Acotiamide Research Articles

Correction to: A double-blind placebo controlled study of acotiamide hydrochloride for efficacy on gastrointestinal motility of patients with functional dyspepsia

Correction to: A double-blind placebo controlled study of acotiamide hydrochloride for efficacy on gastrointestinal motility of patients with functional dyspepsia

Development of UV-Spectrophotometric methods and determination of dissolution profile of Acotiamide Hydrochloride Hydrate

Development of UV-Spectrophotometric methods and determination of dissolution profile of Acotiamide Hydrochloride Hydrate

Solvates of acotiamide hydrochloride: characterization and phase transformation.

Five novel crystals of acotiamide hydrochloride (AH) with solvates dimethyl formide (DMF), dimethyl sulfoxide (DMSO), ethyl acetate (EA) and water (W) [1AH-1W-1DMF, 1AH-1DMSO-I, 1AH-1DMSO-II, 1AH-1W-1DMSO and 2AH-2DMSO-1EA] were characterized using single-crystal X-ray diffraction, powder X-ray diffraction, thermal analysis and Fourier transform infrared spectroscopy. The five crystals can be divided into four distinct structural types based on analysis of their similarities; 1AH-1W-1DMF and 1AH-1W-1DMSO are isostructural. The benzene rings in 1AH-1DMSO-I, 1AH-1DMSO-II and 2AH-2DMSO-1EA can rotate 180°, and the intramolecular hydrogen bond changes from an OH...C=O bond to an NH...OH bond relative to what is seen in 1AH-1W-1DMF and 1AH-1W-1DMSO. Phase transformation experiments show that a humidity-induced phase transformation is closely tied to moisture content.

Efficacy of acotiamide hydrochloride hydrate added to α-blocker plus cholinergic drug combination therapy.

Efficacy of acotiamide hydrochloride hydrate added to α-blocker plus cholinergic drug combination therapy.

Hydrates and Solvates of Acotiamide Hydrochloride: Crystallization, Structure, Stability, and Solubility

This paper elucidated eight crystal structures of acotiamide hydrochloride (AH) via single-crystal X-ray diffraction (SCXRD) with water (1AH-1W-I, 1AH-3W), methanol (1AH-1M), methanol and water (1AH-1W-1M-I, 1AH-1W-1M-II), ethanol (1AH-1E), ethanol and water (1AH-1W-1E), and n-propanol (1AH-1P). Two influencing factors, water content and solvent type, were investigated for their effects on the formation of distinct hydrates and solvates. In addition, the stability and solubility of these solid phase forms were analyzed based on their structures. The results of SCXRD revealed that AH tends to crystallize together with a solvent as both a hydrogen bond donor and acceptor. The control experiments in methanol–water, ethanol–water, n-propanol–water, and acetone–water systems showed that the final crystal form varied with an increase in the water content. The eight crystals fall into three types based on their spatial stacking, corresponding interestingly to different stability and solubility. Furthermore, the ...

Real-World, Non-Interventional, Observational Study to Evaluate Effectiveness and Tolerability of Acotiamide Hydrochloride Hydrate in Treatment of Functional Dyspepsia.

Functional dyspepsia (FD) is a highly prevalent condition which reduces patients' quality of life (QoL) and imparts a significant economic burden on the healthcare system. Acotiamide is a novel prokinetic agent useful in treatment of FD, and this study evaluated the effectiveness of acotiamide hydrochloride hydrate in management of FD over a 4-week period in a real-world setting. This study was a prospective, observational, real-world data collection of 132 patients (85 male, 47 female) over 18years of age diagnosed with FD as per Rome III criteria and treated with acotiamide for 4weeks at a gastroenterology unit of a medical school in India. Those receiving prokinetics and cholinergic drugs, having any structural lesion on endoscopy, with coexisting irritable bowel syndrome and having heartburn in the past 12weeks were excluded. Primary outcome was responders based on overall treatment efficacy (OTE) recorded on a seven-point Likert scale for postprandial distress syndrome (PDS; postprandial fullness, early satiety and upper abdominal bloating), epigastric pain syndrome (EPS; upper abdominal pain and upper abdominal discomfort) and associated symptoms (nausea, vomiting and excessive belching) at the end of 2 and 4weeks. Secondary outcomes were elimination of symptoms of PDS, QoL assessed on the Short-Form Nepean Dyspepsia Index (SFNDI) questionnaire and clinical safety after 2 and 4weeks. The responder rates with acotiamide at 2 and 4weeks were 51.5% and 65.9%, respectively, for PDS. Similarly, the responder rates for EPS were 31.8% and 41.7%, respectively, at 2weeks and 4weeks. The responder rates for associated symptoms of nausea, vomiting and excessive belching were respectively 18.2%, 17.4% and 16.7% at 2weeks and 18.2%, 17.4% and 18.2% at 4weeks. Symptom elimination rates were 9.8% and 18.9% for postprandial fullness, 12.9% and 22.0% for early satiety, and 18.9% and 24.2% for abdominal bloating at 2 and 4weeks, respectively. Significant improvement (p < 0.0001) in the SFNDI total scores from 25.91 (5.00) at 2weeks to 23.76 (4.84) at 4weeks were found at 4weeks compared to 2weeks. A total of 7 (5.30%) patients reported mild adverse events which were dizziness (4), headache (3) and nausea (1). The current study demonstrates that treatment with acotiamide improves symptoms, QoL and is well tolerated in Indian patients with FD. Clinical Trial Registry of India, CTRI/2017/11/010421. Dr. Reddy's Laboratories, India.

PGI3 - Real World, Non-Interventional, Observational Study to Evaluate Effectiveness and Tolerability of Acotiamide Hydrochloride Hydrate in Indian Patients with Functional Dyspepsia

To assess effectiveness & tolerability of Acotiamide hydrochloride hydrate in management of Indian patients with functional dyspepsia over 4 weeks period This was prospective, observational, real world study involving 132 patients (85 male, 47 female), aged >18 years, having functional dyspepsia as per Rome III criteria and treated with Acotiamide 100mg three times daily for 4 weeks at a tertiary care centre in India. Primary outcome was responders based on Overall Treatment Efficacy (OTE) recorded on a 7-point Likert scale for post-prandial distress syndrome (post-prandial fullness, early satiety and upper abdominal bloating), epigastric pain syndrome (Upper abdominal pain & discomfort) and associated symptoms of dyspepsia (nausea, vomiting and excessive belching) at the end of 2 and 4 weeks. Secondary outcomes were elimination of symptoms (post-prandial fullness, early satiety and upper abdominal bloating), quality of life assessed on Short-Form Nepean Dyspepsia Index (SFNDI) questionnaire and tolerability over 4 weeks of treatment The responder rates with Acotiamide at 2 and 4 weeks were 51.5% and 65.9% for post-prandial distress syndrome, 31.8%, and 41.7% for epigastric pain syndrome and 16.7% and 17.4% for associated dyspeptic symptoms respectively. Symptom elimination rates were 9.8% and 18.9% for post-prandial fullness, 12.9% and 22.0% for early satiety, and 18.9% and 24.2% for upper abdominal bloating at 2 and 4 weeks respectively. Significant improvement in quality of life as measured on SFNDI total scores, was reported from 25.91 (5.00) at 2 weeks to 23.76 (4.84) at 4 weeks(p<0.0001). Total 7 (5.30%) patients reported mild intensity adverse events which were dizziness (4 patients), headache (3 patients) and nausea (1 patient). Acotiamide demonstrates effectiveness through improvement in symptoms of post-prandial distress syndrome, epigastric pain syndrome and associated dyspepsia symptoms, along with significant improvement in quality of life over a 4-wk treatment period and is well tolerated in Indian patients with functional dyspepsia.

Spectrofluorimetric determination of acotiamide hydrochloride trihydrate in the presence of its oxidative degradation product.

Acotiamide hydrochloride trihydrate is a novel gastroprokinetic drug which has been recently approved for the treatment of patients with functional dyspepsia. This study presents the first reported to investigate the fluorimetric behavior of acotiamide hydrochloride trihydrate in the presence of its oxidative degradation product. All variables that affect fluorescence intensity were studied and optimized. The described method involved the measurement of native fluorescence of the drug in ethanol at 404nm after excitation at 326nm. Calibration plot was found to be linear over the concentration range 0.1-0.9μg/ml. The specificity of the method has been tested via selective determination of the studied drug in its synthetic mixtures with its degradation product. The proposed method has been successfully applied to the analysis of the drug in its new pharmaceutical dosage form and the results have been statistically compared with the reported HPLC method showing no significant differences by applying t-test and F-test.

Verification of a false positive in a two-year rat carcinogenicity study using dual control groups.

There is sometimes controversy over whether or not statistically significant responses produced in carcinogenicity studies have biologically significance. Ambiguous results from our previous two-year oral carcinogenicity study on acotiamide hydrochloride hydrate (acotiamide-HH), a prokinetic drug for functional dyspepsia, in rats made it unclear whether the drug may exhibit uterine carcinogenicity. To check this finding, we performed a second long-term carcinogenicity study using two identical control groups to more accurately evaluate uterine carcinogenesis by considering the incidence of spontaneous neoplasms. Female Fischer 344 rats were divided into three groups: the two control groups (control 1 and 2) were administered vehicle (0.5% w/v methylcellulose) and the acotiamide-HH-treated group was administered 2,000 mg/kg/day of acotiamide-HH by oral gavage for two years. Among all groups, the incidence of endometrial adenocarcinoma (EmA) was highest in the control 2 group, followed by the acotiamide-HH-treated group and the control 1 group. Moreover, acotiamide-HH did not affect the incidence of precursor lesions of EmA. In cases where an ambiguous difference is observed, the use of two control groups allows for a more informed interpretation of the findings in the drug-treated groups. The outcomes in this study strongly support the hypothesis that the increase in EmA in rats treated with acotiamide-HH in our previous study is unrelated to administration of the drug.

Progression process and safety assessment adaptation of endometrial lesions in ENU-induced 2-stage uterine carcinogenicity in a Tg-rasH2 mouse model.

Although acotiamide hydrochloride hydrate (acotiamide-HH) has not been reported to have genotoxic findings in any of the genotoxicity studies or treatment-related toxicological findings in reproductive and developmental studies, suspicious uterine tumorigenesis was observed in the results of a long-term rat carcinogenicity study. To clarify the uterine tumorigenesis of acotiamide-HH, we performed a 2-stage uterine carcinogenicity model in the transgenic rasH2 mouse initiated by N-Ethyl-N-nitrosourea (ENU). This model facilitated the short-term detection of uterine carcinogenic potential, and it appears to be a very useful testing method for assessing the safety of chemicals that may affect uterine tumorigenesis. However, there have not been many reports on this model, and accumulation of case studies using this model is recommended to support its usability. In this study, we performed this carcinogenesis model to not only confirm uterine tumorigenesis of acotiamide-HH but also to confirm the reliability of the model. The results of this study revealed that the endometrial adenocarcinoma found in the long-term rat carcinogenicity study possibly arose spontaneously. Also, we confirmed early induction of a uterine tumor as in previous reports and confirmed that 26 weeks is the appropriate treatment period for this rasH2 mouse model according to time-course observations of uterine tumor development.

Acotiamide hydrochloride hydrate added to combination treatment with an α-blocker and a cholinergic drug improved the QOL of women with acute urinary retention: case series.

Acute urinary retention is the most common urological emergency. To resolve this emergency, urethral catheterization is performed. If the procedure fails and permanent transurethral catheterization is required, the patient’s quality of life is significantly affected. Therefore, catheter-free treatment is the ideal goal of therapy for patients with acute urinary retention. Especially, for women, placement of a catheter poses a cosmetic problem. Therefore, the aim of this study was to treat female patients who had already received urapidil/distigmine bromide with acotiamide. Acotiamide was administered at a dose of 100 mg three times daily for 2 weeks, and the outcome of trial without catheter was evaluated. Only female patients were enrolled for this study. Treatment proved successful and all patients become catheter free.

In vivo metabolite identification of acotiamide in rats using ultra-performance liquid chromatography-quadrupole/time-of-flight mass spectrometry.

Acotiamide hydrochloride (ACT) is a drug used for the treatment of functional dyspepsia. Understanding which metabolites are likely to be formed in vivo is essential for interpreting pharmacology, pharmacokinetic and toxicology data. The metabolism of ACT has been investigated using a specific and sensitive liquid chromatography positive ion electrospray ionization high-resolution tandem mass spectrometry method. In vivo samples including rat plasma, urine and feces were collected separately after dosing healthy Sprague-Dawley rats at a dose of 20 mg kg -1 ACT at different time points up to 24 h. The metabolites were enriched by optimized sample preparation involving protein precipitation using acetonitrile followed by solid-phase extraction. The mass defect filter technique was used for better detection of both predicted and unexpected drug metabolites with the majority of interference ions removed. The structural elucidation of the metabolites was performed by comparing their [M + H]+ ions and their product ions with those of the parent drug. As a result, a total of seven hitherto unknown metabolites were characterized from the biosamples. The only phase I metabolite detected was N-despropyl acotiamide, whereas six phase II glucuronide conjugate metabolites were identified.

A double-blind placebo controlled study of acotiamide hydrochloride for efficacy on gastrointestinal motility of patients with functional dyspepsia.

Acotiamide is widely used to improve symptoms in patients with functional dyspepsia (FD) in multiple large-scale clinical studies, but there are few reports about the drug's mechanism of action. The aim of this study was to assess the effects of acotiamide on gastric accommodation and gastric emptying, gastrointestinal symptoms, and health-related quality of life (HR-QOL) in a placebo-controlled study. We conducted a randomized, double-blind placebo-controlled study. Fifty Japanese FD patients were randomly assigned to either placebo (n=25) or acotiamide 100mg×3/day for 2weeks (n=25). At baseline and at 2weeks of treatment, we evaluated the patients' gastric motility using scintigraphy to determine the accommodation and emptying values, gastrointestinal symptom rating scale (GSRS), HR-QOL (SF-8), and anxiety and depression scale (HADS). Four patients failed to complete the medication regimen and were omitted from analysis; data from 24 placebo patients and 22 acotiamide patients were analyzed. Acotiamide significantly increased gastric accommodation compared to the placebo (p=0.04 vs. p=0.08; respectively). Acotiamide significantly accelerated gastric emptying (50% half-emptying time) (p=0.02 vs. p=0.59). Acotiamide significantly improved the total GSRS scores compared to placebo (p=0.0007 vs. p=0.14). HR-QOL did not differ significantly between the two groups, but acotiamide significantly improved the HADS anxiety score compared to placebo (p=0.04 vs. p=0.20). Our placebo-controlled study demonstrated that acotiamide significantly increased both gastric accommodation and gastric emptying in Japanese FD patients. Acotiamide also improved the patients' dyspeptic symptoms and anxiety score. Clinical Trials Registry no: UMIN000013544.

773 A Double-Blind Placebo Controlled Study of Acotiamide Hydrochloride for Efficacy on Gastrointestinal Motility of Patients With Functional Dyspepsia

Background Acotiamide is widely used to improve symptoms in patients with functional dyspepsia (FD) in multiple large-scale clinical studies, but there are few reports about the drug’s mechanism of action. The aim of this study was to assess the effects of acotiamide on gastric accommodation and gastric emptying, gastrointestinal symptoms, and health-related quality of life (HR-QOL) in a placebo-controlled study.

Probing the Interaction between Acotiamide Hydrochloride and Pepsin by Multispectral Methods, Electrochemical Measurements, and Docking Studies

The interaction between acotiamide hydrochloride and pepsin was systematically characterized by fluorescence and electrochemical approaches. Fluorescence lifetime measurements showed that acotiamide hydrochloride quenched the intrinsic fluorescence of pepsin with a new complex formation via static mode, which was reconfirmed by cyclic voltammetry results. Both of the binding number and binding constants were calculated from differential pulse voltammetry analysis and fluorescence spectroscopy. The values obtained from the above two methods displayed a relatively high degree of consistency. Thermodynamic parameters suggested that acotiamide hydrochloride interacted with pepsin spontaneously by hydrogen bonding and van der Waals interactions. These results were consistent with the results obtained from molecular docking analysis. As revealed by synchronous fluorescence, three-dimensional fluorescence, Fourier transform infrared spectrometry, and circular dichroism spectra, acotiamide hydrochloride could affect the microenvironment and slightly change the secondary structure of pepsin. Furthermore, acotiamide hydrochloride can inhibit pepsin activity in vitro, as explained by the molecular docking.

Emerging treatments in neurogastroenterology: Acotiamade, a novel treatment option for functional dyspepsia.

Acotiamide hydrochloride (Z-338) is a new therapeutic agent for functional dyspepsia (FD). In 2013, the use of acotiamide was approved by the Japanese health insurance system. The aim of this review is to summarize the present staus of basic and clinical approach to acotiamide for the treatment of functional dyspepsia. The agent inhibits acetylcholinesterase in vitro and enhances muscle motility ex vivo. In phase-II studies, 100 mg three times daily (t.i.d.) was determined to be the optimal dose for the treatment of FD. In phase-III studies, overall treatment efficacy (OTE) was significantly better in the acotiamide group (52.2%) than in the placebo group (34.8%). However, the mechanism of its efficacy needs to be further elucidated. Acotiamide effectively improved FD symptoms, particularly postprandial distress syndrome symptoms, without causing major adverse effects.

Characterization of the interaction between acotiamide hydrochloride and human serum albumin: 1H STD NMR spectroscopy, electrochemical measurement, and docking investigations

The comprehensive investigation of acotiamide hydrochloride and HSA interaction provides a convictive explanation for its binding mechanism.

A study on the influence of acotiamide hydrochloride hydrate on sex hormones, using a uterotrophic bioassay in rat

A study on the influence of acotiamide hydrochloride hydrate on sex hormones, using a uterotrophic bioassay in rat

Acotiamide Hydrochloride, a Therapeutic Agent for Functional Dyspepsia, Enhances Acetylcholine-induced Contraction via Inhibition of Acetylcholinesterase Activity in Circular Muscle Strips of Guinea Pig Stomach.

Acotiamide is a first-in-class prokinetic drug approved in Japan for the treatment of functional dyspepsia. Given that acotiamide enhances gastric motility in conscious dogs and rats, we assessed the in vitro effects of this drug on the contraction of guinea pig stomach strips and on acetylcholinesterase (AChE) activity in stomach homogenate following fundus removal. We also investigated the serotonin 5-HT4 receptor agonist mosapride, dopamine D2 receptor and AChE inhibitor itopride, and representative AChE inhibitor neostigmine. Acotiamide (0.3 and 1 μM) and itopride (1 and 3 μM) significantly enhanced the contraction of gastric body strips induced by electrical field stimulation (EFS), but mosapride (1 and 10 μM) did not. Acotiamide and itopride significantly enhanced the contraction of gastric body and antrum strips induced by acetylcholine (ACh), but not that induced by carbachol (CCh). Neostigmine also significantly enhanced the contraction of gastric body strips induced by ACh, but not that by CCh. In contrast, mosapride failed to enhance contractions induced by either ACh or CCh in gastric antrum strips. Acotiamide exerted mixed inhibition of AChE, and the percentage inhibition of acotiamide (100 μM) against AChE activity was markedly reduced after the reaction mixture was dialyzed. In contrast, itopride exerted noncompetitive inhibition on AChE activity. These results indicate that acotiamide enhances ACh-dependent contraction in gastric strips of guinea pigs via the inhibition of AChE activity, and that it exerts mixed and reversible inhibition of AChE derived from guinea pig stomach.

Quantitation of acotiamide in rat plasma by UHPLC-Q-TOF-MS: method development, validation and application to pharmacokinetics.

A novel, sensitive and selective ultra-high-performance liquid chromatography-electrospray ionization mass spectrometry method was developed and validated for the quantification of acotiamide (ACT), a first-in-class drug used in functional dyspepsia, in rat plasma. A simple protein precipitation method with acetonitrile as precipitating solvent was used to extract ACT from rat plasma. ACT and an internal standard (mirabegron, IS) were separated on an Agilent poroshell EC C18 column (50 × 3.0 mm, 2.7 µm) using methanol-10 mM ammonium acetate binary gradient mobile phase at a flow rate of 0.4 mL/min over 4 min run time. Detection was performed using target ions of [M + H](+) at m/z 451.2010 for ACT and m/z 397.1693 for IS in selective ion mode. The method was validated in the calibration range of 1.31-1000 ng/mL. All the validation parameters were well within the limits. The method demonstrated good performances in terms of intra- and inter-day precision (3.27-12.60% CV) and accuracy (87.96-104.94%). Thus the present ultra-high-pressure liquid chromatograhy-high-resolution mass spectrometry method for determination of ACT in rat plasma, is highly sensitive and rapid with a short run-time of 4 min, can be suitable for high sample throughput and for large batches of biological samples in pharmacokinetic studies. This method can be extended to measure plasma concentrations of ACT in humans to understand drug metabolism, drug interaction and adverse effects.