Nitazoxanide

Nitazoxanide is a synthetic nitrothiazolyl-salicylamide derivative and an antiprotozoal agent. Nitazoxanide has uses in medicine, and is a prodrug.

Chemistry
Nitazoxanide is a light yellow crystalline powder. It is poorly soluble in ethanol and practically insoluble in water.

History
Nitazoxanide was originally discovered in the 1980s by Jean-François Rossignol at the Pasteur Institute. Initial studies demonstrated activity versus tapeworms. In vitro studies demonstrated much broader activity. Dr. Rossignol co-founded Romark Laboratories, with the goal of bringing nitazoxanide to market as an anti-parasitic drug. Initial studies in the USA were conducted in collaboration with Unimed Pharmaceuticals, Inc. (Marietta, GA) and focused on development of the drug for treatment of cryptosporidiosis in AIDS. Controlled trials began shortly after the advent of effective anti-retroviral therapies. The trials were abandoned due to poor enrollment and the FDA rejected an application based on uncontrolled studies.

Rather than abandon their efforts, Romark launched an impressive series of controlled trials. No other agent has proven efficacy in the treatment of cryptosporidiosis. However, a placebo-controlled study of nitazoxanide in cryptosporidiosis demonstrated significant clinical improvement in adults and children with mild illness. Among malnourished children in Zambia with chronic cryptosporidiosis, a three-day course of therapy not only led to clinical and parasitologic improvement, but also improved survival. In Zambia and in a study conducted in Mexico, nitazoxanide was not successful in the treatment of cryptosporidiosis in advanced infection with human immunodeficiency virus at the doses used. However, it was effective in patients with higher CD4 counts. Also, higher doses seem to have some effect in uncontrolled and unpublished studies. In treatment of giardiasis, nitazoxanide was superior to placebo and comparable to metronidazole. Nitazoxanide was successful in the treatment of metronidazole-resistant giardiasis. Studies have suggested efficacy in the treatment of cyclosporiasis, isosporiasis, and amebiasis.

Mechanism of action
The anti-protozoal activity of nitazoxanide is believed to be due to interference with the pyruvate:ferredoxin oxidoreductase (PFOR) enzyme dependent electron transfer reaction which is essential to anaerobic energy metabolism.

Following oral administration, it is rapidly hydrolyzed to its active metabolite, tizoxanide, which is 99% protein bound. Peak concentrations are observed 1–4 hours after administration. It is excreted in the urine, bile and feces.

It has also been shown to have activity against influenza A virus in vitro. The mechanism appears to be by selectively blocking the maturation of the viral hemagglutinin at a stage preceding resistance to endoglycosidase H digestion. This impairs hemagglutinin intracellular trafficking and insertion of the protein into the host plasma membrane.

Uses
Nitazoxanide is a first-line choice for the treatment of illness caused by Cryptosporidium parvum or Giardia lamblia infection in immunocompetent adults and children, and is an option to be considered in the treatment of illness caused by other protozoa and/or helminths.

It is used for the treatment of infectious diarrhea caused by Cryptosporidium parvum and Giardia lamblia in patients 1 year of age and older.

Nitazoxanide is also being looked into for the treatment of chronic hepatitis B and C.

Chronic hepatitis B
Nitazoxanide alone has shown preliminary evidence of efficacy in the treatment of chronic hepatitis B over a one year course of therapy. Nitazoxanide 500 mg twice daily resulted in a decrease in serum HBV DNA in all of 4 HBeAg-positive patients, with undetectable HBV DNA in 2 of 4 patients, loss of HBeAg in 3 patients, and loss of HBsAg in one patient. Seven of 8 HBeAg-negative patients treated with nitazoxanide 500 mg twice daily had undetectable HBV DNA and 2 had loss of HBsAg.Additionally, nitazoxanide monotherapy in one case and nitazoxanide plus adefovir in another case resulted in undetectable HBV DNA, loss of HBeAg and loss of HBsAg. These preliminary studies showed a higher rate of HBsAg loss than any currently licensed therapy for chronic hepatitis B. The similar mechanism of action of interferon and nitazoxanide suggest that stand-alone nitazoxanide therapy or nitazoxanide in concert with nucleos(t)ide analogs have the potential to increase loss of HBsAg, which is the ultimate end-point of therapy. A formal phase Ⅱ study is being planned for 2009. you can see results for off label use of alinia (nitazoxanide) on medhelp hbv community, it is reported a significant drop of more than 50% hbsag quantity from baseline values on hbeag negative hbv at 1,5-2g daily dose (500 mg pills every 6-8hrs with food) already at 3–6 months therapy, especially in combination with peginterferon or entecavir.

Chronic hepatitis C
Romark made the decision to initially focus on the potential treatment of chronic hepatitis C with nitazoxanide. Three phase II studies of nitazoxanide for the treatment of chronic hepatitis C have been completed and communicated in publications or presentations at national and international meetings[6–8]. The first study was a randomized, double-blind, placebo-controlled study of the treatment of chronic hepatitis C with nitazoxanide 500 mg twice daily in 50 adult patients with chronic hepatitis C infected with genotype 4[6]. Seven of 23 patients (30%) had a virologic end-of-treatment response (ETR) with undetectable virus, and a sustained virologic response (SVR) with undetectable virus 24 wk after the completion of treatment was observed in 4 of 23 patients (17%). All responders had low serum HCV RNA levels less than 400 000 IU/mL. This study was the first use of nitazoxanide in patients with chronic hepatitis C and for a longer time period than for its use for cryptosporidiosis and giardiasis, and the drug was well tolerated with the same number of mild gastrointestinal adverse events in the treated and placebo groups.

Small Intestinal Bacterial Overgrowth
There has been a study that claims there is some limited evidence for efficacy in the context of an open label study, but no systematic review and all claims should be taken lightly.

Adverse effects
Side effects are mostly stomach pain, headache, upset stomach, vomiting, discolored urine, skin rash, and itching

Dosage forms
Nitazoxanide is available in two oral dosage forms - tablet (500 mg) and oral suspension (100 mg per 5 ml when reconstituted).

Brand names
Nitazoxanide is sold under the brand names Nizonide, Nitaxide, Nitax, Zox, Netazox, Niazid, Toza, Daxon, Dexidex, Kidonax, Mitafar, Pacovanton, Paramix, Alinia, Adonid, NT-TOX, and Annita.

Clinical trials
Romark Laboratories has announced encouraging results from international Phase I and II clinical trials evaluating a controlled release version of nitazoxanide in the treatment of chronic hepatitis C virus infection. The company used 675 mg and 1,350 mg twice daily doses of controlled release nitazoxanide showed favorable safety and tolerability throughout the course of the study, with mild to moderate adverse events. Primarily GI-related adverse events were reported.

Nitazoxanide is has gone through Phase II clinical trials for the treatment of hepatitis C, in combination with peginterferon alfa-2a and ribavirin.

A randomised double-blind placebo-controlled study published in 2006, with a group of 38 young children (Lancet, vol 368, page 124-129) concluded that a 3-day course of nitazoxanide significantly reduced the duration of rotavirus disease in hospitalized pediatric patients. Dose given was "7.5 mg/kg twice daily" and the time of resolution was "31 hours for those given nitazoxanide compared with 75 hours for those in the placebo group." Rotavirus is the most common infectious agent associated with diarrhea in the pediatric age group worldwide.

Teran et al.. conducted a study at the Pediatric Center Albina Patinö, a reference hospital in the city of Cochabamba, Bolivia, from August 2007 to February 2008. The study compared nitazoxanide and probiotics in the treatment of acute rotavirus diarrhea. They found Small differences in favor of nitazoxanide in comparison with probiotics and concluded that nitazoxanide is an important treatment option for rotavirus diarrhea.

Lateef et al.. conducted a study in India that evaluated the effectiveness of nitazoxanide in the treatment of beef tapeworm (Taenia saginata) infection. They concluded that nitazoxanide is a safe, effective, inexpensive, and well-tolerated drug for the treatment of niclosamide- and praziquantel-resistant beef tapeworm (Taenia saginata) infection.

A retrospective review of charts of patients treated with nitazoxanide for trichomoniasis by Michael Dan and Jack D. Sobel demonstrated negative result. They reported three case studies; two of which with metronidazole-resistant infections. In Case 3, they reported the patient to be cured with high divided dose tinidazole therapy. They used a high dosage of the drug (total dose, 14–56 g) than the recommended standard dosage (total dose, 3 g) and observed a significant adverse reaction (poorly tolerated nausea) only with the very high dose (total dose, 56 g). While confirming the safety of the drug, they showed nitazoxanide is ineffective for the treatment of trichomoniasis.

In the clinical trials no serious adverse events were reported. No serious adverse events were reported in the prescribing information of the parent company. In placebo-controlled trials of HIV-uninfected patients age 12 years and older who received Alinia Tablets for the treatment of diarrhea caused by Giardia lamblia or Cryptosporidium parvum, less than 1% of patients discontinued therapy because of an adverse event. Adverse events occurring in less than 1% of the patients age 12 years and older participating in clinical trials of Alinia Tablets are listed below: Body as a Whole: asthenia, fever, pain, allergic reaction, pelvic pain, back pain, chills, chills and fever, flu syndrome. Nervous System: dizziness, somnolence, insomnia, tremor, hypesthesia. Digestive System: vomiting, dyspepsia, anorexia, flatulence, constipation, dry mouth, thirst. Urogenital System: discolored urine, dysuria, amenorrhea, metrorrhagia, kidney pain, edema labia. Metabolic & Nutrition: increased SGPT. Hemic & Lymphatic Systems: anemia, leukocytosis. Skin: rash, pruritus. Special Senses: eye discoloration, ear ache. Respiratory System: epistaxis, lung disease, pharyngitis. Cardiovascular System: tachycardia, syncope, hypertension. The effects on cardiac repolarisation are currently undisclosed as data from a TQT study in healthy male and female volunteers approved in 2010 in the United Kingdom remains unpublished. Muscular System: myalgia, leg cramps, spontaneous bone fracture.