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Lu Y, Zhang X, Guan Z, Ji R, Peng F, Zhao C, Gao W, Gao F. Molecular pathogenesis of Cryptosporidium and advancements in therapeutic interventions. Parasite 2025; 32:7. [PMID: 39902829 PMCID: PMC11792522 DOI: 10.1051/parasite/2025001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Accepted: 01/14/2025] [Indexed: 02/06/2025] Open
Abstract
Cryptosporidiosis, caused by a Cryptosporidium infection, is a serious gastrointestinal disease commonly leading to diarrhea in humans. This disease poses a particular threat to infants, young children, and those with weakened immune systems. The treatment of cryptosporidiosis is challenging due to the current lack of an effective treatment or vaccine. Ongoing research is focused on understanding the molecular pathogenesis of Cryptosporidium and developing pharmacological treatments. In this review, we examine the signaling pathways activated by Cryptosporidium infection within the host and their role in protecting host epithelial cells. Additionally, we also review the research progress of chemotherapeutic targets against cryptosporidia-specific enzymes and anti-Cryptosporidium drugs (including Chinese and Western medicinal drugs), aiming at the development of more effective treatments for cryptosporidiosis.
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Affiliation(s)
- Yilong Lu
- College of Basic Medical Sciences, Shandong Second Medical University Weifang China
| | - Xiaoning Zhang
- College of Basic Medical Sciences, Shandong Second Medical University Weifang China
| | - Zhiyu Guan
- College of Basic Medical Sciences, Shandong Second Medical University Weifang China
| | - Rui Ji
- College of Traditional Chinese Medicine, Shandong Second Medical University Weifang China
| | - Fujun Peng
- College of Basic Medical Sciences, Shandong Second Medical University Weifang China
| | - Chunzhen Zhao
- College of Pharmacy, Shandong Second Medical University Weifang China
| | - Wei Gao
- College of Clinical Medicine, Shandong Second Medical University Weifang China
| | - Feng Gao
- College of Pharmacy, Shandong Second Medical University Weifang China
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Kosik-Bogacka D, Łanocha-Arendarczyk N, Korzeniewski K, Mularczyk M, Kabat-Koperska J, Ziętek P, Marchelek-Myśliwiec M. Cryptosporidium spp. Infection in Adult Kidney Transplant Patients: A Systematic Review and Meta-Analysis. J Clin Med 2024; 13:6395. [PMID: 39518534 PMCID: PMC11546429 DOI: 10.3390/jcm13216395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 10/15/2024] [Accepted: 10/15/2024] [Indexed: 11/16/2024] Open
Abstract
Background: Diarrhea frequently occurs after vascular organ transplantation, including kidney transplants. This may result from non-infectious factors, adverse effects of immunosuppressive medications, or infections caused by various pathogens, including viruses, bacteria, fungi, or parasites, for example, intestinal protozoan parasites such as Cryptosporidium spp., which are particularly dangerous for immunocompromised patients. Methods: This review is based on scientific articles sourced from validated databases such as PubMed, the National Center for Biotechnology Information (NCBI), ScienceDirect, and Google Scholar. The primary search was conducted on 12-13 July 2024, using the keywords 'Cryptosporidium' AND 'cryptosporidiosis' AND 'kidney' AND 'transplant' AND 'adult'. Inclusion criteria encompassed human studies, case reports, peer-reviewed journal publications, review articles, and research articles in English. Exclusion criteria included studies not in English, gray literature (e.g., conference proceedings and abstracts), and data related to pediatric patients (under 18 years old) and HIV patients. Results: This systematic review and meta-analysis have highlighted an often-overlooked connection between Cryptosporidium spp. infections in adult kidney transplant recipients (KTR). Furthermore, it includes an analysis of the clinical presentation, diagnosis, and treatment of Cryptosporidium spp. infection in these patients, based on available case reports. Our study demonstrates that adult kidney transplant patients are at a significantly higher risk of acquiring Cryptosporidium spp. compared to healthy participants. Conclusions:Cryptosporidium spp. infections can be asymptomatic, making it essential to screen both symptomatic and asymptomatic kidney transplant recipients. The clinical presentation of cryptosporidiosis typically involves digestive symptoms and can be complicated by biliary tract involvement. In KTR patients presenting with diarrhea, it is crucial to not only test for Cryptosporidium spp. but also to rule out bacterial and viral etiologies, including infections such as C. difficile, C. colitis, Clostridium spp., and rotavirus. The diagnosis of Cryptosporidium spp. infections primarily relies on microscopic methods, which are known for their low sensitivity. Therefore, diagnostic approaches should include both direct methods and, where possible, molecular techniques. Based on the analyzed cases, the most effective treatment results were achieved with reduction in immunosuppression if possible (strong, very low) and nitazoxanide at a dose of 500 mg twice daily for 14 days. Considering the public health implications of our findings, the current epidemiological data underscore the need for further research to develop effective prevention and intervention strategies against cryptosporidiosis. Preventive measures, regular screening programs, and the treatment of Cryptosporidium spp. infections should be integrated into the clinical care of transplant patients. It is also important that patients are informed about environmental risk factors.
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Affiliation(s)
- Danuta Kosik-Bogacka
- Independent Laboratory of Pharmaceutical Botany, Pomeranian Medical University in Szczecin, Powstańców Wielkopolskich 72, 70-111 Szczecin, Poland
| | - Natalia Łanocha-Arendarczyk
- Department of Biology and Medical Parasitology, Pomeranian Medical University in Szczecin, Powstańców Wielkopolskich 72, 70-111 Szczecin, Poland;
| | - Krzysztof Korzeniewski
- Department of Epidemiology and Tropical Medicine, Military Institute of Medicine, 04-141 Warsaw, Poland;
| | - Maciej Mularczyk
- Department of Gross Anatomy, Pomeranian Medical University in Szczecin, Powstańców Wielkopolskich 72, 70-111 Szczecin, Poland;
| | - Joanna Kabat-Koperska
- Clinic of Nephrology, Transplantology and Internal Medicine, Pomeranian Medical University in Szczecin, 70-111 Szczecin, Poland; (J.K.-K.); (M.M.-M.)
| | - Paweł Ziętek
- Department of Orthopaedics, Traumatology and Orthopaedic Oncology, Pomeranian Medical University in Szczecin, Unii Lubelskiej 1, 71-252 Szczecin, Poland;
| | - Małgorzata Marchelek-Myśliwiec
- Clinic of Nephrology, Transplantology and Internal Medicine, Pomeranian Medical University in Szczecin, 70-111 Szczecin, Poland; (J.K.-K.); (M.M.-M.)
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Liu B, Schnider A, DeArmond M, Banach DB, Haubrich BA. Cryptosporidiosis in individuals with inflammatory bowel disease: a scoping review protocol. BMJ Open 2024; 14:e086529. [PMID: 39414295 PMCID: PMC11481120 DOI: 10.1136/bmjopen-2024-086529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2024] [Accepted: 09/12/2024] [Indexed: 10/18/2024] Open
Abstract
INTRODUCTION Cryptosporidiosis is a leading cause of moderate-to-severe diarrhoea globally, and, while it is often self-limited, in immunocompromised individuals, the infection can be associated with significant morbidity and mortality. Diagnosis might be missed or delayed in patients with inflammatory bowel disease (IBD) due to similar presentation, and these patients may also be on immunosuppressive therapies, increasing their risk of infection. Additionally, gastrointestinal infection and dysbiosis may be a risk factor for IBD. Diagnosis, presentation and treatment of cryptosporidiosis in individuals with IBD, as well as any epidemiologic correlations between the two diseases, will be investigated. METHODS AND ANALYSIS MEDLINE, Embase, Cochrane Library, CINAHL, Dissertations and Theses Global and grey literature will be searched. Joanna Briggs Institute (JBI) methodology for scoping reviews was used for the protocol and will be for the review. Two reviewers will independently screen studies and extract data. The evidence and presentation of the results will be analysed with input from the review team. Studies of cryptosporidiosis in patients with IBD will be included. Paediatric, adolescent and adult studies in all patient environments will be included. Cases in which Crohn's disease does not affect the intestine and cases in which cryptosporidial infection is not in the intestine will be excluded. ETHICS AND DISSEMINATION Published clinical literature will be systematically reviewed, and this work does not directly involve patients. Consequently, ethical review by an institutional review board is not required. Data will be presented at academic conferences, and a culminating report will be published in a peer-reviewed journal. OPEN SCIENCE FRAMEWORK REGISTRATION: https://osf.io/j47mb.
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Affiliation(s)
- Belinda Liu
- College of Osteopathic Medicine, Touro University Nevada, Henderson, Nevada, USA
| | - Alexander Schnider
- College of Osteopathic Medicine, Touro University Nevada, Henderson, Nevada, USA
| | - Megan DeArmond
- Jay Sexter Library, Touro University Nevada, Henderson, Nevada, USA
- Touro University Nevada: A JBI Affiliated Group, Touro University Nevada, Henderson, Nevada, USA
| | - David B Banach
- School of Medicine, University of Connecticut, Farmington, Connecticut, USA
| | - Brad A Haubrich
- College of Osteopathic Medicine, Touro University Nevada, Henderson, Nevada, USA
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Anand N. Antiparasitic activity of the iron-containing milk protein lactoferrin and its potential derivatives against human intestinal and blood parasites. FRONTIERS IN PARASITOLOGY 2024; 2:1330398. [PMID: 39816822 PMCID: PMC11731944 DOI: 10.3389/fpara.2023.1330398] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Accepted: 12/30/2023] [Indexed: 01/18/2025]
Abstract
An iron-containing milk protein named lactoferrin (Lf) has demonstrated antiparasitic and immunomodulatory properties against a variety of human parasites. This protein has shown its capability to bind and transport iron molecules in the vicinity of the host-pathogen environment. The ability of parasites to sequester the iron molecule and to increase their pathogenicity and survival depends on the availability of iron sources. Lf protein has suggested a iron chelating effect on parasites iron and, hence, has shown its antiparasitic effect. Since the parasites have a complex life cycle and have developed drug resistance, vaccines and other treatments are a handful. Therefore, therapeutic research focusing on natural treatment regimens that target the parasite and are non-toxic to host cells is urgently needed. The antiparasitic efficacy of Lf protein has been extensively studied over the past 40 years using both in vitro and in vivo studies. This review article highlighted past important studies on Lf protein that revealed its potential antiparasitic activity against various intracellular and extracellular intestinal or blood-borne human parasites. This review article structures the role of Lf protein in its various forms, such as native, peptide, and nanoformulation, laying the groundwork for its function as an antiparasitic agent and its possible known mechanisms of action.
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Affiliation(s)
- Namrata Anand
- Department of Pharmacy Practice and Science, College of Pharmacy, University of Kentucky, Lexington, KY, United States
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Shan H, Wei C, Zhang J, He M, Zhang Z. Case Report: Severe Diarrhea Caused by Cryptosporidium Diagnosed by Metagenome Next-Generation Sequencing in Blood. Infect Drug Resist 2023; 16:5777-5782. [PMID: 37675126 PMCID: PMC10478782 DOI: 10.2147/idr.s422799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 08/23/2023] [Indexed: 09/08/2023] Open
Abstract
Background Cryptosporidium is one of the major pathogens causing diarrhea worldwide. At present, cryptosporidiosis is difficult to prevent and control, especially in immunocompromised hosts. It may cause life-threatening diarrhea and malabsorption among children and immunocompromised patients. Therefore, it is very important to explore rapid diagnostic tools and treatment methods for Cryptosporidium infection. Case Presentation We reported a case of severe diarrhea caused by cryptosporidiosis in a liver transplant recipient, whose condition was finally confirmed by metagenomic next-generation sequencing (mNGS) and fecal microscopy. His illness was resolved with immunosuppression regulation, nitazoxanide administration, and infection control. Conclusion So far, nitazoxanide is still the first choice for the treatment of cryptosporidiosis. Our institutional experience suggested that nitazoxanide alone may be effective on the basis of adjusting immunosuppressant. In addition, even though diagnosis of Cryptosporidium infection is a challenge, mNGS can serve as a rapid screening tool in low-prevalence setting.
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Affiliation(s)
- Huifang Shan
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, People’s Republic of China
| | - Chunyan Wei
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, People’s Republic of China
| | - Jingyi Zhang
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, People’s Republic of China
| | - Min He
- Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, People’s Republic of China
| | - Zhongwei Zhang
- Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, People’s Republic of China
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Piacentini S, Riccio A, Santopolo S, Pauciullo S, La Frazia S, Rossi A, Rossignol JF, Santoro MG. The FDA-approved drug nitazoxanide is a potent inhibitor of human seasonal coronaviruses acting at postentry level: effect on the viral spike glycoprotein. Front Microbiol 2023; 14:1206951. [PMID: 37705731 PMCID: PMC10497118 DOI: 10.3389/fmicb.2023.1206951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2023] [Accepted: 08/07/2023] [Indexed: 09/15/2023] Open
Abstract
Coronaviridae is recognized as one of the most rapidly evolving virus family as a consequence of the high genomic nucleotide substitution rates and recombination. The family comprises a large number of enveloped, positive-sense single-stranded RNA viruses, causing an array of diseases of varying severity in animals and humans. To date, seven human coronaviruses (HCoV) have been identified, namely HCoV-229E, HCoV-NL63, HCoV-OC43 and HCoV-HKU1, which are globally circulating in the human population (seasonal HCoV, sHCoV), and the highly pathogenic SARS-CoV, MERS-CoV and SARS-CoV-2. Seasonal HCoV are estimated to contribute to 15-30% of common cold cases in humans; although diseases are generally self-limiting, sHCoV can sometimes cause severe lower respiratory infections and life-threatening diseases in a subset of patients. No specific treatment is presently available for sHCoV infections. Herein we show that the anti-infective drug nitazoxanide has a potent antiviral activity against three human endemic coronaviruses, the Alpha-coronaviruses HCoV-229E and HCoV-NL63, and the Beta-coronavirus HCoV-OC43 in cell culture with IC50 ranging between 0.05 and 0.15 μg/mL and high selectivity indexes. We found that nitazoxanide does not affect HCoV adsorption, entry or uncoating, but acts at postentry level and interferes with the spike glycoprotein maturation, hampering its terminal glycosylation at an endoglycosidase H-sensitive stage. Altogether the results indicate that nitazoxanide, due to its broad-spectrum anti-coronavirus activity, may represent a readily available useful tool in the treatment of seasonal coronavirus infections.
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Affiliation(s)
- Sara Piacentini
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | - Anna Riccio
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | - Silvia Santopolo
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | - Silvia Pauciullo
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | - Simone La Frazia
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | - Antonio Rossi
- Institute of Translational Pharmacology, CNR, Rome, Italy
| | | | - M. Gabriella Santoro
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
- Institute of Translational Pharmacology, CNR, Rome, Italy
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Caravedo MA, White AC. Treatment of cryptosporidiosis: nitazoxanide yes, but we can do better. Expert Rev Anti Infect Ther 2023; 21:167-173. [PMID: 36533398 DOI: 10.1080/14787210.2023.2160704] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
INTRODUCTION Cryptosporidiosis was initially recognized as an important cause of diarrhea in AIDS patients. It has been underdiagnosed in other populations. Recent studies have highlighted the importance of Cryptosporidium as a cause of diarrhea and malnutrition in young children in resource-poor countries and an emerging pathogen in organ-transplant recipients. AREAS COVERED Nitazoxanide is FDA approved for treatment of cryptosporidiosis in immunocompetent people. However, it is less effective in HIV and transplant patients and malnourished children. In transplant recipients, there is emerging data on antiparasitic combinations for cryptosporidiosis, including combinations of nitazoxanide, azithromycin, and in one case rifaximin. High-throughput phenotypic screens have identified some potential treatments. Among them, clofazimine was no better than placebo in a trial in AIDS patients. There have also been efforts to develop drug versus specific parasite targets. However, in part due to safety issues, none of these compounds have advanced into clinical trials. EXPERT OPINION Development of new and more efficacious therapies for cryptosporidium is imperative. Current approve therapy is far from optimal and lacks efficacy in high-risk populations, such as, patients living with HIV. Additionally, there is limited data on patients with other types of immunosuppression (Transplanted, autoimmune conditions, etc).
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Affiliation(s)
- Maria A Caravedo
- Infectious Disease Division Department of Internal Medicine University of Texas Medical Branch, Galveston, Texas, USA
| | - A Clinton White
- Infectious Disease Division Department of Internal Medicine University of Texas Medical Branch, Galveston, Texas, USA
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Khan SM, Witola WH. Past, current, and potential treatments for cryptosporidiosis in humans and farm animals: A comprehensive review. Front Cell Infect Microbiol 2023; 13:1115522. [PMID: 36761902 PMCID: PMC9902888 DOI: 10.3389/fcimb.2023.1115522] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Accepted: 01/09/2023] [Indexed: 01/25/2023] Open
Abstract
The intracellular protozoan parasite of the genus Cryptosporidium is among the leading causes of waterborne diarrheal disease outbreaks throughout the world. The parasite is transmitted by ingestion of infective oocysts that are highly stable in the environment and resistant to almost all conventional disinfection methods and water treatments. Control of the parasite infection is exceedingly difficult due to the excretion of large numbers of oocysts in the feces of infected individuals that contaminate the environment and serve as a source of infection for susceptible hosts including humans and animals. Drug development against the parasite is challenging owing to its limited genetic tractability, absence of conventional drug targets, unique intracellular location within the host, and the paucity of robust cell culture platforms for continuous parasite propagation. Despite the high prevalence of the parasite, the only US Food and Drug Administration (FDA)-approved treatment of Cryptosporidium infections is nitazoxanide, which has shown moderate efficacy in immunocompetent patients. More importantly, no effective therapeutic drugs are available for treating severe, potentially life-threatening cryptosporidiosis in immunodeficient patients, young children, and neonatal livestock. Thus, safe, inexpensive, and efficacious drugs are urgently required to reduce the ever-increasing global cryptosporidiosis burden especially in low-resource countries. Several compounds have been tested for both in vitro and in vivo efficacy against the disease. However, to date, only a few experimental compounds have been subjected to clinical trials in natural hosts, and among those none have proven efficacious. This review provides an overview of the past and present anti-Cryptosporidium pharmacotherapy in humans and agricultural animals. Herein, we also highlight the progress made in the field over the last few years and discuss the different strategies employed for discovery and development of effective prospective treatments for cryptosporidiosis.
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Dillon B, Keefer L, Malone L. Double Trouble: Ten-Year-Old Girl With Chronic Diarrhea and Acute Abdominal Pain. Clin Pediatr (Phila) 2022; 61:654-658. [PMID: 35678012 PMCID: PMC9397393 DOI: 10.1177/00099228221100063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Affiliation(s)
- Bridget Dillon
- Department of Pediatrics, Penn State Hershey Children’s Hospital, Hershey, PA, USA,Bridget Dillon, Department of Pediatrics, Penn State Hershey Children’s Hospital, 500 University Drive, P.O. Box 850, Hershey, PA 17033-0850, USA.
| | - Laura Keefer
- Department of Pediatrics, Penn State Hershey Children’s Hospital, Hershey, PA, USA
| | - Leah Malone
- Department of Pediatrics, Penn State Hershey Children’s Hospital, Hershey, PA, USA
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Abdelmaksoud HF, Aboushousha TS, El-Ashkar AM. Deep glance on the antiparasitic anticancer activities of wheat germ oil in chronically infected immunosuppressed mice with cryptosporidiosis. J Parasit Dis 2022; 46:785-794. [PMID: 36091275 PMCID: PMC9458820 DOI: 10.1007/s12639-022-01497-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 05/07/2022] [Indexed: 11/25/2022] Open
Abstract
Cryptosporidium species are the major cause of water-borne epidemics of diarrhea in both developing and developed countries that vary from self-limited in immunocompetent patients to severe life-threatening in the immunocompromised hosts. There was a proven correlation between cryptosporidiosis and colorectal cancers, although, studies in this field are still limited. Wheat germ oil (WGO) is a natural product with a known antiparasitic effect and potential antiproliferative activities. This study aimed to evaluate the antiparasitic and anticancer activities of WGO in chronically infected immunosuppressed mice compared to Nitazoxanide (NTZ). This experimental case-control study was performed in the period from January till September 2021. Eighty immunosuppressed bred laboratory mice were divided into 4 groups, 20 mice each; GI non-infected; negative control (NC), GII infected non treated; positive control (PC), GII infected, and treated with NTZ, GIV infected, and treated with WGO. Parasitological, histopathological, and immunohistochemical examinations were performed with estimating the rate of maximal survival for the study groups. Parasitological examination revealed a marked reduction in the mean Cryptosporidium spp. oocyst counts in the stool of GIV compared to PC, and GIII (P-value < 0.001). Histopathological and immunohistochemical examinations showed the best results with GIV which revealed restoration of normal villous pattern, with no dysplasia or malignancy could be detected. GIV showed the best survival rate compared to PC and GIII. WGO is an extremely promising agent that has an excellent therapeutic effect against cryptosporidiosis with the ability to control the tumorigenesis process in the chronically infected immunosuppressed hosts.
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Affiliation(s)
| | | | - Ayman M. El-Ashkar
- Department of Medical Parasitology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
- Department of Basic Medical Science, College of Medicine, University of Bisha, Bisha, Kingdom of Saudi Arabia
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Farid A, Yousry M, Safwat G. Garlic (Allium sativum Linnaeus) improved inflammation and reduced cryptosporidiosis burden in immunocompromised mice. JOURNAL OF ETHNOPHARMACOLOGY 2022; 292:115174. [PMID: 35259443 DOI: 10.1016/j.jep.2022.115174] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Revised: 02/24/2022] [Accepted: 03/03/2022] [Indexed: 06/14/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE For thousands of years, garlic (Allium sativum Linnaeus) has been consumed in food and health by numerous civilizations. Cryptosporidium (C.) parvum is an apicomplexan parasite that causes a gastrointestinal disease, with the most common symptoms being watery diarrhea. Although several substances have been tried for its anti-cryptosporidial action, there is no effective treatment for Cryptosporidium disease, especially in immunocompromised individuals. The present study aimed firstly to characterize the bio-active compounds in Allium sativum L. and secondly to evaluate its efficacy as a therapy for cryptosporidiosis especially in immunocompromised mice. MATERIALS AND METHODS This was accomplished by evaluating the parasitological and histopathological parameters in the experimentally infected immunocompetent and immunocompromised mice. Also, the cytokine profile during the experimental time was recorded through the measuring of T helper (h)1, Th2 and Th17 cells cytokines. Immunosuppressed mice were given 0.25 μg/g per day of dexamethasone orally, before infection with Cryptosporidium parvum oocysts, for fourteen consecutive days. Starting 10 days post infection (PI), nitazoxanide (100 mg/kg per day) or Allium sativum (50 mg/kg per day) was given orally for fourteen consecutive days. RESULTS Our results showed that oocyst shedding, on the 32nd day PI, in immunocompromised infected group treated with Allium sativum (354.11, 99.35% PR) showed a significant decrease when compared to its corresponding group treated with nitazoxanide (4369.14, 92.05% PR). On the 32nd day PI, all cytokines levels have been decreased to levels that were similar to those of their uninfected corresponding control groups; also, the histopathological changes and the loss in animals' body weight had been improved. Treatment with nitazoxanide did not result in infection clearance or a reduction in the increased cytokines' levels. CONCLUSION Allium sativum L. displayed high efficacy as a potential therapeutic agent against Cryptosporidium, which supports its traditional usage in parasite diseases.
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Affiliation(s)
- Alyaa Farid
- Zoology Dep, Faculty of Science, Cairo University, Giza, Egypt.
| | - Mona Yousry
- Zoology Dep, Faculty of Science, Cairo University, Giza, Egypt
| | - Gehan Safwat
- Faculty of Biotechnology, October University for Modern Sciences and Arts (MSA), Giza, Egypt
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Dhal AK, Panda C, Yun SIL, Mahapatra RK. An update on Cryptosporidium biology and therapeutic avenues. J Parasit Dis 2022; 46:923-939. [PMID: 35755159 PMCID: PMC9215156 DOI: 10.1007/s12639-022-01510-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 06/07/2022] [Indexed: 12/02/2022] Open
Abstract
Cryptosporidium species has been identified as an important pediatric diarrheal pathogen in resource-limited countries, particularly in very young children (0–24 months). However, the only available drug (nitazoxanide) has limited efficacy and can only be prescribed in a medical setting to children older than one year. Many drug development projects have started to investigate new therapeutic avenues. Cryptosporidium’s unique biology is challenging for the traditional drug discovery pipeline and requires novel drug screening approaches. Notably, in recent years, new methods of oocyst generation, in vitro processing, and continuous three-dimensional cultivation capacities have been developed. This has enabled more physiologically pertinent research assays for inhibitor discovery. In a short time, many great strides have been made in the development of anti-Cryptosporidium drugs. These are expected to eventually turn into clinical candidates for cryptosporidiosis treatment in the future. This review describes the latest development in Cryptosporidium biology, genomics, transcriptomics of the parasite, assay development, and new drug discovery.
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Affiliation(s)
- Ajit Kumar Dhal
- School of Biotechnology, KIIT Deemed to Be University, Bhubaneswar, Odisha 751024 India
| | - Chinmaya Panda
- School of Biotechnology, KIIT Deemed to Be University, Bhubaneswar, Odisha 751024 India
| | - Soon-IL Yun
- Department of Food Science and Technology, Jeonbuk National University, Jeonju, 54896 Republic of Korea
- Department of Agricultural Convergence Technology, Jeonbuk National University, Jeonju, 54896 Republic of Korea
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Riccio A, Santopolo S, Rossi A, Piacentini S, Rossignol JF, Santoro MG. Impairment of SARS-CoV-2 spike glycoprotein maturation and fusion activity by nitazoxanide: an effect independent of spike variants emergence. Cell Mol Life Sci 2022; 79:227. [PMID: 35391601 PMCID: PMC8989121 DOI: 10.1007/s00018-022-04246-w] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 03/03/2022] [Accepted: 03/11/2022] [Indexed: 12/12/2022]
Abstract
SARS-CoV-2, the causative agent of COVID-19, has caused an unprecedented global health crisis. The SARS-CoV-2 spike, a surface-anchored trimeric class-I fusion glycoprotein essential for viral entry, represents a key target for developing vaccines and therapeutics capable of blocking virus invasion. The emergence of SARS-CoV-2 spike variants that facilitate virus spread and may affect vaccine efficacy highlights the need to identify novel antiviral strategies for COVID-19 therapy. Here, we demonstrate that nitazoxanide, an antiprotozoal agent with recognized broad-spectrum antiviral activity, interferes with SARS-CoV-2 spike maturation, hampering its terminal glycosylation at an endoglycosidase H-sensitive stage. Engineering multiple SARS-CoV-2 variant-pseudoviruses and utilizing quantitative cell–cell fusion assays, we show that nitazoxanide-induced spike modifications hinder progeny virion infectivity as well as spike-driven pulmonary cell–cell fusion, a critical feature of COVID-19 pathology. Nitazoxanide, being equally effective against the ancestral SARS-CoV-2 Wuhan-spike and different emerging variants, including the Delta variant of concern, may represent a useful tool in the fight against COVID-19 infections.
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Affiliation(s)
- Anna Riccio
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | - Silvia Santopolo
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | - Antonio Rossi
- Institute of Translational Pharmacology, CNR, Rome, Italy
| | - Sara Piacentini
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | | | - M Gabriella Santoro
- Department of Biology, University of Rome Tor Vergata, Rome, Italy. .,Institute of Translational Pharmacology, CNR, Rome, Italy.
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14
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Advances in therapeutic and vaccine targets for Cryptosporidium: Challenges and possible mitigation strategies. Acta Trop 2022; 226:106273. [PMID: 34906550 DOI: 10.1016/j.actatropica.2021.106273] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 12/07/2021] [Accepted: 12/08/2021] [Indexed: 12/14/2022]
Abstract
Cryptosporidium is known to be the second most common diarrheal pathogen in children, causing potentially fatal diarrhea and associated with long-term growth stunting and cognitive deficits. The only Food and Drug Administration-approved treatment for cryptosporidiosis is nitazoxanide, but this drug has not shown potentially effective results in susceptible hosts. Therefore, a safe and effective drug for cryptosporidiosis is urgently needed. Cryptosporidium genome sequencing analysis may help develop an effective drug, but both in vitro and in vivo approaches to drug evaluation are not fully standardized. On the other hand, the development of partial immunity after exposure suggests the possibility of a successful and effective vaccine, but protective surrogates are not precise. In this review, we present our current perspectives on novel cryptosporidiosis therapies, vaccine targets and efficacies, as well as potential mitigation plans, recommendations and perceived challenges.
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15
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Tomczak E, McDougal AN, White AC. Resolution of Cryptosporidiosis in Transplant Recipients: Review of the Literature and Presentation of a Renal Transplant Patient Treated With Nitazoxanide, Azithromycin, and Rifaximin. Open Forum Infect Dis 2022; 9:ofab610. [PMID: 34993260 PMCID: PMC8719605 DOI: 10.1093/ofid/ofab610] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 12/02/2021] [Indexed: 01/15/2023] Open
Abstract
Background Cryptosporidium is a major cause of diarrheal disease worldwide, including chronic disease in malnourished children and patients with acquired immune deficiency syndrome. There are increasing reports of cryptosporidiosis in transplant patients, especially from middle-income countries. Methods The literature on treatment of cryptosporidiosis in transplant patients was reviewed and included no controlled trials but only small case series. Nitazoxanide, azithromycin, spiramycin, and combination therapies have been used, but none are consistently efficacious. Results We present a case of chronic diarrhea from cryptosporidiosis in a renal transplant patient. His illness resolved with decreasing immunosuppression and treatment with the 3-drug combination of nitazoxanide, azithromycin, and rifaximin. Conclusions Although current therapies are not reliably effective in the absence of an effective cellular immune response, combination therapies hold promise for improved responses.
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Affiliation(s)
- Ewa Tomczak
- Infectious Disease Division, Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA
| | - April N McDougal
- Infectious Disease Division, Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA
| | - A Clinton White
- Infectious Disease Division, Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA
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16
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Prasad N, Bansal S, Akhtar S. Cryptosporidium infection in solid organ transplant recipients in South Asia - Expert group opinion for diagnosis and management. INDIAN JOURNAL OF TRANSPLANTATION 2022. [DOI: 10.4103/ijot.ijot_80_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
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17
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Pharmacokinetics and pharmacodynamics of clofazimine for treatment of cryptosporidiosis. Antimicrob Agents Chemother 2021; 66:e0156021. [PMID: 34748385 PMCID: PMC8765308 DOI: 10.1128/aac.01560-21] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
Infection with Cryptosporidium spp. can cause severe diarrhea, leading to long-term adverse impacts and even death in malnourished children and immunocompromised patients. The only FDA-approved drug for treating cryptosporidiosis, nitazoxanide, has limited efficacy in the populations impacted the most by the diarrheal disease, and safe, effective treatment options are urgently needed. Initially identified by a large-scale phenotypic screening campaign, the antimycobacterial therapeutic clofazimine demonstrated great promise in both in vitro and in vivo preclinical models of Cryptosporidium infection. Unfortunately, a phase 2a clinical trial in HIV-infected adults with cryptosporidiosis did not identify any clofazimine treatment effect on Cryptosporidium infection burden or clinical outcomes. To explore whether clofazimine’s lack of efficacy in the phase 2a trial may have been due to subtherapeutic clofazimine concentrations, a pharmacokinetic/pharmacodynamic modeling approach was undertaken to determine the relationship between clofazimine in vivo concentrations and treatment effects in multiple preclinical infection models. Exposure-response relationships were characterized using Emax and logistic models, which allowed predictions of efficacious clofazimine concentrations for the control and reduction of disease burden. After establishing exposure-response relationships for clofazimine treatment of Cryptosporidium infection in our preclinical model studies, it was unmistakable that the clofazimine levels observed in the phase 2a study participants were well below concentrations associated with anti-Cryptosporidium efficacy. Thus, despite a dosing regimen above the highest doses recommended for mycobacterial therapy, it is very likely the lack of treatment effect in the phase 2a trial was at least partially due to clofazimine concentrations below those required for efficacy against cryptosporidiosis. It is unlikely that clofazimine will provide a remedy for the large number of cryptosporidiosis patients currently without a viable treatment option unless alternative, safe clofazimine formulations with improved oral absorption are developed. (This study has been registered in ClinicalTrials.gov under identifier NCT03341767.)
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18
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Treatment of human intestinal cryptosporidiosis: A review of published clinical trials. INTERNATIONAL JOURNAL FOR PARASITOLOGY-DRUGS AND DRUG RESISTANCE 2021; 17:128-138. [PMID: 34562754 PMCID: PMC8473663 DOI: 10.1016/j.ijpddr.2021.09.001] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/13/2021] [Revised: 09/06/2021] [Accepted: 09/09/2021] [Indexed: 12/01/2022]
Abstract
The global burden of diarrhea caused by Cryptosporidium parasite is underestimated. In immunocompromised hosts, chronic and severe presentation of intestinal cryptosporidiosis can result in long-term morbidity and high illness costs. The evidence of effective treatments for cryptosporidiosis has been lacking. We reviewed the published clinical trials to bring forward the feasible therapeutic options of human cryptosporidiosis in various populations and settings according to clinical improvement and parasite clearance rates. A total of 42 studies consisting of the use of nitazoxanide, paromomycin, macrolides, somatostatin analogues, letrazuril, albendazole, rifaximin, miltefosine, clofazimine, and colostrum were included in the review. The trials were mostly conducted in small number of individuals infected with human immunodeficiency virus (HIV), and there is inadequate data of controlled trials to suggest the use of these treatment modalities. Nitazoxanide was reported to be highly efficacious only in immunocompetent hosts and was found to be superior to paromomycin in the same group of patients. Macrolides showed no effective results in both clinical and parasitological improvement. Human bovine colostrum should possibly be administered as one of complementary therapeutic modalities along with other antimicrobials to reach optimal parasite eradication. Other trials of therapeutic modalities were terminated due to futility. Currently, available data is intended to aid the development of strategies for improving access to treatments in different clinical settings, as well as to help guide further studies on treatments of human intestinal cryptosporidiosis.
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19
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O'Leary JK, Sleator RD, Lucey B. Cryptosporidium spp. diagnosis and research in the 21 st century. Food Waterborne Parasitol 2021; 24:e00131. [PMID: 34471706 PMCID: PMC8390533 DOI: 10.1016/j.fawpar.2021.e00131] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 08/06/2021] [Accepted: 08/17/2021] [Indexed: 01/01/2023] Open
Abstract
The protozoan parasite Cryptosporidium has emerged as a leading cause of diarrhoeal illness worldwide, posing a significant threat to young children and immunocompromised patients. While endemic in the vast majority of developing countries, Cryptosporidium also has the potential to cause waterborne epidemics and large scale outbreaks in both developing and developed nations. Anthroponontic and zoonotic transmission routes are well defined, with the ingestion of faecally contaminated food and water supplies a common source of infection. Microscopy, the current diagnostic mainstay, is considered by many to be suboptimal. This has prompted a shift towards alternative diagnostic techniques in the advent of the molecular era. Molecular methods, particularly PCR, are gaining traction in a diagnostic capacity over microscopy in the diagnosis of cryptosporidiosis, given the laborious and often tedious nature of the latter. Until now, developments in the field of Cryptosporidium detection and research have been somewhat hampered by the intractable nature of this parasite. However, recent advances in the field have taken the tentative first steps towards bringing Cryptosporidium research into the 21st century. Herein, we provide a review of these advances.
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Affiliation(s)
- Jennifer K. O'Leary
- Department of Biological Sciences, Munster Technological University, Bishopstown Campus, Cork, Ireland
| | - Roy D. Sleator
- Department of Biological Sciences, Munster Technological University, Bishopstown Campus, Cork, Ireland
| | - Brigid Lucey
- Department of Biological Sciences, Munster Technological University, Bishopstown Campus, Cork, Ireland
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20
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Golomazou E, Malandrakis EE, Panagiotaki P, Karanis P. Cryptosporidium in fish: Implications for aquaculture and beyond. WATER RESEARCH 2021; 201:117357. [PMID: 34147739 DOI: 10.1016/j.watres.2021.117357] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Aquaculture industries are expanding worldwide and control of Cryptosporidium is of great importance. Cryptosporidiosis is a serious waterborne/foodborne disease, responsible for infectious outbreaks globally. Current knowledge on the Cryptosporidium species in the aquatic environment and their occurrence in piscine hosts is steadily increasing since the Cryptosporidium species have been detected in marine, freshwater, cultured, captive and ornamental fish in a wide range of geographical regions. The zoonotic potential of these parasites and their pathological impact on piscine hosts have been increasingly reported and the fishborne zoonotic risk from Cryptosporidium spp. is of major importance from a public health point of view. Zoonotic subtypes in fish have been described in various studies and are probably related to water contamination from animal and human wastes. This review critically evaluated existing scientific data, related to Cryptosporidium species in piscine hosts, emphasizing transmission routes and the potential impact of piscine cryptosporidiosis in aquaculture. This knowledge will facilitate consumers, authorities and water industries such as fisheries and aquaculture, the prevention and control of waterborne and fishborne cryptosporidiosis in fish products.
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Affiliation(s)
- E Golomazou
- Department of Ichthyology and Aquatic Environment - Aquaculture Laboratory, School of Agricultural Sciences, University of Thessaly, Fytokou str., 38446, Volos, Greece
| | - E E Malandrakis
- Department of Animal Science - Laboratory of Applied Hydrobiology, School of Animal Biosciences, Agricultural University of Athens, 75 Iera Odos str., 11855, Athens, Greece
| | - P Panagiotaki
- Department of Ichthyology and Aquatic Environment - Aquaculture Laboratory, School of Agricultural Sciences, University of Thessaly, Fytokou str., 38446, Volos, Greece
| | - P Karanis
- University of Cologne, Medical Faculty and University Hospital, 50931 Cologne, Germany; University of Nicosia Medical School, Department of Basic and Clinical Sciences, Anatomy Institute, 2408, Nicosia, Cyprus.
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21
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Goel V, Jain A, Sharma G, Jhajharia A, Agarwal VK, Ashdhir P, Pokharna R, Chauhan V. Evaluating the efficacy of nitazoxanide in uncomplicated amebic liver abscess. Indian J Gastroenterol 2021; 40:272-280. [PMID: 33991310 DOI: 10.1007/s12664-020-01132-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Accepted: 11/24/2020] [Indexed: 02/04/2023]
Abstract
BACKGROUND Amebic liver abscess is treated successfully with metronidazole or another nitroimidazole drug followed by a luminal amebicide. Metronidazole has long been preferred, but has been associated with several adverse effects including intolerance in certain clinical situations. Mechanisms of metronidazole resistance and mutagenic potential have been described. Effects of the use of drug in pregnant women and infants of lactating women are unknown. Nitazoxanide was proven to be efficacious in treating invasive intestinal amebiasis. Therefore, the present study was undertaken to assess the efficacy and safety of nitazoxanide as compared to metronidazole in patients with uncomplicated amebic liver abscess. METHODS Patients with clinical and ultrasonography features suggestive of liver abscess, positive amebic serology, and/or anchovy sauce appearance on aspiration of the pus were included in the study and randomized into two parallel treatment groups. Group M received metronidazole, 2-2.5 g/day intravenous (IV), for inpatients, or 2-2.4 g/day oral, for outpatients in three divided doses for 14 days. Group N received nitazoxanide 500 mg BD per oral for 10 days. RESULTS A total of sixty subjects fulfilling the inclusion criteria were randomized equally into two groups, group M and group N. Number of patients achieving symptomatic clinical response (SCR) was similar in the two groups (80% vs. 76.7%, p = 1.00), though time to achieve symptomatic clinical response was significantly lower in metronidazole group as compared to that in nitazoxanide group. Greater proportion of patients achieved early clinical response (ECR) in metronidazole group as compared to nitazoxanide group. Complete resolution of abscess, at 6 months, was noted in 18 (60%) patients in the M group and 22 (73.3%) patients in the N group (p = 0.273). Metronidazole was associated with significantly greater frequency of adverse effects than nitazoxanide. CONCLUSIONS This study shows equivalent efficacy of nitazoxanide in uncomplicated amebic liver abscess as compared to metronidazole, with better tolerability and advantage of simultaneous luminal clearance, thus reducing chances of recurrence. TRIAL REGISTRATION CTRI/2019/01/017249.
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Affiliation(s)
- Vasudha Goel
- Department of Gastroenterology, SMS Medical College and Hospital, Jaipur 302 004, India
| | - Anubhav Jain
- Department of Gastroenterology, SMS Medical College and Hospital, Jaipur 302 004, India
| | - Garima Sharma
- Department of Pathology, SMS Medical College and Hospital, Jaipur, 302 004, India
| | - Ashok Jhajharia
- Department of Gastroenterology, SMS Medical College and Hospital, Jaipur 302 004, India
| | - Vishnu Kumar Agarwal
- Department of Gastroenterology, SMS Medical College and Hospital, Jaipur 302 004, India
| | - Prachis Ashdhir
- Department of Gastroenterology, SMS Medical College and Hospital, Jaipur 302 004, India.
| | - Rupesh Pokharna
- Department of Gastroenterology, SMS Medical College and Hospital, Jaipur 302 004, India
| | - Virender Chauhan
- Department of Gastroenterology, SMS Medical College and Hospital, Jaipur 302 004, India
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22
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Non LR, Ince D. Infectious Gastroenteritis in Transplant Patients. Gastroenterol Clin North Am 2021; 50:415-430. [PMID: 34024449 DOI: 10.1016/j.gtc.2021.02.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Infectious gastroenteritis is common after transplantation and can lead to increased morbidity and mortality. A wide range of organisms can lead to gastroenteritis in this patient population. Clostridioides difficile, cytomegalovirus, and norovirus are the most common pathogens. Newer diagnostic methods, especially multiplex polymerase chain reaction, have increased the diagnostic yield of infectious etiologies. In this review, we describe the epidemiology and risk factors for common infectious pathogens leading to gastroenteritis.
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Affiliation(s)
- Lemuel R Non
- Department of Internal Medicine, University of Iowa, Carver College of Medicine, GH SW34, 200 Hawkins Drive, Iowa City, IA 52242, USA
| | - Dilek Ince
- Department of Internal Medicine, University of Iowa, Carver College of Medicine, GH SE418, 200 Hawkins Drive, Iowa City, IA 52242, USA.
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23
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Opportunities and Challenges in Developing a Cryptosporidium Controlled Human Infection Model for Testing Antiparasitic Agents. ACS Infect Dis 2021; 7:959-968. [PMID: 33822577 PMCID: PMC8154424 DOI: 10.1021/acsinfecdis.1c00057] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Cryptosporidiosis is a leading cause of moderate-to-severe diarrhea in low- and middle-income countries, responsible for high mortality in children younger than two years of age, and it is also strongly associated with childhood malnutrition and growth stunting. There is no vaccine for cryptosporidiosis and existing therapeutic options are suboptimal to prevent morbidity and mortality in young children. Recently, novel therapeutic agents have been discovered through high-throughput phenotypic and target-based screening strategies, repurposing malaria hits, etc., and these agents have a promising preclinical in vitro and in vivo anti-Cryptosporidium efficacy. One key step in bringing safe and effective new therapies to young vulnerable children is the establishment of some prospect of direct benefit before initiating pediatric clinical studies. A Cryptosporidium controlled human infection model (CHIM) in healthy adult volunteers can be a robust clinical proof of concept model for evaluating novel therapeutics. CHIM could potentially accelerate the development path to pediatric studies by establishing the safety of a proposed pediatric dosing regimen and documenting preliminary efficacy in adults. We present, here, perspectives regarding the opportunities and perceived challenges with the Cryptosporidium human challenge model.
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24
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Lu C, Shao X, Zhou S, Pan C. LINC00176 facilitates CD4 +T cell adhesion in systemic lupus erythematosus via the WNT5a signaling pathway by regulating WIF1. Mol Immunol 2021; 134:202-209. [PMID: 33813201 DOI: 10.1016/j.molimm.2021.02.018] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Revised: 01/20/2021] [Accepted: 02/18/2021] [Indexed: 10/21/2022]
Abstract
Accruing research shows the implications of long non-coding RNAs (lncRNAs) in the progression of various autoimmune diseases including systemic lupus erythematosus (SLE). The present study aimed to identify the expression pattern of LINC00176 in SLE and to explore its effects on CD4+T cell adhesion in this context. The biological functions of LINC00176, WIF1 and WNT5a on CD4+T cells in SLE were evaluated via gain- and loss-of-function experiments, following delivery of pcDNA3-LINC00176, siRNA-LINC00176, pcDNA3-WIF1 and WNT-sFRP5 (an inhibitor for the WNT5a signaling pathway). High LINC00176 expression was evident in the CD4+T cells of SLE patients. Additionally, WIF1 was identified as a potential target gene of LINC00176, and was negatively regulated by LINC00176. The overexpression of LINC00176 could promote proliferation and adhesion of CD4+T cells in SLE. Such alternations were reversed following up-regulation of WIF1 or inhibition of the WNT5a signaling pathway. Taken together, the key findings of our study highlight the ability of LINC00176 to potentially promote the proliferation and adhesion of CD4+T cells in SLE by down-regulating WIF1 and activating the WNT5a signaling pathway, providing new insight and a theoretical basis for translation in SLE therapy.
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Affiliation(s)
- Chang Lu
- Department of Anesthesiology, The Second Hospital of Jilin University, Changchun, 130041, PR China
| | - Xue Shao
- Department of Hepatopancreatobiliary Medicine, The Second Hospital of Jilin University, Changchun, 130041, PR China
| | - Shengzhu Zhou
- Department of Anesthesiology, The Second Hospital of Jilin University, Changchun, 130041, PR China
| | - Chenyu Pan
- Department of Anesthesiology, The Second Hospital of Jilin University, Changchun, 130041, PR China.
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25
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Jones KR, Tardieu L. Giardia and Cryptosporidium in Neo-Tropical Rodents and Marsupials: Is There Any Zoonotic Potential? Life (Basel) 2021; 11:life11030256. [PMID: 33804628 PMCID: PMC8003710 DOI: 10.3390/life11030256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 03/16/2021] [Accepted: 03/17/2021] [Indexed: 11/16/2022] Open
Abstract
Cryptosporidiosis and giardiasis have been identified as emerging diseases in both developed and developing countries. Wildlife has been highlighted to play a major role in the spread of these diseases to humans. This review aims to highlight the research findings that relate to Cryptosporidium spp. and Giardia spp., with a focus on (1) parasitism of neo-tropical hystricomorphic rodents and marsupials from the genus Didelphis and (2) prevention and treatment strategies for humans and animals for the neo-tropical region. It was found that there are few studies conducted on neo-tropical rodent and marsupial species, but studies that were found illustrated the potential role these animals may play as zoonotic carriers of these two parasites for the neo-tropical region. Thus, it is recommended that further studies be done to assess the threat of protozoan parasites in neo-tropical wildlife to humans and domestic animals, and to further determine the most effective prophylaxis adapted for the unique conditions of the region.
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Affiliation(s)
- Kegan Romelle Jones
- Department of Food Production (DFP), Faculty of Food and Agriculture (FFA), St. Augustine Campus, University of the West Indies (UWI), St. Augustine, Trinidad and Tobago;
- Department of Basic Veterinary Sciences (DBVS), Faculty of Medical Sciences (FMS), School of Veterinary Medicine (SVM), Mt. Hope Campus, University of the West Indies (UWI), Mount Hope, Trinidad and Tobago
- Correspondence: ; Tel.: +1-868-787-0833
| | - Laura Tardieu
- Department of Food Production (DFP), Faculty of Food and Agriculture (FFA), St. Augustine Campus, University of the West Indies (UWI), St. Augustine, Trinidad and Tobago;
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Ashigbie PG, Shepherd S, Steiner KL, Amadi B, Aziz N, Manjunatha UH, Spector JM, Diagana TT, Kelly P. Use-case scenarios for an anti-Cryptosporidium therapeutic. PLoS Negl Trop Dis 2021; 15:e0009057. [PMID: 33705395 PMCID: PMC7951839 DOI: 10.1371/journal.pntd.0009057] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Cryptosporidium is a widely distributed enteric parasite that has an increasingly appreciated pathogenic role, particularly in pediatric diarrhea. While cryptosporidiosis has likely affected humanity for millennia, its recent "emergence" is largely the result of discoveries made through major epidemiologic studies in the past decade. There is no vaccine, and the only approved medicine, nitazoxanide, has been shown to have efficacy limitations in several patient groups known to be at elevated risk of disease. In order to help frontline health workers, policymakers, and other stakeholders translate our current understanding of cryptosporidiosis into actionable guidance to address the disease, we sought to assess salient issues relating to clinical management of cryptosporidiosis drawing from a review of the literature and our own field-based practice. This exercise is meant to help inform health system strategies for improving access to current treatments, to highlight recent achievements and outstanding knowledge and clinical practice gaps, and to help guide research activities for new anti-Cryptosporidium therapies.
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Affiliation(s)
- Paul G. Ashigbie
- Novartis Institute for Tropical Diseases, Emeryville, California, United States of America
| | - Susan Shepherd
- Alliance for International Medical Action (ALIMA), Dakar, Senegal
| | - Kevin L. Steiner
- The Ohio State University, Columbus, Ohio, United States of America
| | - Beatrice Amadi
- Children’s Hospital, University Teaching Hospitals, Lusaka, Zambia
- Tropical Gastroenterology & Nutrition Group, University of Zambia School of Medicine, Lusaka, Zambia
| | - Natasha Aziz
- Novartis Institute for Tropical Diseases, Emeryville, California, United States of America
| | - Ujjini H. Manjunatha
- Novartis Institute for Tropical Diseases, Emeryville, California, United States of America
| | - Jonathan M. Spector
- Novartis Institute for Tropical Diseases, Emeryville, California, United States of America
| | - Thierry T. Diagana
- Novartis Institute for Tropical Diseases, Emeryville, California, United States of America
| | - Paul Kelly
- Tropical Gastroenterology & Nutrition Group, University of Zambia School of Medicine, Lusaka, Zambia
- Blizard Institute, Barts & The London School of Medicine, Queen Mary University of London, London, United Kingdom
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Madbouly N, El Amir A, Abdel Kader A, Rabee I, Farid A. The immunomodulatory activity of secnidazole-nitazoxanide in a murine cryptosporidiosis model. J Med Microbiol 2021; 70. [PMID: 33625354 DOI: 10.1099/jmm.0.001327] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Introduction. Cryptosporidium parvum causes intestinal parasitic infections affecting both immunosuppressed and immunocompetent individuals.Gap statement. Given the absence of effective treatments for cryptosporidiosis, especially in immunodeficient patients, the present study was designed to assess the therapeutic efficacy of secnidazole (SEC) and its combination with nitazoxanide (NTZ) in comparison to single NTZ treatment in relation to the immune status of a murine model of C. parvum infection.Methodology. The infected groups were administered NTZ, SEC or NTZ-SEC for three or five successive doses. At days 10 and 12 post-infection (p.i.), the mice were sacrificed, and the efficacy of the applied drugs was evaluated by comparing the histopathological alterations in ileum and measuring the T helper Th1 (interferon gamma; IFN-γ), Th2 [interleukin (IL)-4 and IL-10] and Th17 (IL-17) cytokine profiles in serum.Results. The NTZ-SEC combination recorded the maximal reduction of C. parvum oocyst shedding, endogenous stages count and intestinal histopathology, regardless of the immune status of the infected mice. The efficacy of NTZ-SEC was dependent on the period of administration, as the 5 day-based treatment protocol was also more effective than the 3 day-based one in terms of immunocompetence and immunosuppression. The present treatment schedule induced an immunomodulatory effect from SEC that developed a protective immune response against C. parvum infection with reduced production of serum IL-17, IFN-γ, IL-4 and IL-10.Conclusions. Application of NTZ-SEC combined therapy may be useful in treatment of C. parvum, especially in cases involving immunosuppression.
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Affiliation(s)
- Neveen Madbouly
- Department of Zoology, Faculty of Science, Cairo University, Giza, Egypt
| | - Azza El Amir
- Department of Zoology, Faculty of Science, Cairo University, Giza, Egypt
| | - Asmaa Abdel Kader
- Department of Parasitology, Theodore Bilharz Research Institute, Giza, Egypt
| | - Ibraheem Rabee
- Department of Parasitology, Theodore Bilharz Research Institute, Giza, Egypt
| | - Alyaa Farid
- Department of Zoology, Faculty of Science, Cairo University, Giza, Egypt
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Santopolo S, Riccio A, Santoro MG. The biogenesis of SARS-CoV-2 spike glycoprotein: multiple targets for host-directed antiviral therapy. Biochem Biophys Res Commun 2021; 538:80-87. [PMID: 33303190 PMCID: PMC7698684 DOI: 10.1016/j.bbrc.2020.10.080] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Accepted: 10/28/2020] [Indexed: 12/15/2022]
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19 (coronavirus disease-19), represents a far more serious threat to public health than SARS and MERS coronaviruses, due to its ability to spread more efficiently than its predecessors. Currently, there is no worldwide-approved effective treatment for COVID-19, urging the scientific community to intense efforts to accelerate the discovery and development of prophylactic and therapeutic solutions against SARS-CoV-2 infection. In particular, effective antiviral drugs are urgently needed. With few exceptions, therapeutic approaches to combat viral infections have traditionally focused on targeting unique viral components or enzymes; however, it has now become evident that this strategy often fails due to the rapid emergence of drug-resistant viruses. Targeting host factors that are essential for the virus life cycle, but are dispensable for the host, has recently received increasing attention. The spike glycoprotein, a component of the viral envelope that decorates the virion surface as a distinctive crown ("corona") and is essential for SARS-CoV-2 entry into host cells, represents a key target for developing therapeutics capable of blocking virus invasion. This review highlights aspects of the SARS-CoV-2 spike biogenesis that may be amenable to host-directed antiviral targeting.
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Affiliation(s)
- Silvia Santopolo
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | - Anna Riccio
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | - M Gabriella Santoro
- Department of Biology, University of Rome Tor Vergata, Rome, Italy; Institute of Translational Pharmacology, CNR, Rome, Italy.
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Lokhande AS, Devarajan PV. A review on possible mechanistic insights of Nitazoxanide for repurposing in COVID-19. Eur J Pharmacol 2021; 891:173748. [PMID: 33227285 PMCID: PMC7678434 DOI: 10.1016/j.ejphar.2020.173748] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 11/06/2020] [Accepted: 11/17/2020] [Indexed: 02/06/2023]
Abstract
The global pandemic of Coronavirus Disease 2019 (COVID-19) has brought the world to a grinding halt. A major cause of concern is the respiratory distress associated mortality attributed to the cytokine storm. Despite myriad rapidly approved clinical trials with repurposed drugs, and time needed to develop a vaccine, accelerated search for repurposed therapeutics is still ongoing. In this review, we present Nitazoxanide a US-FDA approved antiprotozoal drug, as one such promising candidate. Nitazoxanide which is reported to exert broad-spectrum antiviral activity against various viral infections, revealed good in vitro activity against SARS-CoV-2 in cell culture assays, suggesting potential for repurposing in COVID-19. Furthermore, nitazoxanide displays the potential to boost host innate immune responses and thereby tackle the life-threatening cytokine storm. Possibilities of improving lung, as well as multiple organ damage and providing value addition to COVID-19 patients with comorbidities, are other important facets of the drug. The review juxtaposes the role of nitazoxanide in fighting COVID-19 pathogenesis at multiple levels highlighting the great promise the drug exhibits. The in silico data and in vitro efficacy in cell lines confirms the promise of nitazoxanide. Several approved clinical trials world over further substantiate leveraging nitazoxanide for COVID-19 therapy.
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Affiliation(s)
- Amit S Lokhande
- Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, N. P. Marg, Matunga, Mumbai, 400019, Maharashtra, India
| | - Padma V Devarajan
- Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, N. P. Marg, Matunga, Mumbai, 400019, Maharashtra, India.
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Identification of novel anti-cryptosporidial inhibitors through a combined approach of pharmacophore modeling, virtual screening, and molecular docking. INFORMATICS IN MEDICINE UNLOCKED 2021. [DOI: 10.1016/j.imu.2021.100583] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
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Chadwick DR, Sutherland RK, Raffe S, Pool E, Beadsworth M. British HIV Association guidelines on the management of opportunistic infection in people living with HIV: the clinical management of gastrointestinal opportunistic infections 2020. HIV Med 2020; 21 Suppl 5:1-19. [PMID: 33271637 DOI: 10.1111/hiv.13004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- D R Chadwick
- Centre for Clinical Infection, James Cook University Hospital, Middlesbrough, UK
| | - R K Sutherland
- Regional Infectious Diseases Unit, NHS Lothian, Edinburgh, UK
| | - S Raffe
- Brighton and Sussex University Hospitals NHS Trust, Brighton, UK
| | - Erm Pool
- Mortimer Market Centre, Central and North West London NHS Foundation Trust, London, UK
| | - Mbj Beadsworth
- Tropical and Infectious Disease Unit, Royal Liverpool University Hospital (Liverpool University Hospitals Foundation Trust), Liverpool, UK
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Hashan MR, Elhusseiny KM, Huu-Hoai L, Tieu TM, Low SK, Minh LHN, Nghia TLB, Loc LQ, Y MN, Eid PS, Abed M, Elkolaly SS, Tawfik GM, Huy NT. Effect of nitazoxanide on diarrhea: A systematic review and network meta-analysis of randomized controlled trials. Acta Trop 2020; 210:105603. [PMID: 32598920 DOI: 10.1016/j.actatropica.2020.105603] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2019] [Revised: 06/20/2020] [Accepted: 06/25/2020] [Indexed: 01/30/2023]
Abstract
We aimed to systematically review evidence pertaining to the safety and efficacy of nitazoxanide in treating infectious diarrhea. On September 21, 2017, we identified relevant studies using 12 databases. The estimates of the included studies were pooled as a risk ratio (RR). We conducted a network and pairwise random-effects meta-analysis for both direct and indirect comparisons of different organisms that are known to cause diarrhea. The primary and secondary analysis outcomes were clinical response until cessation of illness, parasitological response and adverse events. We included 18 studies in our analysis. In cryptosporidiosis, the overall estimate favored nitazoxanide in its clinical response in comparison with placebo RR 1.46 [95% CI 1.22-1.74; P-value <0.0001]. Network meta-analysis among patients with Giardia intestinalis showed an increase in the probability of diarrheal cessation and parasitological responses in comparison with placebo, RR 1.69 [95% CI 1.08-2.64, P-score 0.27] and RR 2.91 [95% CI 1.72-4.91, P-score 0.55] respectively. In Clostridium difficile infection, the network meta-analysis revealed a non-significantly superior clinical response effect of nitazoxanide to metronidazole 31 days after treatment RR 1.21 [95% CI 0.87-1.69, P-score 0.26]. In Entamoeba histolytica, the overall estimate significantly favored nitazoxanide in parasitological response with placebo RR 1.80 [95% CI 1.35-2.40, P-value < 0.001]. We highlighted the effectiveness of nitazoxanide in the cessation of diarrhea caused by Cryptosporidium, Giardia intestinalis and Entamoeba histolytica infection. We also found significant superiority of NTZ to metronidazole in improving the clinical response to G. intestinalis, thus it may be a suitable candidate for treating infection-induced diarrhea. To prove the superiority of NTZ during a C. difficile infection may warrant a larger-scale clinical trial since its superiority was deemed insignificant. We recommend nitazoxanide as an appropriate option for treating infectious diarrhea.
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Zhang L, Cao W, Gao Y, Yang R, Zhang X, Xu J, Tang Q. Astaxanthin (ATX) enhances the intestinal mucosal functions in immunodeficient mice. Food Funct 2020; 11:3371-3381. [PMID: 32232254 DOI: 10.1039/c9fo02555c] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Increasing pressure of life may bring some disease risks and stress injuries, which may destroy the immune system and result in intestinal mucosal immune disorders. In this study, the effects of different doses of ATX (30 mg per kg b.w., 60 mg per kg b.w. and 120 mg per kg b.w.) on intestinal mucosal functions were explored in cyclophosphamide (Cy)-induced immunodeficient mice. The results showed that continuous intraperitoneal injection of 100 mg per kg b.w. Cy for three days led to a persistent decrease of body weight and a range of abnormalities in the intestine of C57BL/6 mice. However, administration of ATX at 60 and 120 mg per kg b.w. could effectively prevent intestinal mucosa from this damage, including reduced levels of oxidative stress (MDA, GSH and GSH-PX), increased intestinal morphological structural integrity, stimulative growth of goblet cells and mucous secretion, decreased development of Paneth cells and expression levels of antimicrobial peptides (AMPs) (Reg-3γ and lysozyme), increased IgA secretion, ameliorative main gut flora (especially total bacteria, Lactobacillus and Enterobacteriaceae spp. ) and its metabolites (acetic acid, propionic acid and butyric acid). These protective effects of ATX were better than those of control-β-carotene in general. Our results may provide a new protective measure to keep intestinal mucosal barriers, which is of great significance for maintaining immune function in the body.
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Affiliation(s)
- Lirong Zhang
- College of Food Science and Engineering, Ocean University of China, Yushan Road 5th, Qingdao, Shandong Province 266003, China.
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Siciliano V, Nista EC, Rosà T, Brigida M, Franceschi F. Clinical Management of Infectious Diarrhea. Rev Recent Clin Trials 2020; 15:298-308. [PMID: 32598272 DOI: 10.2174/1574887115666200628144128] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 05/05/2020] [Accepted: 05/11/2020] [Indexed: 06/11/2023]
Abstract
BACKGROUND Infectious diarrhea is the most common cause of diarrhea worldwide and is responsible for more deaths than other gastrointestinal tract diseases such as gastrointestinal cancers, peptic ulcer disease or inflammatory bowel disease. Diarrheal disease still represents the 8th leading cause of death worldwide, with more than 1,6 million attributed fatalities in 2016 alone. The majority of cases can be divided into three principal clinical presentations: acute watery diarrhea lasting 5-10 days and normally self-limiting, bloody diarrhea (dysentery), and persistent diarrhea with or without intestinal malabsorption. METHODS We performed an electronic search on PUBMED of the scientific literature concerning infectious diarrhea and its clinical management. AIM In this review article, we analyze the most important causes of infectious diarrhea and their constellation of signs and symptoms, providing an update on the diagnostic tools available in today's practice and on the different treatment options. CONCLUSION Even though the majority of intestinal infections are self-limiting in immunocompetent individuals, specific diagnosis and identification of the causative agent remain crucial from public health and epidemiological perspectives. Specific diagnostic investigation can be reserved for patients with severe dehydration, more severe illness, persistent fever, bloody stools, immunosuppression, and for cases of suspected nosocomial infection or outbreak and it includes complete blood count, creatinine and electrolytes evaluation, determination of leukocytes and lactoferrin presence in the stools, stool culture, together with C. difficile testing, PCR, ova and parasites' search, endoscopy and abdominal imaging. Since acute diarrhea is most often self-limited and caused by viruses, routine antibiotic use is not recommended for most adults with mild, watery diarrhea. However, when used appropriately, antibiotics are effective against shigellosis, campylobacteriosis, C. difficile colitis, traveler's diarrhea, and protozoal infections. Furthermore, antibiotics use should be considered in patients who are older than 65 years, immunocompromised, severely ill, or septic.
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Affiliation(s)
| | | | - Tommaso Rosà
- Universita Cattolica del Sacro Cuore - Rome, Italy
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Jin Z, Ma J, Zhu G, Zhang H. Discovery of Novel Anti-cryptosporidial Activities From Natural Products by in vitro High-Throughput Phenotypic Screening. Front Microbiol 2019; 10:1999. [PMID: 31551955 PMCID: PMC6736568 DOI: 10.3389/fmicb.2019.01999] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Accepted: 08/15/2019] [Indexed: 01/12/2023] Open
Abstract
Cryptosporidium parvum is a globally distributed zoonotic protozoan parasite of both medical and veterinary importance. Nitazoxanide is the only FDA-approved drug to treat cryptosporidiosis in immunocompetent people, but it is not fully effective. There is no drug approved by FDA for use in immunocompromised patients or in animals. In the present study, we conducted phenotypic screening of 800 nature products with defined chemical structures for potential novel activity against the growth of C. parvum in vitro. We identified a large number of compounds showing low to sub-micromolar anti-cryptosporidial activity, and fully characterized 16 top hits for anti-parasitic efficacies in vitro [EC50 values from 0.122 to 3.940 μM, cytotoxicity (TC50) values from 6.31 to >100 μm] and their safety margins. Among them, 11 compounds were derived from plants with EC50 values from 0.267 to 3.940 μM [i.e., cedrelone, deoxysappanone B 7,4'-dimethyl ether (Deox B 7,4), tanshinone IIA, baicalein, deoxysappanone B 7,3'-dimethyl ether acetate, daunorubicin, dihydrogambogic acid, deacetylgedunin, deacetoxy-7-oxogedunin, dihydrotanshinone I, 2,3,4'-trihydroxy-4-methoxybenzophenone, and 3-deoxo-3beta-hydroxy-mexicanolide 16-enol ether]. Three compounds with sub-micromolar EC50 values (i.e., cedrelone, Deox B 7,4, and baicalein) were further investigated for their effectiveness on various parasite developmental stages in vitro. Cedrelone and baicalein were more effective than Dexo B 7,4 when treating parasite for shorter periods of time, but all three compounds could kill the parasite irreversibly. These findings provide us a large selection of new structures derived from natural products to be explored for developing anti-cryptosporidial therapeutics.
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Affiliation(s)
- Zi Jin
- Department of Veterinary Pathobiology, College of Veterinary Medicine & Biomedical Sciences, Texas A&M University, College Station, TX, United States
| | - Jingbo Ma
- Department of Veterinary Pathobiology, College of Veterinary Medicine & Biomedical Sciences, Texas A&M University, College Station, TX, United States.,Department of Parasitology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
| | - Guan Zhu
- Department of Veterinary Pathobiology, College of Veterinary Medicine & Biomedical Sciences, Texas A&M University, College Station, TX, United States
| | - Haili Zhang
- Department of Veterinary Pathobiology, College of Veterinary Medicine & Biomedical Sciences, Texas A&M University, College Station, TX, United States
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Comparative Pathobiology of the Intestinal Protozoan Parasites Giardia lamblia, Entamoeba histolytica, and Cryptosporidium parvum. Pathogens 2019; 8:pathogens8030116. [PMID: 31362451 PMCID: PMC6789772 DOI: 10.3390/pathogens8030116] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 07/25/2019] [Accepted: 07/25/2019] [Indexed: 02/07/2023] Open
Abstract
Protozoan parasites can infect the human intestinal tract causing serious diseases. In the following article, we focused on the three most prominent intestinal protozoan pathogens, namely, Giardia lamblia, Entamoeba histolytica, and Cryptosporidium parvum. Both C. parvum and G. lamblia colonize the duodenum, jejunum, and ileum and are the most common causative agents of persistent diarrhea (i.e., cryptosporidiosis and giardiasis). Entamoeba histolytica colonizes the colon and, unlike the two former pathogens, may invade the colon wall and disseminate to other organs, mainly the liver, thereby causing life-threatening amebiasis. Here, we present condensed information concerning the pathobiology of these three diseases.
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Lynch C, Mackowiak B, Huang R, Li L, Heyward S, Sakamuru S, Wang H, Xia M. Identification of Modulators That Activate the Constitutive Androstane Receptor From the Tox21 10K Compound Library. Toxicol Sci 2019; 167:282-292. [PMID: 30247703 PMCID: PMC6657574 DOI: 10.1093/toxsci/kfy242] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The constitutive androstane receptor (CAR; NR1I3) is a nuclear receptor involved in all phases of drug metabolism and disposition. However, recently it's been implicated in energy metabolism, tumor progression, and cancer therapy as well. It is, therefore, important to identify compounds that induce human CAR (hCAR) activation to predict drug-drug interactions and potential therapeutic usage. In this study, we screen the Tox21 10,000 compound collection to characterize hCAR activators. A potential novel structural cluster of compounds was identified, which included nitazoxanide and tenonitrozole, whereas known structural clusters, such as flavones and prazoles, were also detected. Four compounds, neticonazole, diphenamid, phenothrin, and rimcazole, have been identified as novel hCAR activators, one of which, rimcazole, shows potential selectivity toward hCAR over its sister receptor, the pregnane X receptor (PXR). All 4 compounds translocated hCAR from the cytoplasm into the nucleus demonstrating the first step to CAR activation. Profiling these compounds as hCAR activators would enable an estimation of drug-drug interactions, as well as identify prospective therapeutically beneficial drugs.
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Affiliation(s)
- Caitlin Lynch
- Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland 20892
| | - Bryan Mackowiak
- Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland 21201
| | - Ruili Huang
- Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland 20892
| | - Linhao Li
- Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland 21201
| | | | - Srilatha Sakamuru
- Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland 20892
| | - Hongbing Wang
- Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland 21201
| | - Menghang Xia
- Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland 20892
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Chavez MA, White AC. Novel treatment strategies and drugs in development for cryptosporidiosis. Expert Rev Anti Infect Ther 2018; 16:655-661. [PMID: 30003818 DOI: 10.1080/14787210.2018.1500457] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
INTRODUCTION Cryptosporidium is a protozoan pathogen that can cause diarrheal disease in healthy and immunosuppressed individuals, worldwide. Recent studies have highlighted the impact of cryptosporidiosis on children in resource-limited countries. Nitazoxanide is the only Food and Drug Administration approved treatment, but it is not consistently effective therapy for cryptosporidiosis in the most vulnerable populations. Areas covered: This review focused on recent published studies evaluating novel drugs and new compounds for the treatment of cryptosporidiosis. Expert commentary: Combinations of approved drugs have demonstrated some activity. Broad screens have demonstrated activity against Cryptosporidium for a number of available drugs, including statins and clofazimine, and the latter has advanced into clinical trials. Cryptosporidium calcium-dependent protein kinase 1 (CDPK1) has been identified as an attractive target for treatment, and bumped kinase inhibitors have been developed which inhibit CDPK1 and are active against Cryptosporidium growth both in vitro and in vivo. Inhibition of Plasmodium lipid kinase PI(4)K8 of Cryptosporidium by KDU731 greatly reduced oocyst shedding and improved diarrhea in calves with limited effects on the human PI(4)K. Another novel potent inhibitor MMV665917 was efficacious in mouse models with cidal activity against Cryptosporidium. Additional compounds have proved active in vitro. So far, only clofazimine has entered human trials.
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Affiliation(s)
- Miguel A Chavez
- a Department of Internal Medicine , University of Texas Medical Branch , Galveston , Texas , USA
| | - A Clinton White
- b Infectious Diseases Division, Department of Internal Medicine , University of Texas Medical Branch , Galveston , Texas , USA
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La Frazia S, Piacentini S, Riccio A, Rossignol JF, Santoro MG. The second-generation thiazolide haloxanide is a potent inhibitor of avian influenza virus replication. Antiviral Res 2018; 157:159-168. [PMID: 29908209 DOI: 10.1016/j.antiviral.2018.06.008] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Revised: 06/07/2018] [Accepted: 06/11/2018] [Indexed: 10/14/2022]
Abstract
The emergence of new avian influenza virus (AIV) strains able to infect humans represents a serious threat to global human health. In addition to surveillance and vaccine development, antiviral therapy remains crucial for AIV control; however, the increase in drug-resistant AIV strains underscores the need for novel approaches to anti-influenza chemotherapy. We have previously shown that the thiazolide anti-infective nitazoxanide (NTZ) inhibits influenza A/PuertoRico/8/1934(H1N1) virus replication, and this effect was associated with inhibition of viral hemagglutinin (HA) maturation. Herein we investigated the activity of the second-generation thiazolide haloxanide (HLN) against H5N9, H7N1 and H1N1 AIV infection in vitro, and explored the mechanism of the antiviral action. Using the A/chicken/Italy/9097/1997(H5N9) AIV as a model, we show that HLN and its precursor p-haloxanide are more effective than NTZ against AIV, with IC50 ranging from 0.03 to 0.1 μg/ml, and SI ranging from 200 to >700, depending on the multiplicity of infection. Haloxanide did not affect AIV entry into target cells and did not cause a general inhibition of viral protein expression, whereas it acted at post-translational level by inhibiting HA maturation at a stage preceding resistance to endoglycosidase-H digestion. Importantly, this effect was independent of the AIV-HA subtype and the host cell. Immunomicroscopy and receptor-binding studies confirmed that HLN-induced alterations impair AIV-HA trafficking to the host cell plasma membrane, a key step for viral morphogenesis. The results indicate that haloxanide could provide a new tool for treatment of avian influenza virus infections.
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Affiliation(s)
- Simone La Frazia
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | - Sara Piacentini
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | - Anna Riccio
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | - Jean-Francois Rossignol
- Division of Infectious Diseases and International Medicine, University of South Florida College of Medicine, Tampa, FL, USA; Romark Laboratories, LC, Tampa, FL, USA
| | - M Gabriella Santoro
- Department of Biology, University of Rome Tor Vergata, Rome, Italy; Institute of Translational Pharmacology, CNR, Rome, Italy.
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Mohapatra S, Singh DP, Alcid D, Pitchumoni CS. Beyond O&P Times Three. Am J Gastroenterol 2018; 113:805-818. [PMID: 29867172 DOI: 10.1038/s41395-018-0083-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Accepted: 02/23/2018] [Indexed: 12/11/2022]
Abstract
Although examination of the stool for ova and parasites times three (O&P ×3) is routinely performed in the United States (US) for the evaluation of persistent and/or chronic diarrhea, the result is almost always negative. This has contributed to the perception that parasitic diseases are nearly non-existent in the country unless there is a history of travel to an endemic area. The increasing number of immigrants from third-world countries, tourists, and students who present with symptoms of parasitic diseases are often misdiagnosed as having irritable bowel syndrome or inflammatory bowel disease. The consequences of such misdiagnosis need no explanation. However, certain parasitic diseases are endemic to the US and other developed nations and affect both immunocompetent and immunocompromised patients. Testing for parasitic diseases either with O&P or with other diagnostic tests, followed by the recommended treatment, is quite rewarding when appropriate. Most parasitic diseases are easily treatable and should not be confused with other chronic gastrointestinal (GI) disorders. In this review, we critically evaluate the symptomatology of luminal parasitic diseases, their differential diagnoses, appropriate diagnostic tests, and management.
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Affiliation(s)
- Sonmoon Mohapatra
- Department of Internal Medicine, Saint Peter's University Hospital - Rutgers Robert Wood Johnson School of Medicine, New Brunswick, NJ, USA. Department of Infectious Diseases, Saint Peter's University Hospital - Rutgers Robert Wood Johnson School of Medicine, New Brunswick, NJ, USA. 3Department of Gastroenterology, Hepatology and Clinical Nutrition Saint Peter's University Hospital - Rutgers Robert Wood Johnson School of Medicine, New Brunswick, NJ, USA
| | - Dhruv Pratap Singh
- Department of Internal Medicine, Saint Peter's University Hospital - Rutgers Robert Wood Johnson School of Medicine, New Brunswick, NJ, USA. Department of Infectious Diseases, Saint Peter's University Hospital - Rutgers Robert Wood Johnson School of Medicine, New Brunswick, NJ, USA. 3Department of Gastroenterology, Hepatology and Clinical Nutrition Saint Peter's University Hospital - Rutgers Robert Wood Johnson School of Medicine, New Brunswick, NJ, USA
| | - David Alcid
- Department of Internal Medicine, Saint Peter's University Hospital - Rutgers Robert Wood Johnson School of Medicine, New Brunswick, NJ, USA. Department of Infectious Diseases, Saint Peter's University Hospital - Rutgers Robert Wood Johnson School of Medicine, New Brunswick, NJ, USA. 3Department of Gastroenterology, Hepatology and Clinical Nutrition Saint Peter's University Hospital - Rutgers Robert Wood Johnson School of Medicine, New Brunswick, NJ, USA
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Waddington CS, McLeod C, Morris P, Bowen A, Naunton M, Carapetis J, Grimwood K, Robins-Browne R, Kirkwood CD, Baird R, Green D, Andrews R, Fearon D, Francis J, Marsh JA, Snelling T. The NICE-GUT trial protocol: a randomised, placebo controlled trial of oral nitazoxanide for the empiric treatment of acute gastroenteritis among Australian Aboriginal children. BMJ Open 2018; 8:e019632. [PMID: 29391385 PMCID: PMC5829923 DOI: 10.1136/bmjopen-2017-019632] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Revised: 11/27/2017] [Accepted: 12/07/2017] [Indexed: 11/03/2022] Open
Abstract
INTRODUCTION 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 with Giardia, amoebiasis, Cryptosporidium, Rotavirus and Norovirus gastroenteritis, as well as in cases where no enteropathogens are found. METHODS AND ANALYSIS This double blind, 1:1 randomised, placebo controlled trial is investigating the impact of oral nitazoxanide on acute gastroenteritis in hospitalised Australian Aboriginal children aged 3 months to <5 years. Dosing is based on age-based dosing. The primary endpoint is the time to resolution of 'significant illness' defined as the time from randomisation to the time of clinical assessment as medically ready for discharge, or to the time of actual discharge from hospital, whichever occurs first. Secondary endpoints include duration of hospitalisation, symptom severity during the period of significant illness and following treatment, duration of rehydration and drug safety. Patients will be followed for medically significant events for 60 days. Analysis is based on Bayesian inference. Subgroup analysis will occur by pathogen type (bacteria, virus or parasite), rotavirus vaccination status, age and illness severity. ETHICS AND DISSEMINATION Ethics approval has been granted by the Central Australian Human Research Ethics Committee (HREC-14-221) and the Human Research Ethics Committee of the Northern Territory Department of Health and Menzies School of Health Research (HREC2014-2172). Study investigators will ensure that the trial is conducted in accordance with the principles of the Declaration of Helsinki. Individual participant consent will be obtained. Results will be disseminated via peer-reviewed publication. TRIAL REGISTRATION NUMBER ACTRN12614000381684.
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Affiliation(s)
- Claire S Waddington
- Wesfarmers Centre of Vaccines and Infectious Diseases, Telethon Kids Institute, Subiaco, Australia
| | - Charlie McLeod
- Infectious Diseases Department, Princess Margaret Hospital for Children, Perth, Australia
| | - Peter Morris
- Menzies School of Health Research, Casuarina, Australia
- Department of Paediatrics, Royal Darwin Hospital, Darwin, Australia
| | - Asha Bowen
- Infectious Diseases Department, Princess Margaret Hospital for Children, Perth, Australia
- Menzies School of Health Research, Casuarina, Australia
| | - Mark Naunton
- Department of Pharmacy, University of Canberra, Bruce, Canberra, Australia
| | - Jonathan Carapetis
- Wesfarmers Centre of Vaccines and Infectious Diseases, Telethon Kids Institute, Subiaco, Australia
- Infectious Diseases Department, Princess Margaret Hospital for Children, Perth, Australia
| | - Keith Grimwood
- Queensland Children’s Medical Research Institute, Brisbane, Queensland, Australia
| | - Roy Robins-Browne
- Department of Microbiology and Immunology, University of Melbourne, Melbourne, Victoria, Australia
| | - Carl D Kirkwood
- Murdoch Children’s Research Institute, Parkville, Victoria, Australia
| | - Robert Baird
- Department of Microbiology, Royal Darwin Hospital, Darwin, Australia
| | - David Green
- Department of Paediatrics, Alice Springs Hospital, Alice Springs, Australia
| | - Ross Andrews
- Menzies School of Health Research, Casuarina, Australia
| | - Deborah Fearon
- Department of Paediatrics, Alice Springs Hospital, Alice Springs, Australia
| | - Joshua Francis
- Menzies School of Health Research, Casuarina, Australia
- Department of Paediatrics, Royal Darwin Hospital, Darwin, Australia
| | - Julie A Marsh
- Wesfarmers Centre of Vaccines and Infectious Diseases, Telethon Kids Institute, Subiaco, Australia
- Centre for Applied Statistics, University of Western Australia, Crawley, Australia
| | - Thomas Snelling
- Wesfarmers Centre of Vaccines and Infectious Diseases, Telethon Kids Institute, Subiaco, Australia
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Pawlowic MC, Vinayak S, Sateriale A, Brooks C, Striepen B. Generating and Maintaining Transgenic Cryptosporidium parvum Parasites. CURRENT PROTOCOLS IN MICROBIOLOGY 2017; 46:20B.2.1-20B.2.32. [PMID: 28800157 PMCID: PMC5556942 DOI: 10.1002/cpmc.33] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The apicomplexan parasite Cryptosporidium is a leading cause of diarrheal disease and an important contributor to overall global child mortality. We currently lack effective treatment and immune prophylaxis. Recent advances now permit genetic modification of this important pathogen. We expect this to produce rapid advances in fundamental as well as translational research on cryptosporidiosis. Here we outline genetic engineering for Cryptosporidium in sufficient detail to establish transfection in any laboratory that requires access to this key technology. This chapter details the conceptual design consideration, as well as the experimental steps required to transfect, select, and isolate transgenic parasites. We also provide detail on key in vitro and in vivo assays to detect, validate, and quantify genetically modified Cryptosporidium parasites. © 2017 by John Wiley & Sons, Inc.
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Affiliation(s)
- Mattie C. Pawlowic
- Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA 30602
| | - Sumiti Vinayak
- Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA 30602
| | - Adam Sateriale
- Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA 30602
| | - Carrie Brooks
- Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA 30602
| | - Boris Striepen
- Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA 30602
- Department of Cellular Biology, University of Georgia, Athens, GA, 30602
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Florescu DF, Sandkovsky U. Cryptosporidium infection in solid organ transplantation. World J Transplant 2016; 6:460-471. [PMID: 27683627 PMCID: PMC5036118 DOI: 10.5500/wjt.v6.i3.460] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2016] [Revised: 04/22/2016] [Accepted: 06/16/2016] [Indexed: 02/05/2023] Open
Abstract
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.
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Manjunatha UH, Chao AT, Leong FJ, Diagana TT. Cryptosporidiosis Drug Discovery: Opportunities and Challenges. ACS Infect Dis 2016; 2:530-7. [PMID: 27626293 DOI: 10.1021/acsinfecdis.6b00094] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The apicomplexan parasite Cryptosporidium is the second most important diarrheal pathogen causing life-threatening diarrhea in children, which is also associated with long-term growth faltering and cognitive deficiency. Cryptosporidiosis is a parasitic disease of public health concern caused by Cryptosporidium parvum and Cryptosporidium hominis. Currently, nitazoxanide is the only approved treatment for cryptosporidium infections. Unfortunately, it has limited efficacy in the most vulnerable patients, thus there is an urgent need for a safe and efficacious cryptosporidiosis drug. In this work, we present our current perspectives on the target product profile for novel cryptosporidiosis therapies and the perceived challenges and possible mitigation plans at different stages in the cryptosporidiosis drug discovery process.
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Affiliation(s)
- Ujjini H. Manjunatha
- Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01, Singapore 138670
| | - Alexander T. Chao
- Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01, Singapore 138670
| | - F. Joel Leong
- Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01, Singapore 138670
| | - Thierry T. Diagana
- Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01, Singapore 138670
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45
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Shoultz DA, de Hostos EL, Choy RKM. Addressing Cryptosporidium Infection among Young Children in Low-Income Settings: The Crucial Role of New and Existing Drugs for Reducing Morbidity and Mortality. PLoS Negl Trop Dis 2016; 10:e0004242. [PMID: 26820408 PMCID: PMC4731073 DOI: 10.1371/journal.pntd.0004242] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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Hoyer AB, Schladow SG, Rueda FJ. A hydrodynamics-based approach to evaluating the risk of waterborne pathogens entering drinking water intakes in a large, stratified lake. WATER RESEARCH 2015; 83:227-236. [PMID: 26162312 DOI: 10.1016/j.watres.2015.06.014] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/07/2014] [Revised: 03/23/2015] [Accepted: 06/08/2015] [Indexed: 06/04/2023]
Abstract
Pathogen contamination of drinking water lakes and reservoirs is a severe threat to human health worldwide. A major source of pathogens in surface sources of drinking waters is from body-contact recreation in the water body. However, dispersion pathways of human waterborne pathogens from recreational beaches, where body-contact recreation is known to occur to drinking water intakes, and the associated risk of pathogens entering the drinking water supply remain largely undocumented. A high spatial resolution, three-dimensional hydrodynamic and particle tracking modeling approach has been developed to analyze the risk and mechanisms presented by pathogen dispersion. The pathogen model represents the processes of particle release, transport and survival. Here survival is a function of both water temperature and cumulative exposure to ultraviolet (UV) radiation. Pathogen transport is simulated using a novel and computationally efficient technique of tracking particle trajectories backwards, from a drinking water intake toward their source areas. The model has been applied to a large, alpine lake - Lake Tahoe, CA-NV (USA). The dispersion model results reveal that for this particular lake (1) the risk of human waterborne pathogens to enter drinking water intakes is low, but significant; (2) this risk is strongly related to the depth of the thermocline in relation to the depth of the intake; (3) the risk increases with the seasonal deepening of the surface mixed layer; and (4) the risk increases at night when the surface mixed layer deepens through convective mixing and inactivation by UV radiation is eliminated. While these risk factors will quantitatively vary in different lakes, these same mechanisms will govern the process of transport of pathogens.
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Affiliation(s)
- Andrea B Hoyer
- Water Research Institute, University of Granada, C/ Ramón y Cajal 4, 18071 Granada, Spain.
| | - S Geoffrey Schladow
- Department of Civil and Environmental Engineering, University of California, Davis, One Shields Avenue, Davis, CA 95616, USA; Tahoe Environmental Research Center, University of California, Davis, 291 Country Club Dr., Incline Village, NV 89451, USA.
| | - Francisco J Rueda
- Water Research Institute, University of Granada, C/ Ramón y Cajal 4, 18071 Granada, Spain; Department of Civil Engineering, University of Granada, Campus Universitario de Fuentenueva (Edificio, Politécnico), 18071 Granada, Spain.
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Huston CD, Spangenberg T, Burrows J, Willis P, Wells TNC, van Voorhis W. A Proposed Target Product Profile and Developmental Cascade for New Cryptosporidiosis Treatments. PLoS Negl Trop Dis 2015; 9:e0003987. [PMID: 26447884 PMCID: PMC4598153 DOI: 10.1371/journal.pntd.0003987] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Affiliation(s)
- Christopher D. Huston
- Department of Medicine, University of Vermont College of Medicine, Burlington, Vermont, United States of America
- * E-mail:
| | | | | | - Paul Willis
- Medicines for Malaria Venture, Geneva, Switzerland
| | | | - Wesley van Voorhis
- Medicines for Malaria Venture, Geneva, Switzerland
- Department of Medicine, University of Washington School of Medicine, Seattle, Washington, United States of America
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Sparks H, Nair G, Castellanos-Gonzalez A, White AC. Treatment of Cryptosporidium: What We Know, Gaps, and the Way Forward. CURRENT TROPICAL MEDICINE REPORTS 2015; 2:181-187. [PMID: 26568906 DOI: 10.1007/s40475-015-0056-9] [Citation(s) in RCA: 90] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Cryptosporidiosis is increasingly recognized as an important global health concern. While initially reported in immunocompromised such as AIDS patients, cryptosporidiosis has now been documented as a major cause of childhood diarrhea and an important factor in childhood malnutrition. Currently, nitazoxanide is the only proven anti-parasitic treatment for Cryptosporidium infections. However, it is not effective in severely immunocompromised patients and there is limited data in infants. Immune reconstitution or decreased immunosuppression is critical to therapy in AIDS and transplant patients. This limitation of treatment options presents a major public health challenge given the important burden of disease. Repurposing of drugs developed for other indications and development of inhibitors for novel targets offer hope for improved therapies, but none have advanced to clinical studies.
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Affiliation(s)
- Hayley Sparks
- Infectious Disease Division, Department of Internal Medicine, University of Texas Medical Branch Galveston, 301 University Boulevard, Route 0435, Galveston, TX 77555-0435 USA, TeL 1-409-747-0236, FAX 1-409-772-6527
| | - Gayatri Nair
- Infectious Disease Division, Department of Internal Medicine, University of Texas Medical Branch Galveston, 301 University Boulevard, Route 0435, Galveston, TX 77555-0435 USA, TeL 1-409-747-0236, FAX 1-409-772-6527
| | - Alejandro Castellanos-Gonzalez
- Infectious Disease Division, Department of Internal Medicine, University of Texas Medical Branch Galveston, 301 University Boulevard, Route 0435, Galveston, TX 77555-0435 USA, TeL 1-409-747-0236, FAX 1-409-772-6527
| | - A Clinton White
- Infectious Disease Division, Department of Internal Medicine, University of Texas Medical Branch Galveston, 301 University Boulevard, Route 0435, Galveston, TX 77555-0435 USA, TeL 1-409-747-0236, FAX 1-409-772-6527
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Bento CF, Empadinhas N, Mendes V. Autophagy in the fight against tuberculosis. DNA Cell Biol 2015; 34:228-42. [PMID: 25607549 DOI: 10.1089/dna.2014.2745] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Tuberculosis (TB), a chronic infectious disease mainly caused by the tubercle bacillus Mycobacterium tuberculosis, is one of the world's deadliest diseases that has afflicted humanity since ancient times. Although the number of people falling ill with TB each year is declining, its incidence in many developing countries is still a major cause of concern. Upon invading host cells by phagocytosis, M. tuberculosis can replicate within infected cells by arresting the maturation of the phagosome whose function is to target the pathogen for elimination. Host cells have mechanisms of controlling this evasion by inducing autophagy, an elaborate cellular process that targets bacteria for progressive elimination, decreasing bacterial loads within infected cells. In addition, autophagy activation also aids in the control of inflammation, contributing to a more efficient innate immune response against M. tuberculosis. Several innovative TB therapies have been envisaged based on autophagy manipulation, with some of them revealing high potential for future clinical trials and eventual implementation in healthcare systems. Thus, this review highlights the recent advances on the innate immune response regulation by autophagy upon M. tuberculosis infection and the promising new autophagy-based therapies for TB.
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Affiliation(s)
- Carla F Bento
- 1 Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge , Cambridge, United Kingdom
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50
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Bhadauria D, Goel A, Kaul A, Sharma RK, Gupta A, Ruhela V, Gupta A, Vardhan H, Prasad N. Cryptosporidium infection after renal transplantation in an endemic area. Transpl Infect Dis 2015; 17:48-55. [PMID: 25620388 DOI: 10.1111/tid.12336] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2014] [Revised: 08/21/2014] [Accepted: 10/26/2014] [Indexed: 12/20/2022]
Abstract
BACKGROUND Cryptosporidium is one of the common causes of infective diarrhea in post-transplant patients in endemic areas. However, data are limited on Cryptosporidium infection in recipients of solid organ transplantation. The aim of this study was to determine the incidence, disease manifestation, management, and outcome of Cryptosporidium infection in living-donor renal transplant recipients (RTR). METHODS We performed a detailed retrospective review of the data on all RTR who had diarrheal illness requiring evaluation and hospitalization, and Cryptosporidium infection. RESULTS During the study period, 119/1235 (8.98%) RTR developed diarrhea, and Cryptosporidium was found in 34/119 (28.5%). Nine of 680 (1.3%) patients were on a cyclosporine (CSA)-based regimen, and 25/643 (3.8%) patients were on a tacrolimus (Tac)-based regimen. The relative risk of developing Cryptosporidium infection was lower on the CSA-based regimen, compared with the Tac-based regimen (odds ratio [OR]: 0.35, 95% confidence interval [CI]: 0.17-0.72, P = 0.003). Twelve of the 34 patients had acute graft dysfunction, mainly caused by combined Tac toxicity and dehydration. Mean serum creatinine and trough Tac level were 2.04 ± 0.65 mg/dL and 8.24 ± 1.19 ng/dL, respectively. Nitazoxanide alone was used in 13 patients, and nitazoxanide in combination with fluoroquinolone in 21 patients, with duration of treatment ranging from 16 to 60 days. Tac was changed to CSA in 8/11 patients. The clearance of cysts and response to nitazoxanide alone were significantly lower, compared with combination therapy (61.53% vs. 95.23%, P = 0.01, 38.46 vs. 85.71%, P = 0.004, respectively). The OR for cyst clearance and response was also significantly lower with nitazoxanide alone, in comparison with combination therapy (OR: 0.65, 95% CI: 0.34-0.92, P = 0.01, OR: 0.45, 95% CI: 0.21-0.81, respectively). Four (16%) of 24 patients with response had relapse. CONCLUSION Patients with Tac and mycophenolate mofetil combination therapy had a significantly high risk of Cryptosporidium infection. Cryptosporidial infection may require prolonged nitazoxanide therapy, either alone or in combination, with or without reduction in immunosuppression.
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Affiliation(s)
- D Bhadauria
- Nephrology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
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