Highly enantioselective Rh-catalyzed asymmetric reductive dearomatization of multi-nitrogen polycyclic pyrazolo[1,5-a]pyrimidines.

A highly enantioselective rhodium-catalyzed reductive dearomatization of 7-substituted pyrazolo[1,5-a]pyrimidines has been realized for the first time by two strategies to afford chiral 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidines with excellent enantioselectivities of up to 98% ee. This method also provides an efficient approach for the synthesis of the powerful BTK inhibitor, zanubrutinib.

Polymyxin B exerts nephrotoxicity effects via inhibition of the Nrf2/NQO1 pathway-mediated antioxidant response.

Polymyxin B (PMB) is a polypeptide antibiotic widely used in treating multidrug-resistant Gram-negative bacteria. However, nephrotoxicity is a serious adverse effect that limits its clinical use. Therefore, clarification of the molecular mechanism of PMB-induced renal injury is essential. Our study aimed to explore possible mechanisms of PMB-induced nephrotoxicity in vivo and in vitro. Mice were treated with PMB to construct the kidney injury model. The antioxidant capacity was assessed by measuring the superoxide dismutase (SOD) and catalase (CAT) activities and the glutathione (GSH) and malondialdehyde (MDA) contents. The pathway of the nuclear factor erythroid 2-related factor 2/NADH quinone oxidoreductase 1 (Nrf2/NQO1) was examined after PMB treatment in NRK-52E cells and mice. Finally, the expressions of genes and proteins (Bax, Bcl-2, Caspase-3, Caspase-9) related to apoptosis were evaluated through quantitative polymerase chain reaction and western blot assay. The study verified PMB-induced nephrotoxicity in mice and NRK-52E cells in a dose- and time-dependent manner. PMB treatment significantly decreased the expression of Nrf2 and its downstream target gene NQO1 and increased the apoptosis-related proteins expression. In summary, our results suggested that PMB-induced oxidative stress damage by inhibiting the Nrf2/NQO1 pathway and promoting apoptosis in kidney tissues.

Potential therapeutic role of pyroptosis mediated by the NLRP3 inflammasome in type 2 diabetes and its complications.

As a new way of programmed cell death, pyroptosis plays a vital role in many diseases. In recent years, the relationship between pyroptosis and type 2 diabetes (T2D) has received increasing attention. Although the current treatment options for T2D are abundant, the occurrence and development of T2D appear to continue, and the poor prognosis and high mortality of patients with T2D remain a considerable burden in the global health system. Numerous studies have shown that pyroptosis mediated by the NLRP3 inflammasome can affect the progression of T2D and its complications; targeting the NLRP3 inflammasome has potential therapeutic effects. In this review, we described the molecular mechanism of pyroptosis more comprehensively, discussed the most updated progress of pyroptosis mediated by NLRP3 inflammasome in T2D and its complications, and listed some drugs and agents with potential anti-pyroptosis effects. Based on the available evidence, exploring more mechanisms of the NLRP3 inflammasome pathway may bring more options and benefits for preventing and treating T2D and drug development.

Does Monitoring Total and Free Polymyxin B1 Plasma Concentrations Predict Polymyxin B-Induced Nephrotoxicity? A Retrospective Study in Critically Ill Patients.

INTRODUCTION: The correlation between total and free polymyxin B (PMB including PMB1 and PMB2) exposure in vivo and acute kidney injury (AKI) remains obscure. This study explores the relationships between plasma exposure of PMB1 and PMB2 and nephrotoxicity, and investigates the risk factors for PMB-induced acute kidney injury (AKI) in critically ill patients. METHODS: Critically ill patients who used PMB and met the criteria were enrolled. The total plasma concentration and plasma binding of PMB1 and PMB2 were analysed by liquid chromatography-tandem mass spectrometry and equilibrium dialysis. RESULTS: A total of 89 patients were finally included, and AKI developed in 28.1% of them. The peak concentration of PMB1 (Cmax (B1)) (adjusted odds ratio (AOR) = 1.68, 95% CI 1.08-2.62, p = 0.023), baseline BUN level (AOR = 1.08, 95% CI 1.01-1.16, p = 0.039) and hypertension (AOR = 3.73, 95% CI 1.21-11.54, p = 0.022) were independent risk factors for PMB-induced AKI. The area under the ROC curve of the model was 0.799. When Cmax (B1) was 5.23 µg/ml or more, the probability of AKI was higher than 50%. The ratio of PMB1/PMB2 decreased after PMB preparation entered into the body. The protein binding rate in critically ill patients indicated significant individual differences. Free Cmax (B) and free Cmax (B1) levels in the AKI group were significantly (p < 0.05) higher than those in the non-AKI group. Total and free concentrations of PMB in patients showed a positive correlation. CONCLUSIONS: Both the ROC curve and logistic regression model showed that Cmax (B1) was a good predictor for the probability of PMB-induced AKI. Early therapeutic drug monitoring (TDM) of PMB should be considered in critically ill patients. Compared with Cmin (B), Cmax (B) and Cmax (B1) may be helpful for the early prediction of PMB-induced AKI in critically ill patients.

Effect of glucagon-like peptide 1 receptor agonists on the renal protection in patients with type 2 diabetes: A systematic review and meta-analysis.

BACKGROUND: Glucagon-like peptide 1(GLP-1) receptor agonists are used in patients with type 2 diabetes as hypoglycemic drugs; a growing body of evidence has clarified their renoprotective benefits. We performed a meta-analysis to summarize the most recent evidence on the renal benefits of GLP-1 receptor agonists from clinical trials of patients with type 2 diabetes. METHODS: This meta-analysis used a fixed-effects model to estimate the risk ratio (RR) with 95% confidence intervals (CIs) to investigate the effect of GLP-1 receptor agonists on the renal protection. The outcomes were a composite renal outcome, estimated glomerular filtration rate (eGFR) decrease, new macroalbuminuria, doubling of serum creatinine, end-stage renal disease (ESRD) and renal death. We also checked the composite renal outcome of the patient subgroups based on the structural source of human GLP-1 or exendin-4. RESULTS: Among the 12 articles screened, seven studies involving 48101 patients met pre-specified criteria and were included. In general, the use of GLP-1 receptor agonists reduced the risk of the composite renal outcome by 17% (RR 0·83 [95% CI 0·79-0·88]; P < 0·00001), with no significant interaction in subgroups analysis (P = 0.66); the risk of new-onset of persistent macroalbuminuria was reduced by 25% (RR 0·75 [95%CI 0·69-0·81]; P < 0·00001) compared to placebo. However, GLP-1 receptor agonists had no significant effect on eGFR decrease (RR 0·92 [95% CI 0·83-1.01]; P = 0·09), doubling of serum creatinine (RR 0·97 [95% CI 0·78-1.21]; P = 0·79), or end-stage renal disease (RR 0·81 [95% CI 0·62-1.06]; P = 0·12) compared to placebo or insulin glargine (AWARD-7) in patients with type 2 diabetes. CONCLUSION: GLP-1 receptor agonists, regardless of their structural homology, have significant benefits in reducing the risk of the composite renal outcome, especially in new macroalbuminuria compared with placebo or insulin glargine in patients with type 2 diabetes.

Nickel-Catalyzed Asymmetric Hydrogenation of γ-Keto Acids, Esters, and Amides to Chiral γ-Lactones and γ-Hydroxy Acid Derivatives.

A highly efficient asymmetric hydrogenation of a series of γ-keto acid derivatives, including γ-keto acids, esters, and amides, using a Ni-(R,R)-QuinoxP* complex as the catalyst has been developed to afford chiral γ-hydroxy acid derivatives with excellent enantioselectivities, up to 99.9% ee. This method provides not only an economical one-pot approach for the synthesis of chiral γ-lactones but also access to (S)-norfluoxetine, an inhibitor of neural serotonin reuptake and an essential intermediate for pharmaceutical synthesis.

Pharmacokinetics and Bioequivalence Studies of Roxatidine Acetate Hydrochloride Sustained-Release Capsule in Healthy Chinese Subjects.

This study aimed to evaluate the bioequivalence between a generic roxatidine acetate hydrochloride (RAH) sustained-release capsule and brand-named formulation (ALTAT) under fasting and fed conditions. An open-label, single-center, randomized 2-period crossover study with a 5-day washout period was conducted. A single oral dose of 75-mg generic RAH sustained-release capsule (test drug) or a commercial capsule (reference drug) was given to healthy volunteers under fasting (n = 36) and fed conditions (n = 36). Blood samples were collected at baseline and during the 24 hours after dosing. The concentrations of roxatidine acetate (ROX) and bioactive metabolite roxatidine in plasma were detected using a validated high-performance liquid chromatography-tandem mass spectrometry method. Pharmacokinetic parameters were analyzed with noncompartmental methods. As prodrug, RAH was dehydrochloric acid to ROX in body and further rapidly converted to roxatidine. Such a rapid metabolism resulted in ROX that was hardly detected in plasma. Active metabolism roxatidine was therefore used to evaluate the pharmacokinetic process. The major pharmacokinetic parameters of roxatidine including peak plasma concentration, area under the plasma concentration-time curve from time 0 to time t, and area under the plasma concentration-time curve from time 0 to infinity were similar between the 2 preparations under fasting and fed conditions. The generic RAH sustained-release capsule is bioequivalent to the reference drug under fasting and fed conditions in healthy Chinese subjects.

Enantioselective Synthesis of Chiral Substituted 2,4-Diketoimidazolidines and 2,5-Diketopiperazines via Asymmetric Hydrogenation.

An enantioselective hydrogenation of 5-alkylidene-2,4-diketoimidazolidines (hydantoins) and 3-alkylidene-2,5-ketopiperazines catalyzed by the Rh/f-spiroPhos complex under mild conditions has been developed, which provides an efficient approach to the highly enantioselective synthesis of chiral hydantoins and 2,5-ketopiperazine derivatives with high enantioselectivities up to 99.9% ee.

Highly Efficient Enantioselective Synthesis of Chiral Sulfones by Rh-Catalyzed Asymmetric Hydrogenation.

A highly efficient and enantioselective Rh-( R, R)-f-spiroPhos complex catalyzed hydrogenation of a series of unsaturated sulfones has been developed. With Rh-( R, R)-f-spiroPhos catalyst under mild conditions, not only the asymmetric hydrogenation of both the 3,3-diaryl and exocyclic α,ß-unsaturated sulfones was first realized with up to 99.9% ee but also 3-alkyl-3-aryl and benzo[ b]thiophene-1,1-dioxides were successfully hydrogenated to the corresponding chiral sulfones with excellent enantioselectivities (up to 99.4% ee) regardless of the steric hindrance, electronic property, and geometry of the substrates. Moreover, this reaction offers a route to ( S)-(+)- ar-turmerone as a spice flavor, which is an important synthetic intermediate of pharmaceuticals.

[Simultaneous determination of 121 veterinary drugs in pork by QuEChERS and ultra performance liquid chromatography-tandem mass spectrometry].

A method has been developed for the simultaneous determination of the 10 kinds of 121 veterinary drugs (including chloramphenicols, ß-agonists, sulfonamides, 4-quinolones, nitroimidazoles, macrolides, avermections, polyether antibiotics, tetracycline antibiotics, cephalosporins, etc.) in pork using QuEChERS method coupled with ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The drugs were extracted with Na2EDTA-McIlvaine buffer solution (pH = 4) and acetonitrile. Anhydrous sodium sulfate was used for the salting-out process. The solutions divided into two groups were cleaned-up by different mixed sorbents. The drugs were analyzed by UPLC-MS/MS in multiple reaction monitoring (MRM) mode via electrospray ionization. Among the 121 drugs, 5 drugs were quantified by internal standard method, and the other 116 drugs were quantified by external standard method. The calibration curves of the 121 drugs were linear in the range of 0.02-40 µg/L with the correlation coefficients more than 0.99. The limits of quantification (LOQs, S/N = 10) were 0.05-10 µg/kg. The average recoveries of 8 drugs at LOQ level in pork ranged from 41.7% to 59.6% with the relative standard deviations (RSDs) of 1.7% - 13.5%. The average recoveries of 10 drugs at LOQ level in pork ranged from 122.6% to 163.2% with the RSDs of 0.6% -14.8%. The average recoveries of 103 drugs at LOQ level in pork ranged from 60.3% to 118.3% with the RSDs of 0.4% - 16.7%. The proposed method is rapid, simple, sensitive, reliable and cost-effective.