Renal Protective Effects of Eucommia Glycosides on Renal Hypertension Rats

Objective:To investigate the antihypertensive,antioxidant and renal protective effects of Eulcommia glycosides on renal hypertensive rats with two-kidney and one-clip type.Materials and Methods:A total of 50 healthy male SD rats were fed adaptive for one week,and after 2 weeks of 2 K1 C operation,they were divided into 5 groups:sham operation group,model control group,benazepri group,ulcommin high-dose group and low-dose group,with 8 rats in each group.Rats in each group were given continuously intragastric administration for 4 weeks,and systolic blood pressure of caudal artery was measured before modeling,2 weeks after modeling,and after treatment.Urinary microalbumin(MALB)was measured at 24 hours.Serum AngⅡand ROS were measured by taking blood from abdominal aorta.The right kidney of rats was taken to measure the expression level of NOX4 m RNA and pathological observation by HE staining.Results:Compared with sham operation group,blood pressure,serum AngⅡ,ROS content,NOX4 m RNA expression level and MALB in kidney tissue of model group were significantly increased(P<0.05).Compared with model control group,the above indexes in treatment groups were significantly decreased(P<0.05).There was no statistical significance among all treatment groups(P<0.05).Under light microscope,normal glomeruli and renal tubules were observed in rats of sham operation group.Slight glomerular atrophy and fibrous hyperplasia were observed in the renal tissue of model control rats,and inflammatory cells were observed in renal interstitium.The above symptoms were slightly relieved in the treatment group compared with the model control group.Conclusion:Eucommia glycosides can reduce blood pressure and protect the kidney,and the mechanism may be related to the inhibition of renal oxidation.

Current trends in drug metabolism and pharmacokinetics

Pharmacokinetics(PK)is the study of the absorption,distribution,metabolism,and excretion(ADME)processes of a drug.Understanding PK properties is essential for drug development and precision medication.In this review we provided an overview of recent research on PK with focus on the following aspects:(1)an update on drug-metabolizing enzymes and transporters in the determination of PK,as well as advances in xenobiotic receptors and noncoding RNAs(ncRNAs)in the modulation of PK,providing new understanding of the transcriptional and posttranscriptional regulatory mechanisms that result in inter-individual variations in pharmacotherapy;(2)current status and trends in assessing drug-drug interactions,especially interactions between drugs and herbs,between drugs and therapeutic biologies,and microbiota-mediated interactions:(3)advances in understanding the effects of diseases on PK,particularly changes in metabolizing enzymes and transporters with disease progression;(4)trends in mathematical modeling including physiologically-based PK modeling and novel animal models such as CRISPR/Cas9-based animal models for DMPK studies:(5)emerging non-classical xenobiotic metabolic pathways and the involvement of novel metabolic enzymes,especially non-P450s.Existing challenges and perspectives on future directions are discussed,and may stimulate the development of new research models,technologies,and strategies towards the development of better drugs and improved clinical practice.

Dose selection of chloroquine phosphate for treatment of COVID-19 based on a physiologically based pharmacokinetic model

Chloroquine(CQ)phosphate has been suggested to be clinically effective in the treatment of coronavirus disease 2019(COVID-19).To develop a physiologically-based pharmacokinetic(PBPK)model for predicting tissue distribution of CQ and apply it to optimize dosage regimens,a PBPK model,with parameterization of drug distribution extrapolated from animal data,was developed to predict human tissue distribution of CQ.The physiological characteristics of time-dependent accumulation was mimicked through an active transport mechanism.Several dosing regimens were proposed based on PBPK simulation combined with known clinical exposure-response relationships.The model was also validated by clinical data from Chinese patients with COVID-19.The novel PBPK model allows indepth description of the pharmacokinetics of CQ in several key organs(lung,heart,liver,and kidney),and was applied to design dosing strategies in patients with acute COVID-19(Day 1:750 mg BID,Days 2-5:500 mg BID,CQ phosphate),patients with moderate COVID-19(Day 1:750 mg and 500 mg,Days 2-3:500 mg BID,Days 4-5:250 mg BID,CQ phosphate),and other vulnerable populations(e.g.,renal and hepatic impairment and elderly patients,Days 1-5:250 mg BID,CQ phosphate).A PBPK model of CQ was successfully developed to optimize dosage regimens for patients with COVID-19.

Evaluation of the efficacy and safety of hydroxychloroquine in comparison with chloroquine in moderate and severe patients with COVID-19

Dear Editor,Since December 2019,severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has been rapidly spreading worldwide.Hydroxychloroquine and chloroquine are candidates for the treatment of coronavirus disease 2019(COVID-19)owing to its antiviral effect and immunomodulation properties.

Manganese nanodepot augments host immune response against coronavirus

Interferon(IFN)responses are central to host defense against coronavirus and other virus infections.Manganese(Mn)is capable of inducing IFN production,but its applications are limited by nonspecific distributions and neurotoxicity.Here,we exploit chemical engineering strategy to fabricate a nanodepot of manganese(nanoMn)based on Mn2+.Compared with free Mn2+,nanoMn enhances cellular uptake and persistent release of Mn2+in a pH-sensitive manner,thus strengthening IFN response and eliciting broad-spectrum antiviral effects in vitro and in vivo.Preferentially phagocytosed by macrophages,nanoMn promotes M1 macrophage polarization and recruits monocytes into inflammatory foci,eventually augmenting antiviral immunity and ameliorating coronavirus-induced tissue damage.Besides,nanoMn can also potentiate the development of virus-specific memory T cells and host adaptive immunity through facilitating antigen presentation,suggesting its potential as a vaccine adjuvant.Pharmacokinetic and safety evaluations uncover that nanoMn treatment hardly induces neuroinflammation through limiting neuronal accumulation of manganese.Therefore,nanoMn offers a simple,safe,and robust nanoparticle-based strategy against coronavirus.