A Review on Acotiamide

Functional dyspepsia (FD) is mainly treated by drugs like H2 receptors antagonists, Proton pump inhibitors, prokinetics. A novel prokinetic drug to treat FD with 2 subtypes: Epigastric pain syndrome (EPS) & postprandial distress syndrome (PDS), has been introduced recently by the approval of Acotiamide, the first in class, muscarinic receptor antagonist & cholinesterase inhibitor. It has shown improvement in gastric motility in rodents & dogs and reduced PDS symptoms in patients in Double- blinded multicentric study.

Digestion-Specific Acupuncture Effect on Feeding Intolerance in Critically Ill Post-Operative Oral and Hypopharyngeal Cancer Patients: A Single-Blind Randomized Control Trial

Malnourishment is prevalent in patients suffering from head and neck cancer. The postoperative period is crucial in terms of nutritional support, especially after composite resection and reconstruction surgery. These patients present with a number of risk factors that aggravate feeding intolerance, including postoperative status, prolonged immobility, decreased head elevation, mechanical ventilation, and applied sedative agents. Routine management protocols for feeding intolerance include prokinetic drug use and post-pyloric tube insertion, which could be both limited and accompanied by detrimental adverse events. This single-blind clinical trial aimed to investigate the effects of acupuncture in postoperative feeding intolerance in critically ill oral and hypopharyngeal cancer patients. Twenty-eight patients were randomized into two groups: Intervention group and Control group. Interventions were administered daily over three consecutive postoperative days. The primary outcome revealed that the intervention group reached 70% and 80% of target energy expenditure (EE) significantly earlier than the control group (4.00 ± 1.22 versus 6.69 ± 3.50 days, p = 0.012), accompanied by higher total calorie intake within the first postoperative week (10263.62 ± 1086.11 kcals versus 8384.69 ± 2120.05 kcals, p = 0.004). Furthermore, the intervention group also needed less of the prokinetic drug (Metoclopramide, 20.77 ± 48.73 mg versus 68.46 ± 66.56 mg, p = 0.010). In conclusion, digestion-specific acupuncture facilitated reduced postoperative feeding intolerance in oral and hypopharyngeal cancer patients.

AN LC-MS/MS BASED BIOANALYTICAL APPROACH TO RESOLVE PHARMACOKINETIC INVESTIGATION OF ACOTIAMIDE HYDROCHLORIDE AND ITS APPLICATION TO BIOEQUIVALENCE STUDY

Objective: Acotiamide, a prokinetic drug used to treat Functional Dyspepsia, which acts by modulating gastric motility. However, in this present study, a simple and accurate bioanalytical method was developed for the estimation of Acotiamide in human plasma using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and validated according to US-FDA guideline. Methods: The method was developed in blank human blood plasma; propranolol was used as internal standard (IS). Protein Precipitation technique was followed for the extraction of the drug from the plasma sample. In liquid chromatography, the C18 analytical column (50 x 3 mm, particle size-5 μm) was used; as a mobile phase, 0.1% formic acid in Mili Q water, and ACN with methanol (1:1) used, at 0.50 ml/min flow rate. Detection was done by positive electrospray ionization (ESI) with a run time of 7 min in multiple reaction monitoring (MRM) mode. Eight calibration concentrations were taken, ranging from 1.5625-200 ng/ml for Acotiamide. Different stability studies were performed and obtained results found within the acceptable range. Moreover, a comparative pharmacokinetic analysis was done in 24 healthy human volunteers in a single dose, randomized, crossover study. Results: The precursor to production reaction was; m/z 451.200 → 271.200 for Acotiamide and m/z 260.300 → 116.100 m/z for IS. The obtained calibration curve was linear, with a mean r2value 0.9953. Among the pharmacokinetic parameters, Cmax and Tmax were 25.71±2.31,23.61±2.32 ng/ml; 2.54±0.12, 2.43±0.21 h for reference and test samples, respectively. Conclusion: No major adverse events were noted in the clinical phase, the developed method was accurate and linear; obtained pharmacokinetic parameters hence represented.

Successful treatment of prolonged postoperative ileus following resection of a small intestinal spindle cell sarcoma in a horse

This case report details the unusual clinical course of a horse that had been hospitalised for recurrent colic prior to an acute colic episode requiring emergency laparotomy. Within the first 24 hours after surgery, the horse developed severe colic and postoperative ileus (POI) requiring repeat laparotomy. The horse suffered persistent ileus with copious reflux for 8 days thereafter, but its clinical condition permitted continued treatment. It was discharged after 4 weeks and returned to its previous performance level. The authors describe clinical decision-making regarding intravenous fluid therapy, prokinetic drug administration, enteral and parenteral nutrition, and institution of physical exercise in the treatment of persistent POI. Economic and welfare considerations allowing, equine POI may resolve even in protracted cases. Patients may benefit from strategies aimed at early enteral feeding and ambulation as have emerged in human POI management.

Difficult To Treat Recurrent Esophageal Dysphagia Due To Secondary Esophageal Motility Disorders: A 24 Weeks Follow Up Case Report

Limited data are available on the prevalence of esophageal motility disorders (OMD) with a suggested range of 4-12% in cases with dysphagia. The proposed pathophysiology is either impairment of inhibitory innervation or overactivity of excitatory innervation. The optimal treatment is not defined until now. This case represented one of the secondary OMD in a 70 years year diabetic patient with ischemic cardiomyopathy, who was complaining of recurrent daily intermittent dysphagia to solids and fluids, with a previous vague history of esophageal dilatation without available documentation. After endoscopy with multiple biopsies and barium imaging, the picture of the corkscrew esophagus was revealed. The patient, who was already on nitrates, failed to respond to twice-daily proton pump inhibitor for two months with a prokinetic drug, calcium channel blocker, and the first session of endoscopic esophageal dilatation. After the second session of dilatation, we add sodium alginate with the substitution of nitrates with sildenafil, and the patient reported a gradual improvement of dysphagia especially to fluids with decreasing in daily attacks. We learn from this case that there is a different patient-to-patient response, which necessitates the use of different treatment modalities even just switching between nitric oxide scavengers for each patient. Keywords: Case Report; Dysphagia; esophageal Motility Disorders.

Determination of the Efficiencies of the Prokinetics in Ruminants with Postoperative Ileus Using Pro-Inflammatory Markers

Background: Recently, the role of inflammation triggered by handling of the intestine various gastrointestinal (GI) surgeries is generally accepted as the key event in postoperative ileus (POI). Because, prokinetics have been increased the smooth muscle contractions and may act by attenuating the inflammatory process in the GI tract, they have been used the treatment of POI in human and animals. There are many in vivo analysis techniques of GI motility. However, there have not yet been studied associated with the evaluation of the inflammatory response. Therefore, it was aimed to evaluate the efficiencies of 3 different prokinetics from inflammatory response during experimentally-induced POI.Materials, Methods & Results: Twenty healthy lambs (30-45 days old) were randomly assigned to four groups. In all groups, enterotomy was performed on the ileum. Erythromycin and metoclopramide were administered to the ERT and MET groups before the surgery, respectively, while lidocaine was administered to the LID group as bolus before and continuous rate infusion during the surgery. Physiological saline was administered to the lambs in control group as placebo before the surgery. Blood samples were collected before surgery (~30-45 min), at the end of surgery (0 h), and at the postoperative 1, 3, 5, 10, 48, 72 and 96 h. The concentrations of serum amyloid A (SAA), haptoglobin (HPT), fibrinogen (FIB) as acute phase proteins (APPs), thiobarbituric acide reactant substrate (TBARs), myeloperoxidase (MPO) as reactive oxygen species, and transforming growth factor-beta (TGF- β) as a cytokine were measured with ELISA reader. In terms of time points, it was found that FIB was statistically higher in ERT group at the 1st h, in MET and LID groups at the 10th h, and in LID group at the 48th and in MET group at the 72 h (P < 0.05). It was found that SAA was higher in MET group at the 1st, 3rd, 5th, 10th, 24th, 48th and 72nd h. HPT was higher in CNTR group until 72th h and MET group at 48th, 72nd and 96th h. TBARs concentrations were statistically higher in MET and LID groups at 0 hour, in ERT and MET groups at the 1st h, in MET group at the 3rd h, in MET and LID groups at the 5th and 10th h, in MET group at the 48th, 72nd and 96th h (P < 0.05). MPO concentrations was higher in LID group at the 3rd, 5th, 10th and 96th h, and in ERT group at the 72nd h (P < 0.05). TGF-β concentrations were particularly high in MET group at the 3rd, 5th, 48th and 72nd h, and in LID group at the 10th, 24th, and 96th h (P < 0.05).Discussion: APPs (HPT, SAA, FIB), which are important regulators of inflammation in cows and sheep, were higher generally in MET and LID groups and inflammation persists in these two groups and, therefore, metoclopramide and lidocaine are less effective in early postoperative POI treatment. Because, significant increase in serum TBARs and MPO concentrations was considered as an important indicator of oxidative stress and inflammatory response MPO concentrations was particularly high until 10th h in LID group, and TBARs concentrations was high both MET and LID groups throughout the study, this was correlated with higher neutrophil infiltration in the postoperative early period than the other groups. It is known that TGF-β, an inflammatory cytokine, is correlated with various smooth muscle disorders in humans. In this study, TGF-β concentration were higher in the MET and LID groups. High concentration of this cytokine might have led to decrease contractions in smooth muscles, thereby slowing down the intestinal transition. In conclusion, based on the presence of pro-inflammatory markers in this study, erythromycin seems to be the most suitable prokinetic drug in lambs. Moreover, lidocaine and metoclopramide are not as successful in small ruminants as reported in other species.

Adherence to an Acotiamide Therapeutic Regimen Improves Long-Term Outcomes in Patients with Functional Dyspepsia

Background & Aims: Long-term outcomes in patients with functional dyspepsia remain elusive. Acotiamide, a prokinetic drug, has been available in Japan since 2013. The aim of this study was to assess long-term outcomes in patients with functional dyspepsia treated with acotiamide.Methods: We retrospectively reviewed 79 consecutive patients with functional dyspepsia whose symptoms improved with acotiamide therapy and who were followed for more than one year. All patients underwent esophagogastroduodenoscopy prior to acotiamide therapy. The mean follow-up was 1.9 (range, 1.0-3.3) years. We assessed the patients’ symptom severity using the Izumo scale, which reflects changes in various abdominal symptoms.Results: At one year, dyspepsia symptoms recurred in 25% (20/79) of the patients. In multivariate analysis, severe dyspepsia was significantly associated with increased recurrence (odds ratio [OR] 15.04, 95% confidence interval [CI] 1.73-130.47, p=0.013). Continued use of acotiamide for one year diminished the recurrence of dyspepsia symptoms significantly (OR 0.16, 95%CI 0.04-0.61, p=0.006). The influence of these significant predictors on long-term outcomes was analyzed using the Kaplan-Meier method. Patients with severe dyspepsia before starting acotiamide had significantly more recurrences than those with mild symptoms (p=0.004, log-rank test). Patients who continued acotiamide therapy throughout the follow-up period had significantly fewer recurrences than those who stopped therapy (p<0.001).Conclusions: Over the long-term, patients with functional dyspepsia have a considerable rate of recurrence of dyspepsia. Severe dyspepsia before treatment increases the recurrence rates, while adherence to an acotiamide therapeutic regimen decreases recurrence rate.Abbreviations: QOL: quality of life; EPS: epigastric pain syndrome; PDS: postprandial distress syndrome; EGD: esophagogastroduodenoscopy; GERD: gastroesophageal reflux disease.

SYNERGISTIC DRUG-DRUG INTERACTION;

Introduction: Ranitidine is known to us all as an anti-ulcer drug which acts byblocking H2 receptors in the stomach parietal cells. However its role in this category has beenunderstated. We studied its prokinetic effect on isolated duodenum of rabbits and its synergisticinteraction with Levosulpiride. The purpose of the study was to see if the two drugs do have aprokinetic effect and whether the combined effect is greater than the individual drugs. StudyDesign: Laboratory based Randomised controlled trial. Period: November 2014 to November2015. Setting: The study was carried out in the multidisciplinary laboratory at Army MedicalCollege after approval from Animals ethics committee. Material and methods: Dose responsecurve was constructed using cumulatively increasing concentrations of Ranitidine (Group 1)and Levosulpiride (Group 2). The synergistic prokinetic drug-drug interaction of Ranitidine andLevosulpiride was observed in Group 3 on iWorx Data acquisition unit (PowerLab). Resultsand Conclusion: Ranitidine produced a dose dependent reversible contraction of the isolatedduodenum and the maximum effect was recorded at 35 μg as 0.136 mV. Levosulpiride produceda maximum contraction of 0.088 mV at 70 μg. Ranitidine and levosulpiride curve was shifted tothe left and upwards of levosulpiride alone. The percent responses of levosulpiride alone was90 percent and with ranitidine was 122 percent. Ranitidine and levosulpiride have a synergisticprokinetic interaction in vitro. Conclusion: Ranitidine and levosulpiride have a synergisticprokinetic drug-drug interaction in vitro.

Acotiamide: a novel drug for the treatment of patients with functional dyspepsia

Functional dyspepsia (FD) is a highly prevalent condition with major socioeconomic and healthcare impact. Previously, no pharmacotherapeutic agent had approved for the treatment of this condition. Acotiamide, a new first-in-class oral prokinetic drug, is an upper gastrointestinal motility modulator for the treatment of abdominal symptoms resulting from hypomotility and delayed gastric emptying in patients with functional dyspepsia. It exerts its activity in the stomach via muscarinic receptor inhibition, resulting in enhanced acetylcholine release and inhibition of acetylcholinesterase activity. Unlike other prokinetic drugs that are utilized in the management of functional dyspepsia, acotiamide shows little/no affinity for serotonin or dopamine D2 receptors. Acotiamide is the world’s first approved treatment for functional dyspepsia diagnosed by Rome III criteria, with its first approval occurring in Japan. A favourable clinical course with acotiamide 100mg t.i.d was demonstrated with high symptom elimination rate for patients of FD.