Нитазоксанид

Описание

Nitazoxanide (NT Z) has been approved as an orphan drug for the treatment of diarrhea in children (age, 1–11 years) and is associated with giardiasis, but it also is approved for diarrhea caused by crytosporidiosis in patients with AIDS. Crytosporidiosis is a protozoal infection caused by Cryptosporidi um parvum. The condition is uncommon in healthy individuals but can be life-threatening in immunosuppressed patients and those with HIV infections.

Химические свойства

Crystalline Solid

Использование

Nitazoxanide has been used:

• to test its anti-viral activity against chikungunya virus
• as an antiprotozoal agent to test its effect on cell viability in various cancer cell lines
• to test its effect on human cytomegalovirus (HCMV) infected human fibroblast HFF cells

Антимикробная активность

In vitro Cryptosporidium parvum sporocytes and oocysts are inhibited by <33 μm, and Giardia lamblia (intestinalis) trophozoites by <10 μm. The metabolite tizoxanide is more active than the parent compound against some isolates. E. histolytica is inhibited by 6–23 μm (parent compound) and 5.6– 28 μm (metabolite), and T. vaginalis by 0.5–15.5 μm (parent compound) and 0.3–12.2 μm (metabolite). Activity against other micro- organisms, including some helminths, bacteria (Clostridium difficile) and viruses (hepatitis C) has also been demonstrated.

Приобретенная устойчивость

Resistance caused by altered expression of genes involved in stress response has been demonstrated in experimental studies with G. lamblia.

Общее описание

Nitazoxanide (NTZ), a thiazolide compound is a antiparasitic drug with structure similar to niclosamide.

Фармацевтические приложения

A synthetic broad-spectrum antiparasitic nitroheterocycle (2-acetyloxy- N-(5-nitro-2-thiazolyl) benzamide), formulated for oral use.

Механизм действия

Nitazoxanide is a pro-drug that is metabolically converted into the deactylated drug tizoxanide (TIZ). The TIZ then undergoes a four-electron reduction of the 5-nitro group giving various short-lived intermediates, which may include the hydroxylamine derivative. It is these reduced products that represent the active form of NTZ. Whereas these intermediates would suggest that NTZ has the same mechanism of action as metronidazole, this does not appear to be the case. Nitazoxanide is thought to inhibit the enzyme pyruvate:ferredoxin oxidoreductase in Trichomonas vaginali s, Entamoeba histolytica, and Cl ostridium perfingens. The results of this inhibition is disruption of the bioenergetics of these organisms. Unlike metronidazole and tinidazole, which fragment DNA and are suspected mutagenic agents, NTZ and TIZ do not cause DNA fragmentation and are not considered to be mutagenic. This might be associated with the higher redox potential found for NTZ, a nitrothiazole, in comparison with very low redox potential found for the nitroimidazoles, such as metronidazole and tinidazole. Additional metabolites of TIZ also includes the glucuronide, which shows some biological activity, and small amounts of an aromatic hydroxylation product.

Фармакокине?тика

After oral administration the major circulating metabolites are tizoxanide (desacetyl nitazoxanide) and its glucuronide. Minor metabolites include salicyluric acid and tizoxanide sulfate. Maximum concentrations of the active metabolites tizoxanide and tizoxanide glucuronide are observed within 1–4 h. Following a single oral dose of 500 mg given with food, the C_max of both metabolites was around 10 mg/L. Tizoxanide has a halflife of around 1–2 h and is >99.9% bound to plasma proteins.

Клиническое использование

It is indicated for the treatment of diarrhea caused by G. lamblia or C. parvum.

Побочные эффекты

Nitazoxanide appears well tolerated. Side effects may include abdominal pain diarrhea, headache and nausea.

Метаболизм

Nitazoxanide is available as powder that is reconstituted and dispensed as an oral suspension. The drug is well absorbed from the GI tract and rapidly metabolized, with elimination products appearing in the urine and feces. The only identified products in the plasma are TIZ and its glucuronide. The product can be taken with food.