Analysis of Mechanism of Chloroform Extract of Gegen Qinliantang on Alleviating Enterotoxicity Induced by Irinotecan / 中国实验方剂学杂志

Objective:Considering the efficacy of Gegen Qinliantang （GQT） in releasing exterior and clearing interior to alleviate dampness-heat dysentery， we analyzed the mechanism of the chloroform extract of GQT in alleviating enterotoxicity caused by irinotecan to provide an experimental basis for the development of GQT. Method:Kunming mice （<italic>n</italic>=60） were randomly divided into a blank group， a model group， a loperamide group （positive drug of loperamide hydrochloride capsule， 0.4 mg·kg^-1）， and high- （2.3 g·kg^-1） and low-dose （1.16 g·kg^-1） GQT chloroform extract groups. The mouse model of delayed diarrhea was established by intraperitoneal injection of irinotecan hydrochloride （CPT-11， 55 mg·kg^-1） for four consecutive days， meanwhile， the mice in the blank group only received the same volume of normal saline. Corresponding drugs were administered by gavage on the fifth day， respectively， while the ones in the blank group and model group were given distilled water for five consecutive days. The general condition of mice in each group was observed， and diarrhea indexes of mice were recorded. Pathological changes in colon tissues of mice were observed by hematoxylin-eosin （HE） staining. The tumor necrosis factor （TNF）-<italic>α</italic>， interleukin （IL）-1<italic>β</italic>， cyclooxygenase （COX）-2， intercellular adhesion molecule （ICAM）-1， glutathione peroxidase （GSH-Px）， superoxide dismutase （SOD）， malondialdehyde （MDA） and nitric oxide （NO） levels in colon tissues were detected with the assay kits. Furthermore， the expression levels of Kelch sample epoxy chloropropane associated protein 1 （Keap1）， nuclear factor E₂ related factor 2 （Nrf2）， tight junction protein-1 （ZO-1）， heme oxygenase-1 （HO-1） and tight junction protein （Occludin） were detected by Western blot. Result:Compared with the blank group， the model group showed declined body weight and reduced contents of GSH-Px and SOD （<italic>P</italic><0.01）， whereas increased diarrhea indexes and TNF-<italic>α</italic>， IL-1<italic>β</italic>， COX-2， ICAM-1， MDA and NO levels （<italic>P</italic><0.01）. Abundant inflammatory cells and colonic mucosa with defects， swelling， bleeding， and inflammatory exudation were revealed by HE staining in the mice of the model group. The expression levels of Keap1， Nrf2， ZO-1， HO-1 and Occludin in colon tissues significantly declined （<italic>P</italic><0.01）. Compared with the model group， the loperamide group and the high- and low-dose GQT chloroform extract groups exhibited improved weight loss， reduced diarrhea indexes， diminished TNF-<italic>α</italic>，<italic> </italic>IL-1<italic>β</italic>， COX-2， ICAM-1， MDA and NO， and elevated GSH-Px and SOD. HE staining indicated that the cells were compactly arranged with clear nuclei in the high- and low-dose GQT chloroform extract groups， and the expression levels of Keap1， Nrf2， HO-1， Occludin， and ZO-1 were up-regulated. Conclusion:GQT chloroform extract may alleviate CPT-11-induced delayed diarrhea by regulating inflammation and oxidative stress for enhancing the intestinal barrier function. These findings are expected to provide a reference for exploring the toxicity-attenuating effect of Chinese medicinals on chemotherapy drugs and for developing famous classical formulas.

Antidiarrhoea Activities of Aqueous Extract of Myrianthus arboreus Leaves in Albino Rats

Diarrhoea is one of the leading causes of morbidity and mortality in children under the age of 5 years. Due to this problem, the World Health Organization has encouraged studies that will bring about the desired treatment and prevention of diarrhoea. Myrianthus arboreus leaves (MA) is used in some tribes of Nigeria for food. In this study, the antidiarrhoea activities of the aqueous extract of Myrianthus arboreus leaveswere investigated with experimental animals via feacal count, measurement gastrointestinal charcoal meal distance and electrolyte composition. The extract (500, 1000 and 2000) mg/kg in comparison with loperamide hydrochloride, decreased the degree of gastrointestinal motility, production of diarrhoea stool, reduced the frequency of defecation and delayed the onset of diarrhoea in castor oil induced in albino rats. Also the extract inhibited the concentration of intestinal fluid electrolytes.

Safety and Tolerability of Nonspecific Antidiarrheals in Children with Acute Diarrhea

Introduction: In clinical practice, nonspecific antidiarrhealsare most commonly used by clinicians along with routinetreatment to hasten the recovery. This study was conductedto to study the safety and tolerability of these nonspecificantidiarrheals in children with acute diarrhea.Material and Methods: This was a prospective, observationalstudy done in clinical settings for a period of 3 years at twopediatric clinics and at a tertiary care hospital. Children weredivided into 5 treatment groups (viz, control, racecadotril,Mebarid, Diarex and loperamide) at the discretion of thepediatrician. One questionnaire was provided to parents torecord the details about the course of diarrhea and parentswere sensitized to report any adverse event.Results: Overall occurrence of adverse events wassignificantly higher in racecadotril group (34.86%) comparedto other groups (C:23.16%, M:21.14%, D:17.95%, L:17.65%).Conclusion: These agents may be safe, effective andinexpensive addition to the routine treatment of acute diarrhea.

LAXATIVE EFFECT OF RHEUM UNDULATUM L. EXTRACT ON LOPERAMIDE INDUCED CONSTIPATION IN WISTAR RATS / Монголын эм зүй, эм судлал

Introduction: Constipation is highly prevalent, often chronic gastrointestinal disorder that affects adults. The treatment with classic drugs did not cut, in one hand with the inadequate relief of bloating and other symptoms, and with the luck of efficacy in relieving constipation. Therefore, the search for novel safe laxative drugs seems, inevitable. Rheum undulatum L. was traditionally used in constipation, thus we have attempted to evaluate the laxative effect of Rheum undulatum L. Purpose: The laxative effect of Rheum undulatum L. was evaluated against loperamide induced constipated rats. Methodology: Fifteen male normal rats were used in this study. Fifteen male constipated wistar albino rats weighing 180-250 g were also used for the study and randomized into three groups (n=5) in each of the experiments. Constipated control group rats oral administrated distilled water. Constipated rats (treatment groups) were treated with 4.1 mg/kg dose body weight /day of the preparation for one day and also Laxing a standard drug was used for the reference group. The fecal weight, the fecal humidity laxative activity were monitored in experimental rats.Results: Constipation was successfully induced in the rats by loperamide as seen in the elevated fecal properties compared to the control rats. The Rheum undulatum L. compounds preparation administered orally produced significant laxative activity and reduced loperamide induced constipation in dose dependent manner as seen in the increase of fecal output. The same doses of the Rheum undulatum L. compounds preparation produced a significant increase (P<0.05) fecal weight, the faeces humidity. The effect of the compounds preparation compares favourably well with Laxing, a standard laxative drug. Conclusion: The results of this study justify the use of Rheum undulatum L. compounds preparation as a laxative in traditional medicine. The produced significantly increase in fecal output of rats and the stimulation of gastrointestinal motility. Keywords: Laxative, gastro intestinal motility, loperamide, constipated

Laxative effect of Rheum undulatum L. Extract on loperamide induced constipation in wistar rats / Монголын эм зүй, эм судлал

Introduction@#Constipation is highly prevalent, often chronic gastrointestinal disorder that affects adults. The treatment with classic drugs did not cut, in one hand with the inadequate relief of bloating and other symptoms, and with the luck of efficacy in relieving constipation. Therefore, the search for novel safe laxative drugs seems, inevitable. Rheum undulatum L. was traditionally used in constipation, thus we have attempted to evaluate the laxative effect of Rheum undulatum L.@*Purpose@#The laxative effect of Rheum undulatum L. was evaluated against loperamide induced constipated rats.@*Methodology@#Fifteen male normal rats were used in this study. Fifteen male constipated wistar albino rats weighing 180-250 g were also used for the study and randomized into three groups (n=5) in each of the experiments. Constipated control group rats oral administrated distilled water. Constipated rats (treatment groups) were treated with 4.1 mg/kg dose body weight /day of the preparation for one day and also Laxing a standard drug was used for the reference group. The fecal weight, the fecal humidity laxative activity were monitored in experimental rats.@*Results@#Constipation was successfully induced in the rats by loperamide as seen in the elevated fecal properties compared to the control rats. The Rheum undulatum L. compounds preparation administered orally produced significant laxative activity and reduced loperamide induced constipation in dose dependent manner as seen in the increase of fecal output. The same doses of the Rheum undulatum L. compounds preparation produced a significant increase (P<0.05) fecal weight, the faeces humidity. The effect of the compounds preparation compares favourably well with Laxing, a standard laxative drug. @*Conclusion@#The results of this study justify the use of Rheum undulatum L. compounds preparation as a laxative in traditional medicine. The produced significantly increase in fecal output of rats and the stimulation of gastrointestinal motility.

Correlation between laxative effects of uridine and suppression of ER stress in loperamide induced constipated SD rats / 한국실험동물학회지

A correlation between endoplasmic reticulum (ER) stress and laxative effects was first reported in a constipation model treated with an aqueous extract of Liriope platyphylla (AEtLP) roots. To investigate the correlation between the laxative effect of uridine (Urd) and ER stress response, alterations in the key parameters for ER stress were measured in loperamide (Lop) induced constipation Sprague Dawley (SD) rats treated with Urd. The efficacy of the laxative effect of Urd was notable on the symptoms of chronic constipation, including alteration of stool parameters and structure of the transverse colon, in Lop induced constipated SD rats. In the PERK/eIF2-ATF4 pathway of ER stress response, the levels of eukaryotic initiation factor 2 alpha (eIF2α) phosphorylation and DNA damage-inducible protein (GADD34) transcripts were significantly enhanced in the Lop+Vehicle treated group. However, the levels were restored in the Lop+Urd treated group, although few differences were detected in the decrease rate. Similar changes were observed for levels of inositol-requiring enzyme 1 beta (IRE1β) phosphorylation and X-box binding protein 1 (XBP-1) transcript in the IRE1α/XBP pathway. Furthermore, the number of ER stress-induced apoptotic cells and Bax and Bcl-2 expression were recovered in the Lop+Urd treated group compared to the Lop+Vehicle treated group. The results of the present study therefore provide first evidence that the laxative effects of Urd may be tightly correlated with the recovery of ER stress response in constipation models.

Characterization the response of Korl:ICR mice to loperamide induced constipation / 한국실험동물학회지

Animal models of constipation induced with drugs and diet have been widely employed to investigate therapeutic effects and the action mechanism of drugs against this disease. ICR mice were selected to produce this disease model through oral administration of loperamide (Lop), even though SD rats are commonly utilized in studies of constipation. To compare the responses of ICR mice obtained from three different sources to constipation inducers, alterations in stool number, histopathological structure, mucin secretion and opioid-receptor downstream signaling pathway were measured in Korl:ICR (Korea FDA source), A:ICR (USA source) and B:ICR (Japan source) injected with low and high concentrations of Lop (LoLop and HiLop). The number, weight and moisture content of stools decreased significantly in the Lop treated group of all ICR relative to the Vehicle treated group. Additionally, decreased mucosa layer thickness, muscle thickness, and mucin secretion were observed in the transverse colon of Lop treated ICR mice, while a similar number of goblet cells and crypt of lieberkuhn were detected in the same group. Furthermore, a similar change in the level of Gα expression and PKC phosphorylation was detected in the Lop treated group relative to the vehicle treated group, while some differences in the change pattern were observed in the B:ICR group. Therefore, these results of the present study provide strong additional evidence that Korl:ICR, A:ICR and B:ICR derived from different sources have a similar overall response to constipation induced by Lop injection, although there were a few differences in the magnitude of their responses.

Therapeutic Effect of He-Mu-Shu Point Combination Acupuncture for Patients with Functional Diarrhea and Its Influence of Anxiety / 广州中医药大学学报

Objective To observe the efficacy of electroacupuncture(EA) on the acupoint combination of He-(sea) points, front-mu points, and shu-points(abbrev. He-Mu-Shu) for the treatment of functional diarrhea, and to explore the effect of He-Mu-Shu point combination EA on the anxiety of patients. Methods A randomized controlled clinical trial was performed in 62 functional diarrhea patients. All of the patients were randomly divided into He-Mu-Shu group(32 cases) and medicine group(30 cases). He-Mu-Shu group was treated with EA on unilateral Quchi, Shangjuxu, Tianshu, Dachangshu point alternatively, and medicine group was treated with oral use of Loperamide hydrochloride capsules. Both groups were treated for 4 continuous weeks. Defecation frequency, stool property and anxiety scores were observed before treatment and 2, 4 weeks after treatment. Results After treatment, weekly defecation frequency, stool property and anxiety scores were improved in both groups, and the differences were statistically significant compared with those before treatment(P < 0.05). He-Mu-Shu point combination EA had better effect on improving weekly defecation frequency, stool property and anxiety scores of functional diarrhea patients than Loperamide hydrochloride capsules, and the differences were statistically significant (P < 0.05). Conclusion The clinical efficacy and anxiety-relief action of He-Mu-Shu point combination EA on functional diarrhea are superior to oral use of Loperamide hydrochloride capsules.

Analysis of One Case of Irinotecan-induced Delayed Diarrhea / 中国药师

Objective:To analyze one case of delayed diarrhea caused by irinotecan. Methods:The pathogeny, mechanism, ge-netics and treatment of the case were analyzed. Results:Delayed diarrhea was the dose-limited toxicity of irinotecan, which was related with the cytotoxicity of the active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38). Genetic polymorphism was one of important risk factors, especially UGT1A1 polymorphisms could be used as a predictor for the diarrhea. The pharmacotherapy of the diarrhea was ef-fective and rational, and the clinical pharmacist provided rational pharmaceutical care for the patient. Conclusion:It is very important to enhance pharmaceutical care for the patients treated with irinotecan.

Laxative effects of Liriope platyphylla are tightly correlated with suppression of endoplasmic reticulum stress in loperamide-induced constipation of SD rats / 한국실험동물학회지

A dysfunction of endoplasmic reticulum (ER) stress response can result in various diseases, including cancer, inflammation, diabetes and neurodegenerative disorders. To investigate whether ER stress response can play an essential role in the induction and treatment of chronic constipation, alterations in the key parameters for ER stress were measured in loperamide (Lop) induced constipation Sprague Dawley (SD) rats treated with aqueous extracts of Liriope platyphylla (AEtLP), which has been shown to have a laxative effect. Symptoms of chronic constipation including alteration of stool parameters and the transverse colon's structure were successfully induced by Lop treatment. Laxative effects such as enhancement of stools parameters, recovery of the mucosa thickness, increased muscle thickness and recovery of flat luminal surface were also observed in the Lop+AEtLP treated group. Furthermore, enhancement of eukaryotic initiation factor 2 alpha (eIF2α) phosphorylation and inositol-requiring enzyme 1 beta (IRE1β) expression, key indicators for ER stress, that were observed in the Lop+vehicle treated group were significantly recovered in the Lop+AEtLP treated group, although the phosphorylation level of c-Jun N-terminal protein kinase (JNK) remained constant. Moreover, alterations in the transcription level of the marker genes X-box binding protein 1 (XBP-1) and growth arrest and DNA damage-inducible protein (GADD34) were similar to those of eIF2α and IRE1β. However, their level was slightly or completely recovered after AEtLP treatment. Overall, this study provides the first evidence that ER stress response may be tightly correlated with chronic constipation induced by Lop treatment, as well as the laxative effects of AEtLP.

Effect of dual-type oligosaccharides on constipation in loperamide-treated rats

BACKGROUND/OBJECTIVES: Constipation is a condition that can result from intestinal deformation. Because humans have an upright posture, the effects of gravity can cause this shape deformation. Oligosaccharides are common prebiotics and their effects on bowel health are well known. However, studies of the physiological functionality of a product that contains both lactulose and galactooligosaccharides are insufficient. We investigated the constipation reduction effect of a dual-type oligosaccharide, Dual-Oligo, in loperamide-treated rats. MATERIALS/METHODS: Dual-Oligo consists of galactooligosaccharides (15.80%) and lactulose (51.67%). Animals were randomly divided into four groups, the normal group (normal), control group (control), low concentration of Dual-Oligo (LDO) group, and high concentration of Dual-Oligo (HDO) group. After 7 days of oral administration, fecal pellet amount, fecal weight, water content of fecal were measured. Blood chemistry, short-chain fatty acid (SCFA), gastrointestinal transit ratio and length and intestinal mucosa were analyzed. RESULTS: Dual-Oligo increased the fecal weight, and water content of feces in rats with loperamide-induced constipation. Gastrointestinal transit ratio and length and area of intestinal mucosa significantly increased after treatment with Dual-Oligo in loperamide-induced rats. A high concentration of Dual-Oligo tended to produce more acetic acid than that observed for the control group, and Dual-Oligo affected the production of total SCFA. Bifidobacteria concentration of cecal contents in the high-concentration oligosaccharide (HDO) and low-concentration oligosaccharide (LDO) groups was similar to the result of the normal group. CONCLUSIONS: These results showed that Dual-Oligo is a functional material that is derived from a natural food product and is effective in ameliorating constipation.

Combination of Loperamide and Niacin modify DENA induced altered Liver enzymes .

Hepatocellular Carcinoma (HCC) is among the most lethal cancers which makes it the third most frequent cause of cancer related deaths. Diethylnitrosamine (DENA) is a potent initiator and hepatocarcinogen in rats. DENA induced Hepatocellular damage clearly demonstrates by the elevated levels of liver enzymes serum glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT), serum alkaline phosphatase (ALP), and α-feto protein (AFP). This work is an attempt to test the hypothesis that Loperamide (5mg/kg) and Niacin in combination restores the DENA (160mg/kg) induced altered enzymes after single i.p administration in Wistar rats. The ability to alter the enzymes was measured by comparing biochemical serum markers and AFP. The results have confirmed the significant elevation of these parameters in DENA control group compared to normal control and the therapeutic groups. Therapeutic group significantly reveals that Loperamide and Niacin restores the altered hepatic enzymes towards the Normal. Key messages: Our data reveals and confirms that this remarkable combination possess the potential for the treatment of hepatocellular carcinomas in rats exposed to DENA. Administration of Loperamide + Niacin relatively improved the biochemical parameters to values approximating those of the normal controls

Antidiarrheal activity of ethanolic extract of Manihot esculenta Crantz leaves in Wistar rats.

Background: Use of Manihot esculenta Crantz (MEC) plant has been mentioned in literature of Food and Agriculture Organization of United Nations, Central Tuber Crops Research Institute and many others. It is also known commonly as tapioca, continues to be a crop of food security for the millions of people, especially in the developing countries of the globe including India. Medicinal uses of this plant including diarrhea have been mentioned in literature, but scientific evidence is lacking. Objective: The objective was to study antidiarrheal activity of ethanolic leaf extract of MEC in Wistar rats. Materials and Methods: Ethanolic extract of MEC leaves in the doses of 50 mg/kg, 100 mg/kg and 200 mg/kg were used in Wistar rats of either sex. Experimental models used were castor oil‑induced intestinal fluid accumulation and charcoal passage test. Loperamide and atropine sulfate were the standard drugs used in these models respectively. Results: MEC extracts decreased intestinal fluid volume in dose dependent manner no extract group was comparable with standard drug loperamide (5 mg/ kg). MEC extracts also significantly inhibited gastrointestinal motility in dose dependent manner. MEC (100 mg/kg) and MEC (200 mg/kg) were comparable with standard drug atropine sulfate (5 mg/kg) in this aspect. <0.05 were considered to be significant. Conclusions: Ethanolic extract of MEC leaves exhibited significant antidiarrheal activity by decreasing intestinal fluid accumulation and the gastrointestinal motility in Wistar rats.

Anti-diarrhea Potential and Acute Toxicity Studies of Methanolic Extract of Vernonia amygdalina and Cymbopogon citratus against Castor Oil Induced Diarrhea Model in Rats.

Diarrhea is a common cause of death in developing countries and second most common cause of infant mortality worldwide. The effect of a methanolic leaf extract of Bitter leaf (Vernonia amygdalina) and Lemon grass (Cymbopogon citratus) on Castor oil-induced diarrhea was investigated. Fifty (50) rats between 120-227g were induced with castor oil for development of diarrhea. They were divided into two sub-groups of twenty-five (25) subsequently divided into five groups treated with 2 mg/kg loperamide, 100, 200, and 400 mg/kg respectively. The cumulative frequencies of wet and formed stools were noted on the 3rd - 6th hour. It was observed that 400 mg/kg body weight of the extracts reduced the fecal spots compared to 200 mg/kg and 100 mg/kg body weight. Plant extracts were found to be non-toxic. The phytochemical screening of the methanolic extract revealed the presence of some bioactive components which may be responsible for the anti-diarrhea properties observed in this study. The above findings suggested that the methanolic extracts contain active constituents that have anti-diarrhea activities that may lead to its use in treating diarrhea.

Pharmacologic Agents for Chronic Diarrhea

Chronic diarrhea is usually associated with a number of non-infectious causes. When definitive treatment is unavailable, symptomatic drug therapy is indicated. Pharmacologic agents for chronic diarrhea include loperamide, 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists, diosmectite, cholestyramine, probiotics, antispasmodics, rifaximin, and anti-inflammatory agents. Loperamide, a synthetic opiate agonist, decreases peristaltic activity and inhibits secretion, resulting in the reduction of fluid and electrolyte loss and an increase in stool consistency. Cholestyramine is a bile acid sequestrant that is generally considered as the first-line treatment for bile acid diarrhea. 5-HT3 receptor antagonists have significant benefits in patients with irritable bowel syndrome (IBS) with diarrhea. Ramosetron improves stool consistency as well as global IBS symptoms. Probiotics may have a role in the prevention of antibiotic-associated diarrhea. However, data on the role of probiotics in the treatment of chronic diarrhea are lacking. Diosmectite, an absorbent, can be used for the treatment of chronic functional diarrhea, radiation-induced diarrhea, and chemotherapy-induced diarrhea. Antispasmodics including alverine citrate, mebeverine, otilonium bromide, and pinaverium bromide are used for relieving diarrheal symptoms and abdominal pain. Rifaximin can be effective for chronic diarrhea associated with IBS and small intestinal bacterial overgrowth. Budesonide is effective in both lymphocytic colitis and collagenous colitis. The efficacy of mesalazine in microscopic colitis is weak or remains uncertain. Considering their mechanisms of action, these agents should be prescribed properly.

Chronic spinal infusion of loperamide alleviates postsurgical pain in rats.

Plantar incision in rat generates spontaneous pain behaviour. The opioid drug, morphine used to treat postsurgical pain produces tolerance after long-term administration. Loperamide, a potent mu-opioid agonist, has documented analgesic action in various pain conditions. However, loperamide analgesia and associated tolerance following continuous spinal administration in postsurgical pain has not been reported. Chronic spinal infusion of drugs was achieved using intrathecal catheters connected to osmotic minipump. Coinciding with the onset of spinal infusion of loperamide or morphine, rats were subjected to plantar incision. Pain-related behaviour was assessed by Hargreaves apparatus (thermal hyperalgesia) and von Frey filaments (mechanical allodynia). Morphine and loperamide (0.5, 1 and 2 µL/h) induced analgesia was observed until 7th day post-plantar incision in Sprague-Dawley rats. Morphine and loperamide produced dose-dependent analgesia. Loperamide, in the highest dose, produced analgesia till 7th day. However, the highest dose of morphine produced inhibition of thermal hyperalgesia till 5th day and mechanical allodynia only till 3rd day post-plantar incision. Morphine and loperamide produced analgesia in postsurgical pain, which may be mediated through different mechanisms. Longer duration of analgesia with loperamide could probably be due sustained blockade of calcium channels.

Metabolomics approach to serum biomarker for loperamide-induced constipation in SD rats / 한국실험동물학회지

Loperamide has long been known as an opioid-receptor agonist useful as a drug for treatment of diarrhea resulting from gastroenteritis or inflammatory bowel disease as well as to induce constipation. To determine and characterize putative biomarkers that can predict constipation induced by loperamide treatment, alteration of endogenous metabolites was measured in the serum of Sprague Dawley (SD) rats treated with loperamide for 3 days using 1H nuclear magnetic resonance (1H NMR) spectral data. The amounts and weights of stool and urine excretion were significantly lower in the loperamide-treated group than the No-treated group, while the thickness of the villus, crypt layer, and muscle layer was decreased in the transverse colon of the same group. The concentrations of aspartate aminotransferase (AST), lactate dehydrogenase (LDH) and creatinine (Cr) were also slightly changed in the loperamide-treated group, although most of the serum components were maintained at a constant level. Furthermore, pattern recognition of endogenous metabolites showed completely separate clustering of the serum analysis parameters between the No-treated group and loperamide-treated group. Among 35 endogenous metabolites, four amino acids (alanine, glutamate, glutamine and glycine) and six endogenous metabolites (acetate, glucose, glycerol, lactate, succinate and taurine) were dramatically decreased in loperamide-treated SD rats. These results provide the first data pertaining to metabolic changes in SD rats with loperamide-induced constipation. Additionally, these findings correlate the changes in 10 metabolites with constipation.

Interacciones farmacológicas de las hojas de Maytenus macrocarpa o ôchuchuhuasiõ con fármacos inhibitorios y estimuladores de la motilidad intestinal / Pharmacological interactions from the leaves of Maytenus macrocarpa \"chuchuhuasi\" with inhibitory and stimulating bowel motility drugs

Objetivo: Determinar las posibles interacciones farmacológicas de las hojas de Maytenus macrocarpa, con fármacos estimulantes e inhibitorios de la motilidad intestinal. Métodos: Se utilizaron 110 ratones albinos machos, con pesos medios de 25 g, se empleó el método de Arbos y col, se administró carbón activado al 5

vía oral, dosis de 0.1ml/10g, como marcador intestinal. Los grupos experimentales fueron: control (agua destilada 0,3ml), hojas de chuchuhuasi 1 (500mg/kg), hojas de chuchuhuasi 2 (3000mg/kg), atropina (1,5mg/kg), loperamida (5mg/kg), neostigmina (0,4mg/kg), metoclopramida (10mg/kg), hojas de chuchuhuasi 1 con metoclopramida, hojas de chuchuhuasi 1 con loperamida, hojas de chuchuhuasi 2 con metoclopramida y hojas de chuchuhuasi 2 con loperamida. Para la validación estadística se usó la prueba de Wilconxon, ANOVA y Tukey. Resultados: El porcentaje de recorrido intestinal de carbón activado fue de 27,04, 34,15, 31,66, 25,57, 15,89, 43,30, 33,99, 32,40, 27,90, 49,34 y 25,36 respectivamente, el test de ANOVA de dos colas revelo una p=0,0007. El test de Tukey indico p<0.05 versus el control para neostigmina, loperamida y la interacción chuchuhuasi 3000 mg/kg con metoclopramida, en este último, el test de Wilconxon presento un valor p<0,05. Conclusiones: Se observó interacciones farmacológicas de antagonismo sobre la motilidad intestinal, entre chuchuhuasi y Loperamida y sinergismo entre chuchuhuasi y metoclopramida.

Objectives: To determine the possible pharmacological interactions from the leaves of Maytenus macrocarpa with inhibitory and stimulating bowel motility drugs. Methods: We used 110 male albino mice with average weight of 25g, Arbos and others method was applied. Activated charcoal was administered at 5

at dose of 0.1ml/10g, as an intestinal marker. The experimental groups included 0.1 ml/10 g of distilled water, leave extract of M. macrocarpa 1 (500mg/kg), leave extract of M. macrocarpa 2 (3000 mg/kg), 1,5mg/kg of atropine, 5mg/kg of loperamide, 0.4mg/kg of neostigmine, 10mg/kg of metoclopramide, leave extract of M. macrocarpa 1 with metoclopramide, leave extract of M. macrocarpa 1 with loperamide, leave extract of M. macrocarpa 2 with metoclopramide and leave extract of M. macrocarpa 2 with loperamide. The statistical validation was based on Wilconxon, ANOVA and Tukey test. Results: The intestinal charcoal run percentage was 27.04, 34.15, 31.66, 25.57, 15.89, 43.30, 33.99, 32.40, 27.9, 49.34 and 25.36 respectively. The ANOVA test result in p= 0.0007. The Tukey test indicated p <0.05 versus the control group for neostigmine, loperamide, and the interaction between leave extract of M. macrocarpa 2 with metoclopramide, for the last the Wilcoxon test result in p <0.05. Conclusions: It was observed antagonism drug interactions on gastrointestinal motility between leaves extract of M. macrocarpa with loperamide and synergism interactions with metoclopramide.

Establishment of a Protocol for Determining Gastrointestinal Transit Time in Mice Using Barium and Radiopaque Markers

OBJECTIVE: The purpose of this study was to establish a minimally invasive and reproducible protocol for estimating the gastrointestinal (GI) transit time in mice using barium and radiopaque markers. MATERIALS AND METHODS: Twenty 5- to 6-week-old Balb/C female mice weighing 19-21 g were used. The animals were divided into three groups: two groups that received loperamide and a control group. The control group (n = 10) animals were administered physiological saline (1.5 mL/kg) orally. The loperamide group I (n = 10) and group II (n = 10) animals were administered 5 mg/kg and 10 mg/kg loperamide orally, respectively. Thirty minutes after receiving the saline or loperamide, the mice was administered 80 microL of barium solution and six iron balls (0.5 mm) via the mouth and the upper esophagus by gavage, respectively. Afterwards, the mice were continuously monitored with fluoroscopic imaging in order to evaluate the swallowing of the barium solution and markers. Serial fluoroscopic images were obtained at 5- or 10-min intervals until all markers had been excreted from the anal canal. For analysis, the GI transit times were subdivided into intestinal transit times (ITTs) and colon transit times (CTTs). RESULTS: The mean ITT was significantly longer in the loperamide groups than in the control group (p < 0.05). The mean ITT in loperamide group II (174.5 +/- 32.3) was significantly longer than in loperamide group I (133.2 +/- 24.2 minute) (p < 0.05). The mean CTT was significantly longer in loperamide group II than in the control group (p < 0.05). Also, no animal succumbed to death after the experimental procedure. CONCLUSION: The protocol for our study using radiopaque markers and barium is reproducible and minimally invasive in determining the GI transit time of the mouse model.

Secondary Prophylaxis of Docetaxel Induced Diarrhea with Loperamide: Case Report

Diarrhea is a common adverse event of docetaxel with 20%-40% of incidence and severe diarrhea occurs in 5%-6%. Several treatment guidelines for chemotherapy induced diarrhea (CID) exist, however the prophylaxis for that is not well known. We describe a new prophylactic approach for the CID with loperamide. A 72-yr-old male patient with stage IV non-small-cell lung cancer developed diarrhea repeatedly after docetaxel-cisplatin chemotherapy. His diarrhea persisted despite treatment including loperamide and fasting. However, the diarrhea was successfully prevented when loperamide was given before and after the chemotherapy. To our knowledge, this is the first report of prophylactic approach for the CID with loperamide.