Current Research in Pharmacology and Drug Discovery最新文献

Background

Hyperglycemia-induced oxidative stress is a significant contributor to diabetic complications, including hepatopathy. The current survey aimed to evaluate the ameliorative effect of quercetin (Q) on liver functional disorders and tissue damage developed by diabetes mellitus in rats.

Methods

Grouping of 35 male Wistar rats was performed as follows: sham; sham + quercetin (sham + Q: quercetin, 50 mg/kg/day in 1 ml 1% DMSO for 6 weeks, by gavage); diabetic control (Diabetes: streptozotocin (STZ), 65 mg/kg, i.p.); diabetic + quercetin 1 (D + Q1: quercetin, 25 mg/kg/day in 1 ml 1% DMSO for 6 weeks, by gavage after STZ injection); and diabetic + quercetin 2 (D + Q2: quercetin, 50 mg/kg/day in 1 ml 1% DMSO for 6 weeks, by gavage after STZ injection). Body weight, food intake, and water intake were measured. Ultimately, the samples of plasma and urine, as well as tissue samples of the liver and pancreas were gathered for later assays.

Results

STZ injection ended in elevated plasma blood glucose levels, decreased plasma insulin levels, liver dysfunction (increased activity levels of AST, ALT, and ALP, increased plasma levels of total bilirubin, cholesterol, LDL, triglyceride, decreased plasma levels of total protein, albumin and HDL), enhanced levels of malondialdehyde, diminished activities of antioxidant enzymes (superoxide dismutase, and catalase), reduced level of glutathione (GSH) increased gene expression levels of apelin and TGF-ꞵ, plus liver histological destruction. All these changes were diminished by quercetin. However, the measure of improvement in the D + Q2 group was higher than that of the D + Q1 group.

Conclusions

Quercetin improved liver function after diabetes mellitus type 1, possibly due to reduced lipid peroxidation, increased antioxidant systems, and inhibiting the apelin/TGF-ꞵ signaling pathway.

Diabetes mellitus (DM) is a global health burden that is characterized by the loss or dysfunction of pancreatic β-cells. In pancreatic β-cells, endoplasmic reticulum (ER) stress is a fact of life that contributes to β-cell loss or dysfunction. Despite recent advances in research, the existing treatment approaches such as lifestyle modification and use of conventional therapeutics could not prevent the loss or dysfunction of pancreatic β-cells to abrogate the disease progression. Therefore, targeting ER stress and the consequent unfolded protein response (UPR) in pancreatic β-cells may be a potential therapeutic strategy for diabetes treatment. Dietary phytochemicals have therapeutic applications in human health owing to their broad spectrum of biochemical and pharmacological activities. Flavonoids, which are commonly obtained from fruits and vegetables worldwide, have shown promising prospects in alleviating ER stress. Dietary flavonoids including quercetin, kaempferol, myricetin, isorhamnetin, fisetin, icariin, apigenin, apigetrin, vitexin, baicalein, baicalin, nobiletin hesperidin, naringenin, epigallocatechin 3-O-gallate hesperidin (EGCG), tectorigenin, liquiritigenin, and acacetin have shown inhibitory effects on ER stress in pancreatic β-cells. Dietary flavonoids modulate ER stress signaling components, chaperone proteins, transcription factors, oxidative stress, autophagy, apoptosis, and inflammatory responses to exert their pharmacological effects on pancreatic β-cells ER stress. This review focuses on the role of dietary flavonoids as potential therapeutic adjuvants in preserving pancreatic β-cells from ER stress. Highlights of the underlying mechanisms of action are also presented as well as possible strategies for clinical translation in the management of DM.

LNA-i-miR-221 is a novel microRNA(miRNA)-221 inhibitor designed for the treatment of human malignancies. It has recently undergone phase 1 clinical trial (P1CT) and early pharmacokinetics (PKs) data in cancer patients are now available. We previously used multiple allometric interspecies scaling methods to draw inferences about LNA-i-miR-221 PKs in humans and estimated the patient dose based on the safe and pharmacodynamic (PD) active dose observed in mice, therefore providing a framework for the definition of safe starting and escalation doses for the P1CT. The preliminary data collected during the P1CT showed that the LNA-i-miR-221 anticipated doses, according to our human PK estimation approach, were indeed well tolerated and effective. PD data demonstrated concentration-dependent downregulation of miR-221 and upregulation of its CDKN1B/p27 and PTEN canonical targets as well as stable disease in 8 (50.0%) patients and partial response in 1 (6.3%) colorectal cancer case. Here, we detail the experimentally evaluated PK parameters of LNA-i-miR-221 in human, using both a non-compartmental and a population PKs approach. The population approach was adequately described by a three-compartments model with first-order elimination. The recorded age, sex and body weight of patients were evaluated as potential covariates. The estimated typical population parameter values were clearance (CL = 200 mL/h/kg), central volume of distribution (V1 = 45 mL/kg), peripheral volume of distribution (V2 = 200 mL/kg, volume of the second peripheral compartment V3 = 930 mL/h/kg) and inter-compartmental clearance (Q2 = 480 mL/h/kg and Q3 = 68 mL/h/kg). Age was found to be a predictor of Q3, with a statistically significant correlation. This work aimed also at retrospectively comparing the measured plasmatic clearance values with those predicted by different allometric scaling approaches. Our comparative analysis showed that the most accurate prediction was achieved by applying the single species allometric scaling approach and that the use of more than one species in allometric scaling to predict therapeutic oligonucleotides PKs would not necessarily generate the best prediction. Finally, our predictive approach was found accurate not only in predicting the main PK parameters in human but suggesting the range of effective and safe dose to be applied in the next clinic phase 2.

Objectives

The persistence in therapy of rheumatoid arthritis drugs and particularly bDMARD is a limiting factor for their long-term use. The randomized controlled trials (RCTs) may not reflect real-world contexts due to strict inclusion and exclusion criteria. Baricitinib, which targets both JAK1 and JAK2, has been used in Italy for several years. The aim of this multi-center study is to assess the real world persistence on therapy of baricitinib in RA patients and to identify predictive factors of baricitinib's survival rate.

Methods

This is a retrospective, multicentric, Italian, longitudinal study. All patients were enrolled according to the following criteria: a) age ≥ 18 years old; b) diagnosed with RA according 2010 ACR/EULAR classification criteria; c) treated with baricitinib. In order to describe baricitinib clinical efficacy, the survival rate was evaluated by The Kaplan–Meier curve. Then, predictive factors of drug retention rate were assessed by performing the Cox analysis, identifying which risk factors influenced treatment persistence.

Results

Overall, we included 478 patients treated with baricitinib. Among them, 380 (79.5%) were females. Baricitinib's survival rate was 94.6% at 6 months, 87.9% at 12 months, 81.7% at 24 months and 53.4% at 48 months. The Cox analysis regression showed that a higher bDMARDs/tsDMARD line of therapy seems to be a negative prognostic factor for the drug retention rate (HR 1.26 CI 95% 1.07–1.49, p = 0.006.

Conclusion

Real-life study confirms baricitinib effectiveness up to 4 years, but previous treatment with bDMARDs was a negative prognostic factor for its survival rate.