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News 18/08/2544

Iron supplementation may provide relief for patients suffering from dry cough induced by an ACE inhibitor.

Moving ahead with plans to remove phenylpropanolamine (PPA) from the US market, the US Food and Drug Administration on Tuesday offered several manufacturers an opportunity for a hearing prior to the withdrawal of their products.

Iron Supplementation May Help Patients With ACE Inhibitor-Induced Cough

August 17, 2001
By Hope Vanderberg

New York - Iron supplementation may provide relief for patients suffering from angiotensin-converting enzyme (ACE) inhibitor-induced dry cough, according to findings published in the August issue of Hypertension.

The ACE inhibitor is one of the most widely used drugs in cardiovascular medicine. Despite its track record in improving survival rates and reducing complications in patients with cardiovascular conditions such as hypertension and heart failure, however, various adverse effects limit its use. Dry cough is the most frequent adverse effect, reportedly occurring in 5%-39% of patients. In most cases, patients with this troublesome complication discontinue the drug. But Korean investigators may have hit on a simple remedy.

In a randomized, double-blind, placebo-controlled trial, the researchers studied 19 patients who had developed persistent dry cough while receiving ACE inhibitors for various heart conditions. The 6 men and 13 women, whose average age was 60 years, first completed a diary during a 2-week observation period, while receiving ACE inhibitors only.
Participants scored their cough severity twice a day using a scale that ranged from no cough (0) to severe cough that persisted and interfered with daily activities and sleep (4). At the end of 2 weeks, participants' blood iron levels were sampled using markers including hemoglobin, hematocrit, serum iron concentration, ferritin levels, and total iron binding capacity. Participants were then given either a daily morning tablet of 256 mg ferrous sulfate or placebo for 4 weeks, during which time monitoring of cough severity was continued. At the end of 4 weeks, iron levels in the blood were measured again.

"Supplementation of iron clearly showed a beneficial effect in most of these subjects, and this effect could not be found in the placebo group," says lead author Kyung Pyo Hong, MD, of the Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Eight of 10 patients who received iron showed improvement, and 3 of these patients had a nearly complete end to their coughing at the end of 4 weeks. The average daily cough score in the iron group was 3.07 (severe) at the end of the first 2 weeks, and 1.69 (mild) after 4 weeks of iron supplementation. There was no significant change in cough scores of the placebo group.

Average ferritin levels increased in the iron group after 2 weeks of iron treatment, but not significantly. Ferritin levels remained about the same in the placebo group throughout the study. None of the other markers of iron levels in the blood changed significantly in either group.

The mechanism of ACE inhibitor-induced dry cough is unclear, but it is thought to be associated with the increase in nitric oxide (NO) generation caused by ACE inhibitors. NO is known to have inflammatory effects on bronchial epithelial cells. Dr. Hong and colleagues embarked on their study based on reports that iron supplementation decreases NO generation or diminishes NO-related cell damage.

Dr. Hong says that further investigation is warranted to verify the findings, which are limited by the relatively small sample size and the inability to perform a crossover study to confirm the effects of iron supplementation. Long-term effects of iron supplementation with ACE inhibitors must also be studied, he says. However, the dramatic and rapid beneficial effects demonstrated in this study are promising. "Iron may be a key element in the control of dry cough," Dr. Hong says.

Hypertension. 2001;38(2):166-170

FDA Moves Ahead With Plans to Ban PPA

WASHINGTON (Reuters Health) Aug 14 - Moving ahead with plans to remove phenylpropanolamine (PPA) from the US market, the US Food and Drug Administration on Tuesday offered several manufacturers an opportunity for a hearing prior to the withdrawal of their products.

In November, the FDA declared its intentions to ban PPA after two studies and a committee of expert advisors to the agency concluded that PPA, found in a number of over-the-counter diet aids and cold medicines, might cause strokes in young, healthy people.

Retailers nationwide already have voluntarily pulled several brands of those products, and a number of the larger manufacturers of cold medications have agreed to substitute ingredients. But there is no alternative to the over-the-counter diet aids, and as a result, not all manufacturers have joined the bandwagon. Some argue that the studies were flawed and that the risk of PPA does not outweigh the benefits of the diet aids, considering the prevalence of obesity in the US population.

The FDA said that it believes PPA was responsible for about 200 to 500 strokes a year, based on reported events in its proprietary database. "The burden of proof now falls upon the industry to show us that it's safe," said Dr. Lois La Gernade, the lead FDA reviewer. "At a minimum, consumers should be adequately informed."

Still, the FDA agreed that the risk is minimal. And in issuing its advisory in November, the agency made sure to note that PPA has been used for about 50 years and that the FDA action was taken simply to ensure that Americans were not taking an unnecessary risk.

Some experts have speculated that in going after PPA, the FDA actually was preparing to go after ephedra, which the body converts into PPA. Also known as ma haung, ephedra is a common ingredient in dietary supplements that claim to help people lose weight and increase their energy levels.

Last year, FDA proposed banning the combination of ephedra with caffeine. Since then, the FDA has hosted a number of meetings regarding the issue, but it has taken no direct action to push or implement its proposed ban.

In total, the FDA's current actions involving PPA include the withdrawal of 16 brand-name drugs and eight generic drugs. The agency said that the sponsors of these drugs would now have 60 days to request a hearing or face forced withdrawal of their products. The sponsors include Novartis, Teva and GlaxoSmithKline, all of which previously announced removal of PPA from their over-the-counter cold products.

A full copy of the FDA notice can be obtained on the agency Web site at It is also available in the August 14th issue of the Federal Register.

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