Thiazolides: a new class of antiviral drugs
ABSTRACT Thiazolides have emerged as a new class of broad-spectrum antiviral drugs, and the first thiazolide, nitazoxanide, is in late-stage clinical trials for treating chronic hepatitis C.
To review the chemistry, pharmacology, toxicology and efficacy of thiazolides as antiviral agents with emphasis on clinical development of nitazoxanide in treating chronic hepatitis C.
Literature search, information from Romark Laboratories and my personal experience with the discovery and development of thiazolides serve as the sources for this review.
Thiazolides are metabolically stable, highly bound to plasma proteins and are associated with a favorable toxicology profile. Phase II clinical trials have demonstrated efficacy and safety of nitazoxanide added to peginterferon with or without ribavirin in treating patients with chronic hepatitis C. More limited clinical data indicated potential in treating chronic hepatitis B, and three randomized controlled trials have demonstrated efficacy in reducing the duration of viral gastroenteritis. New generation thiazolides with the nitro group of nitazoxanide replaced by a non-reducible group are not active against anaerobes but retain broad-spectrum activity against viruses. Further studies are needed. Research indicates that these drugs may play an important and complementary role in combination with other classes of antiviral drugs.
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ABSTRACT: Hepatitis C infection is a disease of the liver caused by the hepatitis C virus. The estimated number of chronically infected people with hepatitis C virus worldwide is about 150 million people. Every year, another three to four million people acquire the infection. Chronic hepatitis C is a leading cause of liver-related mortality and morbidity. It is estimated that around 5% to 20% of people with the infection will develop liver cirrhosis, which increases the risk of hepatocellular carcinoma and liver failure. Until 2011, the combination therapy of pegylated interferon-alpha (peginterferon) and ribavirin was the approved standard treatment for chronic hepatitis C. In 2011, first-generation direct-acting antivirals (DAAs) have been licensed, for use in combination with peginterferon and ribavirin for treating hepatitis C virus genotype 1 infection. Nitazoxanide is another antiviral drug with broad antiviral activity and may have potential as an effective alternative, or an addition to standard treatment for the treatment of the hepatitis C virus. To assess the benefits and harms of nitazoxanide in people with chronic hepatitis C virus infection. We searched The Cochrane Hepato-Biliary Group Controlled Trials Register (last searched April 2013), The Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 3), MEDLINE (Ovid SP, 1948 to April 2013), EMBASE (Ovid SP, 1980 to April 2013), LILACS (1983 to April 2013), and Science Citation Index EXPANDED (ISI Web of Knowledge, 1900 to April 2013), using the search strategies and the expected time spans. We also scanned reference lists of identified studies.We also searched www.clinical trials.gov and the World Health Organisation's International Clinical Trials Registry Platform (ICTRP) search portal (WHO) at apps.who.int/trialsearch/Default.aspx for registered trials, either completed or ongoing (April 2013). We included randomised clinical trials that examined the effects of nitazoxanide versus placebo, no intervention, or any other intervention in patients with chronic hepatitis C. We considered any co-intervention, including standard treatment, if delivered to all intervention groups of the randomised trials concerned. Two review authors extracted data independently. We assessed the risk of systematic errors ('bias') by evaluation of bias risk domains. We used Review Manager 5.2 for the statistical analyses of dichotomous outcome data with risk ratio (RR) and of continuous outcome data with mean difference (MD). For meta-analyses with more than one trial, we used a fixed-effect model and a random-effects model, along with an assessment of heterogeneity. We assessed risk of random errors ('play of chance') using trial sequential analysis. We assessed the quality of the evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to present review results in 'Summary of findings' tables. We included seven randomised clinical trials with a total of 538 participants with chronic hepatitis C, in the review. Participants were 18 years of age or older, all diagnosed with chronic hepatitis C genotype 1 or 4. All of the trials had a high risk of bias. All of the trials compared nitazoxanide with placebo or no intervention, and six out of seven of the trials also assessed different antiviral co-interventions administered equally to all experimental groups. Only one trial, comparing nitazoxanide plus peginterferon plus ribavirin versus peginterferon plus ribavirin, provided information that there were no deaths due to any cause or due to chronic hepatitis C (100 participants, very low quality evidence). The relative effect of nitazoxanide versus placebo or no intervention on adverse events was uncertain (37 out of 179 (21%) versus 30 out of 152 (20%); RR 1.10; 95% CI 0.71 to 1.71; I(2) = 65%; four trials; very low quality evidence). The meta-analyses showed that nitazoxanide decreased the risk of failure to achieve sustained virological response when compared to placebo or no intervention (159 out of 290 (55%) versus 133 out of 208 (64%); RR 0.85; 95% CI 0.75 to 0.97; I(2) = 0%; seven trials; low quality evidence) and also the risk of failure to achieve virological end-of-treatment response (125 out of 290 (43%) versus 110 out of 208 (53%); RR 0.81; 95% CI 0.69 to 0.96; I(2) = 46%; seven trials; low quality evidence). Trial sequential analysis supported the meta-analysis result for sustained virological response; however, it did not support the meta-analysis for virological end-of-treatment response. Meta-analysis also showed that nitazoxanide did not decrease the number of participants who showed no improvement in alanine aminotransferase and aspartate aminotransferase serum levels when compared to placebo or no intervention (52 out of 97 (54%) versus 47 out of 95 (49%); RR 1.09; 95% CI 0.84 to 1.42; I(2) = 0%; three trials; very low quality evidence). None of the included trials assessed the effects of nitazoxanide on morbidity or on quality of life. The included trials assessed only baseline data on morbidity. Histological changes were only reported on a subset of three participants out of thirteen participants included in a long term-follow-up trial. We found very low quality, or no, evidence on nitazoxanide for clinically- or patient-relevant outcomes, such as all-cause mortality, chronic hepatitis C-related mortality, morbidity, and adverse events in participants with chronic hepatitis C genotype 1 or 4 infection. Our results on participants who showed no improvement in alanine aminotransferase and aspartate aminotransferase serum levels were also uncertain. No conclusion could be drawn about liver histology because of a lack of data. Our results indicate that nitazoxanide might have an effect on sustained virological response and virological end-of-treatment response. However, both results could be influenced by systematic errors because all the trials included in the review had a high risk of bias. Furthermore, only the beneficial effect on number of participants achieving sustained virological response was supported when we applied trial sequential analysis. The results on virological end-of-treatment response might, therefore, be caused by a random error. We lack information on the effects of nitazoxanide in participants with chronic hepatitis C genotypes 2 or 3 infection. More randomised clinical trials with a low risk of bias are needed to assess the effects of nitazoxanide for chronic hepatitis C.Cochrane database of systematic reviews (Online) 04/2014; 4:CD009182. DOI:10.1002/14651858.CD009182.pub2 · 5.94 Impact Factor
- Journal of Medicinal Chemistry 01/2011; 54:4119-4132. · 5.48 Impact Factor
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ABSTRACT: Helminth infections are responsible for a considerable public health burden, yet the current drug armamentarium is small. Given the high cost of drug discovery and development, the high failure rates and the long duration to develop novel treatments, drug repurposing circumvents these obstacles by finding new uses for compounds other than those they were initially intended to treat. In the present review, we summarize in vivo and clinical trial findings testing clinical candidates and marketed drugs against schistosomes, food-borne trematodes, soil-transmitted helminths, Strongyloides stercoralis, the major human filariases lymphatic filariasis and onchocerciasis, taeniasis, neurocysticercosis and echinococcosis. While expanding the applications of broad-spectrum or veterinary anthelmintics continues to fuel alternative treatment options, antimalarials, antibiotics, antiprotozoals and anticancer agents appear to be producing fruitful results as well. The trematodes and nematodes continue to be most investigated, while cestodal drug discovery will need to be accelerated. The most clinically advanced drug candidates include the artemisinins and mefloquine against schistosomiasis, tribendimidine against liver flukes, oxantel pamoate against trichuriasis, and doxycycline against filariasis. Preclinical studies indicate a handful of promising future candidates, and are beginning to elucidate the broad-spectrum activity of some currently used anthelmintics. Challenges and opportunities are further discussed.12/2014; DOI:10.1016/j.ijpddr.2014.07.002