer drug" in the true sense of the phrase, customized to have specific characteristics to maximize tolerance. Clinical trials using balsalazide are limited as it is a relatively new compound. In studies involving remission of UC and the treatment of acute relapse, the evidence indicates that balsalazide is not only exceptionally well tolerated but that it has greater efficacy than the two other common UC medications.
Echinacea has a long history of use as a healing herb by Native Americans. for snakebites and other skin wounds. Echinacea became very popular in the medical community of the United States and was officially recognized by the National Formulary from 1916 to 1950 when the proliferation of antibiotics brought the use of Echinacea to a rapid halt.
In last decade several European studies have seemed to demonstrate that Echinacea may lessen the severity of colds and flu, and speed recovery. A well designed study published in February in the American Journal of Medicine(2) found that Echinacea purpurea herba and radix were more effective than a placebo at reducing the twelve most common symptoms of the common cold. The researchers concluded that Echinacea extract represents a low-risk and effective alternative to the standard symptomatic medicines in the acute treatment of common cold.
Many more studies will have to be conducted before the herb is widely accepted by the medical community, but it certainly has gained popularity. The German Commission E recognized Echinacea purpurea herba in 1989 as an approved herb, although two of the most widely studied species, E. purpurea radix and E. angustafolia have yet to be approved. It is currently the most popular herb in the United States, generating more than $300 million in sales annually. The interest in the herb in the United States is due to the herb's positive effect on the immune system. Echinacoside and echinacein are two compounds in the plant that have demonstrated activity. Together, they appear to have varying antibiotic qualities and the ability to an increase the number of circulating white blood cells, enhance neutrophil phagocytosis, stimulate cytokine production, and trigger the alternate complement pathway.(3)
(2) Grimm W, Muller HH A randomized controlled trial of the effect of fluid extract of Echinacea purpurea on the incidence and severity of colds and respiratory infections. Am J Med 1999 Feb;106(2):138-43
(3).Parnham MJ: Benefit-Risk Assessment of the Squeezed Sap of the Purple Coneflower (Echinacea purpurea) for Long-term Oral Immunostimulation, Phytomed, 1996; 3:95-102
ROFECOXIB - ANOTHER COX-2 INHIBITOR GETS FDA APPROVAL
Rofecoxib (Vioxx®/Merck) the second COX-2 inhibitor, has been approved by the FDA for.relief of symptoms of osteoarthritis, acute pain in adults and menstrual pain, but not for treatment of rheumatoid arthritis. Celecoxib (Celebrex®/Searle, Pfizer) has previously been approved for both osteoarthritis and rheumatoid arthritis, but not for acute pain. Vioxx® is primarily indicated for patients at higher risk for GI complications. Examples of high risk patients, according to Merck spokespersons, are patients over age 60 who have cardiovascular disease, patients who have had ulcers in the past, who are on blood thinning medications such as warfarin, or have a history of heavy smoking, alcohol use, steroid use.
Merck conducted clinical trials on 3,900 osteoarthritis patients-using 12.5 mg and 25 mg of rofecoxib once a day and found the drug comparable to ibuprofen 800 mg three times a day and diclofenac 50 mg three times a day. In clinical studies, once-daily treatment with rofecoxib was associated with a significant reduction in early-morning stiffness. Endoscopic studies showed that patients treated with rofecoxib (25 mg or 50 mg daily) experienced significantly fewer gastrointestinal ulcers than those treated with ibuprofen 2,400 mg daily. The most common side effects reported in trials of rofecoxib were upper respiratory tract infection, diarrhea and nausea.
Thanks to: Medical Tribune 40(11):1, 15, 1999.
NEW FINDINGS IN BATTLE AGAINST OSTEPOROSIS
During the annual meeting of the Endocrine society in June, several researchers presented findings in the area of osteoporosis treatment. Most of them included status updates on ongoing trials evaluating medications and hormone replacement therapies. Significant presentations included testosterone replacement therapy in men, a study comparing nasal alendronate to nasal calcitonin, and the results of therapy with parathyroid hormone.
Researchers at the University of Pennsylvania reported that testosterone replacement therapy improves bone mineral density in older men who have low serum testosterone concentrations. The double-blinded, randomized clinical trial found that men with the lowest pretreatment testosterone levels (below 200 ng/dl) achieved significant increases in lumbar bone density when they underwent testosterone replacement therapy. In the treatment group there was no significant increase in the incidence of prostate cancer or other adverse effects relative to the control group.
The data are published in the June issue of The Journal of Clinical Endocrinology and Metabolism (1).
A paper was presented demonstrating that alendronate increases bone density better than intranasal calcitonin in osteoporotic women while being just as well tolerated. The ongoing trial, which was presented by R. W. Downs, of the Medical College of Virginia, is the first reported head-to-head comparison of the two drugs. It involved 299 women with osteoporosis, each taking a daily dose of 10 mg alendronate, 200 IU intranasal calcitonin or an alendronate placebo. The patients also took 400 IU of vitamin D and 1,000 mg of elemental calcium each day. Follow-up evaluation showed that bone mineral density at the lumbar spine increased by about 5% in the alendronate group and only about 0.5% in the calcitonin group, remaining flat in the placebo group. Most of the adverse effects in the alondronate group were GI related.
Another report from Dr. Bruce Roe of the University of California at San Francisco showed that the addition of parathyroid hormone to estrogen replacement restores bone mass to normal levels in nearly two-thirds of postmenopausal women with osteoporosis. He reported data on 60 women with osteoporosis who had been using estrogen replacement therapy for at least 1 year prior to the initiation of the NIH-funded study. The group that received PTH exhibited a 30% gain in bone density at the spine and an 11% gain at the hip, increases which compare favorably to alendronate and other therapies.
The current annual cost of osteoporosis is about $14 billion, and is estimated to increase to as much as $240 billion by the year 2040. This is roughly equivalent to what is spent on defense in the United States annually.
Snyder PJ, et al. J Clin Endocrinol 1999;84:1966-1972.
WARNING TO DISCONTINUE HERBS BEFORE SURGERY
The American Society of Anesthesiologists has issued a statement advising the discontinuation of herbal products at least two weeks before surgery. Substantial changes in heart rate or blood pressure in some patients taking herbals has been reported. Herbals that have been implicated include: St. John’s wort, ginkgo biloba, and ginseng. The society advises that all patients taking any herbals to bring these products in their original containers to the hospital for evaluation of the anesthesiologist before any procedures.
FDA ACTIONS
The FDA has approved alendronate sodium (Fosamax®/Merck) for the new indication of treating corticosteroid-induced osteoporosis (e.g., rheumatoid arthritis and chronic bowel disease).. It is currently marketed in the United States for the treatment and prevention of osteoporosis in postmenopausal women. According to Merck, patients undergoing steroid therapy can losebetween 5% and 15% of their bone mass during the first year of therapy, and up to half of them can suffer an osteoporosis-related fracture.
In cooperation with the FDA, the manufacturer has agreed to issue new labeling for troglitazone (Rezulin®/Parke Davis) which has been used as monotherapy in the treatment of type 2 diabetes mellitus. The new labeling limits use to patients who are not adequately controlled by other therapy. In addition, patients need liver function testing prior to initiation of therapy to be followed by monthly testing during the first year of therapy. After the first year of therapy, patients are to be checked on a quarterly basis. A new indication for use in combination with sulfonylureas and metformin will also be added.
The FDA and the manufacturer have agreed to limit the use of trovafloxacin-alatrofloxacin (Trovan®/Pfizer) to patients who receive initial treatment in a hospital or long-term nursing facility. Use of trovafloxacin should be limited to patients who meet all of the following: $1 of several specified infecitons (e.g., nosocomial pneumonia); complicated intro-abdominal infections that in the judgement of the clinician are serious and life- or limb-threatening; onset of therapy in in-patient health care facilities; and for patients where the clinician believes that, even given the new safety information, the benefit of the product outweighs the potential risks.
Since aspartame was approved in 1981, the FDA has received > 7000 consumer complaints about the product but in a study recently published in the New England Journal of Medicine, a placebo triggered more headaches (which is the most commonly reported side effect) than aspartame. Even with this report, the FDA has stated that it will continue to monitor and follow up on reported adverse reactions.
The manufacturer, in cooperation with the FDA, has issued a "Dear Health Professional" letter warning about concurrent use of celecoxib (Celebrex®/Searle, Pfizer) and warfarin. The labeling now reads: "Anticoagulant activity should be monitored, particularly in the first few days, after initiating or changing Celebrex therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding complications. The effect of celecoxib on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of 2 to 5 mg or warfarin. In these subjects, celecoxib did not alter the anticoagulant effect of warfarin as determined by prothrombin time. However, in post-marketing experience, bleeding events have been reported, predominantly in the elderly, in association with increases in prothrombin time in patients receiving Celebrex concurrently with warfarin."
The information and opinions expressed in the Therapeutics Report do not necessarily reflect the official policy of the sponsoring organizations.