Nitazoxanide

1.2

2.41

Breast Feeding; Lactation; Milk, Human; Anti-Infective Agents; Antiparasitic Agents

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

This chemical does not meet GHS hazard criteria for 4.3% (2 of 47) of reports.

Warning

H302 (95.7%): Harmful if swallowed [Warning Acute toxicity, oral]

P261, P264, P264+P265, P270, P271, P280, P301+P317, P302+P352, P304+P340, P305+P351+P338, P319, P321, P330, P332+P317, P337+P317, P362+P364, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 47 reports by companies from 7 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Nitazoxanide therapy has not been associated with elevations in serum aminotransferase levels nor with clinically apparent acute liver injury. However, there have been few studies of long term therapy with nitazoxanide and most controlled trials of this agent used short term courses without serum aminotransferase monitoring. Nitazoxanide has been used as adjunctive therapy for chronic hepatitis C, usually in combination with peginterferon with or without ribavirin; in these studies, most patients had improvements in serum aminotransferase levels, and no instances of acute exacerbation of hepatitis or jaundice were reported.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Nitazoxanide

vNo-DILI-concern

0

No match

DOI:10.1016/j.drudis.2016.02.015

The general effect of this medication is the prevention of microbe activity through disruption of important energy pathways for survival and proliferation. Nitazoxanide exhibits antiprotozoal activity by interfering with the pyruvate ferredoxin/flavodoxin oxidoreductase dependent electron transfer reaction, an essential reaction need for anaerobic energy metabolism of various microorganisms. Sporozoites of Cryptosporidium parvum and trophozoites of Giardia lamblia are therefore inhibited, relieving symptoms of diahrrea. Interference with the PFOR enzyme-dependent electron transfer reaction may only be one of the many pathways by which nitazoxanide exhibits antiprotozoal activity.

The most widely accepted mechanism of NTZ is believed to be the disruption of the energy metabolism in anaerobic microbes by inhibition of the pyruvate: ferredoxin/flavodoxin oxidoreductase (PFOR) cycle. In parasitic-protozoa, Nitazoxanide also induces lesions in the cell membranes and depolarizes the mitochondrial membrane while inhibiting quinone oxidoreductase NQO1, nitroreductase-1 and protein disulphide isomerase enzymes. In addition, this drug also inhibits the glutathione-S-transferase (a major detoxifying enzyme) and modulates the Avr-14 gene, encoding for the alpha-type subunit of glutamate-gated chloride ion channel present in nematodes. Aside from its well understood non-competitive inhibition of the PFOR in anaerobic bacteria, NTZ also demonstrates various other antibacterial mechanisms. It inhibits pyruvate dehydrogenase in E Coli, disrupts the membrane potential and pH homeostasis in the Mycobacterium tuberculosis, suppresses the chaperone/usher (CU) pathway of the gram-negative bacteria, and stimulates host macrophage autophagy in tuberculosis patients. NTZ also suppresses viral replication by inhibiting the maturation of the viral hemagglutinin and the viral transcription factor immediate early 2 (IE2) as well as by activating the eukaryotic translation initiation factor 2α (an antiviral intracellular protein). Lastly, NTZ exhibits an inhibitory effect on tumor cell progression by altering drug detoxification (glutathione-S-transferase P1), unfolded protein response, autophagy, anti-cytokines activity, and c-Myc inhibition.