Nitazoxanide (NTZ), which is a thiazolyl benzamide compound developed by Romark Laboratory, has multiple bioactivities. NTZ has a chemical name of “2-acetoxy-N-(5-nitro-2-thiazolyl)benzamide”, a chemical formula of C12H9N3O5S, and a melting point of 202° C., and is a light yellow powder, which is insoluble in water, slightly soluble in ethanol, and soluble in organic solvents such as tetrahydrofuran, dimethyl sulfoxide (DMSO) and N,N-dimethylformamide (DMF).
Studies have shown that nitazoxanide is effective in combating a variety of parasites in human such as protozoan and helminth, specifically including: Giardia, Amoeba, Cryptosporidium, Cyclospora, Trichomonad, Encephalitozoon intestinalis, Isospora Blastocystis hominis, Balantidium coli, Ascaris lumbricoides, Enterocytozoon bieneusi, Tapeworm (including Taenia saginata, Hymenolepis nana), Diplacanthus nanus, Giardia Leishmania, Fasciola hepatica, etc. Nitazoxanide has good therapeutic effect on viral infectious diseases such as hepatitis B (HBV), hepatitis C (HCV), influenza (including canine influenza), and viral enterogastritis caused by Rotavirus or Norovirus. Nitazoxanide is also useful in combating infection caused by bacteria such as Clostridium difficile (CD), Tubercle bacillus (including drug-resistant Tubercle bacillus) and Helicobacter pylori, and also has a good inhibitory effect on the biofilm formation caused by bacteria.
Nitazoxanide is a prodrug which is quickly hydrolyzed to its active metabolite tizoxanide (TIZ) in vivo after administration. The pharmacokinetic studies in human show that after oral administration, nitazoxanide is absorbed by gastrointestinal tract, wherein about ⅓ of the oral dose is excreted by urine, and about ⅔ of the oral dose is excreted by feces. In blood, nitazoxanide is quickly metabolized by plasma esterase (the half-life is about 6 min at 37° C.), and is deacetylated by hydrolysis to produce its active metabolite tizoxanide. Therefore, nitazoxanide is not detectable in plasma, urine, bile and feces. Tizoxanide can be further subjected to glucuronidation in vivo to produce tizoxanide glucuronide having no pharmaceutical activity. Tizoxanide is present in plasma, urine, bile and feces, and tizoxanide glucuronide is also present in plasma, urine and bile.
Nitazoxanide has good pharmaceutical properties such as multiple bioactivities and good safety, but also has some obvious disadvantages, which mainly reside in the following two aspects.
(1) Nitazoxanide has the shortcomings such as low bioavailability, short half life, and low blood concentration. It is found by Pharmacokinetic Laboratory of Institute of pharmacology & Toxicology Academy of Military Medical Sciences that when nitazoxanide suspension was orally administered to rats, the absolute bioavailability was only 7.2%. In addition, it is reported in papers that when nitazoxanide was orally administered to healthy adults, after single administration of 500 mg, the active metabolite tizoxanide had a time to peak (Tmax) of 3-4 h, a AUC value of about 3.9-11.3 μg*h/mL, a maximum concentration (Cmax) of 1.9 μg/mL (in the range of 1.1-2.5), and a short half life of only from 1.03 to 1.6 h.
(2) Nitazoxanide has relatively low activity, for example, nitazoxanide has a minimal inhibitory concentration (MIC) of from 12 to 28 μg/mL (the median value is 16 μg/mL) for Mycobacterium tuberculosis; nitazoxanide and tizoxanide have the minimal inhibitory concentrations (MICs) of between 0.25 and 8 μg/mL, the 50% minimal inhibitory concentration (MIC50) of 1 μg/mL, and the 90% minimal inhibitory concentration (MIC90) of 4 μg/mL for 103 strains of Helicobacter pylori; under aerobic or microaerophilic conditions, nitazoxanide and tizoxanide have a minimal inhibitory concentration (MIC) of 8˜16 μg/mL for Staphylococcus epidermidis or other Staphylococcus (including methicillin resistant Staphylococcus aureus); nitazoxanide has an EC50 of 1 μg/mL and an EC90 of 7 μg/mL for PR8 influenza virus in MDCK cells.
As can be seen, nitazoxanide has the shortcomings of low bioavailability, short half life, and low blood concentration. When nitazoxanide is used in the treatment of infections by parasites such as intestinal protozoans and helminths, nitazoxanide can work without entering blood. Therefore, the properties of nitazoxanide, i.e., poor oral absorption, low bioavailability, and low blood concentration, would not influence its therapeutic effect on the treatment of infections by parasites such as intestinal protozoans and helminths. However, if nitazoxanide is applied to the treatment of drug-resistant Tubercle bacillus, Helicobacter pylori or methicillin resistant Staphylococcus aureus, or the treatment of viral infectious diseases caused by influenza virus, Rotavirus and the like, the blood concentration should be at least higher than the minimal inhibitory concentration (MIC) or the minimal effective concentration. The shortcomings of nitazoxanide, i.e., poor oral absorption, low bioavailability, and low blood concentration, are necessarily observed and directly influence its pharmaceutical effect.
Therefore, if nitazoxanide agent is applied to the treatment of drug-resistant tubercle bacillus, Helicobacter pylori or methicillin resistant Staphylococcus aureus, or the treatment of viral infectious diseases caused by influenza virus, Rotavirus and the like, it will be necessary to enhance the bioavailability, increase the blood concentration, and prolong the half life of nitazoxanide calculated as tizoxanide, so as to have therapeutic effects such as anti-bacterial and anti-viral effects.
USPTO Backgrounds
USPTO Backgrounds