Romark Laboratories, L.C. Romark Laboratories, L.C. Romark Laboratories, L.C. Romark Laboratories, L.C. Romark Laboratories, L.C.

News & Events

Research Overview

History of the Science

Nitazoxanide was originally synthesized by Rossignol in 1973 at the Radium Institute where he studied synthetic organic chemistry for his doctorate degree at the University of Paris, also known in those days as La Sorbonne. Raymond Cavier, a Professor of Parasitology in the Parasitology Laboratory at the Faculty of Pharmacy of the University of Paris tested nitazoxanide against a broad range of parasites (Rossignol & Cavier, 1975; Cavier & Rossignol, 1982).

In 1994, Romark initiated the development of nitazoxanide for treatment of a broad range of intestinal parasitic infections caused by the intestinal protozoa Cryptosporidium parvum, Giardia intestinalis, Entamoeba hystolitica, Blastocystis hominis and Balantidium coli, the intestinal nematodes and cestodes Enterobius vermicularis, Ascaris lumbricoides, Necator americanus, Ancylostoma duodenale, Trichuris trichiura, Strongyloides stercoralis, Taenia saginata and Hymenolepis nana, and the liver trematode, Fasciola hepatica (Fox & Saravolatz, 2005).

In developing the drug for treating these infections, the company drew on Rossignol's experience in developing drugs for treating tropical infectious diseases as well as the passion of Rossignol and Ayers to impact the world of health. There was an important need for a new drug for Crypto in developed counties, but perhaps equally important, there was a great need for a drug with broad-spectrum activity against intestinal parasitic infections in low-income countries. Early clinical trials were conducted in the United States, Europe, Mali, Egypt, Zambia, Mexico, Peru and Colombia in persons affected by a broad range of intestinal parasitic infections.

In 1996, Dubreuil et al reported that nitazoxanide and its circulating metabolite, tizoxanide, were active against a broad range of obligate and facultative Gram-positive and Gram-negative anaerobic bacteria, and in 1998, Mégraud et al. reported that the two compounds were also active against Helicobacter pylori (Dubreuil et al., 1976; Mégraud et al., 1998).

In 2006, Rossignol et al. reported the activity of nitazoxanide and tizoxanide in cell culture assays and studies were conducted evaluating nitazoxanide in the treatment of diarrhea caused by rotavirus and norovirus in adults and children (Rossignol et al., 2006; Rossignol & El-Gohary, 2006). In 2008, Korba et al. reported the activity of nitazoxanide and tizoxanide against hepatitis B and C in cell culture assays, and in 2009 Rossignol et al reported studies evaluating nitazoxanide combined with pegylated-interferon and ribavirin in the treatment of chronic hepatitis C genotype 4 in adult patients (Korba et al., 2008; Rossignol et al., 2009). In 2009, Rossignol et al. reported in vitro activity of nitazoxanide and tizoxanide against influenza viruses (Rossignol et al., 2009).

A Phase 2b/3 clinical study conducted in the United States subsequently showed that nitazoxanide 300 mg controlled release tablets (NT-300) administered 600 mg twice daily for 5 days showed potential to significantly reduce the duration of symptoms compared to a placebo (Haffizulla et al., 2014). In early 2013, the U.S. Department of Health and Human Services awarded Romark a contract to complete the development of NT-300 for treatment of acute uncomplicated influenza. The HHS contract (HHSO100201300004C) is administered through the Biomedical Advanced Research and Development Authority (BARDA) and funds clinical and non-clinical development of NT-300 for treatment of acute uncomplicated influenza as well as regulatory activities required to submit a New Drug Application for the product.

While pursuing development work with nitazoxanide, Rossignol and Andrew Stachulski in the United Kingdom at the University of Liverpool Department of Chemistry initiated a drug discovery program in 2000 that focused on synthesis of new derivatives of nitazoxanide. More than 300 chemical compounds were prepared using the scaffold of nitazoxanide, two of them being in preclinical development as broad-spectrum antivirals. Preclinical research is typically performed for Romark under contract with specialty laboratories in academia or contract research organizations. Romark medical personnel are active in directing the company’s clinical development programs.

References:

Rossignol J.F. & Cavier, R. 2-Benzamide 5-Nitrothiazoles. Chemical Abstract. 1975; 83; 28216n.

Cavier, R. & Rossignol, J.F. Etude Comparative des Propriétés Oxyuricides de l’Albendazole, du Mébendazole, du Pamoate de Pyrantel et du Praziquantel chez la Souris Expérimentalement Infestée. Annales Pharmaceutiques Françaises. 1982; 40: 55-60.

Fox, L.M. & Saravolatz, L.D. Nitazoxanide: A New Thiazolide Antiparasitic Agent. Clinical Infectious Diseases. 2005;40:1173-1180.

Dubreuil, L., Houcke, I., Mouton, Y. & Rossignol, J.F. In vitro Evaluation of Activities of Nitazoxanide and Tizoxanide against Anaerobes and Aerobic Organisms. Antimicrobial Agents and Chemotherapy. 1996; 40: 2266-2270.

Mégraud. F., Occhialini, A. & Rossignol, J.F. Nitazoxanide, a Potential Drug to Eradicate Helicobacter pylori with no Cross Resistance to Metronidazole. Antimicrobial Agents & Chemotherapy. 1998; 42: 2836-2840.

Rossignol, J.F., Abou Zekry, M., Abeer Hussein & Santoro, M.G. Effect of Nitazoxanide in Treating Severe Rotavirus Diarrhea: a Randomized, Double-Blind, Placebo-Controlled Trial. Lancet. 2006; 368: 124-129.

Rossignol, J.F. & El-Gohary, Y. M. Nitazoxanide in the Treatment of Viral Gastroenteritis: a Randomized Double Blind Placebo Controlled Trial. Alimentary Pharmacology & Therapeutics. 2006:24:1423-1430.

Korba, B.E., Mueller, A.B., Farrar, K., Gaye, K., Mukerjee, S., Ayers, M.S. & Rossignol, J.F. Nitazoxanide, tizoxanide and other Thiazolides are Potent Inhibitors of Hepatitis B Virus and Hepatitis C Virus Replication. Antiviral Research. 2008;77: 56-63.

Rossignol, J.F., Elfert, A., El-Gohary, Y. & Keefe, E.B. Improved Virologic Response in Chronic Hepatitis C Genotype 4. Patients Given Nitazoxanide, Peginterferon, and Ribavirin. Gastroenterology 2009; 136:856-862.

Rossignol, J.F., La Frazia, S., Chiappa, L., Ciucci, A., Santoro, M.G. Thiazolides, a New Class of Anti-influenza Molecules Targeting Viral Hemagglutinin at Post-Translational Level. Journal of Biological Chemistry. 2009;284:29798-29808.

Haffizulla, J., Hartman, A., Hoppers, M., Resnick, H., Samudrala, S., Ginocchio, C., Bardin, M., Rossignol, J.F. A Randomized, Double-Blind, Placebo Controlled Clinical Trial of Nitazoxanide in Adults and Adolescents with Acute Uncomplicated Influenza. Lancet Infectious Diseases. 2014;14:609-618.