NEW YORK (Reuters Health) - A synthetic antimalarial derivative of artemisinin, trioxolane 7, surpasses the parent compound in ease of synthesis, cost, pharmacokinetics and bioavailability, scientists report in the August 18th issue of Nature.
Dr. Jonathan L. Vennerstrom, at the University of Nebraska Medical Center in Omaha, and his multinational research team set out to develop an alternative to the semisynthetic artemisinins -- artemether and artesunate.
These compounds are effective and safe, and malaria parasites have not developed resistance to them (see Reuters Health report, January 1, 2004), but their therapeutic potential is limited, Dr. Vennerstrom’s team maintains, because of high production costs, poor bioavailability, limiting pharmacokinetics, and the need for long treatment regimens.
After receiving funding from the nonprofit organization Medicines for Malaria Venture in the year 2000, Dr. Vennerstrom told Reuters Health, he and his associates conducted a systematic examination of 1,2,4-trioxolanes.
They generated a “wish-list” of ideal characteristics -- such as straightforward synthesis, a maximum 3-day treatment regimen with once-daily administration, and no evidence for resistance development -- that they used to guide the compound selection process.
Out of several candidates, trioxolane 7 emerged as a drug as potent as artemether against Plasmodium falciparum in vitro, and even more active than artemisinins in the murine P. berghei model. It was able to reduce parasitemia to below quantifiable limits within 24 hours.
Because of its limited tissue distribution after oral administration to rats, trioxolane 7 was deemed safer than other tested compounds. Over an 18-hour sampling period, there were no measurable concentrations in brain tissue, signifying that neurotoxicity is unlikely. Toxicological profiles are similar to that of artesunate, the authors note, and testing revealed “no relevant mutagenic potential.”
Ranbaxy Laboratories Ltd. In India is now working to optimize the production of trioxolane 7, Dr. Vennerstrom noted. “We are optimistic that it will provide a very cost effective drug,” if clinical trials prove its safety and efficacy.
“A clinical phase I trial is ongoing, and so far so good,” the pharmacist added. Testing for its efficacy in malaria patients is expected to begin in early 2005.
“The research that enabled ozonides to be redesigned, not only to increase the chemical and metabolic stability, but also to provide phenomenal antimalarial properties, is impressive,” Dr. Paul M. O’Neill, a chemist at the University of Liverpool, UK, writes in an accompanying News and Views article.
“When combined with a second antimalarial, this new class could offer the best solution to date for destroying drug-resistant malaria parasites,” he concludes.
Source: Nature 2004;430:838-839,900-904. [ Google search on this article ]
MeSH Headings:Biological Sciences: Biopharmaceutics: Chemical and Pharmacologic Phenomena: Health Occupations: Pharmacokinetics: Pharmacology: Toxicology: chemical synthesis: chemistry: Biological SciencesCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
