- Fasciolopsiasis in children: Clinical, sociodemographic profile and outcome. [Journal Article]
- IJIndian J Med Microbiol 2017 Oct-Dec; 35(4):551-554
- CONCLUSIONS: All patients recovered well except one who died due to severe PEM and disseminated tuberculosis and two cases presented with relapse. Most of the cases of polyparasitism were associated with tuberculosis.
- The NICE-GUT trial protocol: a randomised, placebo controlled trial of oral nitazoxanide for the empiric treatment of acute gastroenteritis among Australian Aboriginal children. [Journal Article]
- BOBMJ Open 2018 02 01; 8(2):e019632
- Diarrhoeal disease is the second leading cause of death in children under 5 years globally, killing 525 000 annually. Australian Aboriginal and Torres Strait Islander (hereafter Aboriginal) children ...
Diarrhoeal disease is the second leading cause of death in children under 5 years globally, killing 525 000 annually. Australian Aboriginal and Torres Strait Islander (hereafter Aboriginal) children suffer a high burden of disease. Randomised trials in other populations suggest nitazoxanide accelerates recovery for children withGiardia, amoebiasis,Cryptosporidium, Rotavirus and Norovirusgastroenteritis, as well as in cases where no enteropathogens are found.
- Protein disulfide isomerases as potential therapeutic targets for influenza A and B viruses. [Journal Article]
- VRVirus Res 2018 Jan 31; 247:26-33
- Seasonal flu as well as potential pandemic flu outbreaks continuously underscores the importance of the preventive and therapeutic measures against influenza viruses. During screening of natural and ...
Seasonal flu as well as potential pandemic flu outbreaks continuously underscores the importance of the preventive and therapeutic measures against influenza viruses. During screening of natural and synthetic small molecules against influenza A and B virus, we identified juniferdin as a highly effective inhibitor against both viruses in cells. Since juniferdin is known to inhibit protein disulfide isomerases (PDIs), multiple PDI inhibitors were tested against these viruses. Among PDI inhibitors, 16F16, PACMA31, isoquercetin, epigallocatechin-3-gallate or nitazoxanide significantly reduced the replication of influenza A and B viruses in MDCK and A549 cells. Furthermore, siRNAs specific to three PDI family members (PDI1, PDIA3 or PDIA4) also significantly reduced the replication of influenza A and B viruses in cells. These results suggest that PDIs may serve as excellent targets for the development of new anti-influenza drugs.
- Comparative analysis of the visual performance after implantation of the toric implantable collamer lens in stable keratoconus: a 4-year follow-up after sequential procedure (CXL+TICL implantation). [Journal Article]
- BOBMJ Open Ophthalmol 2017; 2(1):e000090
- CONCLUSIONS: The results from this standardised clinical investigation support TICL implantation from clinical and optical viewpoints in patients with stable keratoconus.
- Development of a Cytopathic Effect-Based Phenotypic Screening Assay against Cryptosporidium. [Journal Article]
- AIACS Infect Dis 2018 Jan 25
- Cryptosporidiosis is a diarrheal disease predominantly caused by Cryptosporidium parvum (Cp) and Cryptosporidium hominis (Ch), apicomplexan parasites which infect the intestinal epithelial cells of t...
Cryptosporidiosis is a diarrheal disease predominantly caused by Cryptosporidium parvum (Cp) and Cryptosporidium hominis (Ch), apicomplexan parasites which infect the intestinal epithelial cells of their human hosts. The only approved drug for cryptosporidiosis is nitazoxanide, which shows limited efficacy in immunocompromised children, the most vulnerable patient population. Thus, new therapeutics and in vitro infection models are urgently needed to address the current unmet medical need. Toward this aim, we have developed novel cytopathic effect (CPE)-based Cp and Ch assays in human colonic tumor (HCT-8) cells and compared them to traditional imaging formats. Further model validation was achieved through screening a collection of FDA-approved drugs and confirming many previously known anti-Cryptosporidium hits as well as identifying a few novel candidates. Collectively, our data reveals this model to be a simple, functional, and homogeneous gain of signal format amenable to high throughput screening, opening new avenues for the discovery of novel anticryptosporidials.
- A Novel Piperazine-Based Drug Lead for Cryptosporidiosis from the Medicines for Malaria Venture Open Access Malaria Box. [Journal Article]
- AAAntimicrob Agents Chemother 2018 Jan 16
- Cryptosporidiosis causes life-threatening diarrhea in children under age five, and prolonged diarrhea in immunodeficient people, especially AIDS patients. The standard of care, nitazoxanide, is modes...
Cryptosporidiosis causes life-threatening diarrhea in children under age five, and prolonged diarrhea in immunodeficient people, especially AIDS patients. The standard of care, nitazoxanide, is modestly effective in children and ineffective in immunocompromised individuals. In addition to a need for new drugs, better knowledge of drug properties that drivein vivoefficacy is needed to facilitate drug development. We report identification of a piperazine-based lead compound forCryptosporidiumdrug development, MMV665917, and a new pharmacodynamic method used for its characterization. MMV665917 was identified from the Medicines for Malaria Venture Malaria Box, followed by dose response studies,in vitrotoxicity studies, and structure activity relationship studies using commercial analogues. Potency againstC. parvumIowa and field isolates, andC. hominiswas comparable. Furthermore, unlike nitazoxanide, clofazimine, and paromomycin, MMV665917 appeared to be curative in a chronic NOD SCID gamma mouse model of cryptosporidiosis. MMV665917 was also efficacious in an acute interferon-γ knockout mouse model. To determine if efficacy in this chronic mouse model might relate to whether compounds are cidal or static forC. parvum, we developed a novelin vitroparasite persistence assay. This assay suggested that MMV665917 was cidal, unlike nitazoxanide, clofazimine, and paromomycin. It also enabled determination of the compound concentration required to maximize the rate of parasite elimination. This time-kill assay can be used to prioritize early-stageCryptosporidiumdrug leads, and may aide in planningin vivoefficacy experiments. Collectively, these results identify MMV665917 as a promising lead, and establish a new method for characterizing potential anticryptosporidial agents.
- The role of adjuvant immunomodulatory agents for treatment of severe influenza. [Review]
- ARAntiviral Res 2018; 150:202-216
- A severe inflammatory immune response with hypercytokinemia occurs in patients hospitalized with severe influenza, such as avian influenza A(H5N1), A(H7N9), and seasonal A(H1N1)pdm09 virus infections...
A severe inflammatory immune response with hypercytokinemia occurs in patients hospitalized with severe influenza, such as avian influenza A(H5N1), A(H7N9), and seasonal A(H1N1)pdm09 virus infections. The role of immunomodulatory therapy is unclear as there have been limited published data based on randomized controlled trials (RCTs). Passive immunotherapy such as convalescent plasma and hyperimmune globulin have some studies demonstrating benefit when administered as an adjunctive therapy for severe influenza. Triple combination of oseltamivir, clarithromycin, and naproxen for severe influenza has one study supporting its use, and confirmatory studies would be of great interest. Likewise, confirmatory studies of sirolimus without concomitant corticosteroid therapy should be explored as a research priority. Other agents with potential immunomodulating effects, including non-immune intravenous immunoglobulin, N-acetylcysteine, acute use of statins, macrolides, pamidronate, nitazoxanide, chloroquine, antiC5a antibody, interferons, human mesenchymal stromal cells, mycophenolic acid, peroxisome proliferator-activated receptors agonists, non-steroidal anti-inflammatory agents, mesalazine, herbal medicine, and the role of plasmapheresis and hemoperfusion as rescue therapy have supportive preclinical or observational clinical data, and deserve more investigation preferably by RCTs. Systemic corticosteroids administered in high dose may increase the risk of mortality and morbidity in patients with severe influenza and should not be used, while the clinical utility of low dose systemic corticosteroids requires further investigation.
- Time-dependent therapeutic roles of nitazoxanide on high-fat diet/streptozotocin-induced diabetes in rats: effects on hepatic peroxisome proliferator-activated receptor-gamma receptors. [Journal Article]
- CJCan J Physiol Pharmacol 2017 Dec 15; :1-13
- Targeting peroxisome proliferator-activated receptor-gamma (PPAR-γ) is an approved strategy in facing insulin resistance (IR) for diabetes mellitus (DM) type 2. The PPAR-γ modulators display improvem...
Targeting peroxisome proliferator-activated receptor-gamma (PPAR-γ) is an approved strategy in facing insulin resistance (IR) for diabetes mellitus (DM) type 2. The PPAR-γ modulators display improvements in the insulin-sensitizing and adverse effects of the traditional thiazolidinediones. Nitazoxanide (NTZ) is proposed as a PPAR-γ receptor ligand with agonistic post-transcriptional effects. Currently, NTZ antidiabetic activities versus pioglitazone (PIO) in a high-fat diet/streptozotocin rat model of type 2 diabetes was explored. Diabetic adult male Wistar rats were treated orally with either PIO (2.7 mg·kg-1·day-1) or NTZ (200 mg·kg-1·day-1) for 14, 21, and 28 days. Body masses, fasting blood glucose, IR, lipid profiles, and liver and kidney functions of rats were assayed. Hepatic glucose metabolism and PPAR-γ protein expression levels as well as hepatic, pancreatic, muscular, and renal histopathology were evaluated. Significant time-dependent euglycemic and insulin-sensitizing effects with preservation of liver and kidney functions were offered by NTZ. Higher hepatic levels of glucose-6-phosphatase and glucose-6-phosphate dehydrogenase enzymes and PPAR-γ protein expressions were acquired by NTZ and PIO, respectively. NTZ could be considered an oral therapeutic strategy for DM type 2. Further systematic NTZ/PPAR-γ receptor subtype molecular activations are recommended. Simultaneous use of NTZ with other approved antidiabetics should be explored.
- Prevention and treatment of respiratory viral infections: Presentations on antivirals, traditional therapies and host-directed interventions at the 5th ISIRV Antiviral Group conference. [Journal Article]
- ARAntiviral Res 2018; 149:118-142
- The International Society for Influenza and other Respiratory Virus Diseases held its 5th Antiviral Group (isirv-AVG) Conference in Shanghai, China, in conjunction with the Shanghai Public Health Cen...
The International Society for Influenza and other Respiratory Virus Diseases held its 5th Antiviral Group (isirv-AVG) Conference in Shanghai, China, in conjunction with the Shanghai Public Health Center and Fudan University from 14-16 June 2017. The three-day programme encompassed presentations on some of the clinical features, management, immune responses and virology of respiratory infections, including influenza A(H1N1)pdm09 and A(H7N9) viruses, MERS-CoV, SARS-CoV, adenovirus Type 80, enterovirus D68, metapneumovirus and respiratory syncytial virus (RSV). Updates were presented on several therapeutics currently in clinical trials, including influenza polymerase inhibitors pimodivir/JNJ6362387, S033188, favipiravir, monoclonal antibodies MHAA45449A and VIS410, and host directed strategies for influenza including nitazoxanide, and polymerase ALS-008112 and fusion inhibitors AK0529, GS-5806 for RSV. Updates were also given on the use of the currently licensed neuraminidase inhibitors. Given the location in China, there were also presentations on the use of Traditional Chinese Medicines. Following on from the previous conference, there were ongoing discussions on appropriate endpoints for severe influenza in clinical trials from regulators and clinicians, an issue which remains unresolved. The aim of this conference summary is to provide information for not only conference participants, but a detailed referenced review of the current status of clinical trials, and pre-clinical development of therapeutics and vaccines for influenza and other respiratory diseases for a broader audience.
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- [Cryptosporidiosis, a cause of acute diarrhea: A review and retrospective study of cases in Rouen university hospital's pediatrics department]. [Journal Article]
- APArch Pediatr 2017; 24(12):1344-1349
- Cryptosporidium is the most important diarrhea-causing protozoan parasite, with severe health consequences for very young, malnourished children living in endemic areas and for immunocompromised indi...
Cryptosporidium is the most important diarrhea-causing protozoan parasite, with severe health consequences for very young, malnourished children living in endemic areas and for immunocompromised individuals. Cryptosporidium is widely distributed and disease transmission can occur through person-to-person or animal-to-person contact, or contaminated food or water (drinking or swimming), leading to large outbreaks. The zoonotic Cryptosporidium parvum and the anthroponotic Cryptosporidium hominis are responsible for the majority of human cases. Specific therapy, primarily nitazoxanide, has some effect in healthy individuals, but drugs effectively preventing or controlling this disease in all clinical situations are not yet available. In France, as elsewhere in Europe, little epidemiological and molecular information is available regarding the burden of cryptosporidiosis in children. Cryptosporidium is usually not tested in all fecal samples submitted for routine parasitological examination and only tested on special request, primarily in immunocompromised patients. Between January 2007 and October 2014, out of a total of 5337 immunocompetent children with diarrhea in Rouen university hospital's pediatrics department, the prevalence of Cryptosporidium infection was 0.97 % (52 infected children). The median age of infected children was 3 years (range, 5 months to 11 years) and 80 % of the cases occurred between July and November. Thirty-six (69.2 %) and 16 (30.8 %) infections were due to C. parvum and C. hominis, respectively. The fact that the species C. parvum, mainly the IIaA15G2R1 subtype, was detected in most locally infected children suggests that cryptosporidiosis must primarily be considered as a zoonotic disease in Upper Normandy.