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Repurposing loperamide as an Anti-Infection Drug for the Treatment of Intracellular Bacterial Pathogens

Engineering 2024年第8期39卷 180-193页

作者： Hongtao Liu Siqi Li Le Deng Zhenxu Shi Chenxiao Jiang Jingyan Shu Yuan Liu Xuming Deng Jianfeng Wang Zhimin Guo Jiazhang Qiu State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases&Key Laboratory of Zoonosis Research Ministry of EducationInstitute of ZoonosisCollege of Veterinary Medicine&Jilin UniversityChangchun 130062China Center for Pathogen Biology and Infectious Diseases The First Hospital of Jilin UniversityChangchun 130031China Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses Institute of Comparative MedicineCollege of Veterinary MedicineYangzhou UniversityYangzhou 225009China

Infections caused by intracellular bacterial pathogens are difficult to treat since most antibiotics have low cell permeability and undergo rapid degradation within *** rapid development and dissemination of antimicrobial–resistant strains have exacerbated this *** the increasing knowledge of host–pathogen interactions,especially bacterial strategies for survival and proliferation within host cells,host-directed therapy(HDT)has attracted increased interest and has emerged as a promising antiinfection method for treating intracellular ***,we applied a cell-based screening approach to a US Food and Drug Administration(FDA)-approved drug library to identify compounds that can inhibit the intracellular replication of Salmonella Typhimurium(***).This screening allowed us to identify the antidiarrheal agent loperamide(LPD)as a potent inhibitor of *** intracellular *** treatment of infected cells markedly promoted the host autophagic response and lysosomal activity.A mechanistic study revealed that the increase in host autophagy and elimination of intracellular bacteria were dependent on the high expression of glycoprotein nonmetastatic melanoma protein B(GPNMB)induced by *** addition,LPD treatment effectively protected against *** infection in Galleria mellonella and mouse ***,our study suggested that LPD may be useful for the treatment of diseases caused by intracellular bacterial ***,LPD may serve as a promising lead compound for the development of anti-infection drugs based on the HDT strategy.

关键词： Intracellular bacteria US Food and Drug Administration(FDA)-approved drugs Drug repurposing loperamide Autophagy Glycoprotein nonmetastatic melanoma protein B

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Systematically optimized topical delivery system for loperamide hydrochloride: Formulation design,in vitro and in vivo biopharmaceutical evaluation

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Asian Journal of Pharmaceutical Sciences 2018年第3期13卷 255-264页

作者： Jianhui Shu Jingjing Zhao Fang Guo Nanjing Sanhome Pharmaceutical CO. LTD.R&D Insititute

This study aimed to develop a suitable topical delivery system containing diethylene glycol monoethyl ether(DGME) for loperamide hydrochloride(Lop). Two factors, three levels CentralComposite design were applied by generating a quadratic polynomial equation to form contour plots and response surface for prediction of responses as two selected independent variables with EtOH-DGME ratio and EtOH concentration. The response variables flux and skin retention were determined in in vitro hairless mouse skin model. The selected optimum formulation was evaluated for the skin transport characteristics by developing dermatokinetic analysis model and the results demonstrated DGME improved the delivery of Lop into skin deep layers, which was further confirmed by confocal laser scanning microscopy(CLSM)study. In vitro skin permeation was found to have triphasic correlation with plasma AUC in the in vivo pharmacokinetic study. The in vitro–in vivo correlation enabled the prediction of pharmacokinetic profile of Lop from in vitro permeation results. Therefore, the optimum formulation capable of enhancing Lop intracutaneous depot could be a candidate for topical delivery of Lop as analgesics.

关键词： loperamide hydrochloride Topical delivery Skin retention In vitro–in vivo correlation

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A blind, randomized comparison of racecadotril and loperamide for stopping acute diarrhea in adults

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World Journal of Gastroenterology 2005年第10期11卷 1540-1543页

作者： Hwang-Huei Wang Ming-Jium Shieh Kuan-Fu Liao Division of Gastroenterology Medical Faculty

AIM: Racecadotril is a specific enkephalinase inhibitor that exhibits intestinal antisecretory activity without affecting intestinal transit. loperamide is an effective anti-diarrheal agent, but it usually induces constipation. This study is to compare the efficacy, safety, and tolerability of racecadotril versus loperamide in the outpatient treatment of acute diarrhea in adults. METHODS: A two-center, randomized, parallel-group, single-blind study was carried out to compare the efficacy, tolerability, and safety of racecadotril (100 mg thrics daily) and loperamide (2.0 mg 2 twics daily) in 62 adult patients suffering from acute diarrhea. The main efficacy criterion used was the duration of diarrhea after beginning the treatment (in hours). Other signs and symptoms were also evaluated. RESULTS: The clinical success rates for these anti-diarrheal treatments were 95.7% and 92.0% for racecadotril and loperamide respectively. Patients on racecadotril had a median duration of diarrhea of 19.5 h compared with a median of 13 h for patients on loperamide. Rapid improvement in anal burn and nausea was found for each drug. However, more patients on loperamide suffered from reactive constipation (29.0% vs 12.9%). Itching, another adverse event was notably higher in the racecadotril group (28.6% vs 0%). With regard to other adverse events, the two medications showed similar occurrence rates and similar concomitant medication usage rates. CONCLUSION: Racecadotril and loperamide are rapid, equally effective treatments for acute diarrhea in adults, but loperamide treatment is associated with a higher incidence of treatment-related constipation.

关键词： Racecadotril loperamide Acute diarrhea

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Hetong decoction(和通汤)relieves loperamide-induced constipation in rats by regulating expression of aquaporins

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Journal of Traditional Chinese Medicine 2023年第6期43卷 1160-1167页

作者： HUANG Xi XIA Youguang HAN Kai QI Weiwei LINGHU Qing ZHANG Qing XUE Jingbo Department of Anorectal Xuzhou Hospital Affiliated to Nanjing University of Chinese MedicineXuzhou 221000China Department of Pathology Xuzhou Hospital Affiliated to Nanjing University of Chinese MedicineXuzhou 221000China

OBJECTIVE:To investigate whether Hetong decoction(和通汤,HTT)alleviates constipation via regulating AQPs ***:Constipation in rats was induced by loperamide,and rats were randomly assigned into model(saline),HHT-low(95 g/kg),HTT-medium(190 g/kg),HTT-high(380 g/kg)and positive control(mosapride)*** the defecation function,the concentration of serum arginine vasopressin(AVP)and cyclic adenosine monophosphate(cAMP),and the expression of AQP3 and AQP8 in colon tissues were ***460 colon cells with AQP3 and AQP8 knockdown or overexpression were exposed to serum from rats that received low or high dose of HTT,followed by detection of AQP3 and AQP8 ***:The model group showed lower fecal weight and water content,weaker intestinal transit,higher serum concentration of AVP and cAMP,increased proximal and distal AQP8 expression,increased proximal but decreased distal AQP3 ***,these trends were reversed in both the HTT group(low,medium and high dose)and the positive control *** NCM460 cells,HTT dose-dependently stabilized AQP3 and AQP8 expression under AQP3/8 plasmid interference or ***:HTT relieves constipation in rats through regulating AQP3 and AQP8 expression.

关键词： aquaporins constipation hetong decoction loperamide

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loperamide counters FOXO inhibitor mediated beta cell dedifferentiation

Loperamide counters FOXO inhibitor mediated beta cell dediff...

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第十一届全国化学生物学学术会议

作者： Yu-Feng Zhang Yao Liu Xiao Guo Jin Li State Key Laboratory of Genetic Engineering and School of Life Sciences Collaborative Innovation Center for Genetics and DevelopmentFudan University

In Type II diabetes, initial peripheral insulin resistance often progresses to insulin deficiency caused by beta cell dedifferentiation and apoptosis. A key regulator of beta cell dedifferentiation is the transcription factor Forkhead box protein O1[1]（FoxO1）（Fig. 1 A）. From a high content screen（Fig. 1 B）, we identify loperamide as small molecule that can overcome FoxO inhibition. loperamide is a mu-opioid receptor agonist which has been used for the treatment of diarrhea since the 1970 s（FDA application No. 017694）. Mechanistically, this drug alter cellular pH（Fig. 1 C） and FoxO1 expression（Fig. 1 D）, consequently perturbing glucagon transcription（Fig. 1 A）. The results should help accelerate our understanding of the mechanisms underlying beta cell dedifferentiation and aid in the development of therapies for beta cell failure in diabetes.

关键词： Beta Cell Dedifferentiation FoxO1 inhibitor loperamide

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Torsades de Pointes Secondary to Excessive loperamide Use

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Journal of Pharmacy and Pharmacology 2016年第7期4卷 322-327页

作者： Joseph S. Van Tuylt Gail Brock Kristen Bova Campbell Sana M. Al-Khatib Department of Pharmacy Practice St. Louis College of Pharmacy 4588 Parkview Place St. Louis MO 63110 Department of Medicine Duke University Hospital DUMC 3850 Durham NC 27710

Abstract： loperamide is a common, over-the-counter, antidiarrheal medication that has been implicated in cases of ventricular tachycardia. A 32 year-old female patient with a history of opioid abuse and no prior history of cardiovascular disease experienced Torsades de pointes. An electrocardiogram at the time of hospital presentation revealed a prolonged QT interval at 636 msec. Diagnostic evaluation was unremarkable for any underlying cardiovascular pathology. Further investigation revealed the patient had been taking 30-40 loperamide 2 mg tablets oral daily for 2 weeks prior to the onset of Torsades de pointes. At high doses, loperamide may prolong the QT interval through antagonism of the human ether-a-go-go potassium current, thus increasing the risk of ventricular arrhythmias. Clinicians should be cautious with administration of high doses of loperamide to all patients, especially patients at high risk for QT interval prolongation.

关键词： Torsades de pointes loperamide QT prolongation.

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洛哌胺(loperamide)治疗老年腹泻

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中国人民解放军军医进修学院学报 1984年第1期 47-50页

作者：陶国枢赵东海中国人民解放军军医进修学院临床三部

老年人消化机能逐渐衰退很易受外界环境或饮食等因素影响而致腹泻。尤其慢性腹泻不仅给病人的工作、生活带来诸多不便,而且影响病人消化吸收,严重危害病人健康。目前常用的止泻药如阿片、可待因、复方苯乙哌啶等,虽有一定效果,但均有些... 详细信息

老年人消化机能逐渐衰退很易受外界环境或饮食等因素影响而致腹泻。尤其慢性腹泻不仅给病人的工作、生活带来诸多不便,而且影响病人消化吸收,严重危害病人健康。目前常用的止泻药如阿片、可待因、复方苯乙哌啶等,虽有一定效果,但均有些付作用,老年人须慎用。近年来报导新型止泻药洛哌胺(loperamide)抗腹泻作用较强,付作

关键词：急性腹泻疗效肠道易激综合征胃肠功能紊乱老年慢性腹泻 loperamide 非特异性结肠炎

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