Pharmacokinetic modeling and simulation of etodolac following single oral administration in dogs

1. Etodolac is a nonsteroidal anti-inflammatory drug with selective cyclooxygenase-2 inhibition to treat pain and inflammation associated with osteoarthritis in humans and dogs. The aim of the study was to investigate the pharmacokinetics of etodolac following single oral administration of 200?mg to 10 healthy beagle dogs.

2. The plasma concentrations of etodolac were detected using liquid chromatography-tandem mass spectrometry. Pharmacokinetic analysis was conducted using the noncompartmental method and modeling approaches.

3. Etodolac was rapidly absorbed (T_max?=?0.85?h, K_a?=?1.49?h^?1) and slowly eliminated (T_1/2?=?39.55?h) following oral administration to the dogs. A two-compartment pharmacokinetic model with first-order absorption and elimination rate constants was successfully explained for the pharmacokinetic aspects of etodolac in dogs. From a Monte Carlo simulation (1000 repetitions), the accumulation index and AUC_τ at steady state were predicted as 1.60 [90% confidence intervals (CI), 1.24–2.81] and 408.18?ng·hr/mL [90% CI, 271.26–590.58?ng·hr/mL], respectively.

4. This study will help to enact a more accurate optimal dosing regimen of etodolac in dogs with osteoarthritis, and may be useful in developing a novel formulation of etodolac for human in the future.

     

Yakima Valley Farm Workers Clinic oral health transformation project

The Yakima Valley Farm Workers Clinic (YVFWC) is one of the largest community health centers in the country with clinics throughout south-central Washington and northern Oregon. Its dental program consists of 14 dental clinics providing general and specialty services to the low-income populations it serves. Modeling itself after the YVFWC medical managed care program; the Dental program recently added value-based metrics to its dental practice after Oregon offered a value-based dental reimbursement plan in 2019. This is the first-step YVFWC's dental program that has taken to prepare for value-based reimbursement and transform its dental practice in order to reduce the disease burden in its patient population. The purpose of this article is to describe the processes YVFWC undertook to prepare itself for the new reimbursement model, which included the development of metrics, a metric validation process, a clinical dashboard, and a method for improving metrics. It also outlines its medical/dental integration improvement brought about by embedding hygienists into the medical primary care teams.     

Population pharmacokinetics of tanezumab in phase 3 clinical trials for osteoarthritis pain

AimsThe aims were to 1) develop the pharmacokinetics model to describe and predict observed tanezumab concentrations over time, 2) test possible covariate parameter relationships that could influence clearance and distribution and 3) assess the impact of fixed dosing vs. a dosing regimen adjusted by body weight.MethodsIndividual concentration–time data were determined from 1608 patients in four phase 3 studies conducted to assess efficacy and safety of intravenous tanezumab. Patients received two or three intravenous doses (2.5, 5 or 10 mg) every 8 weeks. Blood samples for assessment of tanezumab PK were collected at baseline, 1 h post‐dose and at weeks 4, 8, 16 and 24 (or early termination) in all studies. Blood samples were collected at week 32 in two studies. Plasma samples were analyzed using a sensitive, specific, validated enzyme‐linked immunosorbent assay.ResultsA two compartment model with parallel linear and non‐linear elimination processes adequately described the data. Population estimates for clearance (CL), central volume (V ₁), peripheral volume (V ₂), inter‐compartmental clearance, maximum elimination capacity (VM) and concentration at half‐maximum elimination capacity were 0.135 l day^–1, 2.71 l, 1.98 l, 0.371 l day^–1, 8.03 μg day^–1 and 27.7 ng ml^–1, respectively. Inter‐individual variability (IIV) was included on CL, V ₁, V ₂ and VM. A mixture model accounted for the distribution of residual error. While gender, dose and creatinine clearance were significant covariates, only body weight as a covariate of CL, V ₁ and V ₂ significantly reduced IIV.ConclusionsThe small increase in variability associated with fixed dosing is consistent with other monoclonal antibodies and does not change risk : benefit.     

基于证候要素的中风辨证论治

中风病是临床的常见病、多发病。本病病因较多,病情变化迅速,证型繁杂,不同的文献中证候分类差异较大。证候分类的繁杂给临床工作者治疗中风病带来极大不便。本文对以证候要素(内风、内火、痰湿、瘀血、气虚、阴虚)为切入点论治中风病的理论进行探讨,并举例论证其临床疗效。     

疏肝健脾法治疗腹泻型肠易激综合征1例

肠易激综合征（IBS）是一种常见的功能性疾病，中医病名为"肠郁"。郭朋教授根据IBS生理、病理特点，以疏肝健脾法调和肝脾，辨证施治，取得良好疗效。文章从病因病机、辨证论治及经典案例介绍等几个方面对郭教授治疗IBS经验进行系统阐述，以期为中医药治疗IBS提供理论和方法学参考。     

脉络学说营卫理论指导心律失常辨证论治

经脉包括经(气)络和血(脉)络,清代周学海《读医随笔》将气络末端称为"气之细络",脉络末端称为"血之细络"。心之气络涵盖心脏起搏与传导系统等广泛调控机制,心之脉络涵盖冠状动脉循环系统,心之气络与脉络相互协调,营卫相偕而行,共同维持心脏正常功能。各种致病因素导致营卫异常而发为心律失常,基于脉络学说营卫理论"损其心者,调其营卫"(《难经·十四难》)治疗原则指导心律失常辨证论治,同时充分结合现代致病因素和致病特点,分别选用调节卫气营血之方药,标本兼治,以期为临床诊疗提供有益借鉴。     

Systematic review of drug–drug interactions between rifamycins and anticoagulant and antiplatelet agents and considerations for management

Rifamycins (rifampin, rifabutin, and rifapentine) play an essential role in the treatment of mycobacterial and some nonmycobacterial infections. They also induce the activity of various drug transporting and metabolizing enzymes, which can impact the concentrations and efficacy of substrates. Many anticoagulant and antiplatelet (AC/AP) agents are substrates of these enzymes and have narrow therapeutic indices, leading to risks of thrombosis or bleeding when coadministered with rifamycins. The objective of this systematic review was to evaluate the effects on AC/AP pharmacokinetics, laboratory markers, and clinical safety and efficacy of combined use with rifamycins. A systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidance was performed. The PubMed, Embase, and Web of Science databases were queried for English-language reports on combination use of rifamycins and AC/AP agents from database inception through August 2021. The 29 studies identified examined warfarin (n = 17), direct oral anticoagulants (DOACs) (n = 8), and antiplatelet agents (n = 4) combined with rifampin (n = 28) or rifabutin (n = 1). Eleven studies were case reports or small case series; 14 reported on pharmacokinetic or laboratory markers in healthy volunteers. Rifampin-warfarin combinations led to reductions in warfarin area under the curve (AUC) of 15%–74%, with variability by warfarin isomer and study. Warfarin dose increases of up to 3–5 times prerifampin doses were required to maintain coagulation parameters in the therapeutic range. DOAC AUCs were decreased by 20%–67%, with variability by individual agent and with rifampin versus rifabutin. The active metabolite of clopidogrel increased substantially with rifampin coadministration, whereas prasugrel was largely unaffected and ticagrelor saw decreases. Our review suggests most combinations of AC/AP agents and rifampin are problematic. Further studies are required to determine whether rifabutin or rifapentine could be safe alternatives for coadministration with AC/AP drugs.     

Parts‐based representations of perceived face movements in the superior temporal sulcus

Facial motion is a primary source of social information about other humans. Prior fMRI studies have identified regions of the superior temporal sulcus (STS) that respond specifically to perceived face movements (termed fSTS), but little is known about the nature of motion representations in these regions. Here we use fMRI and multivoxel pattern analysis to characterize the representational content of the fSTS. Participants viewed a set of specific eye and mouth movements, as well as combined eye and mouth movements. Our results demonstrate that fSTS response patterns contain information about face movements, including subtle distinctions between types of eye and mouth movements. These representations generalize across the actor performing the movement, and across small differences in visual position. Critically, patterns of response to combined movements could be well predicted by linear combinations of responses to individual eye and mouth movements, pointing to a parts‐based representation of complex face movements. These results indicate that the fSTS plays an intermediate role in the process of inferring social content from visually perceived face movements, containing a representation that is sufficiently abstract to generalize across low‐level visual details, but still tied to the kinematics of face part movements.