An Important Advance in Anti-Parasitic Therapy

EDITORIAL NITAZOXANIDE: AN IMPORTANT ADVANCE IN ANTI-PARASITIC THERAPY

A. CLINTON WHITE, JR. Infectious Diseases Section, Department of Medicine, Baylor College of Medicine, Houston, Texas

The field of anti-parasitic drugs has had a shaky history. maceuticals, Inc. (Marietta, GA) and focused on develop- The major pharmaceutical companies have increasingly fo- ment of the drug for treatment of cryptosporidiosis in ac- cused their drug development efforts on the major markets, quired immunodeficiency syndrome. Controlled trials began with potential annual sales of at least $100 million. This has shortly after the advent of effective anti-retroviral therapies. not worked well for development of anti-parasitic drugs. Most The trials were abandoned due to poor enrollment and the patients develop parasitic infections due to poverty. Thus, Food and Drug Administration rejected an application based while there may be millions of cases in developing countries, on uncontrolled studies. the number able to support the high prices of branded drugs Rather than abandon their efforts, Romark launched an is small. A few new drugs have come into the market. For impressive series of controlled trials. No other agent has example, mefloquine, albendazole, ivermectin, and atova- proven efficacy in the treatment of cryptosporidiosis. How- quone-proguanil have all come to the U.S. market since 1990. ever, a placebo-controlled study of nitazoxanide in cryptospo- However, even this limited number of new drugs is somewhat ridiosis demonstrated significant clinical improvement in deceiving. Mefloquine and atovaquone-proguanil are largely adults and children with mild illness.4 Among malnourished supported by their use in malaria prophylaxis. In this case, the children in Zambiawithchronic cryptosporidiosis, athree- millions of wealthy Western tourists provide a substantial day course of therapy not only led to clinical and parasitologic market for these high-price drugs. In addition, the U.S. mili- improvement, but also improved survival.5 In Zambia5 and in tary initiated the development of mefloquine, and safety data astudy conducted in Mexico, 6 nitazoxanide was not success- for atovaquone was supported by its development for treat- ful in the treatment of cryptosporidiosis in advanced infection ment of Pneumocystis pneumonia, for which there was a sub- with human immunodeficiency virus at the doses used. How- stantial market in the U.S. Ivermectin has never had a large ever, it was effective in patients with higher CD4 counts.6,7 market for human diseases. However, its development and Also, higher doses seem to have some effect in uncontrolled manufacture were supported by the lucrative market as a and unpublished studies. In treatment of giardiasis, nitazox- prophylaxis for canine heartworms. anide was superior to placebo and comparable to metronida- Between 1990 and 2000, the number of anti-parasitic drugs zole.7 Nitazoxanide was successful in the treatment of metro- available for human use in the United States actually shrank. nidazole-resistant giardiasis.8 Studies have suggested efficacy Diethylcarbamazine (DEC), quinacrine, and niclosamide in the treatment of cyclosporiasis, isosporiasis, and amebiasis. were withdrawn from the U.S. market. Eflornithine was her- There have also been several controlled trials of nitazox- alded as the “resurrection” drug for its dramatic effects in anide for treatment of infection with intestinal helminths.9 As West African trypanosomiasis, yet its sole manufacturer shown in the study by Diaz and others in this issue of the stopped production. Finally, praziquantel was withdrawn journal, nitazoxanide is effective against Ascaris, Trichuris, from the U.S. market. It appeared that there was actually a and Hymenolepis.10 However, some patients require repeated “disappearing arsenal” of anti-parasitic drugs.1 dosing. Other controlled trials have demonstrated some ac- Some of these problems have been reversed in response to tivity against chronic fascioliasis, for which there is no cur- political pressure. Eflornithine itself was resurrected. The rently licensed therapy available.11 However, the response drug proved an effective topical depilatory, thus ensuring that rates are lower than those described with triclabendazole. In the base compound was being manufactured. In response to all studies, nitazoxanide has been extremely well tolerated pressure led by World Health Organization, and Médicins with adverse effects similar to placebo. San Frontière, the manufacturer agreed to formulate some Studies have suggested a number of possible indications for drug for intravenous use and make it available for treatment treatment of specific parasites. Given its broad anti-parasitic of trypanosomiasis.2 Praziquantel was re-instated when the spectrum, it is tempting to use nitazoxanide empirically. Can marketing company realized that the public relations losses nitazoxanide be used as an alternative to albendazole or me- from withdrawing the drug out-weighed the cost savings from bendazole in mass chemotherapy of intestinal helminths? Be- ending production. fore this could be done, it will be important to confirm its In this context, the development of nitazoxanide is quite activity against hookworm species. It will also be important to remarkable. Nitazoxanide was originally discovered in the know whether it can be safely used in a variety of patient 1980s by Jean François Rossignol at the Pasteur Institute. groups (e.g., Are there adverse effects in onchocerciasis and Initial studies demonstrated activity versus tapeworms.3 In Loa loa infections seen with DEC in Africa?). vitro studies demonstrated much broader activity. Dr. Ros- In both developing and developed countries, intestinal pro- signol subsequently led the preclinical and clinical develop- tozoans are important causes of persistent and chronic diar- ment of albendazole and halofantrine. He co-founded Ro- rhea. It is difficult to identify specific causes with currently mark Laboratories, with the goal of bringing nitazoxanide to available tests. Multiple stool examinations may be needed to market as an anti-parasitic drug. Initial studies in the United identify Giardia. Cryptosporidium requires specialized tests States were conducted in collaboration with Unimed Phar- (modified acid fast or fluorescent stains), which are not uni- 382 NITAZOXANIDE 383 formly performed by all laboratories unless requested. Anti- 3. Rossignol JF, Maisonneuve H, 1984. Nitazoxanide in the treat- gen-detection assays may improve the diagnostic yield, but ment of Taenia saginata and Hymenolepis nana infections. Am can be expensive and are underused. Currently, cryptospo- J Trop Med Hyg 33: 511–512. 4. Rossignol JF, Ayoub A, Ayers MS, 2001. Treatment of diarrhea ridiosis is underdiagnosed. The cost and inconveniences of caused by Cryptosporidium parvum: aprospective random- multiple stool examinations will usually be greater than the ized, double-blind, placebo-controlled study of nitazoxanide. J cost of treatment. Can nitazoxanide be used empirically in- Infect Dis 184: 103–106. stead of aggressively pursuing a parasitologic diagnosis? A 5. Amadi B, Mwiya M, Musuku J, Watuka A, Sianongo S, Ayoub A, Kelly P, 2002. Effect of nitazoxanide on morbidity and comparison of empirical therapy versus pursuing diagnosis mortality in Zambian children with cryptosporidiosis: a ran- and specific treatment should be compared in post-travel di- domised controlled trial. Lancet 360: 1375–1380. arrhea. 6. Rossignol JF, Hidalgo H, Feregrino M, Higuera F, Gomez WH, Finally, pre-clinical studies have suggested significant activ- Romero JL, Padierna J, Geyne A, Ayers MS, 1998. A double- ity of nitazoxanide against some bacterial pathogens, includ- ‘blind’ placebo-controlled study of nitazoxanide in the treatment of cryptosporidial diarrhoea in AIDS patients in Mexico. ing Campylobacter, Clostridium difficile, and Helicobacter py- Trans R Soc Trop Med Hyg 92: 663–666. lori. Will these observations translate into clinical efficacy? 7. Ortiz JJ, Ayoub A, Gargala G, Chegne NL, Favennec L, 2001. Controlled trials are clearly indicated. If nitazoxanide proves Randomized clinical study of nitazoxanide compared to met- effective for these indications, the potential market associated ronidazole in the treatment of symptomatic giardiasis in chil- with these common infections may provide a major source of dren from northern Peru. Aliment Pharmacol Ther 15: 1409– 1415. revenue that will help insure drug availability. For now, we 8. Abboud P, Lemee V, Gargala G, Brasseur P, Ballet JJ, Borsa- should celebrate the arrival of an important new addition to Lebas F, Caron F, Favennec L, 2001. Successful treatment of the anti-parasitic arsenal. metronidazole- and albendazole-resistant giardiasis with nitazoxanide in a patient with acquired immunodeficiency syn- Clin Infect Dis 32: Author’s address: A. Clinton White, Jr., Infectious Diseases Section, drome. 1792–1794. Department of Medicine, Baylor College of Medicine, 1 Baylor Plaza, 9. Gilles HM, Hoffman PS, 2002. Treatment of intestinal parasitic 535 EA, Houston, TX 77030, Telephone: 713-798-6846, Fax: 713-798- infections: a review of nitazoxanide. Trends Parasitol 18: 95– 0681, E-mail: [email protected] 97. 10. Diaz E, Mondragon J, Ramirez E, Bernal R, 2003. 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