Prokinetic Drugs Research Articles

Erythromycin as a prokinetic drug for the treatment of feeding intolerance in preterm and low birth weight infants at a provincial hospital in Thailand

Erythromycin as a prokinetic drug for the treatment of feeding intolerance in preterm and low birth weight infants at a provincial hospital in Thailand

Prokinetic effect of erythromycin in the management of gastroparesis in critically ill patients-our experience and literature review.

Gastroparesis is a disorder characterized by impaired gastric emptying and the accumulation of food in the intestines without any clear mechanical cause. Gastroparesis in critical care patients is a prevalent issue in the intensive care unit. The disruption of normal gastrointestinal motility in critically ill patients is linked to a significant risk of intolerance to enteral feeding, colonization of the gastrointestinal tract with pathogenic bacterial strains, increased permeability of the intestinal wall, translocation of the intestinal microbiota, leading to progressive malnutrition, and potential development of bacterial infection. The literature was reviewed to assess the benefits and risks associated with the use of this medication. The aim of the study was to treat the symptoms of gastroparesis and stimulate gastrointestinal motility. Consequently, the aim was to reduce the amount of backed-up food content in the stomach, accelerate gastrointestinal motility, and return to intestinal feeding. Gastroparesis is a frequent issue among patients in the intensive care unit. Critical illness can lead to gastrointestinal motility disorders, causing slowed gastric emptying. This increases the risk of problems such as intolerance to enteral feeding, regurgitation, and aspiration of gastrointestinal contents into the respiratory tract, as well as colonization of the gastrointestinal tract by pathogens. Over time, impaired intestinal absorption can result in malnutrition, necessitating the initiation of parenteral nutrition. After analysis of the literature and published scientific reports, as well as considering their own research, it is evident that erythromycin, as a prokinetic drug, effectively enhances gastrointestinal motility. This contributes to stimulating gastric emptying in critically ill patients with gastroparesis who are hospitalized in an intensive care unit. The use of erythromycin in combination with metoclopramide and/or itopride hydrochloride allows for a synergistic effect, leading to the quickest possible return to enteral feeding.

The impact of long-course chemoradiotherapy on the myenteric plexus, neuromuscular functions and responses to prokinetic drugs in the human rectum.

The long-term effects of chemoradiotherapy on human rectum are poorly understood. The aims were to investigate changes in inflammatory status, myenteric neuron numbers/phenotype, neuromuscular functions and prokinetic drug efficacy. Macroscopically normal proximal-to-mid rectum was obtained from 21 patients undergoing surgery for bowel cancer, 98days (range: 63-350) after concurrent capecitabine and pelvic radiotherapy, and 19 patients without chemoradiotherapy. Inflammatory status was measured by H&E, CD45 staining and qPCR. Myenteric neurons were examined by immunohistochemistry. Neuromuscular functions and drug efficacy were studied using exogenous agents and electrical field stimulation (EFS) to activate intrinsic nerves. Inflammation was not detected. Numbers of myenteric ganglia/neurons were unchanged (11.7±2.4 vs. 10.3±2.2 neurons/mm myenteric plexus with/without chemoradiotherapy) as were the numbers of cholinergic/nitrergic neurons. EFS stimulated cholinergic and nitrergic neurons so the contractile response of the muscle was the sum of both but dominated by cholinergic (causing contraction) or less often, nitrergic activity (relaxation), followed, after termination of EFS, by neuronally mediated contraction. Inhibition of nitric oxide synthase (by L-NAME 300μM) more clearly defined EFS-evoked contractions. The 5-HT4 agonist prucalopride 10μM and the cholinesterase inhibitor donepezil 1µM, respectively increased and greatly increased the composite contractile response to EFS (measured as 'area-under-the curve') and the contractions isolated by L-NAME (respectively, by 22±14% and 334±87%; n=11/8). After chemoradiotherapy, nitrergic-mediated muscle relaxations occurred more often during EFS (in 29.8±6.1% preparations vs. 12.6±5.1% without chemoradiotherapy, n=21/18). With L-NAME, the ability of prucalopride to facilitate EFS-evoked contraction was lost and that of donepezil approximately halved (contractions increased by 132±36%; n=8). Several months after chemoradiotherapy, the rectum was not inflamed and myenteric neuron numbers/phenotype unchanged. However, nitrergic activity was increased relative to cholinergic activity, and prokinetic-like drug activity was lost or greatly reduced. Thus, chemoradiotherapy causes long-term changes in neuromuscular functions and markedly reduces the efficacy of drugs for treating constipation.

Usefulness of the Reflux Symptom Index and Reflux Finding Score in the Management of Laryngopharyngeal Reflux.

Laryngopharyngeal reflux (LPR) refers to a condition in which gastroduodenal contents reflux back into the oesophagus and affects the throat, specifically the laryngopharynx. A wide variety of symptoms have been attributed to LPR. To minimize the underdiagnosis, Reflux Symptom Index (RSI) with the Reflux Finding Score(RFS) are useful in ENT practice. LPR treatment typically entails an intensive strategy, applied over an extended period of time, combined with dietary adjustments, exercise, weight loss and lifestyle changes. To study the usefulness of Reflux Symptom Index and Reflux Finding Score in the management of LPR. This study was a descriptive study conducted in the Department of ENT, Bangalore Medical College and Research Institute, Bangalore from February 2021 to August 2022. This study included 90 patients who were diagnosed to have LPR attending the ENT OPD at Bangalore Medical College and Research Institute, Bangalore and attached hospitals. All patients were subjected to detailed history taking using RSI, thorough clinical examination and laryngoscopic examination using RFS and necessary investigation was done. They were treated with proton pump inhibitors and prokinetic drugs and followed up regularly. Treatment was stopped after 6 months to prevent long-term adverse. Our study recruited 90 patients who were diagnosed to have LPR of which 55 were male and 35 female. Most of them were 41-50 years of age. Throat clearing was found to be the most common symptom and erythema/ hyperaemia of larynx was the most common sign. It was found that median RSI score was highest at baseline (13) and lowest 2 months (2) with no RSI score at 3 and 6 months. The median RFS scores was highest at baseline (8) and lowest after 2 months (1) with no RFS score at 3rd and 6th months. The difference was statistically significant. Major improvement in symptoms was seen after 2nd month and major improvement in laryngoscopic signs was seen after 1st month. RSI and RFS are useful diagnostic tools in identifying patients with LPR. It helps in assessing response to treatment during their follow up. Treatment with proton pump inhibitors and prokinetic drugs along with strict dietary modification, stress management and regularization of life style has to be followed for a duration of 6 months with regular follow up for complete resolution of signs and symptoms.

The domperidone dilemma in Pakistan: Balancing access and safety concerns.

Madam, Domperidone is used in the treatment of nausea and vomiting as an antiemetic and prokinetic drug. Its pro-kinetic effects mainly manifest in the upper gastrointestinal tract by acting as a dopamine receptor antagonist [1]. However, the drug has been banned by the FDA in the USA due to its association with cardiac arrhythmias and cardiac arrest. A recent meta-analysis has shown a statistically significant association between sudden cardiac death [2] and the use of domperidone which raises the question of drug usage in Pakistan as an over-the-counter medication. The meta-analysis considers six different case-control studies, between 2005 and 2016, that have shown an increase in the risk of sudden cardiac death and ventricular arrhythmias associated with domperidone. The observational studies were conducted in North America, Asia, and Europe, proving that it is a global phenomenon, stemming from the use of the drug. The forest plot of the studies has been mentioned later in the abstract showing heterogeneity at 0%, OR ratio 1.69 with 95% CI (1.46-1.95). To further highlight the risks associated with domperidone, another study has reported that the safety index of the drug is 5.25, which is remarkably lower than the international safety ratio of 30[3]. The safety index, or therapeutic index, is the ratio of the toxic dose in 50% of the population (TD50) and the effective dose in 50% of the population (ED50) with the same therapeutic effect. A wider safety index indicates more room for error in the drug's therapeutic effect; essentially a larger barrier before the drug is toxic. With a safety index of 5.25, the action potential duration is markedly increased, resulting in arrhythmias. The author also comments on restricting the drug only to patients where the potential benefit is proven to justify the risks. In Pakistan, Domperidone is readily available as an over-the-counter drug. The casual availability raises the concern that the associated safety issues must be critically evaluated to determine whether the uses of the drug outweigh the risk of sudden cardiac death and ventricular arrhythmias [4] mentioned in these studies.

Study of Effects of Preoperative Oral Domperidone on Gastric Residual Volume after Clear Fluid Ingestion in Patients Scheduled for Elective Surgeries

Abstract Background Oral Dopmeridone is a prokinetic drug that enhance gastric emtptying, which has a positive effect in decreasing the gastric residual volume, subsequently decreasing the risk of pulmonary aspiration Aim of the Work This study to aimed to assess the effect of oral Domperidone preoperatively on gastric residual volume by ultrasound for patients undergoing elective surgeries under general anesthesia as a primary outcome and postoperative nausea and vomiting as a secondary outcome. Patients and Methods We applied our study on 40 patients were divided into two equal groups: Group A (study group): The patients received 400 ml of apple juice as a clear fluid, two hours preoperatively, and oral Domperidone tab (Motilium 10mg/tab, Janssen comp.) & Group B (control group): The patients received 400 ml of apple juice as a clear fluid two hours preoperatively with a placebo (Folic acid 500 mcg, dietary supplement), with the same inclusion and exclusion criteria. Results There was statistically significant decrease mean in group A compared to group B according to Ultrasound Measurements in the right lateral position after 2 hrs has been demonstrated about D1 right lateral position; D2 right lateral position; CSA right lateral position and calculated gastric volume right lateral position (ml). In addition to a statistically significant decrease mean in after 2hrs. compared to after 1hr. according to Ultrasound Measurements in the right lateral position about D1 right lateral position; D2 right lateral position; CSA right lateral position and Calculated gastric volume right lateral position (mL) in group A. There is also a statistically significant decrease mean in after 2hrs. compared to after 1hr. according to Ultrasound Measurements in the right lateral position about D1 semi-sitting; D2 right lateral; CSA right lateral position and Calculated gastric volume right lateral position (mL) in group B. At last, there has been a statistically significant higher change (after 2hrs.-1hr.) in group A compared to group B according to Ultrasound Measurements in the right lateral position about D1 right lateral position; D2 right lateral position; CSA right lateral position and Calculated gastric volume right lateral position (mL), with p-value (p < 0.05 significant). Conclusion Preoperative oral Domperidone intake was able to decrease the GRV measured by ultrasound, more than the decrease of GRV by applying placebo.

Modern Possibilities of Using Acotiamide in the Treatment of Functional Dyspepsia

Aim: to evaluate the efficacy and safety of the new prokinetic drug acotiamide in the treatment of functional dyspepsia.Key findings. Acotiamide is an antagonist of inhibitory muscarinic receptors of type 1 and 2 and a reversible inhibitor of acetylcholinesterase activity. In patients with functional dyspepsia acotiamide normalizes the accommodation of the fundal part of the stomach and accelerates delayed gastric emptying. The conducted studies have confirmed the higher efficacy of acotiamide compared to placebo in reducing the severity of such symptoms of functional dyspepsia as a feeling of epigastric postprandial fullness and bloating, early satiation. The advantage of acotiamide in comparison to other prokinetics (in particular, metoclopramide and domperidone) is the high safety of use and the absence of influence on the duration of the Q-T interval.Conclusion. The high efficacy and safety of the application makes it advisable to use acotiamide in the treatment of patients with functional dyspepsia.

Safety of prolonged use of metoclopramide and domperidone as treatment for chronic gastrointestinal dysmotility disorders in patients with systemic sclerosis

BackgroundMetoclopramide and domperidone are prokinetic agents commonly used to treat gastrointestinal dysmotility disorders. This study aimed to evaluate the safety and associated side effects of prolonged-use metoclopramide and domperidone as treatment for chronic gastrointestinal dysmotility disorders in patients with systemic sclerosis (SSc). MethodsA quantitative observational survey was conducted by interview questionnaire in rheumatology outpatients at a tertiary teaching hospital in Riyadh, Saudi Arabia. The study included all patients aged 25–80 years diagnosed with SSc. All patients were on metoclopramide or domperidone for the treatment of chronic gastrointestinal dysmotility symptoms over at least 12 weeks. ResultsEighteen eligible patients were included. Most study participants were diagnosed with SSc complicated by interstitial lung disease (n = 13; 72.2 %). The most frequently reported side effect that occurred while taking prokinetic drugs was shortness of breath (n = 12; 66.7 %). None of the participants reported experiencing depression, galactorrhea, or syncope. CNS side effects were reported in 5.6 %. There were no differences in side effects based on the type and dosage of prokinetic drug used. ConclusionsUse of metoclopramide and domperidone for the treatment of chronic gastrointestinal dysmotility in SSc patients for 12 weeks or longer was not associated with any troublesome side effects. Further studies with more participants are needed to confirm our findings.

Prokinetics-safety and efficacy: The European Society of Neurogastroenterology and Motility/The American Neurogastroenterology and Motility Society expert review.

Prokinetics are a class of pharmacological drugs designed to improve gastrointestinal (GI) motility, either regionally or across the whole gut. Each drug has its merits and drawbacks, and based on current evidence as high-quality studies are limited, we have no clear recommendation on one class or other. However, there remains a large unmet need for both regionally selective and/or globally acting prokinetic drugs that work primarily intraluminally and are safe and without systemic side effects. Here, we describe the strengths and weaknesses of six classes of prokinetic drugs, including their pharmacokinetic properties, efficacy, safety and tolerability and potential indications.

Expert Opinion on the Prescription Practice of Rabeprazole and Other Common Proton Pump Inhibitors for Patients with Gastroesophageal Reflux Disease

Objective: The current survey-based study aims to provide further insights on expert opinion regarding the commonly prescribed PPIs in clinical practice, with a specific focus on the use of oral rabeprazole 20 mg as a treatment for gastroesophageal reflux disease (GERD) maintenance therapy in Indian settings.
 Methodology: The questionnaire-based survey involving 25 questions collected perspectives of experts across various regions of India regarding the prescription practice of rabeprazole 20 mg and other proton-pump inhibitors (PPIs) for treating GERD symptoms.
 Results: Out of 512 study participants, 44% reported obesity as the common comorbid condition observed in GERD patients, while 28% noted co-morbid diabetes mellitus. According to 68% of the respondents, rabeprazole demonstrated superiority over other PPIs in terms of quicker onset of action, maintaining intragastric pH >4 over 24 hours’ post-dose, and reduced nighttime heartburn. For GERD patients with functional dyspepsia and gastroparesis, 52% of responders favored the addition of domperidone as a prokinetic drug to the PPI treatment. Moreover, the majority of participants (61.91%) observed that rabeprazole 20 mg did not cause a delay in stomach emptying, nor did it raise somatostatin levels or alter baseline motilin levels in GERD patients. These findings underscore the effectiveness of rabeprazole 20 mg in comparison to omeprazole and lansoprazole.
 Conclusion: Experts recommended rabeprazole 20 mg as the preferred treatment option over omeprazole and lansoprazole for GERD patients with coexisting obesity and diabetes mellitus conditions. Additionally, over half of the respondents reported using a combination of domperidone and other PPIs for GERD patients with functional dyspepsia and gastroparesis.

Dopamine D2 receptor antagonist counteracts hyperglycemia and insulin resistance in diet-induced obese male mice.

Obesity leads to insulin resistance (IR) and type 2 diabetes. In humans, low levels of the hormone prolactin (PRL) correlate with IR, adipose tissue (AT) dysfunction, and increased prevalence of T2D. In obese rats, PRL treatment promotes insulin sensitivity and reduces visceral AT adipocyte hypertrophy. Here, we tested whether elevating PRL levels with the prokinetic and antipsychotic drug sulpiride, an antagonist of dopamine D2 receptors, improves metabolism in high fat diet (HFD)-induced obese male mice. Sulpiride treatment (30 days) reduced hyperglycemia, IR, and the serum and pancreatic levels of triglycerides in obese mice, reduced visceral and subcutaneous AT adipocyte hypertrophy, normalized markers of visceral AT function (PRL receptor, Glut4, insulin receptor and Hif-1α), and increased glycogen stores in skeletal muscle. However, the effects of sulpiride reducing hyperglycemia were also observed in obese prolactin receptor null mice. We conclude that sulpiride reduces obesity-induced hyperglycemia by mechanisms that are independent of prolactin/prolactin receptor activity. These findings support the therapeutic potential of sulpiride against metabolic dysfunction in obesity.

Expert Opinion on the Utilization of Proton Pump Inhibitors for the Treatment of Gastroesophageal Reflux Disease among Indian Patients

Several studies have demonstrated that esomeprazole enhances the management of gastroesophageal reflux disease (GERD) patients by reducing the incidence of heartburn and epigastric pain, as well as relapse rates. But, there was a dearth of data regarding the preference of esomeprazole. So, this study was conducted to gather expert opinions on the routine use of proton pump inhibitors (PPIs) in clinical practice with a focus on the utilization of esomeprazole as a maintenance therapy for GERD in Indian settings. A cross-sectional, questionnaire based study was conducted to collect opinion among physicians involved in managing GERD symptoms across India between June 2022 and December 2022. The study enrolled 972 participants, and 63% of them noted the frequent occurrence of both erosive and non-erosive reflux disease in GERD patients. Approximately 47% of the respondents identified obesity as a significant GERD risk factor, with 32% attributing it to irregular and unhealthy eating habits. The majority of the clinicians preferred PPIs for the treatment of GERD (90%), particularly esomeprazole (87%). The typical duration of PPIs for GERD patients was reported to be 2-4 weeks by approximately 57% of the experts. Most respondents recommended a combination of PPIs and prokinetic drugs for GERD treatment. When dealing with PPI-resistant patients, 56% of physicians preferred maintaining the same PPI therapy twice daily, while 32% advised switching to another PPI. The majority of the respondents (71.81%) recommended making dietary and lifestyle adjustments for managing GERD, including consuming smaller, more frequent meals, refraining from lying down for at least two hours after eating and addressing excess weight around the midsection. It was noted that clinicians recommended PPIs, especially esomeprazole, as the primary approach for GERD management. Experts advise a regimen of twice-daily PPIs for patients who exhibit resistance to the treatment. They also underscore the importance of dietary and lifestyle adjustments in GERD management.

Efficacy and safety of itopride SR for upper gastrointestinal symptoms in patients with diabetic gastroparesis: real-world evidence from Pakistan.

Gastroparesis is a serious condition that can be caused by diabetes, surgery or infection, or can be idiopathic. When there is no mechanical obstruction, gastroparesis is characterized by delayed stomach emptying. Itopride, a prokinetic drug, inhibits acetylcholinesterase activity in addition to antagonizing dopamine D2 receptors. This prospective, multicentre study is based on real-world data from 988 patients with a diagnosis of diabetic gastroparesis for index (PAGI-SYM2) evaluation at baseline and week 4 of treatment for upper gastrointestinal disorder symptoms. Upper gastrointestinal symptom severity scores improved significantly after 4 weeks of treatment (p<0.001), with significant improvement across all categories of gastroparesis (very mild (37-58.6%), mild degree (24.6-31.6%), moderate (29.3-7.3%) and severe (8.8-2.6%). Itopride SR (Nogerd SR) in a 150 mg once-daily dose showed promising results in reducing the severity of upper gastrointestinal disorder symptoms associated with diabetic gastroparesis. Both statistical and clinical effectiveness were observed. Moreover, the treatment demonstrated a favourable tolerability profile, with a low incidence of adverse effects.

Equilibrium solubilities, model analysis, solvent effect, molecular dynamic simulation, and thermodynamic properties of itopride hydrochloride in eleven organic pure solvents at different temperatures

Itopride hydrochloride is a novel prokinetic drug used to relieve gastrointestinal diseases. In this paper, the equilibrium solubility of itopride hydrochloride in selected eleven pure solvents (methanol, ethanol, 1-propanol, 2-methoxyethanol, 2-ethoxyethanol, 2-propoxyethanol, acetonitrile, N-methyl-2-pyrrolidone, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide) was determined by the laser monitoring technique at temperatures ranging from 278.15 K to 323.15 K and pressures of 101.3 kPa. The experimental results showed that the equilibrium solubility of itopride hydrochloride in the selected pure solvents were all positively correlated with temperature and the order of equilibrium solubility at 298.15 K was: dimethyl sulfoxide (28.06)＞methanol (16.63)＞2-methoxyethanol (12.04)＞N-methyl-2-pyrrolidone (8.020)＞N,N-dimethylformamide (5.117)＞N,N-dimethylacetamide(3.576)＞2-ethoxyethanol (1.463)＞ethanol (0.9341)＞2-propoxyethanol (0.4850)＞1-propanol (0.2504)＞acetonitrile (0.1887). In addition, we used the λh model, modified Apelblat model, NRTL model and van't Hoff model to correlate the experimental data of the equilibrium solubility of itopride hydrochloride. Comparing the ARD and RMSD fitted by the four models, it was found that the NRTL model fitted the best, with the 100ARD value less than 5, and the mean values of 100ARD and 104RMSD were 2.15 and 1.61, respectively. Therefore, the NRTL model is more suitable for the correlation of equilibrium solubility data in this experiment. Furthermore, we analyzed the impact of different solvent properties on the equilibrium solubility of itopride hydrochloride, the molecular dynamics simulation was carried out and the interaction between solute and solvent molecules was analyzed by means of radial distribution functions (RDF). Finally, the apparent thermodynamic properties (ΔdisG°, ΔdisH°, ΔdisS°) of the phase equilibrium process of itopride hydrochloride in eleven organic pure solvents were analyzed by using the van't Hoff equation. The results of the analysis showed that it is entropically increasing and heat absorbing during the dissolution process of itopride hydrochloride.

Nocebo effects and influencing factors in the randomized clinical trials of chronic constipation: A systematic review and meta-analysis.

Nocebo effects are unavoidable in randomized clinical trials. We aimed to assess the magnitude of nocebo effects and explore the influencing factors in chronic constipation. We searched the PubMed, Embase, and Cochrane Library databases up to July 2022. Randomized, placebo-controlled trials investigating interventions in chronic constipation were included. We conducted a random effects meta-analysis of the proportion of adverse events (AEs) in placebo-treated participants and evaluated the effect of trial characteristics on nocebo effects. We identified 20,204 studies from the databases, of which 61 were included in the final analysis. The pooled placebo AE rate was 30.41%, and AE-related withdrawal rate was 1.53%. The most commonly reported AEs were headache (5.67%), diarrhea (4.45%), abdominal pain (3.98%), nasopharyngitis (3.39%), nausea (3.36%), and flatulence (2.95%). The placebo AE rate was lower in trials conducted in Asia compared to those in Europe, North America, and international trials. It was also lower in trials diagnosed by Rome III compared to clinician's opinion and Rome II. Additionally, the placebo AE rate was lower in single-center trials compared to multicenter trials, lower in 5-8 weeks therapy compared to 9-12 weeks therapy, lower in participants with FC compared to those with IBS-C and CC, lower in trials with 2 arms compared to 3 arms, and higher in trials with prokinetic drugs compared to secretagogues and laxatives. The placebo AE rate was 30.41% in patients with chronic constipation. Based on our findings, we recommend that researchers take the nocebo effects into consideration when designing and conducting clinical trials and adopt specific measures to mitigate the negative influence of nocebo effects.

Sensitive spectrofluorimetric determination of the prokinetic drug prucalopride succinate based on supramolecular aggregation approach with evaluation of method greenness: application to content uniformity test.

The prokinetic drug, prucalopride (PCP) succinate, was determined using a new spectrofluorimetric approach with a highly sensitive, rapid, and simple procedure. The method exploited the enhancement of the inherent native fluorescence of PCP by micellar aggregation with sodium lauryl sulfate (SLS) as an anionic surfactant. Different factors that could affect the fluorescence intensity were carefully studied in order to achieve the maximal fluorescence signal. Measurement of the enhanced fluorescence was done at 354 nm after the excitation at 276 nm. The fluorescence intensity-concentration plot was rectilinear in the concentration range of 50-600 ng/ml with detection and quantitation limits of 13.9 and 42.1 ng/ml, respectively. The method underwent validation according to the International Council for Harmonisation criteria in order to assess its analytical performance, and promising results were achieved that proved the validity and reliability of the method. Furthermore, the method was employed effectively for the analysis of the cited drug in commercial pharmaceutical tablets.

4-phenylbutyric acid re-trafficking hERG/G572R channel protein by modulating the endoplasmic reticulum stress-associated chaperones and endoplasmic reticulum-associated degradation gene.

Long QT syndrome type 2 (LQT2) is caused by mutations in the KCNH2/human ether-à-go-go-related gene (hERG). Some hERG genetic mutation-associated diseases are alleviated by hERG-specific drug chaperones (glycerol, dimethyl sulfoxide, trimethylamine N-oxide, thapsigargin), delayed rectifier K+ current (IKr) blockers methanesulfonanilide E4031, the antihistamine astemizole, or the prokinetic drug cisapride, and the anti-arrhythmic drug quinidine. Meanwhile, many in vivo and in vitro studies have reported the efficacy of 4-phenylbutyric acid (4-PBA) in diseases with inherited genetic mutations. This study aims to explore potential therapeutic agents for hERG/G572R mutated ion channel. pcDNA3/hERG [wild type (WT)]-FLAG and pcDNA3/hERG (G572R)-FLAG plasmids were transfected into HEK293 cells. A western blot (WB) experiment was conducted to analyze protein expression. Quantitative real-time polymerase chain reaction (qPCR) was used to analyze the messenger RNA (mRNA) expression levels in the WT/G572R heterozygous HEK293 cell model treated with or without 4-PBA. The interaction between WT/G572R and BIP (GRP78), GRP94, and 3-hydroxy-3-methylglutaryl coenzyme A reductase degradation protein 1 (HRD1) was tested by co-immunoprecipitation (co-IP). To investigate the effect of 4-PBA on the WT/G572R channel current, we used electrophysiological assays (patch-clamp electrophysiological recordings). The results showed that WT/G572R activated the ATF6 pathway in the endoplasmic reticulum stress (ERS), the ERS response markers GRP78, GRP94, and calreticulin (CRT)/calnexin (CNX), and HRD1, which decreased after application of the ERS inhibitor 4-PBA. The results of co-IP confirmed that the ability of hERG interacted with GRP78, GRP94, and HRD1. Moreover, 4-PBA increased the current of WT/G572R and reversed the gating kinetics of the WT/G572R channel. 4-PBA corrects hERG channel transport defects by inhibiting excessive ERS and the endoplasmic reticulum-associated degradation (ERAD)-related gene E3 ubiquitin ligase HRD1. Additionally, 4-PBA improved WT/G572R channel current. 4-PBA is expected to be developed as a new treatment method for LQT2.

Diagnosis and Management of Constipation and Obstipation in Canine: From Current Practices to Future

This study was conducted to understand the present diagnosis and management patterns of constipation and obstipation in dog and accessing about its future holds. A total of 68 dogs both healthy (n=34) and constipated (n=34) brought to a private pet hospital in Kathmandu were included in the study for two-months during Feb-April, 2019 were recorded. The protocol comprised history taking (age, sex, breed and chief complains), physical and clinical examination, hematology/Biochemistry followed by radiography in some cases. Statistical analysis was conducted using MS-Excel 2016 and SPSS v25. We found that starting from the dietary management, rehydration and medical management using laxatives, enemas, antibiotics and supporting liver medications were being followed to manage constipation and obstipation. Anorexia (82.4%) and dehydration were the most common clinical signs. Female dogs (52.9%) were found more affected than male dogs (47.1%). Large and small breed dogs (73.5%) were more prone to constipation than medium sized breeds (26.5%). Older Dogs (&gt;60 months) (34%) were the most affected age groups. Haemato-biochemical blood findings showed significant increase in Total Leucocyte Count (Leukocytosis), Neutrophilia, ALP levels and Blood Urea Nitrogen (p ≤ 0.001) while there was also an increase in Serum bilirubin and Serum albumin levels (p ≤ 0.05) in constipated dog. This research showed increased risk of constipation in old and female dogs. Starting from high fiber diets, mild laxatives and enemas, the treatment can be proceeded to fluid therapy, antibiotic therapy and medications managing liver ailments after haemato-biochemical examination. Use of Novel prokinetic drugs practiced in humans like Cisapride and Pruracalopride, can be considered in veterinary practice. In situations of surgical management, most reliable would be the subtotal colectomy to manage idiopathic megacolon causing constipation and obstipation.

General anaesthesia-related complications of gut motility with a focus on cholinergic mechanisms, TRP channels and visceral pain.

General anesthesia produces multiple side effects. Notably, it temporarily impairs gastrointestinal motility following surgery and causes the so-called postoperative ileus (POI), a multifactorial and complex condition that develops secondary to neuromuscular failure and mainly affects the small intestine. There are currently limited medication options for POI, reflecting a lack of comprehensive understanding of the mechanisms involved in this complex condition. Notably, although acetylcholine is one of the major neurotransmitters initiating excitation-contraction coupling in the gut, cholinergic stimulation by prokinetic drugs is not very efficient in case of POI. Acetylcholine when released from excitatory motoneurones of the enteric nervous system binds to and activates M2 and M3 types of muscarinic receptors in smooth muscle myocytes. Downstream of these G protein-coupled receptors, muscarinic cation TRPC4 channels act as the major focal point of receptor-mediated signal integration, causing membrane depolarisation accompanied by action potential discharge and calcium influx via L-type Ca2+ channels for myocyte contraction. We have recently found that both inhalation (isoflurane) and intravenous (ketamine) anesthetics significantly inhibit this muscarinic cation current (termed mI CAT) in ileal myocytes, even when G proteins are activated directly by intracellular GTPγS, i.e., bypassing muscarinic receptors. Here we aim to summarize Transient Receptor Potential channels and calcium signalling-related aspects of the cholinergic mechanisms in the gut and visceral pain, discuss exactly how these may be negatively impacted by general anaesthetics, while proposing the receptor-operated TRPC4 channel as a novel molecular target for the treatment of POI.

Truptighna mahakashaya is the remedy for Functional Dyspepsia

Functional dyspepsia (FD) is a clinical condition that brings the patient to the doctor with a wide range of symptoms. Many patients go on changing the consultants thinking that they are suffering with a complicated disease. The prevalence of FD is 20% worldwide. But, in India, the prevalence of FD ranges from 7-49% as per data published in one of the studies. Modern medical science treats the condition with PPI, H2 blockers, prokinetic drugs, Probiotics and many more to provide symptomatic relief. Likewise, Ayurveda, an age old health care system of India has developed its own way of treating this condition based on symptoms. Charaka has classified 500 drugs in 50 groups known as Maha kashaya. Each group of Maha kashaya consists of 10 drugs. Among these groups, a class known as Truptighna maha kashaya contains those drugs that relieve the early satiety and abdominal discomfort. But, the interesting fact is that these drugs have additional pharmacological actions that can be utilized to bring relief to the patients of FD of modern era. The drugs have 11 prominent actions that help relieving the symptoms and also prevent the complication of the condition. This class becomes a good alternative, appropriate, well-meant, nicely formulated remedy for functional dyspepsia.