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Paul M. Arguin, M.D.
Centers for Disease Control and Prevention
Atlanta, GA 30333
Peter J. Weina, M.D., Ph.D.
Walter Reed Army Institute of Research
Silver Spring, MD 20910
Cindy P. Dougherty, Pharm.D.
Centers for Disease Control and Prevention
Atlanta, GA 30333
References
A colleague and I have argued that changes in the pharmacokinetics of artemisinins due to a prolonged absorption after repeated oil-based intramuscular injections cause the observed toxic effects in animals.2 Oral and intravenous injections are the most common routes of administration in humans, and with the short half-life of these drugs, the risk of toxic effects seems minimal. Even the intramuscular injections may not be of concern because of the limited number of injections.
When investigating the efficacy and toxicity of drugs, it is imperative to consider their pharmacokinetic properties.
Toufigh Gordi, Ph.D.
University at Buffalo
Buffalo, NY 14260
tgordi{at}buffalo.edu
References
From 1992 to 1998, a total of 5185 cases of malaria were diagnosed in the United States. In 35% of the patients, the symptoms started more than 2 months after a return from travel.1 Malaria typically occurs in travelers because of a lack of pretravel health information and poor compliance with a recommended antimalarial regimen. The diagnosis of late-onset illness in travelers who have used such a regimen is more challenging for physicians and may be more difficult for patients to associate with previous travel. Physicians should consider malaria in patients whose symptoms started more than 2 months after a return from international travel.
Marc S. Itskowitz, M.D.
Allegheny General Hospital
Pittsburgh, PA 15212
mitskowi{at}wpahs.org
References
In India, counterfeit drugs are estimated to account for 13 to 30% of the pharmaceutical market; this has led to a recent discussion of the death penalty for counterfeiters.2 Fake artesunate contributes to the morbidity and mortality associated with malaria and gives rise to misperceptions of artesunate "resistance."3 International organizations, including the World Health Organization and member countries, have been unable to counter this lethal trade.2,4
Ajit Singh Kashyap, M.D.
Command Hospital (Central Command)
Lucknow Cantonment 226002, India
kashyapajits{at}gmail.com
Kuldip Parkash Anand, M.D.
Command Hospital (Eastern Command)
Kolkata 700027, India
Surekha Kashyap, M.D.
Command Hospital (Central Command)
Lucknow Cantonment 226002, India
References
The neurotoxicity of artemisinins, which has been shown in laboratory animals that receive dosages much higher than those used to treat malaria, has been extensively studied.1 I agree with Gordi's impression that neurotoxicity is unlikely to be of relevance with the clinical use of artemisinins, and in particular artesunate. Indeed, the test of time has shown artemisinins to be remarkably safe. However, formal surveillance for artemisinin toxicity has to date been somewhat limited, and it is important to maintain vigilance regarding the possibility of rare but potentially life-threatening toxic effects from this very important class of antimalarial agents.
Itskowitz notes that presentation with malaria may be delayed until well after the time of exposure. This is a valuable point, and malaria should be considered to be a cause of fever, even many months after a return from travel. However, patients with malaria caused by Plasmodium falciparum, which is responsible for nearly all cases of severe malaria, are much less likely to present late than are patients with malaria caused by other species. CDC statistics show that among the 668 patients with a diagnosis of malaria in the United States in 2005 for whom the timing of presentation was known, 94% of those with falciparum malaria became ill before or within 1 month after a return from travel in a country where malaria is endemic.2
The concern raised by Kashyap and colleagues regarding counterfeit artemisinins is well founded. The use of substandard or counterfeit drugs may seriously jeopardize the successful use of artemisinin-based combination therapies, the new standard for the treatment of uncomplicated falciparum malaria in most of the world.3 My review focused on intravenous artesunate for severe malaria. There is also a risk of counterfeit intravenous formulations in some developing countries, but it is unlikely that counterfeit drugs will endanger the supply of intravenous artesunate in the United States.
Philip J. Rosenthal, M.D.
University of California, San Francisco
San Francisco, CA 94143
prosenthal{at}medsfgh.ucsf.edu
References
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