Cryptosporidiosis+Sp14

DISEASE/DRUG OF INTEREST:

Cryptosporidiosis/Nitazoxanide

MOTIVATION AND BACKGROUND:

Cryptosporidiosis, most commonly caused by the protozoan parasites //Cryptosporidium parvum// and //Cryptosporidium homini//, is an infectious disease characterized by acute gastroenteritis and bouts of watery diarrhea [1]. Vomiting, low-grade fever, abdominal pain, and loss of appetite may also occur. In some cases, those infected are asymptomatic,although the high rate of transmission is not decreased, regardless of outward signs of the disease. It manifests in various hosts, including cows, birds, humans, and mice. In the United States, about 748,000 people are infected each year [1, 2]. The protozoa spreads through infective oocysts, microgametes that contain Cryptosporidium spores and can survive outside the host body to spread infection. Since the protozoan’s oocysts are well-protected by a thick external casing, it is resistant to chlorine and can remain outside of a host organism for several weeks. Most cleaning solutions are completely ineffective in eliminating these microgametes, and drying and exposure to the ultraviolet parts of natural light are the only methods that have been shown to kill the oocysts. The disease is spread orally, through direct contact with feces from an infected animal or person or through contact with a contaminated object or substance. The most common routes of transmission are swallowing contaminated water from pools and lakes, by putting infected objects in the mouth, and by touching the mouth with contaminated hands. Susceptible populations include young children, especially those of preschool age, childcare workers, international travelers and immunocompromised individuals, such as HIV/AIDS patients [3]. Cryptosporidiosis has been found around the world, in 95 different countries, from Costa Rica to Wales. Its high prevalence worldwide makes this disease a worthwhile topic to study [4].

** Figure 1: Artist rendition of the //Cryptosporidium// parasite in the host body. **

Nitazoxanide’s effectiveness against cryptosporidiosis comes from its inhibitory effects on the protein pyruvate-ferredoxin oxidoreductase (PFOR) [2]. This protein regulates reduction-oxidation reactions of the Cryptosporidium organism by reducing ferredoxin using the oxidation of pyruvate as an electron source [5]. Its molecular weight is approximately 200 kDa when measured through gel filtration, although the subunits of the protein have been measured at 120 kDa each [5, 6]. Since it participates in cell respiration, it is located in the mitochondrion of cells and is always expressed. As it catalyzes the oxidative decarboxylation of pyruvate to acetyl-coA and CO2, it is extremely necessary for a metabolizing cell [7].

** Figure 2: Micrograph of Cryptosporidiosis ** DRUG INFORMATION:

Nitazoxanide, formula name C12H9N3O5S, is a synthetic nitrothiazolyl-salicylamide derivative that is structurally similar to aspirin with a molecular weight of 307.282 grams per mole. It works by interfering with the electron transfer reaction that pyruvate-ferredoxin oxidoreductase catalyzes. It prevents anaerobic energy metabolism in protozoa-like organisms through its greater than 99% binding rate to the pyruvate-ferredoxin oxidoreductase protein [8]. Its CAS Number is 55981-09-4 and Nitazoxanide is manufactured under the brand names Alinia and Mitazoxanid, among other [9, 2].Alinia is manufactured solely by the Romark Laboratories, of which Nitazoxanide’s inventor, Jean-Francois Rossignol is cofounder. Although it was first discovered in the 1980s by Rossignol, it took until 2002 for the drug to be approved by the United States Federal Drug Administration for treating disease caused by Cryptosporidium parvum. The drug was patented under patent numbers 5578621, 6117894, and a few others in 2002 with Rossignol credited as the inventor [10]. In the early 1990s, the drug Paromomycin was commonly prescribed to patients suffering from Cryptosporidiosis, but in clinical trials testing the efficacy of Paromomycin to Nitazoxanide, Nitazoxanide was found to provide better treatment at a lower dosage and concentration [11].



** Figure 3. Structural Schematic of Nitazoxanide **

It will usually eliminate symptoms of Cryptosporidiosis within 5 days of beginning treatment, complete resolution of symptoms, including the characteristic diarrhea, will occur in 72-88 percent of patients. However, only 60-75 percent of patients will have complete elimination of Cryptosporidium parvum from their feces, indicating that even without symptoms, transmission of the disease is still possible [3]. Nitazoxanide has been proven to treat Cryptosporidiosis in all patients, especially in children under 3 years of age, although adults and adolescents also show improvement. The effect of Nitazoxanide on those with suppressed immune systems, such as HIV/AIDS patients, has not been fully explored, and caution is advised for these patients if they need to start taking this drug. Nitazoxanide has been found to cause some adverse side effects in patients, including abdominal pain, headaches, and, in less than 2 percent of patients, vomiting, diarrhea and hypotension. This medication is delivered orally, either by suspension or tablet, 100mg/5ml and 500 mg, respectively [8]. 36 clinical trials are listed on the National Institute of Health’s website as having Nitazoxanide as their main object of study, and 5 are currently still in progress [12]. This molecule is synthetic and originated in the lab of Jean-Francois Rossignol at the Pasteur Institute in France. In order to further develop his invention, Rossignol cofound his own private company, Romark Laboratories, with Marc S. Ayers [10]. Metronidazole and Atocaquone are current alternatives to Nitazoxanide. In the past Paromomycin has been used to treat Cryptosporidiosis, but the high dosages needed for treatment have made it obsolete [11]. Nitazoxanide can also be used in the treatment of diarrhea caused by the Giardia protozoan [2]. Studies have shown that even in cases of undefined pathogens, patient’s symptoms of diarrhea have been treated by the administration of Nitazoxanide [13].

REFERENCES/WEB LINKS:

[1]. U.S. Department of Health & Human Services. U.S. Food and Drug Administration. BBB – Cryptosporidium parvum. [] (accessed 2/3/14) [2]. Clincial Edit Criteria Proposal. Alinia (Nitazoxanide). [] (accessed 2/3/2014). [3]. Centers for Disease Control and Prevention. Parasites – Cryptosporidium (also known as “Crypto”). [|http://cdc.gov.](accessed 2/3/14). [4]. U.S. Environmenal Protection Agency. Cryptosporidium: Human Health Criteria Document. [] (accessed 2/3/14). [5]. EcoCyc. A member of the BioCyc database collection. Escherichia coli K-12 substr. MG1655 Enzyme: pyruvate: ferredoxin oxidoreductase. [] (Accessed 2/3/14). [6]. MetaCyc. A member of the BioCyc database collection. MetaCyc Enyzme: pyruvate: ferredoxin oxidoreductase. [] (accessed 2/3/14). [7]. Furdui, C. and Ragsdale, S.W. The Role of Pyruvate Ferrdoxin Oxioreductase in Pyruvate Synthesis during Autotrophic Growth by the Wood-Ljungdahl Pathway. J. Biol. Chem. [Online Early Access] DOI: 10.1074/jnc/MOO3291200. Published Online: June 30, 2000. [] (accessed 2/3/2014). [8]. Drug Bank. Open Data Drug & Drug Target Database. Nitazoxanide. [] (accessed 2/3/14). [9]. National Library of Medicine – Medical Subject Headings. 2009 MeSH. CAS Registry/EC Number (RN). Nitazoxanide. [|http://lhm.nih.gov.](accessed 2/3/14). [10]. Romark Laboratories, L.C.. About Romark. History. [] (accessed 2/3/14). [11]. Theodos, C.M., Griffiths, J.K., Fairfield, A. and Tzipori, S. Efficacy of Nitazoxanide against Cryptosporidium parvum in Cell Culture and in Animal Models. <span style="color: #51215f; font-family: 'Lucida Sans Unicode','Lucida Grande',sans-serif;">Antimicrob Agents Chemother. [Online] 1998, 42, 1959-1965 [|http://www.ncbi.nlm.nig.gov.](accessed 2/3/2014). <span style="color: #51215f; font-family: 'Lucida Sans Unicode','Lucida Grande',sans-serif;">[12]. Clinical Trials.gov. A service of the U.S. National Institutes of Health. Nitazoxanidde. [|http://clincicaltrials.gov.](accessed 2/3/2014). <span style="color: #51215f; font-family: 'Lucida Sans Unicode','Lucida Grande',sans-serif;">[13]. Rossignol, J.F., Lopez-Chegne, N., Julcamoro, L.M., Carrion, M.E., and Bardin M.C. Nitazoxanide for the empiric treatment of pediatric infectious diarrhea. Trans. R. Soc. Trop. Med. Hyg. [Online] 2012 106, 167-173. [] (accessed 2/3/2014).