Cost-effectiveness of immune checkpoint inhibition and targeted treatment in combination as adjuvant treatment of patient with BRAF-mutant advanced melanoma.

BACKGROUND: Immune checkpoint inhibitors (ICIs) and targeted treatments have improved the health outcomes of patients with advanced melanoma. However, due to the high cost of novel therapies, it is crucial to evaluate their value by considering both effectiveness and cost. To compare the cost-effectiveness of these novel agents (atezolizumab-vemurafenib-cobimetinib, vemurafenib-plus-cobimetinib, dabrafenib-plus-trametinib, and encorafenib-plus-binimetinib) for first-line treatment of metastatic melanoma with the BRAFV600 mutation. METHODS: A patient-level model was developed to project the health outcomes of 4 strategies for patients with advanced melanoma. We estimated transition probabilities from the IMspire150 (ClinicalTrials.gov, NCT02908672), COMBI-AD (NCT01682083), and COLUMBUS (NCT01909453) trials using a parametric survival model. All health outcomes, including direct cost, quality-adjusted life-years (QALYs) and the incremental cost-effectiveness ratio (ICER), were estimated from the US payer perspective. Lifetime cost, QALYs, life-years (LYs), and ICERs were calculated. Univariable and probabilistic sensitivity analyses were performed to test model robustness, along with multiple scenario analyses. RESULTS: Of the 4 competing strategies, atezolizumab-vemurafenib-cobimetinib produced the best health outcomes, and the vemurafenib-cobimetinib strategy was the least expensive option. Atezolizumab-vemurafenib-cobimetinib, dabrafenib-plus-trametinib, and vemurafenib-cobimetinib formed the cost-effective frontier, indicating that the ordered ICERs were $325,113/QALYs for dabrafenib-plus-trametinib vs. vemurafenib-cobimetinib strategies and $2,247,500/QALYs for atezolizumab-vemurafenib-cobimetinib vs. dabrafenib-plus-trametinib strategies. Encorafenib-plus-binimetinib was dominated by the other 3 competing strategies. The drug price and first-line utility significantly influenced the model utcomes. CONCLUSIONS: For BRAF-mutant advanced melanoma, the vemurafenib-cobimetinib strategy could be considered the most cost-effective treatment at the willingness-to-pay threshold of $150,000.

[In vitro evaluation, cellular uptake and anti-acute myocardial ischemia effect of puerarin PEG-PLGA micelles].

PUE@PEG-PLGA micelles has excellent characteristics such as small particle size, high drug loading and slow drug release. The results of TEM electron microscopy showed that PUE@PEG-PLGA micelles had obvious core-shell structure. The critical micelle concentration(CMC) of PEG-PLGA micelles determined by pyrene assay was about 4.8 mg·L~(-1). Laser confocal experiments showed that PEG-PLGA micelles can enhance the cellular uptake of coumarin-6 and aggregate around the mitochondria; quantitative results of extracellular drug residues also indirectly confirmed that PEG-PLGA micelles can promote cellular uptake of the drug. Acute ischemic myocardial model rats were prepared by coronary artery ligation, and then the model rats were randomly divided into six groups: Sham operation group, model group, puerarin(PUE) group, as well as low-, mid-, and high-dose PUE@PEG-PLGA micelles groups. Drugs were given by iv administration 5 min after the ligation. The ST segment changes in the electrocardiogram were monitored; serum creatine kinase(CK), lactate dehydrogenase(LDH), aspartate aminotransferase(AST), and malondialdehyde(MDA) levels were detected and myocardial infarct size was also measured. Both PUE and PUE@PEG-PLGA micelles can reduce the elevated ST segment, reduce serum CK, LDH, AST and MDA levels, and reduce myocardial infarct size. The efficacy of PUE@PEG-PLGA medium and high dose groups was significantly better than that in the PUE group, and the efficacy in PUE@PEG-PLGA low dose group was basically equivalent to that in the PUE group. PUE@PEG-PLGA micelles can greatly improve the cardiomyocytes uptake of PUE, enhance the anti-acute myocardial ischemia effect of drugs, and reduce its dosage.

Piperazine ferulate ameliorates the development of diabetic nephropathy by regulating endothelial nitric oxide synthase.

Diabetic nephropathy (DN) is among the most common complications of diabetes mellitus. The disorder is associated with a decrease in the activity of the nitric oxide synthase/nitric oxide system. Piperazine ferulate (PF) is widely used for the treatment of kidney disease in China. The aim of the present study was to examine the effects of PF on streptozotocin (STZ)­induced DN and the underlying mechanism of this process. STZ­induced diabetic mice were intragastrically administered PF (100, 200 and 400 mg/kg/body weight/day) for 12 weeks. At the end of the treatment period, the parameters of 24­h albuminuria and blood urea nitrogen, creatinine and oxidative stress levels were measured. Hematoxylin and eosin staining, periodic acid­Schiff staining and electron microscopy were used to evaluate the histopathological alterations. mRNA and protein expression of endothelial nitric oxide synthase (eNOS) were measured by quantitative polymerase chain reaction and western blotting, respectively. PF significantly decreased blood urea nitrogen and creatinine levels and 24­h albuminuria, and it alleviated oxidative stress, improved glomerular basement membrane thickness and caused an upregulation in eNOS expression and activity levels in diabetic mice. In addition, high glucose decreased eNOS expression levels, whereas PF caused a reversal in the nitric oxide (NO) levels of glomerular endothelial cells. The present results suggested that PF exhibited renoprotective effects on DN. The mechanism of its action was associated with the regulation of eNOS expression and activity.

[Protective effect of yixinshu capsule on myocardial ischemia reperfusion injury in rats].

OBJECTIVE: To observe the protective effect of Yixinshu capsule on myocardial ischemia reperfusion injury (MIRI) in SD rats. METHOD: Sixty healthy SD rats were randomized into six groups: sham group, MIRI model group, Xinsuning capsule group, low, middle or high dose Yixinshu capsule. Acute MIRI rat models were created by reperfusion for 120 min after anterior interventricular branch of the left coronary artery for 30 min. The serum creatine kinase (CK), lactic dehydrogenase (LDH), aspartate aminotransferase (AST) and malondialdehyde(MDA), blood viscosity, and infarction area of myocardium were determined. RESULT: Yixinshu capsule could reduce serum CK, LDH, AST and LDH activity, improve the blood viscosity, and reduced the myocardial infarct size. CONCLUSION: Yixinshu capsule can protect against MIRI in rats.

[In vitro dissolution of forsythin in Forsythia suspensa powder of different particle diameter].

OBJECTIVE: To examine the in vitro dissolution of forsythin in Forsythia suspensa powder of different particle diameter, in order to give guidance to the grinding process. METHOD: HPLC was used to determine the in vitro dissolution quantity and dissolution velocity of forsythin coarse powder, fine powder and ultramicroscopic powder. RESULT: The dissolution curves of Forsythia suspensa coarse powder, fine powder and ultramicroscopic powder were basically inconformity to Weibull distribution. Specifically, T50 was 11.8, 10.5 and 6.8 min, respectively, and Q45 was 78.22%, 81.91% and 90.76%, respectively. CONCLUSION: The superfine milling process can significantly increase the dissolution quantity and dissolution velocity of forsythin.

[Stability of PEGylated puerarin under different storage conditions].

OBJECTIVE: To detect the stability of PEGylated puerarin (PEG-PUE), in order to provide experimental basis for storage conditions of PEGylated puerarin. METHOD: First, a method for determining the content of PEG-PUE was established. Next, a system study was conducted for the stability of PEG-PUE affected by different factors such as temperature, humidity, light and light avoidance. RESULT: PEG-PUE was severely degraded under the conditions of high temperature, high humidity and light. It was also seriously degraded under high temperature. CONCLUSION: PEG-PUE shall be stored under low temperature and in a dark and dry environment.