Background: Many treatments are being assessed for repurposing to treat coronavirus disease 2019 (COVI D-19). One drug that has shown promising results in vitro is nitazoxanide. Unlike other postulated drugs, nitazoxanide shows a high ratio of maximum plasma concentration (Cmax), after 1 day of 500 mg twice daily (BD), to the concentration required to inhibit 50% replication (EC50) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Cmax: E C50 roughly equal to 14:1). As such, it is important to investigate the safety of nitazoxanide for further trials. Furthermore, treatments for COVI D-19 should be cheap to promote global access, but prices of many drugs are far higher than the costs of production. We aimed to conduct a review of the safety of nitazoxanide for any prior indication and calculate its minimum costs of production. Methods: A review of nitazoxanide clinical research was conducted using EMBASE and MEDLINE databases, supplemented by ClinicalTrials.gov. We searched for phase 2 or 3 randomised controlled trials (RCTs) comparing nitazoxanide with placebo or active control for 5-14 days in participants experiencing acute infections of any kind. Data extracted were grade 1-4 and serious adverse events (AEs). Data were also extracted on gastrointestinal (GI) AEs, as well as hepatorenal and cardiovascular effects. Active pharmaceutical ingredient cost data from 2016 to 2019 were extracted from the Panjiva database and adjusted for 5% loss during production, costs of excipients, formulation, a 10% profit margin and tax. Two dosages, at 500 mg BD and a higher dose of 1100 mg three times daily (TDS), were considered. Our estimated costs were compared with publicly available list prices from a selection of countries. Results: Nine RCTs of nitazoxanide were identified for inclusion. These RCTs accounted for 1514 participants and an estimated 95.3 person-years-of-follow-up. No significant differences were found in any of the AE endpoints assessed, across all trials or on subgroup analyses of active- or placebo-controlled trials. Mild GI AEs increased with dose. No hepatorenal or cardiovascular concerns were raised, but few appropriate metrics were reported. There were no teratogenic concerns, but the evidence base was very limited. Based on a weighted-mean cost of US $61/kg, a 14-day course of treatment with nitazoxanide 500 mg BD would cost $1.41. The daily cost would therefore be $0.10. The same 14-day course could cost $3944 in US commercial pharmacies, and $3 per course in Pakistan, India and Bangladesh. At a higher dose of 1100 mg TDS, our estimated cost was $4.08 per 14-day course, equivalent to $0.29 per day. Conclusion: Nitazoxanide demonstrates a good safety profile at approved doses. However, further evidence is required regarding hepatorenal and cardiovascular effects, as well as teratogenicity. We estimate that it would be possible to manufacture nitazoxanide as generic for $1.41 for a 14-day treatment course at 500 mg BD, up to $4.08 at 1100 mg TDS. Further trials in COVI D-19 patients should be initiated. If efficacy against SARS-CoV-2 is demonstrated in clinical studies, nitazoxanide may represent a safe and affordable treatment in the ongoing pandemic.
BACKGROUND: Infection with the protozoan Entamoeba histolytica is common in low- and middle-income countries, and up to 100,000 people with severe disease die every year. Adequate therapy for amoebic colitis is necessary to reduce illness, prevent development of complicated disease and extraintestinal spread, and decrease transmission.
OBJECTIVES: To evaluate antiamoebic drugs for treating amoebic colitis.
SEARCH METHODS: We searched the available literature up to 22 March 2018. We searched the Cochrane Infectious Diseases Group Specialised Register, CENTRAL, MEDLINE, Embase, LILACS, mRCT, and conference proceedings. We contacted individual researchers, organizations, and pharmaceutical companies, and we checked reference lists.
SELECTION CRITERIA: Randomized controlled trials of antiamoebic drugs given alone or in combination, compared with placebo or another antiamoebic drug, for treating adults and children with a diagnosis of amoebic colitis.
DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the eligibility and methodological quality of trials and extracted and analysed the data. We calculated clinical and parasitological failure rates and rates of relapse and adverse events as risk ratios (RRs) with 95% confidence intervals (CIs), using a random-effects model. We determined statistical heterogeneity and explored possible sources of heterogeneity using subgroup analyses. We carried out sensitivity analysis by using trial quality to assess the robustness of reported results.
MAIN RESULTS: In total, 41 trials (4999 participants) met the inclusion criteria of this review. In this update, we added four trials to the 37 trials included in the first published review version. Thirty trials were published over 20 years ago. Only one trial used adequate methods of randomization and allocation concealment, was blinded, and analysed all randomized participants. Only one trial used an E histolytica stool antigen test, and two trials used amoebic culture.Tinidazole may be more effective than metronidazole for reducing clinical failure (RR 0.28, 95% CI 0.15 to 0.51; 477 participants, eight trials; low-certainty evidence) and is probably associated with fewer adverse events (RR 0.65, 95% CI 0.46 to 0.92; 477 participants, 8 trials; moderate-certainty evidence). Compared with metronidazole, combination therapy may result in fewer parasitological failures (RR 0.36, 95% CI 0.15 to 0.86; 720 participants, 3 trials; low-certainty evidence), but we are uncertain which combination is more effective than another. Evidence is insufficient to allow conclusions regarding the efficacy of other antiamoebic drugs.
AUTHORS' CONCLUSIONS: Compared with metronidazole, tinidazole may be more effective in reducing clinical failure and may be associated with fewer adverse events. Combination drug therapy may be more effective for reducing parasitological failure compared with metronidazole alone. However, these results are based mostly on small trials conducted over 20 years ago with a variety of poorly defined outcomes. Tests that detect E histolytica more accurately are needed, particularly in countries where concomitant infection with other bacteria and parasites is common.
INTRODUCTION: Acute diarrhea continues to be a leading cause of morbidity, hospitalization and mortality worldwide and probiotics have been proposed as a complementary therapy in the treatment of acute diarrhea. Regarding the treatment of acute diarrhea, a few probiotics including Saccharomyces boulardii seem to be promising therapeutic agents.
AREAS COVERED: We performed a systematic review and meta-analysis regarding the use of S. boulardii in the treatment of acute infectious diarrhea with relevant studies that searched with the PubMed, Embase, Scopus, Google Scholar, the Cochrane Controlled Trials Library, and the Cochrane Database of Systematic Reviews through October 2011. This review describes the effects of S. boulardii on the duration of diarrhea, the risk of diarrhea during the treatment (especially at the third day) and duration of hospitalization in patients with acute infectious diarrhea. This review also focused on the potential effects of S. boulardii for acute infectious diarrhea due to different etiological causes.
EXPERT OPINION: S. boulardii significantly reduced the duration of diarrhea approximately 24 h and that of hospitalization approximately 20 h. S. boulardii shortened the initial phase of watery stools; mean number of stools started to decrease at day 2; moreover, a significant reduction was reported at days 3 and 4. This systematic review and meta-analysis of the efficacy of S. boulardii in the treatment of acute infectious diarrhea show that there is strong evidence that this probiotic has a clinically significant benefit, whatever the cause, including in developing countries. Therefore, with S. boulardii, the shortened duration of diarrhea and the reduction in hospital stay result in social and economic benefits.
This article reviews the evidence for efficacy and safety of Saccharomyces boulardii (S. boulardii) for various disease indications in adults based on the peer-reviewed, randomized clinical trials and pre-clinical studies from the published medical literature (Medline, Clinical Trial websites and meeting abstracts) between 1976 and 2009. For meta-analysis, only randomized, blinded controlled trials unrestricted by language were included. Pre-clinical studies, volunteer studies and uncontrolled studies were excluded from the review of efficacy and meta-analysis, but included in the systematic review. Of 31 randomized, placebo-controlled treatment arms in 27 trials (encompassing 5029 study patients), S. boulardii was found to be significantly efficacious and safe in 84% of those treatment arms. A meta-analysis found a significant therapeutic efficacy for S. boulardii in the prevention of antibiotic-associated diarrhea (AAD) (RR = 0.47, 95% CI: 0.35-0.63, P < 0.001). In adults, S. boulardii can be strongly recommended for the prevention of AAD and the traveler's diarrhea. Randomized trials also support the use of this yeast probiotic for prevention of enteral nutrition-related diarrhea and reduction of Helicobacter pylori treatment-related symptoms. S. boulardii shows promise for the prevention of C. difficile disease recurrences; treatment of irritable bowel syndrome, acute adult diarrhea, Crohn's disease, giardiasis, human immunodeficiency virus-related diarrhea; but more supporting evidence is recommended for these indications. The use of S. boulardii as a therapeutic probiotic is evidence-based for both efficacy and safety for several types of diarrhea.
Background: Many treatments are being assessed for repurposing to treat coronavirus disease 2019 (COVI D-19). One drug that has shown promising results in vitro is nitazoxanide. Unlike other postulated drugs, nitazoxanide shows a high ratio of maximum plasma concentration (Cmax), after 1 day of 500 mg twice daily (BD), to the concentration required to inhibit 50% replication (EC50) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Cmax: E C50 roughly equal to 14:1). As such, it is important to investigate the safety of nitazoxanide for further trials. Furthermore, treatments for COVI D-19 should be cheap to promote global access, but prices of many drugs are far higher than the costs of production. We aimed to conduct a review of the safety of nitazoxanide for any prior indication and calculate its minimum costs of production. Methods: A review of nitazoxanide clinical research was conducted using EMBASE and MEDLINE databases, supplemented by ClinicalTrials.gov. We searched for phase 2 or 3 randomised controlled trials (RCTs) comparing nitazoxanide with placebo or active control for 5-14 days in participants experiencing acute infections of any kind. Data extracted were grade 1-4 and serious adverse events (AEs). Data were also extracted on gastrointestinal (GI) AEs, as well as hepatorenal and cardiovascular effects. Active pharmaceutical ingredient cost data from 2016 to 2019 were extracted from the Panjiva database and adjusted for 5% loss during production, costs of excipients, formulation, a 10% profit margin and tax. Two dosages, at 500 mg BD and a higher dose of 1100 mg three times daily (TDS), were considered. Our estimated costs were compared with publicly available list prices from a selection of countries. Results: Nine RCTs of nitazoxanide were identified for inclusion. These RCTs accounted for 1514 participants and an estimated 95.3 person-years-of-follow-up. No significant differences were found in any of the AE endpoints assessed, across all trials or on subgroup analyses of active- or placebo-controlled trials. Mild GI AEs increased with dose. No hepatorenal or cardiovascular concerns were raised, but few appropriate metrics were reported. There were no teratogenic concerns, but the evidence base was very limited. Based on a weighted-mean cost of US $61/kg, a 14-day course of treatment with nitazoxanide 500 mg BD would cost $1.41. The daily cost would therefore be $0.10. The same 14-day course could cost $3944 in US commercial pharmacies, and $3 per course in Pakistan, India and Bangladesh. At a higher dose of 1100 mg TDS, our estimated cost was $4.08 per 14-day course, equivalent to $0.29 per day. Conclusion: Nitazoxanide demonstrates a good safety profile at approved doses. However, further evidence is required regarding hepatorenal and cardiovascular effects, as well as teratogenicity. We estimate that it would be possible to manufacture nitazoxanide as generic for $1.41 for a 14-day treatment course at 500 mg BD, up to $4.08 at 1100 mg TDS. Further trials in COVI D-19 patients should be initiated. If efficacy against SARS-CoV-2 is demonstrated in clinical studies, nitazoxanide may represent a safe and affordable treatment in the ongoing pandemic.
