RESUMEN
Racecadotril, an anti-secretory medication, has been used as an adjuvant in an oral rehydration therapy for children experiencing severe diarrhea. Racecadotril is quickly converted to thiorphan, an active metabolite, after oral treatment, which mediates all subsequent activities. An efficient and rapid liquid chromatography-tandem mass spectrometry method was developed and fully validated to measure thiorphan in human plasma, using thiorphan-d7 as an internal standard. The extraction method used was protein precipitation while chromatographic separation was achieved using InertSil CN-3 (50 × 2.1 mm, 5 µm column). The assay was linear over the concentration range of 1-200 ng/ml with correlation coefficients of ≥0.9991. The intra- and inter-day precisions were less than 10.0 % for all concentrations investigated. 0.02 % aqueous formic acid and methanol (30:70 v: v) were used as mobile phases, with an analysis time of less than 1 min. This method proved stable under several conditions. The developed method worked well in a three-period pharmacokinetic bioequivalence study after a single oral administration of 100 mg racecadotril to 15 healthy Jordanian volunteers under fasting conditions.
Asunto(s)
Espectrometría de Masas en Tándem , Equivalencia Terapéutica , Tiorfan , Humanos , Espectrometría de Masas en Tándem/métodos , Reproducibilidad de los Resultados , Cromatografía Liquida/métodos , Masculino , Tiorfan/análogos & derivados , Tiorfan/sangre , Tiorfan/farmacocinética , Tiorfan/química , Modelos Lineales , Adulto , Femenino , Sensibilidad y Especificidad , Cromatografía Líquida con Espectrometría de MasasRESUMEN
PURPOSE: There is currently no gold standard for the management of acute radiation enteritis. We compared the efficacy and safety of Racecadotril, an anti-hypersecretory drug, versus Loperamide, an anti-motility agent, in acute radiation enteritis. METHODS AND MATERIALS: We conducted a randomized, double-masked, non-inferiority trial at a single research institute. Patients receiving curative radiation for pelvic malignancies, who developed grade 2 or 3 diarrhea (as per Common Terminology Criteria for Adverse Events, v 4.0) were included in the study. Patients in the intervention arm received Racecadotril and placebo. Patients in the control arm received Loperamide and placebo. The primary outcome was the resolution of diarrhea, 48 hours after the start of treatment. RESULTS: 162 patients were randomized between 2019 and 2022. On intention-to-treat analysis, 68/81 patients, 84%, (95% CI, 74.1%-91.2%) in the Racecadotril arm and 70/81, 86.4%, (95% CI, 77.0%-93.0%) in the Loperamide arm improved from grade 2 or 3 diarrhea to grade 1 or 0, (P= .66, χ2 test). The difference in proportion was 2.4% (95% CI: -8.5% to 13.4%). Since the upper boundary of the 95% CI crossed our non-inferiority margin of 10% (13.4%) we could not prove the non-inferiority of Racecadotril over Loperamide. Rebound constipation was more in the Loperamide arm compared to Racecadotril (17.3% vs 6.2%; P = .028) CONCLUSIONS: The non-inferiority of Racecadotril to Loperamide in acute radiation enteritis could not be demonstrated. However, Racecadotril can be the preferred drug of choice in acute radiation enteritis because Racecadotril does not affect bowel motility, achieved a high clinical success rate similar to that of Loperamide, and was associated with lesser side effects.
Asunto(s)
Síndrome de Radiación Aguda , Enteritis , Tiorfan , Humanos , Enfermedad Aguda , Síndrome de Radiación Aguda/tratamiento farmacológico , Antidiarreicos/efectos adversos , Diarrea/tratamiento farmacológico , Diarrea/etiología , Método Doble Ciego , Enteritis/etiología , Enteritis/inducido químicamente , Loperamida/efectos adversos , Tiorfan/análogos & derivadosRESUMEN
This study was aimed to determine the pharmacokinetics of antisecretory-acting racecadotril, used in the treatment of diarrhea in humans and dogs, following oral administration in both neonatal calves with healthy and neonatal calves with infectious diarrhea. The study was carried out on a total of 24 Holstein calves (2-20 days), of which 6 were healthy and 18 were infectious diarrhea. Calves with infectious diarrhea were divided into 3 groups according to the infectious agent (Escherichia coli, Cryptosporidium parvum, and rotavirus/coronavirus). Racecadotril was administered orally at 2.5 mg/kg dose to calves. The plasma concentrations of racecadotril and its main active metabolite (thiorphan) were determined using HPLC-UV. The pharmacokinetic parameters were analyzed using the non-compartmental method. In healthy calves, the t1/2Êz , Cmax , Tmax, and AUC0-12 of racecadotril were determined 4.70 h, 377 ng/ml, 0.75 h, and 1674 h × ng/ml, respectively. In the plasma of calves with infectious diarrhea, racecadotril and thiorphan were only detected at the sampling time from 0.25 to 1.5 h. As in calves with infectious diarrhea, thiorphan in plasma was only detected in healthy calves from 0.25 to 1.5 h. Racecadotril showed a large distribution volume, rapid elimination, and low metabolism to thiorphan in healthy calves.
Asunto(s)
Enfermedades de los Bovinos , Criptosporidiosis , Cryptosporidium , Animales , Antidiarreicos/uso terapéutico , Bovinos , Enfermedades de los Bovinos/tratamiento farmacológico , Criptosporidiosis/tratamiento farmacológico , Diarrea/tratamiento farmacológico , Diarrea/veterinaria , Tiorfan/análogos & derivados , Tiorfan/uso terapéuticoRESUMEN
AIM: To evaluate the cost utility of adjunct racecadotril and oral rehydration solution (R + ORS) versus oral rehydration solution (ORS) alone for the treatment of diarrhoea in children under five years with acute watery diarrhoea in four low-middle income countries. METHOD: A cost utility model, previously developed and independently validated, has been adapted to Egypt, Morocco, Philippines and Vietnam. The model is a decision tree, cohort model programmed in Microsoft Excel. The model structure represents the country-specific clinical pathways. The target population is children under the age of five years presenting with symptoms of acute watery diarrhea to an outpatient clinic or general physician practice. A healthcare payer perspective has been analysed with the model parameterised with local data, where available. Most recent cost data has been used to inform the drug, outpatient and inpatient costs. Uncertainty has been explored with univariate deterministic sensitivity. RESULTS: According to the base case models, R + ORS is dominant (cost-saving, more effective) versus ORS alone in Egypt, Morocco, Philippines and Vietnam. The incremental cost-effectiveness ratios in each country fall in the southeast (cost-saving, more effective) quadrant and represent a cost savings of -304,152 EGP per QALY gain in Egypt; -6,561 MAD per QALY gain in Morocco; -428,612 PHP per QALY gain in Philippines and -113,985,734 VND per QALY gain in Vietnam. Univariate deterministic sensitivity analysis shows that the three most influential parameters across all country adaptations are the utility of children without diarrhea; the utility of inpatient children with diarrhea and the cost of one night of inpatient care. CONCLUSION: In keeping with similar findings in upper-middle and high-income countries, the cost utility of R + ORS versus ORS is favourable in low-middle income countries for the treatment of children under five with acute watery diarrhoea.
PLAIN LANGUAGE SUMMARYDecision-makers rely on cost utility models to inform decisions about whether to publicly fund treatments as part of Universal Health Care. In low-middle income countries, the capacity to prepare cost utility models may be limited and using existing validated models is a practical solution to assist decision making. This study uses a cost utility model developed and independently validated for the United Kingdom, and adapts it to Philippines, Egypt, Morocco and Vietnam. The model evaluates the clinical benefit and economic impact of using racecadotril in addition to rehydration solution to treat diarrhoea in children. The results show that racecadotril is cost-saving and improves the quality of life for children in Philippines, Egypt, Morocco and Vietnam.
Asunto(s)
Antidiarreicos , Países en Desarrollo , Diarrea , Soluciones para Rehidratación , Tiorfan , Antidiarreicos/economía , Antidiarreicos/uso terapéutico , Niño , Preescolar , Diarrea/tratamiento farmacológico , Diarrea/economía , Egipto/epidemiología , Fluidoterapia , Humanos , Lactante , Marruecos , Filipinas , Soluciones para Rehidratación/economía , Soluciones para Rehidratación/uso terapéutico , Tiorfan/análogos & derivados , Tiorfan/economía , Tiorfan/uso terapéutico , VietnamRESUMEN
The present study endeavored to develop orodispersible films (ODFs) containing 30 mg racecadotril for pediatric use, which focuses on improving the compliance of pediatric patients and reducing risk of choking. The challenge of this study is to prepare high drug loading ODFs with successful mechanical and physicochemical properties. Compatibilities between drug and different polymers (hydroxypropyl methylcellulose, HPMC; polyvinyl alcohol, PVA; low-substituted hydroxypropyl cellulose, L-HPC; pullulan, PU) were investigated to select stable and safe film-forming polymers. Afterwards, the study explored the maximum amount of racecadotril incorporated into PVA films and PU films. Subsequently, disintegrant (Lycoat RS720, 4-10%, w/w) and plasticizers (glycerol, 2-6%, w/w) were investigated to reduce disintegration time of PVA films and enhance the flexibility of PU films, respectively. Formulation characteristics (appearance, tensile strength, percent elongation, disintegration time, drug content, weight, thickness, pH value, moisture content, moisture uptake, and Q5min) of prepared ODFs were examined to obtain the optimal compositions of racecadotril ODFs. Differential scanning calorimetry (DSC) study, powder X-ray diffraction (XRD) study, Fourier transform infrared (FTIR) study, comparative in vitro dissolution study, and pharmacokinetic study in Beagle dogs of optimized racecadotril ODFs were then conducted. Eventually, ODFs containing 50% racecadotril, 38% PVA, 7% Lycoat RS720, 2% sucralose, 2% apricot, and 1% titanium dioxide could achieve desirable mechanical properties, disintegrating within a few seconds and releasing more than 85% drug within 5 min in four dissolution media. An in vivo study showed optimized racecadotril ODF and Hidrasec were bioequivalent in Beagle dogs. In summary, ODFs containing 30 mg racecadotril were successfully prepared by solvent casting method, and it was suitable for the administration to the pediatric patients.
Asunto(s)
Antidiarreicos/farmacología , Tiorfan/análogos & derivados , Resinas Acrílicas/química , Administración Oral , Antidiarreicos/administración & dosificación , Rastreo Diferencial de Calorimetría , Celulosa/análogos & derivados , Niño , Formas de Dosificación , Excipientes/química , Humanos , Derivados de la Hipromelosa/química , Técnicas In Vitro , Pediatría , Alcohol Polivinílico/química , Polvos , Solubilidad , Solventes/química , Tiorfan/administración & dosificación , Tiorfan/farmacología , Difracción de Rayos XRESUMEN
OBJECTIVE: The objective of this study was to use LC-MS/MS to compare the pharmacodynamic properties and bioequivalence of two 200-mg formulations of racecadotril: suspension formulation (test) and granule formulation (reference) in healthy Chinese subjects. MATERIALS AND METHODS: A single-dose, randomized, two-period crossover study was conducted in fasted healthy Chinese subjects, who received a single oral dose of the test or reference formulation, followed by a 7-day washout period and administration of the alternate formulation. RESULTS: The rapid and highly sensitive LC-MS/MS method exhibited a reasonable linearity range (2.324 - 952.000 ng/mL) and high sensitivity (LLOQ of 2.324 ng/mL). The within- and between-run precision, accuracy, and stability results were within the acceptable limits, and no matrix effect was observed. The 90% CI of the ratio of geometric means for AUC0-t, AUC0-∞, and Cmax were 88.1 - 102.3%, 87.9 - 101.5% and 99.5 - 113%, respectively, which met the regulatory criteria for bioequivalence. CONCLUSION: The method is suitable for quantification of thiorphan in human plasma. In addition, the results indicated that the test and reference formulations were bioequivalent in terms of both rate and extent of absorption.
Asunto(s)
Inhibidores de Proteasas , Espectrometría de Masas en Tándem , Tiorfan/análogos & derivados , Área Bajo la Curva , Disponibilidad Biológica , Cromatografía Liquida , Estudios Cruzados , Humanos , Inhibidores de Proteasas/sangre , Comprimidos , Equivalencia Terapéutica , Tiorfan/sangreRESUMEN
Acute diarrhoea is a leading cause of morbidity and mortality in the paediatric population. Racecadotril is an antisecretory drug recommended as an adjuvant antidiarrhoeal treatment.In the small bowel, the enzyme neutral endopeptidase (NEP) inhibits the action of enkephalins, which prevent water and electrolyte hypersecretion. By inhibiting NEP, racecadotril allows enkephalins to exhibit their antisecretory effects. Consequently, racecadotril reduces the secretion of water and electrolytes in the small intestine, without having an effect on intestinal motility. No serious adverse events related to racecadotril have been reported.Racecadotril has proven its efficacy as an adjuvant antidiarrhoeal drug with a good safety profile. Its addition to oral rehydration solution (ORS) appears clinically beneficial and potentially leads to health care savings.
Asunto(s)
Enfermedades Gastrointestinales , Preparaciones Farmacéuticas , Antidiarreicos/uso terapéutico , Niño , Diarrea/tratamiento farmacológico , Enfermedades Gastrointestinales/tratamiento farmacológico , Humanos , Tiorfan/análogos & derivados , Tiorfan/uso terapéuticoRESUMEN
BACKGROUND: Acute diarrhoea is a leading cause of death for children under five years of age. Most deaths are caused by excessive fluid and electrolyte losses. Racecadotril is an anti-secretory drug that has been used for acute diarrhoea in children as an adjunct to oral rehydration therapy. OBJECTIVES: To assess the efficacy and safety of racecadotril for treating acute diarrhoea in children under five years of age. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL, published in the Cochrane Library Issue 3, March 2019); MEDLINE; Embase; LILACS; ClinicalTrials.gov; and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), up to 4 March 2019, for clinical trials regardless of publication language or status. SELECTION CRITERIA: Randomized controlled trials (RCTs) that compared racecadotril to placebo or no intervention in addition to standard care (oral rehydration therapy) in children under five with acute diarrhoea. The primary outcomes were failure of oral rehydration, duration of diarrhoea, and number of stools. The secondary outcomes were stool output, length of the hospital stay, and adverse events. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility, extracted the data and assessed risk of bias. We presented dichotomous data with risk ratios (RR) and continuous data with mean difference (MD) or standardized mean difference (SMD). Where appropriate, we combined trials with meta-analysis and used a random-effects model if there was significant heterogeneity (I² ≥ 50%). We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: Seven RCTs with a total of 1140 participants met the inclusion criteria. The trials were carried out on children aged three months to five years, in outpatient and inpatient facilities from France, Spain, Peru, India, Kenya, and Ecuador. The efficacy and safety of racecadotril were compared to placebo or no treatment. Racecadotril may reduce the risk of rehydration failure (RR 0.41, 95% CI 0.13 to 1.23; 2 RCTs, 192 participants; low-certainty evidence). Data on duration of diarrhoea, number of stools in the first 48 hours are insufficient to reach a conclusion; stool output in the first 48 hours appears to be lower in the two trials measuring this, although the data is not combinable. Length of hospital stay was similar in two studies measuring this, and overall there was no evidence that racecadotril increased overall rate of adverse events (RR 0.90, 95% CI 0.66 to 1.22; 5 RCTs, 688 participants; low-certainty evidence). Most adverse events in the racecadotril group were mild or moderate. AUTHORS' CONCLUSIONS: Racecadotril seems to be a safe drug but has little benefit in improving acute diarrhoea in children under five years of age. Current evidence does not support routine use of racecadotril in management of acute diarrhoea in children under five outside of the context of placebo controlled RCTs. 18 December 2019 Up to date All studies incorporated from most recent search All studies identified during the most recent search (4 Mar, 2019) have been incorporated in the review, and no ongoing studies identified.
Asunto(s)
Diarrea/tratamiento farmacológico , Tiorfan/análogos & derivados , Preescolar , Fluidoterapia , Humanos , Lactante , Tiempo de Internación , Ensayos Clínicos Controlados Aleatorios como Asunto , Tiorfan/uso terapéutico , Resultado del TratamientoRESUMEN
A stereoselective synthetic strategy for the preparation of trifluoromethylamine mimics of retro-thiorphan, involving a diastereoselective, metal-free catalytic step, has been studied in batch and afforded the target molecule in good yields and high diastereoselectivity. A crucial point of the synthetic sequence was the catalytic reduction of a fluorinated enamine with trichlorosilane as reducing agent in the presence of a chiral Lewis base. The absolute configuration of the key intermediate was unambiguously assigned by X-ray analysis. The synthesis was also investigated exploiting continuous flow reactions; that is, an advanced intermediate of the target molecule was synthesized in only two in-flow synthetic modules, avoiding isolation and purifications of intermediates, leading to the isolation of the target chiral fluorinated amine in up to an 87:13 diastereoisomeric ratio.
Asunto(s)
Tiorfan/análogos & derivados , Catálisis , Halogenación , Modelos Moleculares , Estructura Molecular , Oxidación-Reducción , Estereoisomerismo , Tiorfan/química , Tiorfan/metabolismoRESUMEN
BACKGROUND: Racecadotril is a guideline-recommended option for the treatment of acute diarrhea in children but existing guidelines and previous reviews of the field are based on a small fraction of published evidence. Therefore, we have performed a systematic search for randomized controlled trials evaluating racecadotril as add-on or in comparison to other treatments. METHODS: A search was performed in PubMed, Scopus and Google Scholar without limits about country of origin or reporting language. A meta-analysis was conducted for the five most frequently used efficacy parameters. RESULTS: We have retrieved 58 trials, from nine countries including six in comparison to placebo, 15 in comparison to various active treatments and 41 as add-on to various standard treatments (some multi-armed studies allowing more than one comparison). Trials used 45 distinct efficacy parameters, most often time to cure, % of cured children after 3 days of treatment, global efficacy and number of stools on second day of treatment. Racecadotril was superior to comparator treatments in outpatients and hospitalized patients with a high degree of consistency as confirmed by meta-analysis for the five most frequently used outcome parameters. For instance, it reduced time to cure from 106.2 h to 78.2 h (mean reduction 28.0 h; P < 0.0001 in 24 studies reporting on this parameter). Tolerability of racecadotril was comparable to that of placebo (10.4% vs. 10.6% adverse events incidence) or that of active comparator treatments other than loperamide (2.4% in both groups). CONCLUSIONS: Based on a comprehensive review of the existing evidence, we conclude that racecadotril is more efficacious than other treatments except for loperamide and has a tolerability similar to placebo and better than loperamide. These findings support the use of racecadotril in the treatment of acute diarrhea in children.
Asunto(s)
Antidiarreicos/uso terapéutico , Diarrea/tratamiento farmacológico , Tiorfan/análogos & derivados , Enfermedad Aguda , Antidiarreicos/efectos adversos , Niño , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Tiorfan/efectos adversos , Tiorfan/uso terapéuticoRESUMEN
Anaplastic lymphoma kinase is a tyrosine kinase receptor protein belonging to insulin receptor superfamily. Gene fusions in anaplastic lymphoma kinase are associated with non-small cell lung cancer development. Hence, they are of immense importance in targeted therapies. Thus, for the treatment of non-small cell lung cancer, effective anaplastic lymphoma kinase inhibitors are of great significance. Therefore, our objective is to find hit compounds that could have better inhibitory activity than the existing anaplastic lymphoma kinase inhibitors. Keeping this in mind, in the present study pharmacophore based virtual screening was performed to identify possible anaplastic lymphoma kinase inhibitors. Initially, a five-point common pharmacophore hypothesis was generated based on twelve anaplastic lymphoma kinase inhibitors using PHASE module of Schrödinger. Subsequently, common pharmacophore hypothesis-based screening was conducted against in-trials subset of ZINC database and a total of 1000 hits were identified. The molecules obtained were further screened by three stages of docking using GLIDE software. The docking results reveal that six hit molecules showed higher glide score in comparison with the reference molecules. Finally, pharmacokinetic properties of the hit molecules were also analysed using QikProp programme. The results indicate that molecules namely videx, dexecadotril, chloramphenicol, naficillin were found to have good pharmacokinetic properties and human oral absorption. Moreover, videx, naficillin and chloramphenicol were found to have significant inhibitory activity for mutant (F1174L) anaplastic lymphoma kinase. It was also found that videx exhibited crucial interactions with the Met1199 residue of the native and mutant anaplastic lymphoma kinase protein. Furthermore, PASS algorithm predicted anti-neoplastic activity for all the four molecules. Thus these hits are found to be promising leads for anaplastic lymphoma kinase inhibitors. We believe that this study will be useful for the discovery and designing of more potent anaplastic lymphoma kinase inhibitors in the near future.
Asunto(s)
Inhibidores de Proteínas Quinasas/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismo , Algoritmos , Quinasa de Linfoma Anaplásico , Sitios de Unión , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Dominio Catalítico , Cloranfenicol/química , Cloranfenicol/metabolismo , Bases de Datos de Compuestos Químicos , Bases de Datos de Proteínas , Didanosina/química , Didanosina/metabolismo , Evaluación Preclínica de Medicamentos , Humanos , Ligandos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Conformación Molecular , Simulación del Acoplamiento Molecular , Mutagénesis Sitio-Dirigida , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Proteínas Tirosina Quinasas Receptoras/genética , Termodinámica , Tiorfan/análogos & derivados , Tiorfan/química , Tiorfan/metabolismoRESUMEN
Enantioseparation of the antidiarrheal drug, racecadotril, was investigated by liquid chromatography using polysaccharide-type chiral stationary phases in polar organic mode. The enantiodiscrimininating properties of 4 different chiral columns (Chiralpak AD, Chiralcel OD, Chiralpak AS, Chiralcel OJ) with 5 different solvents (methanol, ethanol, 1-propanol, 2-propanol, and acetonitrile) at 5 different temperatures (5-40 °C) were investigated. Apart from Chiralpak AS column the other 3 columns showed significant enantioseparation capabilities. Among the tested mobile phases, alcohol type solvents were superior over acetonitrile, and significant differences in enantioselective performance of the selector were observed depending on the type of alcohol employed. Van't Hoff analysis was used for calculation of thermodynamic parameters which revealed that enantioseparation is mainly enthalpy controlled; however, enthropic control was also observed. Enantiopure standard was used to determine the enantiomer elution order, revealing chiral selector-and mobile-phase dependent reversal of enantiomer elution order. Using the optimized method (Chiralcel OJ stationary phase, thermostated at 10 °C, 100% methanol, flow rate: 0.6 mL/min) baseline separation of racecadotril enantiomers (resolution = 3.00 ± 0.02) was achieved, with the R-enantiomer eluting first. The method was validated according to the ICH guidelines, and its application was tested on capsule and granules containing the racemic mixture of the drug.
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2-Propanol/química , Amilosa/análogos & derivados , Carbamatos/química , Fenilcarbamatos/química , Polisacáridos/química , Tiorfan/análogos & derivados , Amilosa/química , Cromatografía Líquida de Alta Presión , Estructura Molecular , Solventes , Estereoisomerismo , Termodinámica , Tiorfan/químicaRESUMEN
Diarrheal disease is the second leading cause of death in children younger than 5 y, and the most common cause of acute watery diarrhea in young children worldwide is rotaviral infection. Medicines to specifically reduce diarrhea would be a desirable adjunctive treatment to supportive fluid therapy to decrease the mortality rate of diarrheal diseases. In this study, we evaluated the efficacy of an antisecretory drug, racecadotril, in treating human rotavirus (HRV)-induced diarrhea in a neonatal gnotobiotic pig model. In total, 27 gnotobiotic pigs were randomly assigned (n = 9 per group) to receive either racecadotril, chlorpromazine (positive-control drug), or PBS (mock treatment) after inoculation with HRV. Pigs were weighed daily and rectal swabs were collected to determine fecal consistency scores and virus shedding. Rotaviral infection was confirmed by ELISA and cell culture immunofluorescence. Overall, the racecadotril-treated pigs had less severe illness than either the chlorpromazine- or mock-treated groups; this conclusion was supported by the lower fecal-consistency scores, shorter duration of diarrhea, and significant gain in body weight during the course of the study of the racecadotril-treated pigs. Through its influence on decreasing intestinal hypersecretion, racecadotril was better able to control the clinical signs of rotaviral infection in the gnotobiotic pigs. These results lend support for using racecadotril as a treatment for rotaviral diarrhea.
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Antidiarreicos/uso terapéutico , Diarrea/tratamiento farmacológico , Infecciones por Rotavirus/tratamiento farmacológico , Tiorfan/análogos & derivados , Animales , Diarrea/virología , Evaluación Preclínica de Medicamentos , Rotavirus , Sus scrofa , Tiorfan/uso terapéutico , Pérdida de Peso/efectos de los fármacosRESUMEN
The purpose of this study was to discriminate the release behavior from three differently formulated racecadotril (BCS II) granules and to establish an in vitro-in vivo correlation. Three granule formulations of the lipophilic drug were prepared with equivalent composition but prepared with different manufacturing processes (dry granulation, wet granulation with or without binder). In vitro release of the three granules was investigated using a biphasic dissolution system (phosphate buffer pH6.8 and octanol) and compared to the conventional single phase USP II dissolution test performed under sink and non-sink conditions. In vivo studies with each granule formulation were performed in rats. Interestingly, the granule formulations exhibited pronouncedly different behavior in the different dissolution systems depending on different wetting and dissolution conditions. Single phase USP II dissolution tests lacked discrimination. In contrast, remarkable discrimination between the granule formulations was observed in the octanol phase of biphasic dissolution system with a rank order of release from granules prepared by wet granulation with binder>wet granulation without binder>dry granulation. This release order correlated well with the wettability of these granules. An excellent correlation was also established between in vitro release in the octanol phase of the biphasic test and in vivo data (R2=0.999). Compared to conventional dissolution methods, the biphasic method provides great potential to discriminate between only minor formulation and process changes within the same dosage form for poorly soluble drugs.
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Tiorfan/análogos & derivados , Animales , Química Farmacéutica , Liberación de Fármacos , Masculino , Modelos Teóricos , Ratas Sprague-Dawley , Solubilidad , Tiorfan/sangre , Tiorfan/química , Tiorfan/farmacocinéticaRESUMEN
BACKGROUND: In times of mass tourism, traveler's diarrhea is one of the most common health problems of long-distance travel. Globally, some 40 million cases occur annually. Travellers to risk areas should therefore be comprehensively advised beforehand, as to what action to take in case of an acute traveler's diarrhea and what drugs to add to their first-aid kit. To date none, or hardly any specific studies or valid specific guidelines for the treatment of traveler's diarrhea are available for Germany. METHOD: Drafting a consensus paper based on results of a specialists' meeting to evaluate therapeutic options in the treatment of acute uncomplicated travelers' diarrhea. The foundation for the present consensus recommendations is current evidence on antidiarrheals available in Germany for symptomatic treatment of gastrointestinal infections, summarized in the S2k guideline for gastrointestinal infections and Whipple's disease. Further taken into account for the present consensus recommendations were Pubmed-listed publications on symptomatic treatment of traveler's diarrhea, practical aspects, and the experts' experience in travel medicine. RESULTS AND CONCLUSION: For the treatment of acute uncomplicated traveler's diarrhea - more than 90 % of all cases - the secretion inhibitor racecadotril is considered first choice, based on our evaluation criteria. The previously usual practice of recommending the antimotility drug loperamide as first choice should be reconsidered, in favor of the recent active ingredient racecadotril. Antibiotics should be used only in complicated cases. A large number of travelers who generally demand antibiotic therapy should be disabused of their expectations. Other therapeutic measures that are currently available for the treatment of acute diarrhea while traveling play a subordinate role.
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Diarrea/tratamiento farmacológico , Disentería/tratamiento farmacológico , Tiorfan/análogos & derivados , Viaje , Antibacterianos/uso terapéutico , Antidiarreicos/uso terapéutico , Consenso , Diarrea/etiología , Disentería/etiología , Alemania , Humanos , Guías de Práctica Clínica como Asunto , Tiorfan/uso terapéuticoAsunto(s)
Antidiarreicos/uso terapéutico , Diarrea/tratamiento farmacológico , Síndromes de Malabsorción/tratamiento farmacológico , Microvellosidades/patología , Mucolipidosis/tratamiento farmacológico , Tiorfan/análogos & derivados , Preescolar , Diarrea/etiología , Humanos , Masculino , Tiorfan/uso terapéuticoRESUMEN
OBJECTIVE: To study the effect of racecadotril on reduction in the duration of acute rotavirus and non-rotavirus diarrhea. DESIGN: Two randomized double-blind placebo-controlled trials. SETTING: Community-based trial in an urban area in Vellore, hospital-based trial at a secondary hospital in Vellore. PARTICIPANTS: 199 and 130 3-59 month old children in the community- and hospital-based trials, respectively. METHODS: Racecadotril (1.5 mg/kg/dose, thrice a day for three days) or placebo were given to manage acute diarrhea in both trials. MAIN OUTCOME MEASURE: Median duration of diarrhea. RESULTS: Among 124 children completing the hospital trial, the median duration of diarrhea was 25 h in both arms (P=0.5); median total stool weight was 74 g/kg and 53.5 g/kg in racecadotril group and placebo group, respectively (P=0.4); and average fluid intake per day was 3.6 mL/kg/h and 3mL/kg/h in racecadotril and placebo arms, respectively (P=0.3). Among rotavirus-positive children, median duration of diarrhea was 26.9 h and 30.2 h in racecadotril and placebo arms, respectively (P=0.7). In the community, 196 completed the trial, the median duration of diarrhea was 2 days for both arms (P=0.8) and rotavirus positive children had similar outcomes with median diarrheal duration of 3 d in both arms (P=0.4). CONCLUSIONS: Treatment with racecadotril did not reduce diarrheal duration, stool volume or the requirement for fluid replacement in children with acute gastroenteritis, both with and without rotavirus infection.
Asunto(s)
Antidiarreicos/uso terapéutico , Diarrea/tratamiento farmacológico , Infecciones por Rotavirus/tratamiento farmacológico , Tiorfan/análogos & derivados , Preescolar , Femenino , Humanos , Lactante , Masculino , Tiorfan/uso terapéuticoRESUMEN
This article updates the December 2015 Living FRISBEE (Living FRISBEE: Living FRIendly Summary of the Body of Evidence using Epistemonikos), based on the detection of two systematic reviews not identified in the previous version. Gastroenteritis or acute watery diarrhea is usually a self-limited disease, but it is still associated to substantial healthcare costs and remains a frequent demand for medical care. Racecadotril, an intestinal enkephalinase inhibitor, has been used as treatment because it would decrease the duration of acute diarrhea and fluid loss. However there is still no evidence supporting its routine use. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified five systematic reviews including nine randomized trials relevant for our question. We combined the evidence using meta-analysis and generated a summary of findings table following the GRADE approach. We concluded racecadotril probably reduces the duration of acute diarrhea in pediatric patients, without increasing adverse effects.
Este resumen Epistemonikos (Living FRISBEE: Living FRIendly Summary of the Body of Evidence using Epistemonikos) es una actualización del resumen publicado en Diciembre de 2015, basado en la detección de dos nuevas revisiones sistemáticas que no habían sido identificadas en la versión anterior. La gastroenteritis o diarrea aguda es una enfermedad habitualmente autolimitada, pero que consume recursos sanitarios y constituye un motivo de consulta frecuente en pediatría. El racecadotrilo, un inhibidor de la encefalinasa intestinal, se ha usado como tratamiento porque disminuiría la duración de la diarrea y la pérdida de líquidos, pero no hay evidencia que justifique su uso rutinario. Utilizando la base de datos Epistemonikos, la cual es mantenida mediante búsquedas en 30 bases de datos, identificamos cinco revisiones sistemáticas que en conjunto incluyen nueve estudios aleatorizados relevantes para nuestra pregunta. Realizamos un metanálisis y tablas de resumen de los resultados utilizando el método GRADE. Concluimos que el uso de racecadotrilo probablemente disminuye la duración del cuadro de diarrea aguda en población pediátrica y que no se asociaría a mayor tasa de eventos adversos.