Cardiovascular co-morbidity in chronic kidney disease:Current knowledge and future research needs

Chronic kidney disease(CKD) is recognised as a health concern globally and leads to high rates of morbidity,mortality and healthcare expenditure.CKD is itself an independent risk factor for unfavorable health outcomes that include cardiovascular disease(CVD).Coronary artery disease is the primary type of CVD in CKD patients and a significant cause of death among renal transplant patients.Traditional and non-traditional risk factors for CVD exist in patients with CKD.Traditional factors include smoking,hypertension,dyslipidemia and diabetes which are highly prevalent in CKD patients.Non-traditional risk factors of CKD are mainly uraemiaspecific and increase in prevalence as kidney function declines.Some examples of uraemia-specific risk factors that have been well documented include low levels of haemoglobin,albuminuria,and abnormal bone and mineral metabolism.Therapeutic interventions targeted at more traditional risk factors which contribute to CVD,have not had the desired effect on lowering CVD events and mortality in those suffering with CKD.Future research is warranted to delineate clear evidence to the benefit of modifying non-traditional risk factors.

Pharmacological inhibition of diacylglycerol acyltransferase-1 and insights into postprandial gut peptide secretion

AIM To examine the role that enzyme Acyl-CoA:diacylglycerol acyltransferase-1(DGAT1) plays in postprandial gut peptide secretion and signaling.METHODS The standard experimental paradigm utilized to evaluate the incretin response was a lipid challenge.Following a lipid challenge,plasma was collected via cardiac puncture at each time point from a cohort of 5-8 mice per group from baseline at time zero to 10 h.Incretin hormones [glucagon like peptide-1(GLP-1),peptide tyrosine-tyrosine(PYY) and glucose dependent insulinotropic polypeptide(GIP)] were then quantitated.The impact of pharmacological inhibition of DGAT1 on the incretin effect was evaluated in WT mice.Additionally,a comparison of loss of DGAT1 function either by genetic ablation or pharmacological inhibition.To further elucidate the pathways and mechanisms involved in the incretin response to DGAT1 inhibition,other interventions [inhibitors of dipeptidyl peptidase-IV(sitagliptin),pancreatic lipase(Orlistat),GPR119 knockout mice] were evaluated.RESULTS DGAT1 deficient mice and wildtype C57/BL6J mice werelipid challenged and levels of both active and total GLP-1 in the plasma were increased.This response was further augmented with DGAT1 inhibitor PF-04620110 treated wildtype mice.Furthermore,PF-04620110 was able to dose responsively increase GLP-1 and PYY,but blunt GIP at all doses of PF-04620110 during lipid challenge.Combination treatment of PF-04620110 and Sitagliptin in wildtype mice during a lipid challenge synergistically enhanced postprandial levels of active GLP-1.In contrast,in a combination study with Orlistat,the ability of PF-04620110 to elicit an enhanced incretin response was abrogated.To further explore this observation,GPR119 knockout mice were evaluated.In response to a lipid challenge,GPR119 knockout mice exhibited no increase in active or total GLP-1 and PYY.However,PF-04620110 was able to increase total GLP-1 and PYY in GPR119 knockout mice as compared to vehicle treated wildtype mice.CONCLUSION Collectively,these data provide some insight into the mechanism by which inhibition of DGAT1 enhances intestinal hormone release.

Recent advances in the translation of drug metabolism and pharmacokinetics science for drug discovery and development

Drug metabolism and pharmacokinetics(DMPK) is an important branch of pharmaceutical sciences.The nature of ADME(absorption,distribution,metabolism,excretion) and PK(pharmacokinetics) inquiries during drug discovery and development has evolved in recent years from being largely descriptive to seeking a more quantitative and mechanistic understanding of the fate of drug candidates in biological systems.Tremendous progress has been made in the past decade,not only in the characterization of physiochemical properties of drugs that influence their ADME,target organ exposure,and toxicity,but also in the identification of design principles that can minimize drug-drug interaction(DDI) potentials and reduce the attritions.The importance of membrane transporters in drug disposition,efficacy,and safety,as well as the interplay with metabolic processes,has been increasingly recognized.Dramatic increases in investments on new modalities beyond traditional small and large molecule drugs,such as peptides,oligonucleotides,and antibody-drug conjugates,necessitated further innovations in bioanalytical and experimental tools for the characterization of their ADME properties.In this review,we highlight some of the most notable advances in the last decade,and provide future perspectives on potential major breakthroughs and innovations in the translation of DMPK science in various stages of drug discovery and development.

肺PET图像的定量分析:挑战和机遇

数百万人受呼吸系统疾病的影响,导致巨大的全球性健康困扰。由于目前对导致呼吸系统疾病发展和进展的潜在机制认识不足,治疗选择仍然有限。为克服此局限和理解相关分子变化,将无创影像技术如PET和SPECT用于探索生物标志物,其中18F-脱氧葡萄糖(FDG)PET显像的研究最多。由于肺内组织、气体、血液和水的构成比变异,定量分析肺的分子影像数据仍具挑战性。这些成分的比例随着肺部疾病的不同而不同,因此有不同的定量分析方法来显示这种变化,但迄今为止还没有开发出对数据标准化的方法。该文回顾了肺部疾病中18F-FDG PET定量分析方法的数据,聚焦于解释肺内成分变化的方法,解读衍生参数。分析的疾病包括急性呼吸窘迫综合征、慢性阻塞性肺疾病、肺间质性疾病如特发性肺纤维化。基于对既往文献、进行中的研究以及作者间讨论的回顾,作者提出了建议性的注意事项,以协助解读从这些方法及未来研究设计中衍生的参数。