Core Learning Model and Mathematical Disposition, Against Mathematics Problem Solving Ability of Elementary School Students

This research is aimed to reveal the effects of the core learning model and mathematical disposition model to problem-solving skills in elementary school. This research is experimental research with a 2x2 factorial design. The research sample is fourth-grade students, i.e., 44 persons. The instrument is the mathematical disposition and problem-solving skill instrument. The research result shows that the core learning model is a suitable mathematical learning model to develop mathematical problem-solving skills. The core learning model is more appropriately applied on a group of students with a high mathematical disposition. Meanwhile, the conventional model is more suitable to be applied on a group of students with a low mathematical disposition

Population Pharmacokinetics Modeling of Levofloxacin In Rabbit By Intravenous Bolus Injection and Peroral Administration

The population-based approach has been widely applied to describe the pharmacokinetic profile of many drugs. The aim of this current research was to study the implementation of the population-based pharmacokinetics of levofloxacin in rabbits administered by intravenous bolus injection and peroral delivery. Modeling analyses were performed using Monolix, one of the alternative tools for the population-based approach. Monolix works based on the Stochastic Approximation Expectation-Maximization (SAEM) method. The analysis was performed based on the population model using one-compartmental and two-compartmental disposition models. The combination error model was used during the analyses. Modeling appropriateness was determined based on the goodness of fit analyses, i.e., 1) the individual fit, 2) the observed versus population prediction values; and 3) the observed versus individual prediction values Plasma concentration profiles of levofloxacin by intravenous bolus injection and oral administration are better described by an appropriate model using a two-compartmental disposition model. All goodness of fit analyses demonstrates the power of the chosen model. However, the estimated disposition parameter values obtained based on the intravenous bolus injection and peroral administration are different for each subject. To confirm this phenomenon, we performed a simultaneous fitting of all intravenous bolus as well as peroral administration data. The goodness of fit analyses indicates an adequate fitting of all data.

The effect of isoniazid intake on ethionamide pharmacokinetics and target attainment in multidrug-resistant tuberculosis patients.

Ethionamide is recommended as part of regimens to treat multidrug-resistant and rifampicin-resistant tuberculosis. The study was conducted to (i) describe the distribution of ethionamide minimum inhibitory concentrations (MICs), (ii) describe the pharmacokinetics of ethionamide, and (iii) determine the probability of attaining target AUC 0-24 /MIC values associated with suppression of resistant subpopulation and microbial kill. Participants received 15–20 mg/kg of ethionamide daily (in 500 or 750 mg doses), as part of a multidrug regimen. Pretreatment MICs of ethionamide for M. tuberculosis sputum isolates were determined using Sensititre MYCOTB MIC plates. Plasma concentrations of ethionamide (measured pre-dose and at 2, 4, 6, 8 and 10 hours post-dose) were available for 84 patients. A one-compartment disposition model including a liver compartment capturing hepatic extraction, best described ethionamide pharmacokinetics. Clearance and volume were allometrically scaled using fat-free mass. Isoniazid co-administration reduced ethionamide clearance by 31% resulting in a 44% increase in AUC 0-24 . The median (range) MIC (n=111) was 2.5 mg/L (<0.3 to >40 mg/L). Simulations showed increased daily doses of ethionamide (1 250 mg, 1 500 mg, and 1 750 mg for patients weighing ≤45 kg, 46-70 kg, and >70 kg, respectively) resulted in the probability of attaining a f AUC 0-24 /MIC ratio ≥ 42 in more than 90% of patients, only at the lowest MIC of 0.3 mg/L. The WHO recommended doses of ethionamide do not achieve target concentrations even for the lowest MIC measured in the cohort.

Translational CNS Steady-State Drug Disposition Model in Rats, Monkeys, and Humans for Quantitative Prediction of Brain-to-Plasma and Cerebrospinal Fluid-to-Plasma Unbound Concentration Ratios

Capturing unbound drug exposure in the brain is crucial to evaluate pharmacological effects for drugs acting on the central nervous system. However, to date, there are no reports of validated prediction models to determine the brain-to-plasma unbound concentration ratio (Kp,uu,brain) as well as the cerebrospinal fluid (CSF)-to-plasma unbound concentration ratio (Kp,uu,CSF) between humans and other species. Here, we developed a translational CNS steady-state drug disposition model to predict Kp,uu,brain and Kp,uu,CSF across rats, monkeys, and humans by estimating the relative activity factors (RAF) for MDR1 and BCRP in addition to scaling factors (γ and σ) using the molecular weight, logD, CSF bulk flow, and in vitro transport activities of these transporters. In this study, 68, 26, and 28 compounds were tested in the rat, monkey, and human models, respectively. Both the predicted Kp,uu,brain and Kp,uu,CSF values were within the 3-fold range of the observed values (71, 73, and 79%; 79, 88, and 78% of the compounds, respectively), indicating successful prediction of Kp,uu,brain and Kp,uu,CSF in the three species. The overall predictivity of the RAF approach is consistent with that of the relative expression factor (REF) approach. As the established model can predict Kp,uu,brain and Kp,uu,CSF using only in vitro and physicochemical data, this model would help avoid ethical issues related to animal use and improve CNS drug discovery workflow.

Simplified Iohexol-Based Method for Measurement of Glomerular Filtration Rate in Goats and Pigs

The preclinical evaluation of novel therapies for chronic kidney disease requires a simple method for the assessment of kidney function in a uremic large animal model. An intravenous bolus of iohexol was administered to goats (13 measurements in n = 3 goats) and pigs (23 measurements in n = 5 pigs) before and after induction of kidney failure, followed by frequent blood sampling up to 1440 min. Plasma clearance (CL) was estimated by a nonlinear mixed-effects model (CLNLME) and by a one-compartmental pharmacokinetic disposition model using iohexol plasma concentrations during the terminal elimination phase (CL1CMT). A simple method (CLSM) for the calculation of plasma clearance was developed based on the most appropriate relationship between CLNLME and CL1CMT. CLSM and CLNLME showed good agreement (CLNLME/CLSM ratio: 1.00 ± 0.07; bias: 0.03 ± 1.64 mL/min; precision CLSM and CLNLME: 80.9% and 80.7%, respectively; the percentage of CLSM estimates falling within ±30% (P30) or ±10% (P10) of CLNLME: 53% and 12%, respectively). For mGFRNLME vs. mGFRSM, bias was −0.25 ± 2.24 and precision was 49.2% and 53.6%, respectively, P30 and P10 for mGFR based on CLSM were 71% and 24%, respectively. A simple method for measurement of GFR in healthy and uremic goats and pigs was successfully developed, which eliminates the need for continuous infusion of an exogenous marker, urine collection and frequent blood sampling.

Population pharmacokinetics and outcomes of critically ill pediatric patients treated with intravenous colistin at higher than recommended doses

Limited pharmacokinetic (PK) data suggest that currently recommended pediatric dosages of colistimethate sodium (CMS) by the Food and Drug Administration and European Medicines Agency may lead to suboptimal exposure, resulting in plasma colistin concentrations frequently <2 mg/L. We conducted a population PK study in 17 critically ill patients 3 months-13.75 years (median 3.3 years) old, who received CMS for infections caused by carbapenem-resistant Gram-negative bacteria. CMS was dosed at 200,000 IU/kg/d [6.6 mg colistin base activity (CBA)/kg/d, 6 patients], 300,000 IU/kg/d (9.9 mg CBA/kg/d, 10 patients) and 350,000 IU/kg/d (11.6 mg CBA/kg/d, 1 patient). Plasma colistin concentrations were determined using ultra-performance liquid chromatography combined with electrospray ionization tandem mass spectrometry. Colistin PK was described by a one-compartment disposition model including creatinine clearance, body weight and the presence or absence of systemic inflammatory response syndrome (SIRS) as covariates (p<0.05 for each). The average colistin plasma steady-state concentration (Css,avg) ranged from 1.11-8.47 mg/L (median 2.92 mg/L). Ten patients had Css,avg ≥2 mg/L. The presence of SIRS was associated with decreased apparent clearance of colistin (47.8% of that without SIRS). The relationship between the mg/day of CBA to achieve each 1 mg/L of plasma colistin Css,avg and creatinine clearance (mL/min) was described by linear regression with different slopes for patients with and without SIRS. Nephrotoxicity, probably colistin-unrelated, was observed in one patient. In conclusion, administration of CMS at the above doses improved exposure and was well tolerated. Apparent clearance of colistin was influenced by creatinine clearance and the presence or absence of SIRS.

Effects of Carbamazepine and Phenytoin on Pharmacokinetics and Pharmacodynamics of Rivaroxaban

Rivaroxaban (RIV) is commonly prescribed with carbamazepine or phenytoin (CBZ/PHT) in post-stroke seizure or post-stroke epilepsy patients. Although adverse events have been reported in several previous studies when they are coadministered, there are no studies of the interactions between these drugs. Therefore, our study was conducted to solve this lack of information. The potential effects of CBZ/PHT were investigated by comparing the pharmacokinetic (PK) and pharmacodynamic (PD) parameters of RIV between the control group (RIV alone) and the test groups (RIV administered with CBZ/PHT) in rats using the noncompartmental analysis (NCA) and the compartmental model approach. The NCA results indicate that AUCt of RIV decreased by 57.9% or 89.7% and Cmax of RIV decreased by 43.3% or 70.0% after administration of CBZ/PHT, respectively. In addition, both CBZ and PHT generally reduced the effects of RIV on the prothrombin times of the blood samples. PK profiles of RIV were most properly described by a two-compartment disposition model with a mixed first- and zero-order absorption kinetics and a first-order elimination kinetics. The compartmental model approach showed that a 211% or 1030% increase in CL/F of RIV and a 33.9% or 43.4% increase in D2 of RIV were observed in the test groups by the effects of CBZ/PHT, respectively. In conclusion, CBZ and PHT significantly reduced RIV exposure and therefore reduced the therapeutic effects of RIV. Consequently, this might result in adverse events due to insufficient RIV concentration to attain its therapeutic effects. Further studies are needed to validate this finding.