Pharmacokinetic/Pharmacodynamic Modeling of a Cell-Penetrating Peptide Phosphorodiamidate Morpholino Oligomer in mdx Mice.

PURPOSE: Peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) have shown promise in treating Duchenne muscular dystrophy (DMD). We evaluated a semi-mechanistic pharmacokinetic (PK) and pharmacodynamic (PD) model to capture the relationship between plasma and muscle tissue exposure/response in mdx mice treated by mouse surrogate PPMO. METHODS: A single or repeated (every 4 weeks for 20 weeks) intravenous PPMO dose was administered to mdx mice (n = 6/timepoint). A PK/PD model was built to characterize data via sequential modeling. A 2-compartment model was used to describe plasma PK. A simultaneous tissue PK/PD model was subsequently developed: 2-compartment model to describe muscle PK; linked to an indirect response model describing stimulation of synthesis of skipped transcript, which was in turn linked to stimulation of synthesis of dystrophin protein expression. RESULTS: Model performance assessment via goodness-of-fit plots, visual predictive checks, and accurate parameter estimation indicated robust fits of plasma PK and muscle PK/PD data. The model estimated a PPMO tissue half-life of 5 days-a useful parameter in determining the longevity of PPMOs in tissue and their limited accumulation after multiple doses. Additionally, the model successfully described dystrophin expression after single dosing and associated protein accumulation after multiple dosing (increasing ~ twofold accumulation from the first to last dose). CONCLUSIONS: This first PK/PD model of a PPMO in a DMD disease model will help characterize and predict the time course of PK/PD biomarkers in mdx mice. Furthermore, the model framework can be used to develop clinical PK/PD models and can be extended to other exon-skipping therapies and species.

Substituted diaryl ether compounds as retinoic acid-related orphan Receptor-γt (RORγt) agonists.

The discovery of a series of substituted diarylether compounds as retinoic acid related orphan receptor γt (RORγt) agonists is described. Compound 1 was identified from deck mining as a RORγt agonist. Hit-to-lead optimization led to the identification of lead compound 5, which possesses improved potency (10x). Extensive SAR exploration led to the identification of a potent and selective compound 22, that demonstrated an improved pharmacokinetic profile and a dose-dependent pharmacodynamic response. However, when dosed in a MC38 syngeneic tumor model, no evidence of efficacy was observed. ©2020 Elsevier Science Ltd. All rights reserved.

Substituted benzyloxytricyclic compounds as retinoic acid-related orphan receptor gamma t (RORγt) agonists.

Substituted benzyloxy aryl compound 2 was identified as an RORγt agonist. Structure based drug design efforts resulted in a potent and selective tricyclic compound 19 which, when administered orally in an MC38 mouse tumor model, demonstrated a desired pharmacokinetic profile as well as a dose-dependent pharmacodynamic response. However, no perceptible efficacy was observed in this tumor model at the doses investigated.

Identification of bicyclic hexafluoroisopropyl alcohol sulfonamides as retinoic acid receptor-related orphan receptor gamma (RORγ/RORc) inverse agonists. Employing structure-based drug design to improve pregnane X receptor (PXR) selectivity.

We disclose the optimization of a high throughput screening hit to yield benzothiazine and tetrahydroquinoline sulfonamides as potent RORγt inverse agonists. However, a majority of these compounds showed potent activity against pregnane X receptor (PXR) and modest activity against liver X receptor α (LXRα). Structure-based drug design (SBDD) led to the identification of benzothiazine and tetrahydroquinoline sulfonamide analogs which completely dialed out LXRα activity and were less potent at PXR. Pharmacodynamic (PD) data for compound 35 in an IL-23 induced IL-17 mouse model is discussed along with the implications of a high Ymax in the PXR assay for long term preclinical pharmacokinetic (PK) studies.

Metabolite Kinetics: The Segregated Flow Model for Intestinal and Whole Body Physiologically Based Pharmacokinetic Modeling to Describe Intestinal and Hepatic Glucuronidation of Morphine in Rats In Vivo.

We used the intestinal segregated flow model (SFM) versus the traditional model (TM), nested within physiologically based pharmacokinetic (PBPK) models, to describe the biliary and urinary excretion of morphine 3ß-glucuronide (MG) after intravenous and intraduodenal dosing of morphine in rats in vivo. The SFM model describes a partial (5%-30%) intestinal blood flow perfusing the transporter- and enzyme-rich enterocyte region, whereas the TM describes 100% flow perfusing the intestine as a whole. For the SFM, drugs entering from the circulation are expected to be metabolized to lesser extents by the intestine due to the segregated flow, reflecting the phenomenon of shunting and route-dependent intestinal metabolism. The poor permeability of MG crossing the liver or intestinal basolateral membranes mandates that most of MG that is excreted into bile is hepatically formed, whereas MG that is excreted into urine originates from both intestine and liver metabolism, since MG is effluxed back to blood. The ratio of MG amounts in urine/bile [Formula: see text] for intraduodenal/intravenous dosing is expected to exceed unity for the SFM but approximates unity for the TM. Compartmental analysis of morphine and MG data, without consideration of the permeability of MG and where MG is formed, suggests the ratio to be 1 and failed to describe the kinetics of MG. The observed intraduodenal/intravenous ratio of [Formula: see text] (2.55 at 4 hours) was better predicted by the SFM-PBPK (2.59 at 4 hours) and not the TM-PBPK (1.0), supporting the view that the SFM is superior for the description of intestinal-liver metabolism of morphine to MG. The SFM-PBPK model predicts an appreciable contribution of the intestine to first pass M metabolism.

Vitamin D receptor activation induces P-glycoprotein and increases brain efflux of quinidine: an intracerebral microdialysis study in conscious rats.

PURPOSE: Since the vitamin D receptor (VDR) was found to up-regulate cerebral P-glycoprotein expression in vitro and in mice, we extend our findings to rats by assessing the effect of rat Vdr activation on brain efflux of quinidine, a P-gp substrate that is eliminated primarily by cytochrome P450 3a. METHODS: We treated rats with vehicle or the active VDR ligand, 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] (4.8 or 6.4 nmol/kg i.p. every 2nd day × 4) and examined P-gp expression and cerebral quinidine disposition via microdialysis in control and treatment studies conducted longitudinally in the same rat. RESULTS: The 6.4 nmol/kg 1,25(OH)2D3 dose increased cerebral P-gp expression 1.75-fold whereas hepatic Cyp3a remained unchanged. Although there was no change in systemic clearance elicited by 1,25(OH)2D3, brain extracellular fluid quinidine concentrations were lower in treated rats. We noted that insertion of indwelling catheters increased plasma protein binding of quinidine and serial sampling decreased the blood:plasma concentration ratio, factors that alter distribution ratios in microdialysis studies. After appropriate correction, KECF/P,uu and KECF/B,uu, or ratios of quinidine unbound concentrations in brain extracellular fluid to plasma or blood at steady-state, were more than halved. CONCLUSION: We demonstrate that VDR activation increases cerebral P-gp expression and delimits brain penetration of P-gp substrates.

Facile Preparation of Polysiloxane-Modified Asphalt Binder Exhibiting Enhanced Performance.

The development of polymer-modified asphalt (asphalt = asphalt binder) is significant because the polymer modifier can improve the performance of asphalt mixture and meet the requirements of the modern asphalt pavement. Herein, we present a novel polysiloxane-modified asphalt with enhanced performance, formed by simply mixing hydroxy-terminated polysiloxane (HO-PDMS) into base asphalt at 140 °C. The interaction mechanism of HO-PDMS in base asphalt was characterized by FT-IR, GPC, and DSC. It reveals that HO-PDMS polymers have been chemically bonded into the asphalt, and, thus, the resultant asphalt exhibits optimal compatibility and storage stability. The results based on fluorescence microscopy and a segregation test prove that HO-PDMS has good compatibility with base asphalt. Moreover, by virtue of the intriguing properties of polysiloxane, the present asphalt possesses improved low- and high-temperature properties, higher thermal stability, and enhanced hydrophobicity compared to conventional asphalt when using an appropriate dosage of HO-PDMS. DSC indicated that the Tg of modified asphalt (-12.8 °C) was obviously lower than that of base asphalt (-7.1 °C). DSR shows that the rutting parameter of modified asphalt was obviously higher than that of base asphalt. BBR shows that modified asphalt exhibited the lowest stiffness modulus and the highest creep rate with an HO-PDMS dosage of 6% and 4%, respectively. These results demonstrate that polysiloxane-modified asphalt can be promisingly utilized in realistic asphalt pavement with specific requirements, particularly high-/low-temperature resistance.

Effect of Graphene on Modified Asphalt Microstructures Based on Atomic Force Microscopy.

Atomic force microscopy (AFM) was used to explore the effects of graphene modifier on the microstructure of asphalt. The morphologies of the before- and after-aged base asphalt and modified asphalt were performed and compared with analysis. The formation mechanism of asphaltic "bee structures" and the influence mechanism of graphene on asphalt were discussed from the classical theory of material science (phase transformation theory and diffusion theory). The results show that graphene facilitates the nucleation of "bee structures", resulting in an increasing number and decreasing volume of "bee structures" in modified asphalt. Additionally, the anti-aging performance of the modified asphalt improved significantly because of graphene incorporation.

Ribavirin Treatment for Critically Ill COVID-19 Patients: An Observational Study.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has spread all over the world resulting in high mortality, yet no specific antiviral treatment has been recommended. METHODS: A retrospective descriptive study was conducted involving 19 consecutive critically ill patients during January 27, 2020 to April 18, 2020. Ribavirin was given at 0.15g q8h orally upon ICU admission for 7 to 21 days. Here, 28-day mortality, lower respiratory tract specimens (ETA), and ribavirin side effect on the day of ICU admission (Day 1), Day 7, Day 14 and Day 21 were analyzed. RESULTS: All the nineteen critically ill COVID-19 patients (14 males and 5 females, median age 56yr) survived through to the 28th day of observations with 6 patients (31.58%) being discharged from the ICU. The SARS-CoV-2 viral positivity in sputum/ETA was 100% (19/19) on Day 1, 73.68% (14/19) on Day 7, 57.89% (11/19) on Day 14 and 36.84% (7/19) on Day 21. Ribavirin side effect was not observed in these patients. CONCLUSION: Ribavirin is well tolerated in critically ill patients with COVID-19 and may benefit COVID-19 patients through increasing the virus clearance.

The Prevalence, Risk Factors, and Prognosis of Acute Kidney Injury After Lung Transplantation: A Single-Center Cohort Study in China.

PURPOSE: The aim of this study is to evaluate the incidence, risk factors, and prognosis of acute kidney injury (AKI) after lung transplantation (LTx). METHODS: Records of patients who underwent LTx in a single center were retrospectively reviewed. The prevalence of post-transplant AKI, the use of continuous renal replacement therapy (CRRT), and the risk factors for AKI were investigated. The effects of AKI and CRRT on short-term outcomes and long-term survival were measured. RESULTS: This study included 148 patients, 67 of which developed postoperative AKI. Of these, 31 patients underwent CRRT; the percentage of cases with no AKI was 6.2%, and the percentage of cases with stage 1, 2, and 3 who used CRRT was 0%, 10%, and 86.2%, respectively. Patients with AKI had significantly higher intensive care unit mortality and in-hospital mortality. The 1-year post-LTx survival rate of patients with AKI was 47.8%, significantly lower than those without AKI (74.1%). There was no difference in 1-year survival rate of those with stage 1 and stage 2 AKI, but patients with stage 3 AKI showed the worst survival. Patients who underwent CRRT had an inferior survival outcome (9.7% vs 76.1%, P < .05). We found that higher acute physiologic assessment and chronic health evaluation (APACHE) II scores (odds ratio [OR] 1.082, P = .009) and higher intraoperative fluid balance (OR 1.001, P = .012) were independent risk factors, and female sex (OR 2.539) and pulmonary hypertension (OR 2.869) were potential risk factors for post-LTx AKI. A prediction model integration of the above factors showed a good concordance with actual risks and had a concordance index (C-index) of 0.76 (95% confidence interval [CI], 0.66-0.87). CONCLUSION: Severe AKI requiring CRRT had a negative impact on the short-term and long-term outcomes of patients.

Quantification of surrogate monoclonal antibodies in mouse serum using LC-MS/MS.

Background: Surrogate monoclonal antibodies (mAbs) used in preclinical in vivo studies can be challenging to quantify due to lack of suitable immunoaffinity reagents or unavailability of the mAb protein sequence. Generic immunoaffinity reagents were evaluated to develop sensitive LC-MS/MS assays. Peptides of unknown sequence can be used for selective LC-MS quantification. Results: anti-mouse IgG1 was found to be an effective immunoaffinity reagent, enabling quantification of mouse IgG1 mAbs in mouse serum. Selective peptides of unknown sequence were applied for multiplex LC-MS quantification of two rat mAbs co-dosed in mouse. Conclusion: Generic anti-mouse IgG subtype-specific antibodies can be used to improve assay sensitivity and peptides of unknown sequence can be used to quantify surrogate mAbs when the mAb protein sequence in unavailable.

Population Pharmacokinetic Analysis of BMS-986166, a Novel Selective Sphingosine-1-Phosphate-1 Receptor Modulator, and Exposure-Response Assessment of Lymphocyte Counts and Heart Rate in Healthy Participants.

Sphingosine-1-phosphate (S1P) binding to the S1P-1 receptor (S1P1R) controls the egress of lymphocytes from lymphoid organs and targets modulation of immune responses in autoimmune diseases. Pharmacologic modulation of S1P receptors has been linked to heart rate reduction. BMS-986166, a prodrug of the active phosphorylated metabolite BMS-986166-P, presents an improved cardiac safety profile in preclinical studies compared to other S1P1R modulators. The pharmacokinetics, safety, and pharmacodynamics of BMS-986166 versus placebo after single (0.75-5.0 mg) and repeated (0.25-1.5 mg/day) oral administration were assessed in healthy participants after a 1-day lead-in placebo period. A population model was developed to jointly describe BMS-986166 and BMS-986166-P pharmacokinetics and predict individual exposures. Inhibitory sigmoid models described the relationships between average daily BMS-986166-P concentrations and nadir of time-matched (day -1) placebo-corrected heart rate on day 1 (nDDHR, where DD represents ∆∆) and nadir of absolute lymphocyte count (nALC). Predicted decreases in nDDHR and nALC were 9 bpm and 20% following placebo, with maximum decreases of 10 bpm in nDDHR due to drug effect, and approximately 80% in nALC due to drug and placebo. A 0.5-mg/day dose regimen achieves the target 65% reduction in nALC associated with a 2-bpm decrease in nDDHR over placebo.

Bicyclic Ligand-Biased Agonists of S1P1: Exploring Side Chain Modifications to Modulate the PK, PD, and Safety Profiles.

Sphingosine-1-phosphate (S1P) binds to a family of sphingosine-1-phosphate G-protein-coupled receptors (S1P1-5). The interaction of S1P with these S1P receptors has a fundamental role in many physiological processes in the vascular and immune systems. Agonist-induced functional antagonism of S1P1 has been shown to result in lymphopenia. As a result, agonists of this type hold promise as therapeutics for autoimmune disorders. The previously disclosed differentiated S1P1 modulator BMS-986104 (1) exhibited improved preclinical cardiovascular and pulmonary safety profiles as compared to earlier full agonists of S1P1; however, it demonstrated a long pharmacokinetic half-life (T1/2 18 days) in the clinic and limited formation of the desired active phosphate metabolite. Optimization of this series through incorporation of olefins, ethers, thioethers, and glycols into the alkyl side chain afforded an opportunity to reduce the projected human T1/2 and improve the formation of the active phosphate metabolite while maintaining efficacy as well as the improved safety profile. These efforts led to the discovery of 12 and 24, each of which are highly potent, biased agonists of S1P1. These compounds not only exhibited shorter in vivo T1/2 in multiple species but are also projected to have significantly shorter T1/2 values in humans when compared to our first clinical candidate. In models of arthritis, treatment with 12 and 24 demonstrated robust efficacy.

Interplay of phase II enzymes and transporters in futile cycling: influence of multidrug resistance-associated protein 2-mediated excretion of estradiol 17beta-D-glucuronide and its 3-sulfate metabolite on net sulfation in perfused TR(-) and Wistar rat liver preparations.

The hepatic disposition of estradiol 17beta-D-glucuronide (E(2)17G), a substrate of the organic anion-transporting polypeptides Oatp1a1, Oatp1a4, and Oatp1b2, was investigated in Wistar and TR(-) [multidrug resistance-associated protein (Mrp) 2-mutant] rats to elucidate how absence of Mrp2, the major excretory transporter for both E(2)17G and its 3-sulfate metabolite (E(2)3S17G), affected the net sulfation. With absence of Mrp2, lower microsomal desulfation activity and higher Mrp3 but unchanged immunoreactive protein expression of other transporters (Oatps and Mrp4) and estrogen sulfotransferase were found in TR(-) rats. In recirculating, perfused liver preparations, the rapid decay of E(2)17G and sluggish appearance of low levels of E(2)3S17G in perfusate for Wistar livers were replaced by a protracted, biexponential decay of E(2)17G and greater accumulation of E(2)3S17G, whose levels reached plateaus upon the almost complete obliteration of biliary excretion of E(2)17G and E(2)3S17G in the TR(-) liver. Much higher amounts of E(2)17G (28x) and E(2)3S17G (11x) in liver and reduced net sulfation (40 +/- 6 from 77 +/- 6% dose, P < 0.05) were observed at 2 h for the TR(-) versus the Wistar rats. With use of a physiologically based pharmacokinetic model, analytical solutions for the areas under the curve for the precursor and metabolite were obtained to reveal how enzyme- and transporter-mediated processes affected the hepatic disposition of the precursor and metabolite in futile cycling. The analytical solutions were useful to explain transporter-enzyme interplay in futile cycling and predicted that a shutdown of Mrp2 function led to decreased net sulfation of E(2)17G by raising the intracellular concentration of the metabolite, E(2)3S17G, which readily refurnished E(2)17G via desulfation.

Physiological modeling to understand the impact of enzymes and transporters on drug and metabolite data and bioavailability estimates.

PURPOSE: To obtain mathematical solutions that correlate drug and metabolite exposure and systemic bioavailability (F (sys)) with physiological determinants, transporters and enzymes. METHODS: A series of physiologically-based pharmacokinetic (PBPK) models that included renal excretion and sequential metabolism within the intestine and/or liver as metabolite formation organs were developed. The area under the curve for drug (AUC) and formed metabolite (AUC{mi,P}) were solved by matrix inversion. RESULTS: The PBPK models revealed that AUC{mi,P} was dependent on dispositional parameters (transport and elimination) for the drug and metabolite. The solution was unique for each metabolite formation organ and was dependent on the type of drug and metabolite elimination organs. The AUC ratio of the formed metabolite after oral and intravenous drug dosing was useful for determination of the fraction absorbed (F (abs)) and not the systemic bioavailability (F (sys)) when either intestine or liver was the only drug elimination organ. CONCLUSIONS: The AUC ratio of the formed metabolite after oral and intravenous drug dosing differed from that for drug and would not provide F (sys). However, the AUC ratio of the formed metabolite for oral and intravenous drug dosing furnished the estimate of F (abs) when intestine or liver was the only drug metabolic organ.

Effects of 1alpha,25-dihydroxyvitamin D3 on transporters and enzymes of the rat intestine and kidney in vivo.

1alpha,25-Dihydroxyvitamin D3 (1,25(OH)2D3), the natural ligand of the vitamin D receptor (VDR), was found to regulate bile acid related transporters and enzymes directly and indirectly in the rat intestine and liver in vivo. The kidney is another VDR-rich target organ in which VDR regulation on xenobiotic transporters and enzymes is ill-defined. Hence, changes in protein and mRNA expression of nuclear receptors, transporters and enzymes of the rat intestine and kidney in response to 1,25(OH)2D3 treatment (0 to 2.56 nmol/kg/day intraperitoneally in corn oil for 4 days) were studied. In the intestine, protein and not mRNA levels of Mrp2, Mrp3, Mrp4 and PepT1 in the duodenum and proximal jejunum were induced, whereas Oat1 and Oat3 mRNA were decreased in the ileum after 1,25(OH)2D3 treatment. In the kidney, VDR, Cyp24, Asbt and Mdr1a mRNA and protein expression increased significantly (2- to 20-fold) in 1,25(OH)2D3-treated rats, and a 28-fold increase of Cyp3a9 mRNA but not of total Cy3a protein nor Cyp3a1 and Cyp3a2 mRNA was observed, implicating that VDR played a significant, renal-specific role in Cyp3a9 induction. Additionally, renal mRNA levels of PepT1, Oat1, Oat3, Ostalpha, and Mrp4, and protein levels of PepT1 and Oat1 were decreased in a dose-dependent manner, and the approximately 50% concomitant reduction in FXR, SHP, HNF-1alpha and HNF-4alpha mRNA expression suggests the possibility of cross-talk among the nuclear receptors. It is concluded that the effects of 1,25(OH)2D3 changes are tissue-specific, differing between the intestine and kidney which are VDR-rich organs.

Texture recognition of pulmonary nodules based on volume local direction ternary pattern.

In recent years, the incidence of lung cancer has been increasing. Lung cancer detection is based on computed tomography (CT) imaging of the lung area to determine whether there are pulmonary nodules. And then judge what's good and what's bad. However, due to the traditional way of manual reading and lack of experience and other problems. This leads to visual fatigue and misdiagnosis and missed diagnosis. In order to detect pulmonary nodules early and accurately, a new assistant diagnosis method for pulmonary nodules is proposed. Firstly, the image is preprocessed and denoised by median filter, the lung parenchyma is segmented by random walk algorithm and the region of interest is extracted, and then, according to the continuity of the CT slices, the texture feature extraction method of pulmonary nodules based on volume local direction ternary pattern is used to extract the features. Finally, the pulmonary nodules are identified and classified by the assistant diagnosis model of pulmonary nodules based on Stacking algorithm. In order to illustrate the validity of the diagnosis model, the experiments are carried out by cross-validation of ten folds. Experiments using data from LIDC database show that the accuracy, sensitivity and specificity of the proposed method are 82.2%, 85.7%, and 78.8%, respectively. Texture Recognition method based on volume vocal direction ternary pattern is feasible for the identification of pulmonary nodules and provides a reference value for doctor-assisted diagnosis.

A Nonenzymatic Glucose Sensor Platform Based on Specific Recognition and Conductive Polymer-Decorated CuCo2O4 Carbon Nanofibers.

CuCo2O4 decoration carbon nanofibers (CNFs) as an enzyme-free glucose sensor were fabricated via electrospinning technology and carbonization treatment. The CNFs with advantages of abundant nitrogen amounts, porosity, large surface area, and superior electrical conductivity were used as an ideal matrix for CuCo2O4 decoration. The resultant CuCo2O4-CNF hybrids possessed favorable properties of unique three-dimensional architecture and good crystallinity, accompanied by the CuCo2O4 nanoparticles uniformly growing on the CNF skeleton. To further enhance the selective molecular recognition capacity of the developed sensor, a conductive film was synthesized through the electropolymerization of thiophene and thiophene-3-boronic acid (TBA). Based on the synergistic effects of the performances of CNFs, CuCo2O4 nanoparticles, and boronic acid-decorated polythiophene layer, the obtained poly(thiophene-3-boronic acid) (PTBA)/CuCo2O4-CNF-modified electrodes (PTBA/CuCo2O4-CNFs/glassy carbon electrode (GCE)) displayed prominent electrocatalytic activity toward electro-oxidation of glucose. The fabricated sensor presented an outstanding performance in the two linear ranges of 0.01-0.5 mM and 0.5-1.5 mM, with high selectivity of 2932 and 708 µA·mM-1·cm-2, respectively. The composite nanofibers also possessed good stability, repeatability, and excellent anti-interference selectivity toward the common interferences. All these results demonstrate that the proposed composite nanofibers hold great potential in the application of constructing an enzyme-free glucose sensing platform.

Modeling and Simulation of the Pharmacokinetics and Target Engagement of an Antagonist Monoclonal Antibody to Interferon-γ-Induced Protein 10, BMS-986184, in Healthy Participants to Guide Therapeutic Dosing.

BMS-986184 is a human, second-generation, anti-interferon-γ-induced protein 10 (IP-10) monoclonal antibody. In this study the pharmacokinetics and target engagement (TE) of BMS-986184 in healthy participants were characterized using population-based target-mediated drug disposition (TMDD) modeling and data from a first-in-human study (NCT02864264). The results of the first-in-human study and the model generated were used to conduct stochastic simulations of a virtual population of healthy participants to predict pharmacokinetic exposures and TE responses for different dosage regimens. A 2-compartment, 2-target, TMDD structural model, assuming quasi-steady-state and stimulated production on treatment, was developed by simultaneous fitting of the total drug, serum-free IP-10, and serum total IP-10 concentration data, with the second unobservable target contribution to drug elimination described by the Michaelis-Menten elimination term. Model evaluation confirmed agreement between model predictions and observed data. Simulation of a virtual population of healthy individuals demonstrated that steady state was reached at the eighth dosing interval, and that around 150 mg subcutaneously every other week could be a suitable target dosage regimen for future clinical trials. Integrated modeling strategies such as this can be used to help guide rational clinical trial development of drugs with TMDD, leading to improved dose selection and greater patient benefits.

Mesenteric Lymph Duct Drainage Attenuates Lung Inflammatory Injury and Inhibits Endothelial Cell Apoptosis in Septic Rats.

The present study was to investigate the effect of mesenteric lymph duct drainage on lung inflammatory response, histological alteration, and endothelial cell apoptosis in septic rats. Animals were randomly assigned into four groups: control, sham surgery, sepsis, and sepsis plus mesenteric lymph drainage. We used the colon ascendens stent peritonitis (CASP) procedure to induce the septic model in rats, and mesenteric lymph drainage was performed with a polyethylene (PE) catheter inserted into mesenteric lymphatic. The animals were sacrificed at the end of CASP in 6 h. The mRNA expression levels of inflammatory mediators were measured by qPCR, and the histologic damage were evaluated by the pathological score method. It was found that mesenteric lymph drainage significantly reduced the expression of TNF-α, IL-1ß, and IL-6 mRNA in the lung. Pulmonary interstitial edema and infiltration of inflammatory cells were alleviated by mesenteric lymph drainage. Moreover, increased mRNA levels of TNF-α, IL-1ß, IL-6 mRNA, and apoptotic rate were observed in PMVECs treated with septic lymph. These results indicate that mesenteric lymph duct drainage significantly attenuated lung inflammatory injury by decreasing the expression of pivotal inflammatory mediators and inhibiting endothelial apoptosis to preserve the pulmonary barrier function in septic rats.