Real world effectiveness of PCSK-9 inhibitors combined with statins versus statins-based therapy among patients with very high risk of atherosclerotic cardiovascular disease in China(RWE-PCSK study)

BACKGROUND The efficacy and safety of proprotein convertase subtilisin/kexin type 9(PCSK-9) inhibitors were confirmed by several clinical trials, but its effectiveness in routine clinical practice in China has not been evaluated. This study aims to describe the real world effectiveness of PCSK-9 inhibitors combined with statins compared with statins-based therapy among patients with very high risk of atherosclerotic cardiovascular disease(ASCVD).METHODS This is a multi-center observational study, enrolled patients from 32 hospitals who underwent percutaneous coronary intervention(PCI) from January to June in 2019. There are 453 patients treated with PCSK-9 inhibitors combined with statins in PCSK-9 inhibitor group and 2,610 patients treated with statins-based lipid lowering therapies in statins-based group. The lipid control rate and incidence of major adverse cardiovascular events(MACE) over six months were compared between two groups.A propensity score-matched(PSM) analysis was used to balance two groups on confounding factors. Survival analysis using Kaplan-Meier methods was applied for MACE.RESULTS In a total of 3,063 patients, 89.91% of patients had received moderate or high-intensity statins-based therapy before PCI, but only 9.47% of patients had low-density lipoprotein cholesterol(LDL-C) levels below 1.4 mmol/L at baseline. In the PSM selected patients, LDL-C level was reduced by 42.57% in PCSK-9 inhibitor group and 30.81%(P < 0.001) in statins-based group after six months. The proportion of LDL-C ≤ 1.0 mmol/L increased from 5.29% to 29.26% in PCSK-9 inhibitor group and 0.23% to 6.11% in statins-based group, and the proportion of LDL-C ≤ 1.4 mmol/L increased from 10.36% to 47.69% in PCSK-9 inhibitor group and 2.99% to 18.43% in statins-based group(P < 0.001 for both). There was no significant difference between PCSK-9 inhibitor and statins-based treatment in reducing the risk of MACE(hazard ratio = 2.52, 95% CI: 0.49-12.97, P = 0.250).CONCLUSIONS In the real world, PCSK-9 inhibitors combined with statins could significantly reduce LDL-C levels among patients with very high risk of ASCVD in China. The long-term clinical benefits for patients received PCSK-9 inhibitor to reduce the risk of MACE is still unclear and requires further study.

The combination therapy of imatinib and dasatinib achieves long-term molecular response in two imatinib-resistant and dasatinibintolerant patients with advanced chronic myeloid leukemia

For patients with chronic myeloid leukemia（CML） failing imatinib therapy,second-generation tyrosine kinase inhibitors（TKIs） are recommended.Here,we describe two patients with advanced CML who failed imatinib therapy and did not tolerate the recommended dose of dasatinib,but then achieved a major molecular response with the combination of imatinib and dasatinib with no significant extramedullar/ toxicity.Our observations suggest that combination of TKIs may provide an additive/synergistic antileukemic effect.

Enhanced inhibition of talc flotation using acidified sodium silicate and sodium carboxymethyl cellulose as the combined inhibitor

The flotation separation of chalcopyrite and talc is challenging due to their similar natural floatability characteristics.Besides,it is usually difficult to effectively inhibit talc by adding sodium carboxymethyl cellulose(CMC)alone during chalcopyrite flotation.Here,a combined inhibitor comprising acidified sodium silicate(ASS)and CMC was employed to realize effective flotation separation of chalcopyrite and talc,and the combined inhibition mechanism was further investigated.Microflotation results showed that adding ASS strengthened the inhibitory effect of CMC on talc and improved the separation of chalcopyrite and talc.The zeta potential,Fourier transform infrared,and X-ray photoelectron spectroscopy analysis indicated that CMC was mainly adsorbed on the talc surface via hydroxyl and carboxyl groups.Moreover,the addition of ASS improved the adsorption of carboxyl groups.Furthermore,the adsorption experiments and apparent viscosity measurements revealed that adding ASS dispersed the pulp well,which reduced the apparent viscosity,improved the adsorption amount of CMC on the talc surface,and enhanced the inhibition of talc in chalcopyrite flotation.

Kinetic hydrate inhibitor performance of new copolymer poly(N-vinyl-2-pyrrolidone-co-2-vinyl pyridine)s with TBAB

In oil and gas field, the application of kinetic hydrate inhibitors （KHIs） independently has remained problematic in high subcooling and high water-cut situation. One feasible method to resolve this problem is the combined use of KHIs and some synergists, which would enhance KHIs’ inhibitory effect on both hydrate nucleation and hydrate crystal growth. In this study, a novel kind of KHI copolymer poly（N-vinyl-2-pyrrolidone-co-2-vinyl pyridine）s （HGs） is used in conjunction with TBAB to show its high performance on hydrate inhibition. The performance of HGs with different monomer ratios in structure II tetrahydrofuran （THF） hydrate is investigated using kinetic hydrate inhibitor evaluation apparatus by step-cooling method and isothermal cooling method. With the combined gas hydrate inhibitor at the concentration of 1.0 wt%, the induction time of 19 wt% THF solution could be prolonged to 8.5 h at a high subcooling of 6℃. Finally, the mechanism of HGs inhibiting the formation of gas hydrate is proposed.

EFFECTS OF BLEOMYCIN A5 COMBINED WITH CALMODU-LIN INHIBITOR ON THE PROLIFERATION OF S-180 CELLS IN VITRO

The effects of bleomycin A5 (BLM A5) alone and combined with calmodulin inhibitor N-(4-aminobutyl)-5-chloro-2-naphthalene sulfonamide (W-13) on the proliferation on S-180 cells in vitro were studied. IC50 of BLM used alone for the cells was about 2.63 μg/ml, but it was reduced to 1/3.8 and 1/9.5 of 2.63 μg/ml when plus W-13 1, 5 μg/ml respectively. The results indicated that nontoxic doses of W-13 enhanced the hinibition of cell proliferation under the condition of BLM 0.5 - 2.5 μg/ ml. In colony forming test, the survival fraction of S-180 cells treated with BLM plus W-13 was decreased to 1/87 - 240 of that of the cells treated with BLM alone. The results suggest that W-13 can enhance antitumor activity of BLM in vitro and may be used as an synergist of BLM A5 in vivo.

Systems analysis of the“weights”of Bcl-2 and Mcl-1 in mitochondrial apoptosis pathway establishes a predictor for best drug combination ratio

Background:Inhibitors of B-cell CLL/Iymphoma 2(Bcl-2)family proteins have shown hope as antitumor drugs.While the notion that it is efficient to coordinate,balance,and neutralize both arms of the anti-apoptotic Bcl-2 family has been validated in many cancer cells,the weights of the two arms contributing to apoptosis inhibition have not been explored.This study analyzed the best combination ratio for different Bcl-2 selective inhibitors.Methods:We used a previously established mathematical model to study the weights of Bcl-2(representing both Bcl-2 and BcI-xL in this study)and myeloid cell leukemia-1(Mcl-1).Correlation and single-parameter sensitivity analysis were used to find the major molecular determinants for Bcl-2 and Mcl-1 dependency,as well as their weights.Biological experiments were used to verify the mathematical model.Results:Bcl-2 protein level and Mcl-1 protein level,production,and degradation rates were the major molecular determinants for Bcl-2 and Mcl-1 dependency.The model gained agreement with the experimental assays for ABT-737/A-1210477 and ABT-737/compound 5 combination effect in MCF-7 and MDA-MB-231.Two sets of equations composed of Bcl-2 and Mcl-1 levels were obtained to predict the best combination ratio for Bcl-2 inhibitors with Mcl-1 inhibitors that stabilize and downregulate Mcl-1,respectively.Conclusions:The two sets of equations can be used as tools to bypass time-consuming and laborious experimental screening to predict the best drug combination ratio for treatment.

Synthesis and application of a novel combined kinetic hydrate inhibitor

In oil and gas exploration and transportation, low dosage hydrate inhibitors （LDHIs） are more favorably utilized to inhibit the formation of hydrates than thermodynamic inhibitors （THs） as a trend. However, there are no industrial products of LDHIs available domestically, and the corresponding application experience is in urgent need. In this paper, a combined hydrate inhibitor （HY-1） was synthesized after a series of reaction condition optimization, and its performance on THF hydrate inhibition was investigated using kinetic hydrate inhibitor evaluation apparatus with 6 cells bathing in air. The results show that when the reaction temperature is 60℃, the reaction time is 6 h, and the monomer： solvent ratio is 1：2, the product has the best kinetic hydrate inhibitor performance on THF hydrate. On these bases, the scale-up production of this combined hydrate inhibitor was carried out. Although the scale-up product （HY-10） performs less effectively on the THF hydrate inhibition than HY-1, it functions better than a commercial product （Inhibex501） during in-house tests. HY-10 was successfully applied to the gas production process. Field trials in northem Shaanxi PetroChina Changqing Oilfield Company （PCOC） show that 2 wt% of HY-10 is effective on natural gas hydrate inhibition. It is found through economic analysis that the use of HY-10 has obvious economi- cal advantage over methanol and Inhibex501.