ABSTRACT
BACKGROUND/OBJECTIVES: Okra seed is a rich source of various nutritional and bioactive constituents, but its mechanism of action is still unclear. The aim of this study was to evaluated the effects on glucose uptake and serum lipid profiles of unsaponifiable matter (USM) from okra seed in adipocytes and diabetic animal models. MATERIALS/METHODS: USM was prepared from okra seed powder by saponification. The contents of phytosterols and vitamin E in USM were measured. 3T3-L1 preadipocytes were cultured for 6 days with different concentrations of USM (0-200 µg/mL). The diabetic rats were administered with or without USM for 5 wk. RESULTS: In the USM, the contents of phytosterols and vitamin E were 394.13 mg/g USM and 31.16 mg/g USM, respectively. USM showed no cytotoxicity and led to an approximately 1.4-fold increase in glucose uptake in 3T3-L1 adipocytes. The treatment of USM also increased the expressions of peroxisome proliferator-activated receptor-γ and glucose transporter-4 in a dose-dependent manner in adipocytes. The body weight change was not significantly different in all diabetic rats. However, blood glucose and the weights of liver and adipose tissues were significantly reduced compared to those in the control diabetic rats. Treatment with USM decreased the levels of triglycerides, total cholesterol, and low-density lipoprotein cholesterol compared to the control group. The USM group also showed significantly decreased atherogenic indices and cardiac risk factors. CONCLUSION: These results suggest that USM from okra seed improves the hypoglycemic and hypolipidemic effects in diabetic rats, and provides valuable information for improving the functional properties of okra seed.
ABSTRACT
Fibroblast growth factor (FGF)-21 analogs are potential therapeutic candidates for metabolic dysfunction-associated steatohepatitis (MASH). This systematic review and meta-analysis aimed to assess the efficacy and safety of the FGF-21 analogs, efruxifermin, pegbelfermin, and pegozafermin for MASH treatment. A comprehensive systematic review and meta-analysis of randomized controlled trials from five major databases was conducted. Primary efficacy outcomes focused on liver histological improvement, while secondary efficacy outcomes encompassed reductions in liver fat content and improvements in biochemical parameters. Safety outcomes examined included treatment-emergent adverse events (TEAEs), treatment-related TEAEs, TEAEs leading to discontinuation, and serious TEAEs. Eight eligible studies involving 963 patients were included in this review. Compared with the placebo group, the FGF-21 analog-treated group exhibited significantly improved primary efficacy outcomes, specifically ≥1 stage improvement in fibrosis with no worsening of MASH (risk ratio [RR] = 1.83; 95% confidence interval [CI] = 1.27-2.62) and at least two-point improvement in the non-alcoholic fatty liver disease activity score with no worsening of fibrosis (RR = 2.85; 95% CI = 2.06-3.95). Despite an increased risk of TEAEs (RR = 1.17; 95% CI = 1.08-1.27) and treatment-related adverse events (RR = 1.75; 95% CI = 1.40-2.19), FGF-21 analogs exhibited an acceptable safety profile. FGF-21 analogs were significantly better in achieving liver histological improvements and beneficial biochemical outcomes compared with placebo, with a tolerable safety pattern. These findings shed light on the efficacy and safety of FGF-21 analogs and provide valuable evidence for their application as MASH therapeutics.
Subject(s)
Fibroblast Growth Factors , Humans , Fibroblast Growth Factors/therapeutic use , Treatment Outcome , Randomized Controlled Trials as Topic , Non-alcoholic Fatty Liver Disease/drug therapy , Fatty Liver/drug therapy , Metabolic Diseases/drug therapyABSTRACT
STUDY OBJECTIVES: Dual orexin receptor antagonists (DORAs) are emerging treatments for insomnia. This meta-analysis study aimed to assess the safety of FDA-approved DORAs (suvorexant, lemborexant, and daridorexant), focusing on narcolepsy-like symptoms associated with these drugs. METHODS: Five prominent databases were searched to identify randomized controlled trials (RCTs) on this topic. Primary safety outcomes included treatment-emergent adverse events (TEAEs), treatment-related TEAEs, TEAEs leading to discontinuation, and serious TEAEs. Excessive daytime sleepiness (EDS), sleep paralysis, and hallucinations were categorized as adverse events (AEs)-related narcolepsy-like symptoms. RESULTS: Eleven RCTs with 7703 patients were included. DORAs were associated with a higher risk of TEAEs (risk ratio [RR], 1.09; 95% confidence interval [CI], 1.03 to 1.15) and treatment-related TEAEs (RR, 1.69; 95% CI: 1.49 to 1.92) when compared to placebo. The DORA group exhibited a significantly higher risk of EDS (RR, 2.15; 95% CI: 1.02 to 4.52) and sleep paralysis (RR, 3.40; 95% CI: 1.18 to 9.80) compared to the placebo group. CONCLUSION: This meta-analysis achieved a comparative evaluation of the clinical safety and tolerability of FDA-approved DORAs for primary insomnia, specifically focusing on AEs-related narcolepsy-like symptoms. This study contributes to understanding the safety profile of FDA-approved DORAs for treating insomnia.
Subject(s)
Narcolepsy , Sleep Initiation and Maintenance Disorders , Sleep Paralysis , Humans , Sleep Initiation and Maintenance Disorders/drug therapy , Orexin Receptor Antagonists/adverse effects , Narcolepsy/drug therapyABSTRACT
In this study, an amorphous solid dispersion containing the poorly water-soluble drug, bisacodyl, was prepared by hot-melt extrusion to enhance its therapeutic efficacy. First, the miscibility and interaction between the drug and polymer were investigated as pre-formulation strategies using various analytical approaches to obtain information for selecting a suitable polymer. Based on the calculation of the Hansen solubility parameter and the identification of the single glass transition temperature (Tg), the miscibility between bisacodyl and all the investigated polymers was confirmed. Additionally, the drug-polymer molecular interaction was identified based on the comprehensive results of dynamic vapor sorption (DVS), Fourier transform infrared spectroscopy (FT-IR), Raman spectroscopy, and a comparison of the predicted and experimental values of Tg. In particular, the hydroxypropyl methylcellulose (HPMC)-based solid dispersions, which exhibited large deviation between the calculated and experimental values of Tg and superior physical stability after DVS experiments, were selected as the most appropriate solubilized bisacodyl formulations due to the excellent inhibitory effects on precipitation based on the results of the non-sink dissolution test. Furthermore, it was shown that the enteric-coated tablets containing HPMC-bisacodyl at a 1:4 ratio (w/w) had significantly improved in vivo therapeutic laxative efficacy compared to preparations containing un-solubilized raw bisacodyl in constipation-induced rabbits. Therefore, it was concluded that the pre-formulation strategy, using several analyses and approaches, was successfully applied in this study to investigate the miscibility and interaction of drug-polymer systems, hence resulting in the manufacture of favorable solid dispersions with favorable in vitro and in vivo performances using hot-melt extrusion processes.
ABSTRACT
Obeticholic acid (OCA) is the second-line therapy for primary biliary cholangitis (PBC), as well as an attractive candidate as a treatment for metabolic dysfunction-associated steatohepatitis (MASH). This meta-analysis aims to assess the impact of OCA on lipid profiles and clinical outcomes in patients with PBC and MASH. A comprehensive systematic review and meta-analysis of randomized controlled trials (RCTs) from five major databases were conducted. Changes in lipid profiles from baseline were compared between groups receiving placebo and OCA. Efficacy outcomes were evaluated separately for PBC and MASH trials, while safety outcomes included pruritus, gastrointestinal disturbances, and headache. OCA treatment exhibited a significant increase in low-density lipoprotein cholesterol (LDL-C) (standardized mean difference [SMD] = 0.39; 95 % confidence interval [CI] = 0.15 to 0.63) and a decrease in high-density lipoprotein cholesterol (HDL-C) (SMD = -0.80; 95 % CI = -1.13 to -0.47) in both PBC and MASH patients compared to placebo. OCA demonstrated superior efficacy to placebo in treating PBC and MASH, evident in both primary and secondary outcomes. The incidence of pruritus was significantly higher with OCA compared to placebo (risk ratio = 1.78, 95 % CI = 1.42 to 2.25). OCA is more efficacious than a placebo in the treatment of PBC and MASH. However, caution is needed given the association of OCA use with a significant increase in LDL-C levels and a decrease in HDL-C levels among patients with these conditions.
Subject(s)
Fatty Liver , Liver Cirrhosis, Biliary , Humans , Liver Cirrhosis, Biliary/complications , Liver Cirrhosis, Biliary/drug therapy , Cholesterol, LDL , Pruritus/drug therapy , Pruritus/etiologyABSTRACT
Propafenone (PPF) is a class 1C antiarrhythmic agent mainly metabolized by cytochrome (CYP) 2D6, CYP1A2, and CYP3A4. Previous studies have shown that CYP2D6 polymorphism influences the pharmacokinetics (PK) of PPF. However, the small sample sizes of PK studies can lead to less precise estimates of the PK parameters. Thus, this meta-analysis was performed to merge all current PK studies of PPF to determine the effects of the CYP2D6 phenotype more accurately on the PPF PK profile. We searched electronic databases for published studies to investigate the association between the PPF PK and CYP2D6 phenotype. Four PK-related outcomes were included: area under the time-concentration curve (AUC), maximum concentration (Cmax), apparent clearance (CL/F), and half-life (t1/2). A total of five studies were included in this meta-analysis (n = 56). Analyses were performed to compare PK parameters between poor metabolizers (PMs) versus extensive metabolizers (EMs). PPF has a non-linear pharmacokinetics; therefore, analyses were performed according to dose (300 mg and 400 mg). At 300 mg, the AUC mean (95% CI), Cmax, and t1/2 of PPF in PMs were 15.9 (12.5-19.2) µg·h/mL, 1.10 (0.796-1.40) µg/mL, and 12.8 (11.3-14.3) h, respectively; these values were 2.4-, 11.2-, and 4.7-fold higher than those in the EM group, respectively. At 400 mg, a comparison was performed between S- and R-enantiomers. The CL/F was approximately 1.4-fold higher for the R-form compared with the S-form, which was a significant difference. This study demonstrated that CYP2D6 metabolizer status could significantly affect the PPF PK profile. Adjusting the dose of PPF according to CYP2D6 phenotype would help to avoid adverse effects and ensure treatment efficacy.
ABSTRACT
OBJECTIVE: Calcitonin gene-related peptide (CGRP) receptor antagonists have been suggested as novel treatments for acute migraine. This study aimed to use meta-analysis to compare the safety and tolerability of five existing oral CGRP receptor antagonists (BI44370TA, MK-3207, rimegepant, telcagepant, and ubrogepant) with that of a placebo or triptans against acute migraine. METHODS: Five prominent databases were searched to identify randomized controlled trials on this topic. The primary safety outcomes of interest were any adverse events (AEs) and treatment-related adverse events (TRAEs), and secondary outcomes were individual events, namely diarrhea, dizziness, dry mouth, fatigue, nausea, paresthesia, somnolence, upper abdominal pain, and vomiting. RESULTS: Fifteen studies met the eligibility criteria and were examined in detail. Although, compared to placebo, oral CGRP receptor antagonists significantly increased the incidence of any AEs (risk ratio [RR] = 1.15; 95% confidence interval [CI] = 1.07-1.23), there was no difference in the incidence of TRAEs (RR = 1.18; 95% CI = 1.00-1.38). Moreover, CGRP receptor antagonists were safer than triptans with respect to primary safety outcomes, such as any AEs (RR = 0.78; 95% CI = 0.63-0.98) and TRAEs (RR = 0.68; 95% CI = 0.58-0.79). CONCLUSION: Despite oral CGRP receptor antagonists posing a significantly higher risk of AEs when compared to placebo, CGRP receptor antagonists have a favorable safety profile compared to triptans. Our findings inform strategies to enhance safety and tolerability in the treatment of acute migraine.
Subject(s)
Calcitonin Gene-Related Peptide Receptor Antagonists , Migraine Disorders , Calcitonin/therapeutic use , Calcitonin Gene-Related Peptide Receptor Antagonists/adverse effects , Humans , Migraine Disorders/drug therapy , Receptors, Peptide/therapeutic use , Tryptamines/adverse effectsABSTRACT
Esculetin is the main active ingredient isolated from Artemisia montana (Nakai) Pamp. and Euphorbia lathyris L. The present study investigated the oral bioavailability and pharmacokinetics of esculetin in rats, following intravenous and oral administration.Twenty Sprague-Dawley rats were randomly assigned to receive 10 mg/kg of esculetin either by the intravenous or oral route. Plasma concentrations of esculetin were measured using liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were estimated using non-compartmental analysis as well as a compartmental modelling approach using WinNonlinTM and ADAPT 5 software, respectively.According to non-compartmental analysis, the mean oral bioavailability of esculetin was 19%. Mean ± standard deviation values of esculetin half-life, steady-state volume of distribution and clearance, following intravenous dosing, were 2.08 ± 0.46 h, 1.81 ± 0.52 L/kg and 1.27 ± 0.26 L/h/kg, respectively. As indicated by compartmental modelling, a two-compartment pharmacokinetic model with first-order absorption and elimination rate constants of 0.98 ± 0.18 h-1 and 2.47 ± 0.28 h-1, respectively, sufficiently described the plasma concentration-time curve of esculetin.Improving our understanding of the pharmacokinetic properties of esculetin could help with future development of herbal medicine products with appropriate bioactivity.
Subject(s)
Biological Availability , Administration, Intravenous , Administration, Oral , Animals , Half-Life , Injections, Intravenous , Rats , Rats, Sprague-Dawley , UmbelliferonesABSTRACT
Eperisone is an oral muscle relaxant used to treat musculoskeletal diseases, which exhibits high pharmacokinetic (PK) variability in bioequivalence studies. The aim of this study was to characterize the PKs of eperisone following its oral administration to Korean volunteers through the conduct of a noncompartmental and population analysis. A total of 360 concentration-time measurements collected on two separate occasions from 15 healthy volunteers during a bioequivalent study of eperisone 50 mg (Murex® ) were used in the PK analysis. Noncompartmental analysis was performed using WinNonLinTM and population analysis was performed using NONMEM® . The possible influence of thirty demographic and pathophysiological characteristics on the PKs of eperisone were explored. Based on noncompartmental analysis mean eperisone elimination half-life, apparent clearance (CL/F), and apparent volume of distribution were estimated to be 3.81 h, 39.24 × 103 l/h × 103 L, respectively. During population PK modeling a two-compartment model with first-order absorption rate constant (typical population K a = 1.5 h-1 ) and first-order elimination (typical population CL/F and apparent volume of distribution in the central compartment [V c /F] = 30.8 × 103 l/h and 86.2 × 103 l, respectively) best described the PKs of eperisone. Interindividual variability in CL/F and V c /F were estimated to be 87.9% and 130.3%, respectively and interoccasion variability in CL/F and V c /F were estimated to be 23.8% and 30.8%, respectively. Aspartate aminotransferase level and smoking status were identified as potential covariates that may influence the CL/F of eperisone. This is the first study to develop a disposition model for eperisone and investigate the potential influence of covariate factors on it PK variability.
Subject(s)
Models, Biological , Muscle Relaxants, Central/pharmacokinetics , Propiophenones/pharmacokinetics , Administration, Oral , Adult , Cross-Over Studies , Healthy Volunteers , Humans , Male , Muscle Relaxants, Central/blood , Propiophenones/blood , Republic of Korea , Therapeutic Equivalency , Young AdultABSTRACT
Sample sizes for single-period clinical trials, including pharmacokinetic studies, are statistically determined by within-subject variability (WSV). However, it is difficult to determine WSV without replicate-designed clinical trial data, and statisticians typically estimate optimal sample sizes using total variability, not WSV. We have developed an efficient population-based method to predict WSV accurately with single-period clinical trial data and demonstrate method performance with eperisone. We simulated 1000 virtual pharmacokinetic clinical trial datasets based on single-period and dense sampling studies, with various study sizes and levels of WSV and interindividual variabilities (IIVs). The estimated residual variability (RV) resulting from population pharmacokinetic methods were compared with WSV values. In addition, 3 × 3 bioequivalence results of eperisone were used to evaluate method performance with a real clinical dataset. With WSV of 40% or less, regardless of IIV magnitude, RV was well approximated by WSV for sample sizes greater than 18 subjects. RV was underestimated at WSV of 50% or greater, even with datasets having low IIV and numerous subjects. Using the eperisone dataset, RV was 44% to 48%, close to the true value of 50%. In conclusion, the estimated RV accurately predicted WSV in single-period studies, validating this method for sample size estimation in clinical trials.
ABSTRACT
BACKGROUND AND OBJECTIVE: The calcitonin gene-related peptide (CGRP) is a new therapeutic target in migraine-a common disorder resulting in reduced quality of life. The aim of this study was to compare the clinical efficacy of five oral CGRP antagonists with that of a placebo and triptans against acute migraine via meta-analysis. METHODS: Suitable randomized controlled trials (RCTs) were searched in PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane Library, ClinicalTrials.gov, and World Health Organization International Clinical Trials Registry Platform (WHO-ICTRP) to compare the efficacy of oral CGRP antagonists with that of a placebo and triptans against acute migraine. Review Manager 5.4 was used for data analysis. RESULTS: A total of 17 trials met the eligibility criteria and were studied in detail. The CGRP antagonists were significantly more effective than the placebo with respect to outcomes such as pain freedom at 2 h post-dose (odds ratio = 2.11; 95% confidence intervals [CIs] = 1.90-2.35) and pain relief at 2 h post-dose (odds ratio = 1.94; 95% CIs = 1.70-2.21). Similar results were found in the subgroup analysis conducted to compare the clinical efficacy of the FDA-approved oral CGRP antagonists (ubrogepant and rimegepant) and placebo. However, the CGRP antagonists were less effective than the triptans with respect to outcomes such as pain freedom at 2 h post-dose (odds ratio = 0.66; 95% CIs = 0.55-0.78) and pain relief at 2 h post-dose (odds ratio = 0.78; 95% CIs = 0.66-0.93). CONCLUSION: CGRP antagonists are more effective than placebo against acute migraine; however, further studies are required to consider CGRP antagonists as standard first-line treatment for acute migraine instead of triptans, especially in patients with co-existing cardiovascular diseases.
Subject(s)
Calcitonin Gene-Related Peptide Receptor Antagonists/therapeutic use , Calcitonin Gene-Related Peptide/antagonists & inhibitors , Migraine Disorders/drug therapy , Humans , Pyridines/therapeutic use , Pyrroles/therapeutic use , Quality of Life , Randomized Controlled Trials as Topic , Treatment OutcomeABSTRACT
In this study, we designed amorphous solid dispersions based on Eudragit E/HCl (neutralized Eudragit E using hydrochloric acid) to maximize the dissolution of trans-resveratrol. Solid-state characterization of amorphous solid dispersions of trans-resveratrol was performed using powder X-ray diffraction, scanning electron microscopy, and particle size measurements. In addition, an in vitro dissolution study and an in vivo pharmacokinetic study in rats were carried out. Among the tested polymers, Eudragit E/HCl was the most effective solid dispersion for the solubilization of trans-resveratrol. Eudragit E/HCl significantly inhibited the precipitation of trans-resveratrol in a pH 1.2 dissolution medium in a dose-dependent manner. The amorphous Eudragit E/HCl solid dispersion at a trans-resveratrol/polymer ratio of 10/90 exhibited a high degree of supersaturation without trans-resveratrol precipitation for at least 48 h by the formation of Eudragit E/HCl micelles. In rats, the absolute oral bioavailability (F%) of trans-resveratrol from Eudragit E/HCl solid dispersion (10/90) was estimated to be 40%. Therefore, trans-resveratrol-loaded Eudragit E/HCl solid dispersions prepared by spray drying offer a promising formulation strategy with high oral bioavailability for developing high-quality health supplements, nutraceutical, and pharmaceutical products.
ABSTRACT
Dronedarone and ticagrelor have high co-administration potential in patients with both acute coronary syndrome and atrial fibrillation. The objective of the present in vivo study was to investigate the potential interaction between dronedarone (5 and 10 mg/kg) and ticagrelor (5 and 10 mg/kg) when administered orally to rats. Forty Sprague-Dawley rats were randomly distributed into eight groups; consisting of a dronedarone only group, a ticagrelor only group, a dronedarone with ticagrelor-pretreatment group, and a ticagrelor with dronedarone-pretreatment group. Pharmacokinetic exposure (AUCinf = 1472 ng·h/mL) associated with administration of 10 mg/kg of dronedarone increased significantly, with delayed T max in the group that received ticagrelor-pretreatment when compared to the dronedarone only group (AUCinf = 723 ng·h/mL). In addition, pharmacokinetic exposure (AUCinf = 2391 ng·h/mL) associated with administration of 10 mg/kg of ticagrelor increased significantly, with increased K el (0.31 h-1) and decreased V z/F (14.6 L/kg) in the dronedarone-pretreatment group when compared to the ticagrelor only group (AUCinf = 1616 ng·h/mL; K el = 0.21 h-1; V z/F = 31.3 L/kg). Results of our study suggest that further investigation of a potential interaction between dronedarone and ticagrelor in humans is justified and that caution may need to be exercised when dronedarone and ticagrelor pharmacotherapies concomitantly.
Subject(s)
Dronedarone/pharmacokinetics , Ticagrelor/pharmacology , Administration, Oral , Animals , Anti-Arrhythmia Agents/pharmacokinetics , Humans , Male , Platelet Aggregation Inhibitors/pharmacokinetics , Rats , Rats, Sprague-DawleyABSTRACT
Simvastatin, used orally to treat hyperlipidemia, exhibits highly variable pharmacokinetics (PKs) in humans. The aim of this study was to investigate simvastatin PKs using noncompartmental analysis and population PK models following a single oral administration of two doses (20 and 80 mg) in dogs. Forty beagle dogs were randomly divided into two groups corresponding to the two doses. Blood samples were collected from each group according to the assigned schedule after oral administration. The plasma concentration of simvastatin was determined using liquid chromatography-tandem mass spectrometry. The area under the curve and maximum concentration of simvastatin increased in a dose-dependent manner with high variability. A two-compartment model with first-order absorption (Ka = 1.83 hr-1 ) and first-order elimination (clearance [CL/F] = 292 L/h; volume of distribution in the central compartment [Vc /F] = 1506 L) well described the PKs of simvastatin in dogs. Large variability in the PKs of simvastatin was quantitated via modeling approaches, allowing the differentiation of between-subject variability (144.8 CV% for Ka ; 94.7 CV% for CL/F; 97.5 CV% for Vc /F) and residual variability (62.7%). These findings will help facilitate the development of an optimal dose regimen of simvastatin in canines with hypercholesterolemia and may be useful in developing novel formulations.
Subject(s)
Simvastatin , Administration, Oral , Animals , Chromatography, Liquid/veterinary , Dogs , Mass Spectrometry/veterinaryABSTRACT
Udenafil is a long-acting oral phosphodiesterase type 5 inhibitor used to treat erectile dysfunction which may also have beneficial effects on cardiovascular diseases. Udenafil is mainly biotransformed to the active metabolite N-dealkylated udenafil via cytochrome P450 3A. The aim of this study was to investigate the gender differences and dose proportionality of the toxicokinetics of udenafil and its metabolite N-dealkylated udenafil in rodents. Udenafil was administered orally by gavage to male and female B6C3F1/N mice (100, 240, 350, and 500 mg/kg) and F344 rats (60, 120, and 240 mg/kg). Plasma concentrations of udenafil and N-dealkylated udenafil were simultaneous measured via liquid chromatography-tandem mass spectrometry. Female mice showed higher systemic exposure to udenafil than male mice, whereas female rats showed lower systemic exposure to udenafil than male rats after repeated administration at high dose. Systemic exposure to the metabolite, N-dealkylated udenafil, was lower in female than male mice and rats. A dose proportionality assessment by power model revealed a lack of dose proportionality in systemic exposure (Cmax, AUC24h and AUCinf) after administration of 100-500 mg/kg of udenafil in mice and 60-240 mg/kg in rats. This study thus demonstrates gender and species differences with regard to the toxicokinetic profiles of udenafil and its active metabolite N-dealkylated udenafil after oral administration of udenafil to mice and rats of both sexes. Our findings suggest the possibility of gender differences in the toxicokinetics of udenafil in humans and suggests that further study is needed in this cohort.
Subject(s)
Phosphodiesterase 5 Inhibitors/metabolism , Phosphodiesterase 5 Inhibitors/toxicity , Pyrimidines/metabolism , Pyrimidines/toxicity , Sex Characteristics , Sulfonamides/metabolism , Sulfonamides/toxicity , Administration, Oral , Animals , Female , Male , Mice , Rats , Rats, Inbred F344 , Rodentia , ToxicokineticsABSTRACT
Rebamipide is used widely in East Asia for the treatment of gastric ulcers, acute gastritis, and exacerbated chronic gastritis. The objective of this study was to investigate the pharmacokinetic (PK) properties of rebamipide following single oral administration in rats and dogs. Eleven rats and dogs received single oral administrations of rebamipide (35 mg/kg and 100 mg, respectively). Blood samples were collected according to the assigned schedule, and the plasma concentration of rebamipide was determined using liquid chromatography-tandem mass spectrometry. A double-peak phenomenon was observed in the PK profile of rebamipide in rats. In contrast, rebamipide showed a conventional PK profile without double peaks in dogs. The half-life of rebamipide in rats (12.85 ± 7.86 h) was longer than that in dogs (5.62 ± 2.24 h), and the apparent total clearance (Clt /F) of rebamipide in rats (3.32 ± 1.18 L/h) was lower than that in dogs (105.01 ± 42.37 L/h). Simple allometric approaches showed that the correlation between body weight and Clt /F (R2 = 0.9287) among rats, dogs, and humans appeared satisfactory. This finding will help not only in understanding the pharmacology of rebamipide but also in establishing a strategy for in vivo evaluation of novel rebamipide formulations.
Subject(s)
Alanine/analogs & derivatives , Gastrointestinal Agents/pharmacokinetics , Quinolones/pharmacokinetics , Administration, Oral , Alanine/blood , Alanine/pharmacokinetics , Animals , Dogs , Gastrointestinal Agents/blood , Half-Life , Male , Quinolones/blood , Rats , Rats, Sprague-Dawley , Species SpecificityABSTRACT
The aim of this study was to investigate the pharmacokinetic properties of mosapride after intravenous and oral administration to beagle dogs. To obtain the advanced pharmacokinetic parameters of mosapride, both noncompartmental analysis and pharmacokinetic modeling were performed. Twenty beagle dogs were randomly sorted into intravenous (1 mg single administration of mosapride) and oral (5 mg once a day administration of mosapride) groups. Blood samples were collected according to the reported schedule for pharmacokinetics. The plasma concentration of mosapride was analyzed using liquid chromatography-tandem mass spectrometry. According to the pharmacokinetic analysis, the absorption rate of mosapride was 3.14 ± 1.14 hr-1 and oral bioavailability of mosapride was approximately 1%. The one-compartment model well described the pharmacokinetics of mosapride after both intravenous and oral administration to dogs. These findings will help facilitate the determination of the optimal dose regimen of mosapride for dogs with gastrointestinal disorder.
Subject(s)
Benzamides/pharmacokinetics , Dogs/metabolism , Gastrointestinal Agents/pharmacokinetics , Morpholines/pharmacokinetics , Administration, Oral , Animals , Area Under Curve , Benzamides/administration & dosage , Gastrointestinal Agents/administration & dosage , Half-Life , Injections, Intravenous , Male , Morpholines/administration & dosageABSTRACT
Orlistat, an anti-obesity drug, has two critical issues-the first is its low efficacy due to low water solubility and the second is side effects such as oily spotting due to its lipase inhibition. The present study was designed to propose a solution using a formulation with mesoporous silica to simultaneously overcome two issues. Orlistat was loaded onto mesoporous silica by the supercritical melt-adsorption (SCMA) method, using carbon dioxide (CO2). Various types of mesoporous silica were used as adsorbents, and the effects of the pore volume, diameter and particle size of mesoporous silica on the pharmaceutical characteristics were evaluated by various solid-state characterization methods and in vitro and in vivo studies in relation to pharmacological efficacy and the improvement of side effects. The results showed that the pore volume and diameter determine loadable drug amount inside pores and crystallinity. The dissolution was significantly influenced by crystallinity, pore diameter and particle size, and the inhibition of lipase activity was in proportion to the dissolution rate. In vivo studies revealed that the serum triglyceride (TG) concentration was significantly decreased in the group administered amorphous orlistat-loaded Neuisilin®UFL2 with the highest in vitro dissolution rate and lipase activity inhibition in comparison to the commercial product. Furthermore, oily spotting tests in rats revealed that undigested oil was adsorbed onto mesoporous silica after orlistat was released in the gastro-intestinal tract, and it correlated with in vitro result that oil adsorption capacity was dependent on the surface area of empty mesoporous silica. Therefore, it was concluded that mesoporous silica type plays a major role in determining the pharmaceutical characteristics of orlistat formulation prepared using SCMA with CO2 for improving the low solubility and overcoming the side effects.
ABSTRACT
The aim of this study was to prepare pure trans-resveratrol nanoparticles without additives (surfactants, polymers, and sugars) using a supercritical antisolvent (SAS) process with alcohol (methanol or ethanol) and dichloromethane mixtures. In addition, in order to investigate the effect of particle size on the dissolution and oral bioavailability of the trans-resveratrol, two microparticles with different sizes (1.94 µm and 18.75 µm) were prepared using two different milling processes, and compared to trans-resveratrol nanoparticles prepared by the SAS process. The solid-state properties of pure trans-resveratrol particles were characterized. By increasing the percentage of dichloromethane in the solvent mixtures, the mean particle size of trans-resveratrol was decreased, whereas its specific surface area was increased. The particle size could thus be controlled by solvent composition. Trans-resveratrol nanoparticle with a mean particle size of 0.17 µm was prepared by the SAS process using the ethanol/dichloromethane mixture at a ratio of 25/75 (w/w). The in vitro dissolution rate of trans-resveratrol in fasted state-simulated gastric fluid was significantly improved by the reduction of particle size, resulting in enhanced oral bioavailability in rats. The absolute bioavailability of trans-resveratrol nanoparticles was 25.2%. The maximum plasma concentration values were well correlated with the in vitro dissolution rate. These findings clearly indicate that the oral bioavailability of trans-resveratrol can be enhanced by preparing pure trans-resveratrol nanoparticles without additives (surfactants, polymers, and sugars) by the SAS process. These pure trans-resveratrol nanoparticles can be applied as an active ingredient for the development of health supplements, pharmaceutical products, and cosmetic products.
ABSTRACT
The glimepiride/L-arginine (GA) binary systems were prepared at various molar ratios by using a supercritical antisolvent (SAS) process. For comparison, the GA system was also prepared by physical mixing (PM), melt quenching (MQ), and solvent evaporation (SE) methods. Analyses by DSC and PXRD showed that only the GA binary mixture at 1:1 M ratio prepared by the SAS process was a pure co-amorphous mixture with an excellent content uniformity. On the other hand, GA mixture prepared by PM and SE were not pure co-amorphous systems and contained crystalline eutectic mixture, and MQ method at 170 °C induced the decrease in drug content due to decomposition of glimepiride. The positive deviation of experimentally measured glass transition temperature (Tg) compared to predicted Tg by the Gordon Taylor equation suggests specific molecular interactions between glimepiride and L-arginine in solid-state GA co-amorphous (GACA) mixture. The intermolecular interactions between glimepiride and L-arginine in GACA system were characterized by FT-IR and solid-state NMR analyses. Improved glimepiride dissolution rate of GACA formulation were confirmed using the solubility test, contact angle measurement, and dissolution test. Furthermore, the evaluation of pharmacodynamic hypoglycemic effect demonstrated that GACA prepared by the SAS process significantly improved the therapeutic efficacy of glimepiride.