治疗肠道寄生虫和细菌感染的新药—nitazoxanide

Nitazoxanide是国外上市的一种高效、广谱的治疗人、畜寄生虫和细菌感染的新药 ,目前国内尚无该产品上市。该文对其理化性质、药代动力学研究、药理毒理学研究和应用等作简要介绍。

Treatment of chronic viral hepatitis with nitazoxanide and second generation thiazolides

Nitazoxanide,the first thiazolide,was originally developed for the treatment of Cryptosporidium parvum.More recently,antiviral activity of nitazoxanide against hepatitis B virus(HBV)and hepatitis C virus was recognized in in vitro systems.These basic studies led to phaseⅡclinical trials that demonstrated the safety and efficacy of nitazoxanide in combination with peginterferon,with or without ribavirin,in the treatment of chronic hepatitis C genotype 4.The sustained virologic response rate was 79%and 80%in two studies,which was higher than the response rate of 50%with the standard of care with peginterferon plus ribavirin.In very preliminary studies of patients with chronic hepatitis B,nitazoxanide suppressed serum HBV DNA and led to loss of hepatitis B e antigen in the majority of patients and hepatitis B surface antigen in approximately a quarter of patients.Randomized controlled studies of naive and nonresponder patients with chronic hepatitis C genotype 1 are underway,new second generation and controlled release thiazolides are being developed,and future studies of patients with chronic hepatitis B are planned.

Validated stability indicating methods for determination of nitazoxanide in presence of its degradation products

Three sensitive,selective and reproducible stability-indicating methods are presented for determination of nitazoxanide (NTZ),a new anti-protozoal drug,in presence of its degradation products.Method A utilizes the first derivative of ratio spectra spectrophotometry by measurement of the amplitude at 364.4 nm using one of the degradation products as a divisor.Method B is a chemometric-assisted spectrophotometry,where principal component regression (PCR) and partial least squares (PLS) were applied.These two approaches were successfully applied to quantify NTZ in presence of degradation products using the information included in the absorption spectra in the range 260-360 nm.Method C is based on the separation of NTZ from its degradation products followed by densitometric measurement of the bands at 254 nm.The separation was carried out on silica gel 60F 254,using chloroform-methanol-ammonia solution-glacial acetic acid (95:5:1:1 by volume,pH=5.80) as a developing system.These methods are suitable as stability-indicating methods for the determination of NTZ in presence of its degradation products either in bulk powder or in pharmaceutical formulations.Statistical analysis of the results has been carried out revealing high accuracy and good precision.

Introducing nitazoxanide as a promising alternative treatment for symptomatic to metronidazole-resistant giardiasis in clinical isolates

Objective:To identify the frequencies(F) of ferredoxin and nitroreductase mutations were identified on Iranian clinical isolates of Giardia lamblia in order to predict whether the nitazoxanide can be prescribed as suitable drug for symptomatic to metronidazoleresistant giardiasis.Methods:Forty Giardia lamblia isolates as of 38 symptomatic and two metronidazole-resistant patients were collected from Iran.DNAs were extracted and amplified by targeting ferredoxin and Gl NR genes.The amplicons were directly sequenced to determine gene mutations.Results:The various amino acid substitutions(F:20%,Haplotype diversity:0.891,Tajima's D:-0.44013) were identified by analyzing ferredoxin gene in four symptomatic and two resistant isolates.Only,two haplotypes(F:5%,HD:0.345; Tajima's D:0.77815) characterized in metronidazole-resistant isolates of Gl NR,however,no point mutations was found in symptomatic isolates.Conclusions:Non-synonymous mutations of ferredoxin oxidoreductase gene reduce translational regulatory protein's binding affinity which concludes reduction of ferredoxin expression and its activity.This leads to decrease in metronidazole drug delivery into the cells.Mutations in these isolates may lead to their resistance to metronidazole.No to low synonymous mutations of Gl NR demonstrates that nitazoxanide can be prescribed as promising alternative treatment for symptomatic to metronidazole-resistant giardiasis in Iranian clinical isolates.

Voltammetric quantitation of nitazoxanide by glassy carbon electrode

The present study reports voltammetric reduction of nitazoxanide in Britton-Robinson （B-R） buffer by cyclic and square-wave voltammetry at glassy carbon electrode. A versatile fully validated voltammetric method for quantitative determination of nitazoxanide in pharmaceutical formulation has been proposed. A squrewave peak current was linear over the nitazoxanide concentration in the range of 20-140 ~tg/mL. The limit of detection （LOD） and limit of quantification （LOQ） was calculated to be 5.23 la~/mL and 17.45 la~/mL, respectively.

Nitazoxanide治疗小肠贾第鞭毛虫、溶组织内阿米巴/迪斯帕内阿米巴引起的腹泻的随机、双盲、安慰剂对照研究

腹泻是肠道原虫感染的典型症状,以贾第鞭毛虫和溶组织内阿米巴最常见。nita-zoxanide是一种广谱抗微生物制剂,本研究以随机、双盲并设安慰剂对照的方法研究该药治疗贾第鞭毛虫和溶组织内阿米巴原虫感染引起腹泻的效果。

The clinical antiprotozoal drug nitazoxanide and its metabolite tizoxanide extend Caenorhabditis elegans lifespan and healthspan

The drugs extending healthspan in clinic have always been searched.Nitazoxanide is an FDA-approved clinical antiprotozoal drug.Nitazoxanide is rapidly metabolized to tizoxanide after absorption in vivo.Our previous studies find that nitazoxanide and its metabolite tizoxanide induce mild mitochondrial uncoupling and activate cellular AMPK,oral nitazoxanide protects against experimental hyperlipidemia,hepatic steatosis,and atherosclerosis.Here,we demonstrate that both nitazoxanide and tizoxanide extend the lifespan and healthspan of Caenorhabditis elegans through Akt/AMPK/sir 2.1/daf16 pathway.Additionally,both nitazoxanide and tizoxanide improve high glucose-induced shortening of C.elegans lifespan.Nitazoxanide has been a clinical drug with a good safety profile,we suggest that it is a novel anti-aging drug.

Anthelmintics nitazoxanide protects against experimental hyperlipidemia and hepatic steatosis in hamsters and mice

Lipid metabolism disorders contribute to hyperlipidemia and hepatic steatosis.It is ideal to develop drugs simultaneous improving both hyperlipidemia and hepatic steatosis.Nitazoxanide is an FDA-approved oral antiprotozoal drug with excellent pharmacokinetic and safety profile.We found that nitazoxanide and its metabolite tizoxanide induced mild mitochondrial uncoupling and subsequently activated AMPK in Hep G2 cells.Gavage administration of nitazoxanide inhibited high-fat diet(HFD)-induced increases of liver weight,blood and liver lipids,and ameliorated HFD-induced renal lipid accumulation in hamsters.Nitazoxanide significantly improved HFD-induced histopathologic changes of hamster livers.In the hamsters with pre-existing hyperlipidemia and hepatic steatosis,nitazoxanide also showed therapeutic effect.Gavage administration of nitazoxanide improved HFD-induced hepatic steatosis in C57BL/6J mice and western diet(WD)-induced hepatic steatosis in Apoe-/-mice.The present study suggests that repurposing nitazoxanide as a drug for hyperlipidemia and hepatic steatosis treatment is promising.

Discovery of nitazoxanide-based derivatives as autophagy activators for the treatment of Alzheimer’s disease

Drug repurposing is an efficient strategy for new drug discovery.Our latest study found that nitazoxanide(NTZ),an approved anti-parasite drug,was an autophagy activator and could alleviate the symptom of Alzheimer’s disease(AD).In order to further improve the efficacy and discover new chemical entities,a series of NTZ-based derivatives were designed,synthesized,and evaluated as autophagy activator against AD.All compounds were screened by the inhibition of phosphorylation of p70S6K,which was the direct substrate of mammalian target of rapamycin(mTOR)and its phosphorylation level could reflect the mTOR-dependent autophagy level.Among these analogs,compound 22 exhibited excellent potency in promotingβ-amyloid(Aβ)clearance,inhibiting tau phosphorylation,as well as stimulating autophagy both in vitro and in vivo.What’s more,22 could effectively improve the memory and cognitive impairments in APP/PS1 transgenic AD model mice.These results demonstrated that 22 was a potential candidate for the treatment of AD.

Cryptosporidium infection in solid organ transplantation

Diarrhea is a common complication in solid organ transplant(SOT) recipients and may be attributed to immunosuppressive drugs or infectious organisms such as bacteria, viruses or parasites. Cryptosporidium usually causes self-limited diarrhea in immunocompetent hosts. Although it is estimated that cryptosporidium is involved in about 12% of cases of infectious diarrhea in developing countries and causes approximately 748000 cases each year in the United States, it is still an under recognized and important cause of infectious diarrhea in SOT recipients. It may run a protracted course with severe diarrhea, fluid and electrolyte depletion and potential for organ failure. Although diagnostic methodologies have improved significantly, allowing for fast and accurate identification of the parasite, treatment of the disease is difficult because antiparasitic drugs have modest activity at best. Current management includes fluid and electrolyte replacement, reduction of immunosuppression and single therapy with Nitazoxanide or combination therapy with Nitazoxanide and other drugs. Future drug and vaccine development may add to the currently poor armamentarium to manage the disease. The current review highlights key epidemiological, diagnostic and management issues in the SOT population.