Infections caused by intracellular bacterial pathogens are difficult to treat since most antibiotics have low cell permeability and undergo rapid degradation within cells.The rapid development and dissemination of ant...Infections caused by intracellular bacterial pathogens are difficult to treat since most antibiotics have low cell permeability and undergo rapid degradation within cells.The rapid development and dissemination of antimicrobial–resistant strains have exacerbated this dilemma.With 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 infection.Herein,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(S.Typhimurium).This screening allowed us to identify the antidiarrheal agent loperamide(LPD)as a potent inhibitor of S.Typhimurium intracellular proliferation.LPD 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 LPD.In addition,LPD treatment effectively protected against S.Typhimurium infection in Galleria mellonella and mouse models.Thus,our study suggested that LPD may be useful for the treatment of diseases caused by intracellular bacterial pathogens.Moreover,LPD may serve as a promising lead compound for the development of anti-infection drugs based on the HDT strategy.展开更多
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 con...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.展开更多
OBJECTIVE:To investigate whether Hetong decoction(和通汤,HTT)alleviates constipation via regulating AQPs expression.METHODS:Constipation in rats was induced by loperamide,and rats were randomly assigned into model(sal...OBJECTIVE:To investigate whether Hetong decoction(和通汤,HTT)alleviates constipation via regulating AQPs expression.METHODS: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)groups.Then 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 assessed.NCM460 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 expression.RESULTS: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 expression.However,these trends were reversed in both the HTT group(low,medium and high dose)and the positive control group.In NCM460 cells,HTT dose-dependently stabilized AQP3 and AQP8 expression under AQP3/8 plasmid interference or overexpression.CONCLUSIONS:HTT relieves constipation in rats through regulating AQP3 and AQP8 expression.展开更多
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 ge...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.展开更多
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 hist...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.展开更多
AIM： To investigate the role of opioid p-receptor subtype in opiate-induced constipation （OIC）.METHODS： The effect of Ioperamide on intestinal transit was investigated in mice. Ileum strips were isolated from 12-w...AIM： To investigate the role of opioid p-receptor subtype in opiate-induced constipation （OIC）.METHODS： The effect of Ioperamide on intestinal transit was investigated in mice. Ileum strips were isolated from 12-wk-old male BALB/c mice for identification of isometric tension. The ileum strips were precontracted with 1 μmol/L acetylcholine （ACh）. Then, decrease in muscle tone （relaxation） was characterized after cumu- lative administration of 0.1-10μ~mol/L Ioperamide into the organ bath, for a concentration-dependent study. Specific blockers or antagonists were used for pretreat- ment to compare the changes in Ioperamide-induced relaxation.RESULTS： In addition to the delay in intestinal transit, Ioperamide produced a marked relaxation in isolated ileum precontracted with ACh, in a dose-dependent manner. This relaxation was abolished by cyprodime,a selective opioid p-receptor antagonist, but not modified by naloxonazine at a dose sufficient to block opioid μ-1 receptors. Also, treatment with opioid μ-1 receptor agonist failed to modify the muscle tone. Moreover, the relaxation by Ioperamide was attenuated by glibenclamide at a dose sufficient to block ATP-sensitive K^＋ （KATP） channels, and by protein kinase A （PKA） inhibitor, but was enhanced by an inhibitor of phosphodiesterase for cyclic adenosine monophosphate （cAMP）.CONCLUSION： Loperamide induces intestinal relaxa- tion by activation of opioid μ-2 receptors via the cAMP- PKA pathway to open KATp channels, relates to OIC.展开更多
Objective:To evaluate the pharmacological activity against diarrhea of methanol and petroleum ether extract ofDesmodium puchellum(Family:Fabaceae)leaves.Methods:The extract was evaluated for castor oil-induced diarrhe...Objective:To evaluate the pharmacological activity against diarrhea of methanol and petroleum ether extract ofDesmodium puchellum(Family:Fabaceae)leaves.Methods:The extract was evaluated for castor oil-induced diarrhea and enteropooling as well as intestinal motility in rats.Both of the extracts were given to the rats at 200 mg/kg orally.Loperamide was used as a standard drug for diarrhea.Results:The diarrheal severity was reduced significantly(P<0.05)by methanol and petroleum ether extracts by 31.95% and 28.33%,respectively,whereas 54.75% inhibition was found for standard drug loperamide at 5 mg/kg.The two extracts also significantly(P<0.05) reduced the intestinal volume in case of castor oil induced enteropooling.Conclusions:It is concluded that both fractions contain some biologically active ingredients that are active for anti-diarrheal actions whereas methanol fraction has better potential.展开更多
Objective:To evaluate the antidiarrheal activity of the hydromethanolic extract of Combretum dolichopetalum(C.dolichopetalum)leaves.Methods:The antidiarrheal activity of the hydromethanolic extract of C.dolichopetalum...Objective:To evaluate the antidiarrheal activity of the hydromethanolic extract of Combretum dolichopetalum(C.dolichopetalum)leaves.Methods:The antidiarrheal activity of the hydromethanolic extract of C.dolichopetalum leaves was evaluated by inducing diarrhea with castor oil,testing small intestinal motility and establishing enteropooling models in mice.Five groups of animals were used for each model and were treated as follows:Group A received 10 mL/kg of distilled water,and Group B received loperamide(5 mg/kg)while Groups C,D,E received 50,100 and 200 mg/kg of hydromethanolic C.dolichopetalum extract,respectively.Results:The pre-treatment of the mice with the extract(50,100 and 200 mg/kg)caused a significantly dose-dependent decrease in the mean percentage of wet faeces(P<0.05),compared with the negative control in diarrhea induced by castor oil.The extract reduced the distance travelled by the charcoal meal in the small intestine in a dose-dependent manner in the treated groups,compared with the negative control.The charcoal meal travelled 64.71%,49.13%,55.21%,51.75%and 32.95%of the small intestine length in the groups treated with distilled water,loperamide,50 mg/kg,100 mg/kg and 200 mg/kg of C.dolichopetalum extract,respectively.The extract treatment produced a dose-dependent decrease in the mean small intestinal fluid volume,but there was no significant difference(P>0.05),compared with the negative control.Conclusions:The study shows that C.dolichopetalum leaves possess antidiarrheal activity and validate its use in ethnomedicine for that purpose.展开更多
Anal incontinence(AI)in adults is a troublesome condition that negatively impacts upon quality of life and results in significant embarrassment and social isolation.The conservative management of AI is the first step ...Anal incontinence(AI)in adults is a troublesome condition that negatively impacts upon quality of life and results in significant embarrassment and social isolation.The conservative management of AI is the first step and targets symptomatic relief.The reported significant improvement with conservative treatments for AI is close to 25%and involves prescribed changes in lifestyle habits,a reduced intake of foods that may cause or aggravate diarrhea or rectal urgency,and the use of specific anti-diarrheal agents.The use of a mechanical barrier in the form of an anal plug and the outcomes and principles of pelvic kinesitherapies and biofeedback options are outlined.This review discusses a gastroenterologist’s approach towards conservative therapy in patients referred with anal incontinence.展开更多
基金supported by the National Key Research and Development Program of China(2021YFD1801000)the Natural Science Foundation of China(32373066)+1 种基金the Natural Science Foundation of Jilin Province(20230101142JC)the Fundamental Research Funds for the Central Universities.
文摘Infections caused by intracellular bacterial pathogens are difficult to treat since most antibiotics have low cell permeability and undergo rapid degradation within cells.The rapid development and dissemination of antimicrobial–resistant strains have exacerbated this dilemma.With 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 infection.Herein,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(S.Typhimurium).This screening allowed us to identify the antidiarrheal agent loperamide(LPD)as a potent inhibitor of S.Typhimurium intracellular proliferation.LPD 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 LPD.In addition,LPD treatment effectively protected against S.Typhimurium infection in Galleria mellonella and mouse models.Thus,our study suggested that LPD may be useful for the treatment of diseases caused by intracellular bacterial pathogens.Moreover,LPD may serve as a promising lead compound for the development of anti-infection drugs based on the HDT strategy.
文摘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.
文摘OBJECTIVE:To investigate whether Hetong decoction(和通汤,HTT)alleviates constipation via regulating AQPs expression.METHODS: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)groups.Then 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 assessed.NCM460 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 expression.RESULTS: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 expression.However,these trends were reversed in both the HTT group(low,medium and high dose)and the positive control group.In NCM460 cells,HTT dose-dependently stabilized AQP3 and AQP8 expression under AQP3/8 plasmid interference or overexpression.CONCLUSIONS:HTT relieves constipation in rats through regulating AQP3 and AQP8 expression.
文摘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.
文摘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.
基金Supported by A grant from E-Da Hospital (in part)
文摘AIM： To investigate the role of opioid p-receptor subtype in opiate-induced constipation （OIC）.METHODS： The effect of Ioperamide on intestinal transit was investigated in mice. Ileum strips were isolated from 12-wk-old male BALB/c mice for identification of isometric tension. The ileum strips were precontracted with 1 μmol/L acetylcholine （ACh）. Then, decrease in muscle tone （relaxation） was characterized after cumu- lative administration of 0.1-10μ~mol/L Ioperamide into the organ bath, for a concentration-dependent study. Specific blockers or antagonists were used for pretreat- ment to compare the changes in Ioperamide-induced relaxation.RESULTS： In addition to the delay in intestinal transit, Ioperamide produced a marked relaxation in isolated ileum precontracted with ACh, in a dose-dependent manner. This relaxation was abolished by cyprodime,a selective opioid p-receptor antagonist, but not modified by naloxonazine at a dose sufficient to block opioid μ-1 receptors. Also, treatment with opioid μ-1 receptor agonist failed to modify the muscle tone. Moreover, the relaxation by Ioperamide was attenuated by glibenclamide at a dose sufficient to block ATP-sensitive K^＋ （KATP） channels, and by protein kinase A （PKA） inhibitor, but was enhanced by an inhibitor of phosphodiesterase for cyclic adenosine monophosphate （cAMP）.CONCLUSION： Loperamide induces intestinal relaxa- tion by activation of opioid μ-2 receptors via the cAMP- PKA pathway to open KATp channels, relates to OIC.
基金Financially supported by the Bangladesh Council of Scientific and Industrial Research(BCSIR),Chittagong(Grant No.1217)
文摘Objective:To evaluate the pharmacological activity against diarrhea of methanol and petroleum ether extract ofDesmodium puchellum(Family:Fabaceae)leaves.Methods:The extract was evaluated for castor oil-induced diarrhea and enteropooling as well as intestinal motility in rats.Both of the extracts were given to the rats at 200 mg/kg orally.Loperamide was used as a standard drug for diarrhea.Results:The diarrheal severity was reduced significantly(P<0.05)by methanol and petroleum ether extracts by 31.95% and 28.33%,respectively,whereas 54.75% inhibition was found for standard drug loperamide at 5 mg/kg.The two extracts also significantly(P<0.05) reduced the intestinal volume in case of castor oil induced enteropooling.Conclusions:It is concluded that both fractions contain some biologically active ingredients that are active for anti-diarrheal actions whereas methanol fraction has better potential.
文摘Objective:To evaluate the antidiarrheal activity of the hydromethanolic extract of Combretum dolichopetalum(C.dolichopetalum)leaves.Methods:The antidiarrheal activity of the hydromethanolic extract of C.dolichopetalum leaves was evaluated by inducing diarrhea with castor oil,testing small intestinal motility and establishing enteropooling models in mice.Five groups of animals were used for each model and were treated as follows:Group A received 10 mL/kg of distilled water,and Group B received loperamide(5 mg/kg)while Groups C,D,E received 50,100 and 200 mg/kg of hydromethanolic C.dolichopetalum extract,respectively.Results:The pre-treatment of the mice with the extract(50,100 and 200 mg/kg)caused a significantly dose-dependent decrease in the mean percentage of wet faeces(P<0.05),compared with the negative control in diarrhea induced by castor oil.The extract reduced the distance travelled by the charcoal meal in the small intestine in a dose-dependent manner in the treated groups,compared with the negative control.The charcoal meal travelled 64.71%,49.13%,55.21%,51.75%and 32.95%of the small intestine length in the groups treated with distilled water,loperamide,50 mg/kg,100 mg/kg and 200 mg/kg of C.dolichopetalum extract,respectively.The extract treatment produced a dose-dependent decrease in the mean small intestinal fluid volume,but there was no significant difference(P>0.05),compared with the negative control.Conclusions:The study shows that C.dolichopetalum leaves possess antidiarrheal activity and validate its use in ethnomedicine for that purpose.
文摘Anal incontinence(AI)in adults is a troublesome condition that negatively impacts upon quality of life and results in significant embarrassment and social isolation.The conservative management of AI is the first step and targets symptomatic relief.The reported significant improvement with conservative treatments for AI is close to 25%and involves prescribed changes in lifestyle habits,a reduced intake of foods that may cause or aggravate diarrhea or rectal urgency,and the use of specific anti-diarrheal agents.The use of a mechanical barrier in the form of an anal plug and the outcomes and principles of pelvic kinesitherapies and biofeedback options are outlined.This review discusses a gastroenterologist’s approach towards conservative therapy in patients referred with anal incontinence.
