Evaluation of the relationship between polymorphisms in CYP2C19 and the single-dose pharmacokinetics of omeprazole in healthy Chinese volunteers: A multicenter study.

The aim of this study was to evaluate the relationship between polymorphisms in CYP2C19 and the single-dose pharmacokinetics (PKs) of omeprazole in healthy Chinese volunteers. A 20 mg single dose of omeprazole (Losec) enteric-coated capsules or tablets was orally administered to 656 healthy subjects from eight subcenters. The polymorphic alleles of CYP2C19*2, *3, and *17 were determined by Sanger sequencing and Agena mass array. Plasma concentrations of omeprazole were determined by high-performance liquid-chromatography tandem mass spectrometry. PK parameters of area under the concentration versus time curve (AUC)0-t , AUC from zero to infinity (AUC0-∞ ), maximum plasma concentration (Cmax ), and terminal half-life (t1/2 ) were significantly influenced by CYP2C19 phenotype (all p < 0.001) and diplotype (all p < 0.001), and the same results were obtained in the subgroup analysis of the effects of diet and dosage form. The polymorphisms of CYP2C19*2(rs4244285; all PK parameters p < 0.001) and *3(rs4986893; pCmax  = 0.020, and the p values of other PK parameters were less than 0.001) were significantly associated with the PKs of omeprazole. For CYP2C19*17 (rs12248560), only t1/2 showed a significant correlation (p = 0.032), whereas other PK parameters did not. The present study demonstrated that the Pks of omeprazole is greatly influenced by CYP2C19.

Glutaraldehyde-crosslinked chitosan-polyethylene oxide nanofibers as a potential gastroretentive delivery system of nizatidine for augmented gastroprotective activity.

Nizatidine (NIZ), a histamine H2-receptor antagonist, is soluble and stable in the stomach, however, it exhibits a short half-life and a rapid clearance. Therefore, chitosan (CS) and polyethylene oxide (PEO) nanofibers (NFs) at different weight ratios were prepared by electrospinning and characterized. The selected uncrosslinked and glutaraldehyde-crosslinked NFs were investigated regarding floating, solid-state characteristics, in vitro release, and in vitro cytotoxicity. The cytoprotective activity against ethanol-induced gastric injury in rats was evaluated through macroscopical, histopathological, immunohistochemical, and oxidative stress examinations. NFs based on 8:2 CS:PEO exhibited the smallest diameter (119.17 ± 22.05 nm) and the greatest mucoadhesion (22.82 ± 3.21 g/cm2), so they were crosslinked with glutaraldehyde. Solid-state characterization indicated polymers interaction, a successful crosslinking, and NIZ dispersion in NFs. Crosslinking maintained swollen mats at pH 1.2 (swelling% = 29.47 ± 3.50% at 24 h), retarded their erosion at pH 6.8 (swelling%= 84.64 ± 4.91% vs. 25.40 ± 0.79% for the uncrosslinked NFs at 24 h), augmented the floating up to 24 h vs. 10 min for the uncrosslinked NFs at pH 1.2 and prolonged the drug release (%drug released ≥ 93% at 24 h vs. 4 and 5 h for the uncrosslinked NFs at pHs 1.2 and 6.8, respectively). The viability of Caco-2 cells ≥ 86.87 ± 6.86% revealed NFs biocompatibility and unreacted glutaraldehyde removal. Crosslinking of 8:2 CS:PEO NFs potentiated the antiulcer activity (38.98 vs. 8.67 for the uncrosslinked NFs) as well as it preserved the gastric wall architecture, COX-2 expression, and oxidative stress markers levels of the normal rats.

Exploiting drug delivery systems for oral route in the peptic ulcer disease treatment.

Peptic ulcer disease (PUD) is a common condition that is induced by acid and pepsin causing lesions in the mucosa of the duodenum and stomach. The pathogenesis of PUD is a many-sided scenario, which involves an imbalance between protective factors, such as prostaglandins, blood flow, and cell renewal, and aggressive ones, like alcohol abuse, smoking, Helicobacter pylori colonisation, and the use of non-steroidal anti-inflammatory drugs. The standard oral treatment is well established; however, several problems can decrease the success of this therapy, such as drug degradation in the gastric environment, low oral bioavailability, and lack of vectorisation to the target site. In this way, the use of strategies to improve the effectiveness of these conventional drugs becomes interesting. Currently, the use of drug delivery systems is being explored as an option to improve the drug therapy limitations, such as antimicrobial resistance, low bioavailability, molecule degradation in an acid environment, and low concentration of the drug at the site of action. This article provides a review of oral drug delivery systems looking for improving the treatment of PUD.

Pretreatment of Blumea lacera leaves ameliorate acute ulcer and oxidative stress in ethanol-induced Long-Evan rat: A combined experimental and chemico-biological interaction.

Blumea lacera (Burm.f.) DC. is described as a valuable medicinal plant in various popular systems of medicine. The aim of the experiment reports the in vivo antiulcer activity of methanol extract of Blumea lacera (MEBLL) and in silico studies of bioactive constituents of MEBLL. In this study, fasted Long-Evans rat treated with 80 % ethanol (0.5 mL) to induce gastric ulcer, were pretreated orally with MEBLL at different doses (250 and 500 mg/kg, p.o., b.w) and omeprazole (20 mg/kg, p.o.) and distilled water were used as a reference drug and normal control respectively. In silico activity against gastric H+-K+ATPase enzyme was also studied. The findings demonstrated that the treatment with MEBLL attenuated markedly ulcer and protected the integrity of the gastric mucosa by preventing the mucosal ulceration altered biochemical parameters of gastric juice such total carbohydrate, total protein and pepsin activity. Additionally, the experimental groups significantly (p < 0.001) inhibited gastric lesions and malondealdehyde (MDA) levels and upregulated antioxidant enzymes level. Furthermore, nine compounds were documented as bioactive, displayed good binding affinities to against gastric H+-K+ATPase enzyme while these compounds illustrated inhibitory effect. From these studies, it is established MEBLL has ulcer healing property as unveiled by in vivo and in silico studies.

Silk industry waste protein: isolation, purification and fabrication of electrospun silk protein nanofibers as a possible nanocarrier for floating drug delivery.

Amongst assorted regio-selective and targeted oral drug delivery strategies accepted for the gastro-retentive drug delivery system (GRDDS), the floating drug delivery system (FDDS) holds a major share as clinically accepted formulations. The major objective of the present investigation was to explore the silk industry waste protein, silk fibroin (SF) as a possible electrospun nanocarrier for the FDDS. In a nutshell, electrospinning (ES) is one of the flexible and astonishing strategies for the fabrication of porous electrospun nanofibers (NFs), which offers the potential to amend the floating profile, dissolution rate, solubility, and release patterns of the drug, etc as per compendial requirements. Looking at the prospects of floating SF-NFs preparation, we have isolated and lyophilized the SF from industrial waste cocoons and prepared drug-loaded SF single polymer nanofibers (SPN). Lafutidine (LF) being a good candidate for GRDDS selected as a model drug, which is an excellent proton pump inhibitor, mainly used in the treatment of gastric ulcers. Finally, the obtained LF loaded SF-NFs (LF-SF-NFs) were successfully analyzed for physicochemical characteristics, porosity, swelling index, antioxidant activity, mucoadhesion strength, floating properties, enzymatic degradation, and accelerated stability study, etc. Further, these LF-SF-NFs were evaluated for percent drug content, weight variation, in-vitro dissolution in 0.1 N hydrochloric acid (HCl, pH:1.2) and fasted state simulated gastric fluid (FSSGF), and accelerated stability study. It has shown significant floating time >18 h, about 99% ± 0.58% floating buoyancy with sustained release up to 24 h. LF-SF-NFs showed good compatibility, entrapment efficiency, antioxidant activity, mucoadhesion strength, enzymatic degradation, and long term stability. Soon, the essential floating and drug release profiles can claim single polymer (SF) based electrospun protein NFs as a possible novel oral nanocarrier for FDDS.

Effect of food on the pharmacokinetics of omeprazole, pantoprazole and rabeprazole.

BACKGROUND: The pharmacokinetics of proton pump inhibitors (PPIs) may be affected by food intake. We aimed to evaluate the effect of food on the pharmacokinetics of omeprazole, rabeprazole, and pantoprazole. SETTING: The study population comprised 186 healthy volunteers participating in 6 bioequivalence clinical trials. METHOD: Subjects were evaluated to determine the effect of a high-fat breakfast on the pharmacokinetics of omeprazole (n = 36), rabeprazole (n = 69), and pantoprazole (n = 81). MAIN OUTCOME MEASURE: Drug plasma concentrations were measured using high-performance liquid chromatography coupled to mass spectrometry. RESULTS: Food affected the pharmacokinetics of omeprazole (increased Tmax and decreased AUC and Cmax), pantoprazole (increased Tmax and decreased AUC), and rabeprazole (increased Tmax, Cmax and half-life). Food increased variability in Tmax for all 3 drugs, delaying absorption around 3 to 4 h and until 20 h in some subjects. CONCLUSION: As food delays the absorption of PPIs and increases their variability, it would be better to administer these drugs under fasting conditions. TRIAL REGISTRATION: European Union Drug Regulating Authorities Clinical Trials Database: EudraCT : 2004-003863-59 (registration date 05/MAR/2004), EudraCT 2006-001162-17 (registration date 17-MAR-2006), EudraCT: 2007-002489-37 (registration date 12-JUN-2007), EudraCT: 2007-002490-31 (registration date 12-JUN-2007), EudraCT: 2010-024029-19 (registration date 23-NOV-2010).

Utilization of In Vitro, In Vivo and In Silico Tools to Evaluate the pH-Dependent Absorption of a BCS Class II Compound and Identify a pH-Effect Mitigating Strategy.

PURPOSE: To describe a stepwise approach to evaluate the pH effect for a weakly basic drug by in vitro, in vivo and in silico techniques and identify a viable mitigation strategy that addresses the risk. METHODS: Clinical studies included assessment of the pH effect with famotidine. In vitro dissolution was evaluated in various biorelevant media and in a pH-shift test. PK studies in dogs were conducted under pentagastrin or famotidine pre-treatment and GastroPlus was employed to model human and dog PK data and simulate the performance in human. RESULTS: Clinical data indicated considerable pH dependent absorption of the drug when dosed in the presence of H2-antagonists. In vitro dissolution and in vivo dog data confirmed that the observed pH effect was due to reduced dissolution rate and lower solubility at increased gastric and intestinal pH. A salt form was identified to overcome the effect by providing fast dissolution and prolonged supersaturation. GastroPlus simulations predicted a mitigation of the pH effect by the salt. CONCLUSIONS: The drug exhibited a strong pH-effect in humans. The in vitro, in vivo and modeling approach provides a systematic workflow to evaluate the risk of a new drug and identify a strategy able to mitigate the risk.

CSF omeprazole concentration and albumin quotient following high dose intravenous omeprazole in dogs.

Clinical signs of syringomyelia and hydrocephalus occur secondary to cerebrospinal fluid (CSF) accumulation within the central nervous system. Omeprazole is recommended to treat these conditions despite little evidence of its capacity to decrease CSF production in the dog. Studies into new treatments are hampered by difficulties in measuring CSF production. The albumin quotient (QAlb), the ratio between CSF and serum albumin concentrations, may reflect CSF production and any decrease in CSF production should be associated with an increase in QAlb. The primary objective of this study was to determine CSF omeprazole concentration after administration of a high intravenous dose of omeprazole and to evaluate its impact on QAlb in the dog. The second aim was to validate QAlb as a surrogate marker of CSF production. Eighteen dogs were included in this prospective crossover placebo-controlled study. Each dog received omeprazole (10 mg/kg), acetazolamide (50 mg/kg) combined with furosemide (1 mg/kg) and saline. Blood and CSF samples were obtained on day 0 and then every 7 days, one hour after drug administration. Omeprazole concentrations (2.0 ±â€¯0.4 µmol/L) reached in CSF after high dose omeprazole were lower than the concentrations previously described as decreasing CSF production in dogs. There was no significant increase in QAlb following administration of acetazolamide/furosemide, prohibiting validation of QAlb as a surrogate marker for CSF production. Several dogs presented transient mild side effects after injection of acetazolamide/furosemide. High dose omeprazole was well tolerated in all dogs.

Preclinical development of gastro-protective botanical candidate from Woodfordia fruticosa (Linn.) Kurz: Chemical standardization, efficacy, pharmacokinetics and safety pharmacology.

ETHNOPHARMACOLOGICAL RELEVANCE: Woodfordia fruticosa is traditionally used in the Ayurvedic system of medicine for the treatment of diarrhoea, poisoning, menstrual disorders, ulcers and fertility. In the present study, we report a standardized extract preparation through modern scientific approach for anti-ulcer activity. MATERIALS AND METHODS: The hydro-alcoholic extract of flowers of W. fruticosa was standardized using four chemical markers. The standardized extract was coded as ICB014. HPLC method was developed for identification and quantification of Gallic Acid, Oenothein-C, Quercetin and Kaempferol. Based on the prior published H+, K+-ATPase activity and Anti-bacterial activity against Helicobacter pylori of ICB014, was evaluated for its in-vivo efficacy in gastric ulcers models in rats followed by regulatory safety studies. RESULTS: The extract demonstrated efficacy at 31.25-62.5 mg/kg in gastric ulcer models. The extract was safe by oral route up to 2000 mg/kg in a single dose and NOAEL of 800 mg/kg in 28 days repeat study. Bioequivalent capsule formulation was prepared. CONCLUSIONS: The extract showed anti-ulcer potential and is ready for clinical evaluation.

Lipid Nanoemulsions of Rebamipide: Formulation, Characterization, and In Vivo Evaluation of Pharmacokinetic and Pharmacodynamic Effects.

Rebamipide has low oral bioavailability (10%) due to its low solubility and permeability. Lipid nanoemulsions (LNEs) were prepared in order to improve its oral bioavailability. Rebamipide-loaded lipid nanoemulsions were formulated by hot homogenization and ultrasonication method. Olive oil and egg lecithin in various concentrations as emulsifier were used in the preparation of LNEs. The lipid nanoemulsions were evaluated for various parameters. The globule size, polydispersity index (PDI), and zeta potential (ZP) of the formulations ranged from 230.3 ± 3.88 to 279.8 ± 5.76 nm, 0.204 ± 0.008 to 0.246 ± 0.029, and - 27.7 ± 2.05 to - 31.0 ± 1.87 mV, respectively. Entrapment efficiency and assay values ranged from 99.90 ± 0.006 to 99.92 ± 0.002% and 99.3 ± 0.808 to 99.6 ± 0.360, respectively. Physical stability test results revealed that the optimized LNEs were stable for 2 months at both room (25°C) and refrigerated temperature (4°C). The optimized LNE showed 4.32-fold improvement in the oral bioavailability in comparison to a marketed tablet suspension. In vivo anti ulcer activity of rebamipide LNE was studied by testing the prophylactic effect in preventing the mucosal damage in stomach region. The mucosa of stomach in animals was damaged by per oral administration of 80% alcohol. Maximum prophylactic antiulcer activity was observed by per oral delivery of rebamipide as LNE. Our results indicated that LNEs were a promising approach for the oral delivery of rebamipide for systemic effects along with local effects in protecting gastric region, which gets damaged during peptic ulcers.

Relative potency of proton-pump inhibitors, Helicobacter pylori therapy cure rates, and meaning of double-dose PPI.

BACKGROUND: Helicobacter pylori treatment recommendations often recommend use of double-dose PPI or greater. This is confusing because PPIs very markedly in relative potency such that a double dose of one may not even be equivalent to the single dose of another. OBJECTIVE: To relate the concept of double-dose to specific amounts of the different PPIs METHODS: We used data standardizing PPI potency in terms of the duration of intragastric pH >4/24 hours (pH4-time) to rank PPIs. Relative potency varies from 4.5 mg omeprazole equivalents (20 mg pantoprazole) to 72 mg omeprazole equivalents (40 mg rabeprazole). RESULTS: We defined PPI dosing for H. pylori therapy as low dose (eg, approximately 20 mg omeprazole equivalents, b.i.d.), high or double dose as approximately 40 mg omeprazole equivalents, b.i.d.) and high dose as approximately 60 mg omeprazole equivalents, b.i.d.). For example, standard double dose PPI would thus be 40 mg of omeprazole, 20 mg of esomeprazole or rabeprazole, 45 mg of lansoprazole, or 120 mg of pantoprazole each given b.i.d. CONCLUSIONS: Simply doubling the dose of any PPI achieves markedly different effects on pH4-time. However, PPIs can be used interchangeably and cost effectively based on their omeprazole equivalency.

Oil-entrapped ranitidine HCl beads heal peptic ulcers via local and systemic mechanisms.

OBJECTIVE: Oral gastroretentive system is one of the site-specific drug delivery system, which is designed to be retained in upper GIT for a prolonged time. Ranitidine hydrochloride (RHCl), which is used frequently in treatment of peptic ulcer, is a suitable candidate for gastroretentive delivery systems. Dependently, floating oil-entrapped alginate beads of RHCl were developed and evaluated as an approach to site-specific delivery avoiding colonic degradation and enhancing both bioavailability and the proposed local effect. METHODS: Different formulations of floating beads were suggested and randomized using 24 full factorial design. Optimized formulation was subjected for in vivo studies to measure the oral bioavailability and the healing effect of induced peptic ulcers. RESULTS: Beads size ranged from 1.32 to 2.3 mm. All beads revealed excellent floating capabilities. Optimum formulation (F12) has entrapment efficiency of 70%, drug loading of 7% and 71% RHCl released after 6 h. SEM of F12 shows a grossly spherical structure with presence of oil droplets distributed throughout structure. AUC obtained from F12 was nonsignificantly higher than that of a commercial tablet. Signs of ulcer healing appeared clearly with F12 through appearance of granulation tissue, collagen fibers and newly formed blood vessels. Healing rate and extent obtained with a commercial tablet were less than F12. Quantitative analysis confirmed histopathological findings. CONCLUSION: Floating oil-entrapped beads are a promising approach for RHCl delivery to remain in stomach for a longer time ensuring site-specific delivery and consequently, enhancing local healing effect of peptic ulcers.

Pharmacokinetics and pharmacodynamics of intravenous esomeprazole at 2 different dosages in dogs.

BACKGROUND: Although the demand for esomeprazole is increasing in veterinary medicine, the pharmacokinetics (PK) and pharmacodynamics of esomeprazole have been described in only a few studies. OBJECTIVE: To determine the PK of 0.5 and 1 mg/kg esomeprazole administered IV q12h and to investigate its effects on intragastric pH in healthy dogs. ANIMALS: Six adult Beagles. METHODS: Open-label, randomized, and crossover design. The dogs received 0.5 or 1 mg/kg esomeprazole IV q12h for 48 hours. Plasma concentrations of esomeprazole were measured by high-performance liquid chromatography-tandem mass spectrometry. Intragastric pH was determined using the Bravo pH monitoring system and recorded as mean percentage time (MPT) for which pH was ≥3 and ≥4 for 24 hours in each group. RESULTS: The peak plasma concentration and area under the curve from the time of dosing to the last measurable concentration in the 1 mg/kg group were higher than those in the 0.5 mg/kg group. However, when the dosage normalized, intergroup differences were not significant. The MPTs for which intragastric pH was ≥3 and ≥4 for 48 hours were 88% ± 7% and 81% ± 9% for the 0.5 mg/kg group and 90% ± 9% and 85% ± 11% for the 1 mg/kg group, respectively, with no significant intergroup differences. CONCLUSIONS AND CLINICAL IMPORTANCE: The pharmacokinetic parameters and acid suppressant effect for 0.5 and 1 mg/kg esomeprazole were not significantly different. Furthermore, the efficacy of esomeprazole 0.5 mg/kg IV q12h was sufficient to increase intragastric pH in Beagles.

Synthesis, biological evaluation and docking study of N-(2-(3,4,5-trimethoxybenzyl)benzoxazole-5-yl) benzamide derivatives as selective COX-2 inhibitor and anti-inflammatory agents.

A series of N-(2-(3,4,5-trimethoxybenzyl)-benzoxazole-5-yl)benzamide derivatives (3a-3n) was synthesized and evaluated for its in vitro inhibitory activity against COX-1 and COX-2. The compounds with considerable in vitro activity (IC50 < 1 µM), were evaluated in vivo for their anti-inflammatory and ulcerogenic potential. Out of the fourteen newly synthesized compounds; 3b, 3d, 3e, 3h, 3l and 3m were found to be most potent COX-2 inhibitors in in vitro enzymatic assay with IC50 in the range of 0.14-0.69 µM. In vivo anti-inflammatory activity of these six compounds (3b, 3d, 3e, 3h, 3l and 3m) was assessed by carrageenan induced rat paw edema method. The compound 3b (79.54%), 3l (75.00%), 3m (72.72%) and 3d (68.18%) exhibited significant anti-inflammatory activity than standard drug ibuprofen (65.90%). Ulcerogenic activity with histopathological studies was performed, and the screened compounds demonstrated significant gastric tolerance than ibuprofen. Molecular Docking study was also performed with resolved crystal structure of COX-2 to understand the interacting mechanisms of newly synthesized inhibitors with the active site of COX-2 enzyme and the results were found to be in line with the biological evaluation studies of the compounds.

Comparative pharmacokinetics of Omeprazole and its metabolites in poor and extensive metabolizer Pakistani healthy volunteers and a review of different studies.

This study was designed to evaluate a comparative single dose (40mg) pharmacokinetics (PK) of Omeprazole (OMP) and its two metabolites, 5-hydroxy Omeprazole (5-OH-OMP) and Omeprazole sulphone (OMP-S) in poor (PM) and extensive (EM) metabolizer Pakistani healthy adult volunteers. The frequency of CYP2C19 and CYP3A4 varies widely in different populations. The present study was conducted to evaluate the PK of OMP and its two metabolites in Pakistani population and to review different studies conducted after administration of single dose of OMP. Twenty two subjects were enrolled in this study and divided into two groups. The CYP2C19 phenotyping was evaluated by the metabolic ratio of OMP to 5-OH-OMP. It was a single dose, open label study and the blood samples from subjects were collected at different time intervals until 24 hours. The PK parameters were calculated using the PK-summit software. The metabolic ratio of area under the plasma concentration-time curve AUCOMP/5-OH-OMP was 1.86 ± 0.572 and13.84 ± 2.504 for EM and PM, respectively; maximum plasma concentration (Cmax) of OMP was increased by two folds for PM while the AUC∞ was increased by 3 folds; the Cmax and AUC∞ of 5-OH-OMP decreased for PM by 2 folds while there was 3 fold increase observed in the Cmax and AUC∞ of OMP-S. The PK of OMP and its metabolites in different populations were also discussed, and issues regarding CYP2C19 and CYP3A4 genotyping were also extensively reviewed. In EM of CYP2C19 the concentration of 5-OH-OMP is higher while that of OMP-S is lower. This study as well as reported studies reveals that in PM of CYP2C19 more drugs are available for CYP3A4 to be metabolized. A correlation between CYP2C19 EM and PM activity with CYP3A4 needs to be established.

Evaluation of Omeprazole Limited Sampling Strategies to Estimate Constitutive Cytochrome P450 2C19 Activity in Healthy Adults.

BACKGROUND: Limited sampling strategy (LSS) is a validated method to estimate pharmacokinetic (PK) parameters from a reduced number of samples. Omeprazole is used to phenotype in vivo cytochrome P450 (CYP) 2C19 activity. This study examined an LSS using 2 estimation methods to determine apparent oral clearance (CL/F) and thus CYP2C19 activity. METHODS: Data from 7 previously published studies included healthy subjects receiving a single, oral dose of omeprazole with intensive PK sampling. CL/F was estimated using noncompartmental analysis (NCA) and population PK modeling. LSS was simulated by selecting the 1, 2, 4, and/or 6-hour postdose time points. Linear regression was performed to assess whether CL/F estimated from limited sampling could accurately predict CL/F from the full PK profile. RESULTS: Median CL/F was 23.7 L/h by NCA and 19.3 L/h by population PK modeling. In comparing the LSS NCA estimated versus observed CL/F, all evaluated linear regression models had unacceptable coefficients of determination (r, range: 0.14-0.81). With the population PK approach, 737 plasma concentrations (n = 71) and CYP2C19 genotype data were described with a 1-compartment structural model with mixed zero and first-order absorption and lag time. In comparing the population PK LSS estimated versus observed CL/F, all evaluated linear regression models had unacceptable r (range: 0.02-0.74). Post hoc comparison of CYP2C19 poor metabolizers versus CYP2C19 extensive metabolizers resulted in significantly lower CL/F in poor metabolizers versus extensive metabolizers. CONCLUSIONS: Omeprazole LSS performed poorly in estimating CL/F using 2 separate estimation approaches and does not seem to be a suitable method for determining CYP2C19 activity.

Safety, tolerability, pharmacodynamics and pharmacokinetics of DWP14012, a novel potassium-competitive acid blocker, in healthy male subjects.

BACKGROUND: A novel potassium-competitive acid blocker, DWP14012, is in clinical development as a potential alternative to proton pump inhibitors for the treatment of acid-related diseases. AIMS: To evaluate the safety, tolerability, pharmacodynamics and pharmacokinetics of DWP14012 in humans. METHODS: A randomised, double-blind, double-dummy, placebo- and active-controlled, single- and multiple-ascending dose (SAD and MAD, respectively) study was conducted in healthy male subjects without Helicobacter pylori infection. Subjects randomly received a single oral dose of 10-320 mg DWP14012, esomeprazole (active comparator) or placebo in the SAD study (n = 72) and once daily doses of 20-160 mg DWP14012, esomeprazole or placebo for 7 days in the MAD study (n = 48; 8:2:2). Tolerability was evaluated using a microRNA-122 assay. Pharmacodynamics were evaluated through 24-hour gastric pH monitoring, and pharmacokinetics were evaluated plasma and urine DWP14012 concentrations. RESULTS: DWP14012 was generally well tolerated. The liver toxicity of DWP14012 was not higher than that of placebo after multiple oral administrations. DWP14012 showed rapid and sustained suppression of gastric acid secretion for 24 hours after dosing. Clear dose-response and exposure-response relationships were observed. Plasma concentrations of DWP14012 increased in a dose-proportional manner in the MAD study, whereas in the SAD study, DWP14012 did not significantly accumulate in the plasma. CONCLUSIONS: DWP14012 was well tolerated, and showed a rapid and long-lasting gastric acid suppression effect in healthy subjects. These results justify further investigation of DWP14012 in patients with acid-related disorders.

The effect of the composition of a fixed dose combination on bioequivalence results.

The purpose of this work was to develop a new supergeneric product Meloxicam/Omeprazole. Such a combination brings a benefit in terms of decreasing side effects for the patients using meloxicam. The new combination is composed of a meloxicam powder blend (MPB) and omeprazole gastro-resistant pellets (OAP) in hard gelatin capsules. The main tasks were to select the excipients to keep the functional layer of OAP active and to prove the bioequivalence to the original products of meloxicam tablets together with omeprazole capsules. Although dissolution profiles similar to the original product were obtained, the unexpected results of omeprazole low bioavailability in the fed bioequivalence study (BES I) showed the necessity to investigate the formulation in greater depth. A modified more complex dissolution method was developed in order to understand the release of omeprazole under gastric conditions. This method revealed the degradation of omeprazole in the formulation when exposed to the fed conditions because of the increase in microenvironmental pH in the capsule caused by trisodium citrate, commonly used for improving solubility of meloxicam. This pH increase dissolved the gastro-resistant layer of OAP and caused the chemical degradation. To prevent this effect, a trisodium citrate-free formulation was developed. Reformulated capsules passed the repeated fed bioequivalence study (BES II).

Therapeutic efficacy of rebamipide-loaded PLGA nanoparticles coated with chitosan in a mouse model for oral mucositis induced by cancer chemotherapy.

Oral mucositis is one of the most common side effects induced by cancer therapy, and the prevention or rapid treatment of the symptoms of oral mucositis can improve patients' quality of life and reduce the need for treatment interruption. In this study, poly(dl-lactide-co-glycolide) (PLGA) nanoparticles coated with chitosan hydroxypropyltrimonium chloride was used as a carrier of rebamipide, and its usefulness was evaluated using a mouse model for oral mucositis. The surface properties and particle size of this nanoparticle were considered to be advantageous for the treatment of oral mucositis. Positively charged nanoparticles with an average particle diameter of 97.0 ±â€¯36.7 nm were prepared. From the results of the mucin adsorption study using a periodic acid/Schiff colorimetric method, it was confirmed that the mucin adsorptive capacity of chitosan-coated nanoparticles was 2.3 times higher than that of bare nanoparticles. This result was consistent with the results of the oral retention study of chitosan-coated nanoparticles using an in vivo optical imaging system. Therapeutic efficacy of the nanoparticles on oral mucositis was evaluated using a mouse model for oral mucositis induced by cancer chemotherapy. The chitosan-coated nanoparticles administration group significantly decreased the ulcer area at day 9, 11, and 13 compared with the non-treated control group. Moreover, this group significantly shortened the treatment period by 3.6 days compared to the bare nanoparticles administration group. Therefore, it was suggested that rebamipide-loaded PLGA nanoparticles coated with chitosan hydroxypropyltrimonium chloride were beneficial for the treatment of oral mucositis induced by cancer chemotherapy.

Establishing an in vitro permeation model to predict the in vivo sex-related influence of PEG 400 on oral drug absorption.

The notion that certain formerly regarded "inert" pharmaceutical excipients are capable of modifying the bioavailability of oral drugs has gained increasing attention in recent years. For instance, the commonly-used solubilizing agent polyethylene glycol 400 (PEG 400) exhibits a sex-specific effect on the bioavailability of ranitidine in both humans and rats, mediated by the efflux transporter P-glycoprotein (P-gp). To determine whether such in vivo effect could be predicted by in vitro tests, an in vitro/ex vivo model was established using tissues from male and female rats to characterize the influence of PEG 400 on the intestinal transport of ranitidine in the absence and/or presence of a Pgp inhibitor, cyclosporine A (CsA). We found the absorptive permeability of ranitidine in the small intestine (duodenum, jejunum, ileum) and colon was higher in females compared with males. PEG 400 significantly increased the absorption and decreased the secretion of ranitidine in the intestine of male rats (p < 0.05), but no such effects were observed in female intestines. In addition, while the P-gp inhibitor CsA increased the intestinal uptake of ranitidine in both male and female rats, a greater extent of intestinal transport modulation was observed in males compared to females. These in vitro data on the influence of PEG 400 on the intestinal transport of ranitidine in a sex-dependent manner are in agreement with previously published in vivo data. This good in vivo-in vitro correlation means that the in vitro method will be quicker, cheaper and easier to investigate any sex-related influence of pharmaceutical excipients on oral drug bioavailability.