|March 1998||Bruce H. Woolley, Pharm.D., Editor||Vol. 5, No.3|
IRON AND MEGA-DOSES OF VITAMIN C, ADOUBLE-EDGED SWORD?
In an article in Nutrition Today (Feb 1993), Victor Herbert Herbert, M.D. J.D.wrote: "The representation of vitamin C and -carotene as antioxidants is both truthand misperception, because both are in fact redox agents and pro-oxidant rather andantioxidant in appropriate circumstances...Lipid peroxidation studies show that atphysiologic levels ascorbate acts primarily as an antioxidant; however, as pharmacologiclevels are reached, its pro-oxidant effects predominate."
Dr. Herbert continued: "In the presence of iron, vitamin C is one of the mostpotent pro-oxidants known. It converts iron stores to catalytic iron, one of the mostoxidant of substances...About 10% of Caucasians and about 8% of African-Americans are bornwith a gene for increased iron absorption and about 1 in 250 have two genes for enhancediron absorption...Vitamin C supplements, which enhance both iron absorption and therelease of iron from body deposits, can act as a second gene for iron overload in thoseborn with 1 gene for enhanced iron absorption. By producing iron overload in these peopleand releasing catalytic iron from their body stores, vitamin C supplements can main andkill."
Margit Krikker of the Hemochromatosis Research Foundation wrote: "Vitamin C, whichaccelerates iron absorption, has also been responsible for cardiac deaths in at leastthree athletes, unaware of their predisposition to iron-loading or of the hazards of dailymegadoses for years." (FDA Dockets Management Branch, Docket No. 90N-194)
Olson and Hodges list potential harms from excess vitamin C (Am J Clin Nutr1987; 45:693-703): "Occasional large intakes of vitamin C may cause stomach cramps,nausea and diarrhea in some fasting persons but have no long-term adverse effects. Whendaily large doses are ingested routinely for months or years, however, a number of adverseeffects may occur, including uricosuria, reduced bactericidal activity of leukocytes,secondary hyperoxalemia (producing metastatic oxalosis) in hemodialysis patients, enhancedmobilization of bone calcium, impaired blood coagulation time, lowered plasma B12levels, interruption of pregnancy, reduced insulin production and interference withanticoagulant therapy."
BREAST IMPLANTS AND CONNECTIVE TISSUEDISORDERS
According to the February 9 issue of the British Medical Journal, women whohave received breast implants have no increased risk of developing connective tissuedisorders. The study included 7,442 Swedish women who had received breast implants from1964 to 1993 and 3,353 women who had breast reduction surgery during the same period.Twenty-nine of the women who had breast implants were hospitalized with connective tissuedisorders. That compared to 25.5 cases that would be expected in a group matched in thegeneral population. Fourteen connective tissue disorders were reported in those receivingbreast reduction; that compared to the 10.5 expected cases.
NEW FDA LABELING REGULATIONS
The FDA Cardiovascular and Renal Advisory Committee has proposed new labeling for IVpositive inotropic agents for congestive heart failure. It is proposed to state:"Experience with intravenous <drug name>, long-term use was associated with anincreased risk of hospitalization and death, and patients with NYHA class IV symptomsappeared to be at particular risk. Similar trials of other drugs with similar mechanismsof action have given similar results. There is no evidence that long-term intravenousregimens of <drug name> do not carry a similar risk."
SENATE CONFIRMS SATCHER AS SURGEON GENERAL
With a vote of 63-35, the United States Senate confirmed David Satcher, M.D. (formerdirector of the Centers for Disease Control) for the position of Surgeon General. He wasalso confirmed for the position of assistant secretary for health. He was nominated forthe post last September by President Clinton to fill the vacancy created by theresignation of Joycelyn Elders in 1994. Prior to his position at CDC, he served aspresident of Meharry Medical College in Nashville for 10 years.
FIRST COMT INHIBITOR APPROVED
The FDA has granted approval for tolcapone (Tasmar ®/Roche) foruse in combination therapy in treating Parkinson's disease. It will be the first agentnoted as being a catechol-O-methyl transferase (COMT) inhibitor. COMT is a mitochondrialenzyme that, in addition to monoamine oxidase, inactivates catecholamineneurotransmitters. A Roche release stated that tolcapone significantly improves apatient's ability to perform basic activities when taken in combination withlovodopa/carbidopa (the current standard of therapy). The most common adverse effect isdiarrhea. The company also recommends that liver enzymes be monitored for the first sixmonths of therapy.
CHANGES IN ASTEMIZOLE INTERACTION LABELING
Astemizole (Hismanal ®/Janssen) labeling will be changed toreflect potential drug interactions that may induce irregular heart rhythms or severalallergic reactions. The new labeling also will emphasize that patients with liverdisorders should refrain from taking the drug. The new interactions include: SSRIs(fluoxetine, paroxetine, sertraline), protease inhibitors (indinavir, ritonavir,nelfinavir), and grapefruit juice.
BROMFENAC ASSOCIATED WITH LIVER DAMAGE
The FDA has advised physicians that bromfenac (Duract ®/AmericanHome Products) has been associated with liver damage in patients taking the drug for morethan 10 days. According to the agency, "The FDA is advising that doctors whodetermine that use of Duract beyond 10 days is warranted must closely monitor patients forliver problems." FDA is also requesting that the company add a warning to thelabeling as an additional warning to physicians.
GLAXO TO MARKET SECOND 5-HT1RECEPTOR AGONIST
Naratriptan hydrochloride (Amerge ®/Glaxo Wellcome) has beengranted marketing approval for the acute treatment of migraine. Glaxo already is marketinganother agent in the same category sumatriptan (Imitrex ®). The newproduct is contraindicated in patients with a history, symptoms, or signs of ischemiccardiac, cerebrovascular or peripheral vascular syndromes. The most common adversereaction is nausea.
SIBUTRAMINE NOW AVAILABLE IN PHARMACIES
Sibutramine (Meridia ®/Knoll), which was approved by theFDA in November is now available in pharmacies. The agent is a neurotransmitter reuptakeinhibitor that enhances the body's normal function and supresses appetite. Based ondosage, in blinded clinical trials involving 6,000 patients, those taking sibutramineexhibited a 5 to 10 percent weight reduction from baseline. Mild and transient adverseeffects include headache, dry mouth, constipation and insomnia.
NEW TRIGLYCERIDE LOWERING AGENT APPROVED
Micronized fenobrate (Tricor ®/Abbott) has been approvedas a lipid-lowering drug indicated as an adjunct to diet for the treatment of adults withvery high serum triglyceride levels who are not appropriately controlled by diet alone andare at risk for pancreatitis. Abbott will be marketing the medication for themanufacturer, Dijon, France-based Groupe Fournier. It is contraindicated in patients withgall bladder, liver or kidney disease.
LEUKOTRIENE BLOCKER FOR ASTHMA
Marketing clearance has been granted for a once daily treatment for the prevention andchronic treatment of asthma. Montelukast sodium (Singulair ®/Merck)is part of a new class of asthma drugs called leukotriene blockers, The most frequentlyreported adverse effects during the clinical trials included headache, influenza andabdominal pain.
LOWER ALENDRONATE DOSAGES
Hosking D. et al. recently reported a study that shows women can have increased bonemineral density and reduced adverse effects on doses of 2.5 or 5 mg. (N Engl J Med1998; 338:485-92) The recommended dose is 10 mg. Reported bone mineral gains weresignificant in the hips, spine and total body on 5 mg and were almost as significant asthose patients on estrogen therapy.
CHANGES IN ATORVASTATIN LABELING
Atorvastatin (Lipitor ®/Parke Davis) will have an additionaladverse warning in its labeling. Angioneurotic edema will be added. Additional additionsto the side effect profile ( < 2%) will include: nausea, bronchitis, rhinitis, chestpain, insomnia, arthritis urinary tract infection and peripheral edema.
NEW CONTRAINDICATION FOR METFORMIN
The package insert for metformin (Glucophage ®/Bristol-MyersSquibb) will have an additional boxed warning that will state: "Patients withcongestive heart failure (CHF) requiring pharmacologic management, in particular thosewith unstable or acute CHF who are at risk of hypoperfusion and hypoxemia, are atincreased risk of lactic acidosis."
REVIEW OF ECHINACEA CONTROLLEDCLINICAL TRIALS
Echinacea angustifolia or purpurea has become very popular lately forstrengthening the immune system and for treatment of colds and influenza. Advocates claimefficacy when the herb is ingested early in the disease state. In order to evaluate theseclaims, Melchart, et.al. (Phytomedicine 1994; 1:245-54) conducted a systematicreview of twenty-six controlled clinical trials using either pure extracts or mixtures ofechinacea. Eighteen of the trials were randomized and eleven were double-blinded. Nineteenof the trials evaluated whether the preparation prevented or cured respiratory infections;three evaluated whether the preparation had any effect on the indicators of immunefunction; and four evaluated whether echinacea reduced adverse effects of chemotherapy.
There were a total of 34 groups in the trials and the authors of the trials claimedpositive results in 30 of the trials. Melchart et.al. found that most of the trials hadpoor methodology and the data were not incomplete enough to form clear relationships. Thiswas particularly true as to dose and administration relationships. However, there wasevidence that echinacea had a positive effect on the immune system.
The information and opinions expressed in the Therapeutics Letter do not necessarilyreflect the official policy of the sponsoring organizations.