顶空气相色谱法测定雷诺嗪中5种有机溶剂残留量

目的 采用顶空进样毛细管气相色谱法测定雷诺嗪原料药中甲醇、乙醇、甲苯、二氯甲烷及二氧六环5种有机溶剂的残留量.方法 使用HP-INNOWAX毛细管色谱柱(0.32 mm×30 m×0.25 μm),柱温45 ℃,FID检测器,以水为溶剂,载气为氮气,进样口温度180 ℃,检测器温度250 ℃.结果 5种有机溶剂分离完全,线性范围分别为甲醇3.96～39.6 μg·ml-1,乙醇7.89～78.9 μg·ml-1,二氯甲烷3.34～33.4 μg·ml-1,甲苯11.2～111.8 μg·ml-1,二氧六环8.80～88.0 μg·ml-1.在所考察的浓度范围内线性关系良好,r为0.9 994～0.9 988,平均回收率为89.4%～104.0%,精密度、重复性RSD均小于8%.结论 本方法适用于雷诺嗪原料药中有机溶剂残留量的测定.     

盐酸雷诺秦对豚鼠乳头肌动作电位及收缩力的影响

目的通过盐酸雷诺秦对离体豚鼠心室乳头肌动作电位及收缩力的影响,探讨其抗心律失常及心肌缺血的机制。方法健康成年豚鼠18只,随机分为H2O2(200 mmol.L-1)组、雷诺嗪(10 mmol.L-1)+H2O2组和TTX(2 mmol.L-1)+H2O2组,每组6只,采用给药前后自身对照的方法观察雷诺秦对豚鼠乳头肌的作用。结果H2O2可使对照组动作电位APD50、APD90明显增加(P0.001),心肌收缩力降低(P0.05),雷诺嗪可抑制H2O2引起的动作电位时程APD50、APD90的延长(P0.05和P0.01),但作用弱于TTX(P0.05和P0.001),雷诺嗪、TTX可改善H2O2引起的心肌收缩力降低。结论盐酸雷诺嗪可降低H2O2引起的豚鼠乳头肌动作电位动时程的增加和增强心肌收缩力,作用和TTX结果相似。     

Effects of the Antianginal Drugs Ranolazine,Nicorandil, and Ivabradine on Coronary Microvascular Function in Patients With Nonobstructive Coronary Artery Disease: A Meta-analysis of Randomized Controlled Trials

PurposeThe goal of this study was to investigate the effects of the antianginal drugs ranolazine, nicorandil, and ivabradine on coronary microvascular function.MethodsElectronic scientific databases were searched for randomized trials investigating the effects of antianginal drugs on coronary microvascular function. Primary outcomes were changes in the coronary flow reserve (CFR), index of microvascular resistance (IMR), and myocardial perfusion reserve index (MPRI). The secondary outcome was the Seattle Angina Questionnaire scores. The standardized mean difference or weighted mean difference (WMD) (95% CI) served as a summary statistic.FindingsThe antianginal drugs ranolazine, nicorandil, and ivabradine did not increase the CFR compared with the control drugs (standardized mean difference, 0.39; 95% CI, −0.08 to 0.85; P = 0.10). Ranolazine did not increase the global MPRI compared with the control drugs (weighted mean difference [WMD], 0.11; 95% CI, −0.06 to 0.29; P = 0.21). However, in the subgroups with a baseline CFR <2.5 or a global MPRI <2, ranolazine increased the global MPRI (WMD, 0.19; 95% CI, 0.10 to 0.27; P < 0.0001). In addition, the subendocardial midventricular MPRI (mid-subendocardial MPRI) was improved after ranolazine treatment (WMD, 0.12; 95% CI, 0.03 to 0.20; P = 0.007). Moreover, nicorandil significantly reduced the IMR compared with the control drugs (WMD, −7.63; 95% CI, −11.82 to −3.44; P = 0.0004). In addition, ranolazine and ivabradine improved 3 of the 5 Seattle Angina Questionnaire scores.ImplicationsRanolazine improved the global MPRI in patients with definite coronary microvascular dysfunction and the mid-subendocardial MPRI with suspicious coronary microvascular dysfunction, and nicorandil reduced the IMR. In addition, ranolazine and ivabradine reduced angina. Moreover, it is possible that the IMR and mid-subendocardial MPRI are more sensitive than the CFR and global MPRI for evaluating coronary microvascular function.     

Ranolazine selectively blocks persistent current evoked by epilepsy-associated NaV1.1 mutations

BACKGROUND AND PURPOSE

Mutations of SCN1A, the gene encoding the pore-forming subunit of the voltage-gated sodium channel Na_V1.1, have been associated with a spectrum of genetic epilepsies and a familial form of migraine. Several mutant Na_V1.1 channels exhibit increased persistent current due to incomplete inactivation and this biophysical defect may contribute to altered neuronal excitability in these disorders. Here, we investigated the ability of ranolazine to preferentially inhibit increased persistent current evoked by mutant Na_V1.1 channels.

EXPERIMENTAL APPROACH

Human wild-type (WT) and mutant Na_V1.1 channels were expressed heterologously in human tsA201 cells and whole-cell patch clamp recording was used to assess tonic and use-dependent ranolazine block.

KEY RESULTS

Ranolazine (30 µM) did not affect WT Na_V1.1 channel current density, activation or steady-state fast inactivation but did produce mild slowing of recovery from inactivation. Ranolazine blocked persistent current with 16-fold selectivity over tonic block of peak current and 3.6-fold selectivity over use-dependent block of peak current. Similar selectivity was observed for ranolazine block of increased persistent current exhibited by Na_V1.1 channel mutations representing three distinct clinical syndromes, generalized epilepsy with febrile seizures plus (R1648H, T875M), severe myoclonic epilepsy of infancy (R1648C, F1661S) and familial hemiplegic migraine type 3 (L263V, Q1489K). In vitro application of achievable brain concentrations (1, 3 µM) to cells expressing R1648H channels was sufficient to suppress channel activation during slow voltage ramps, consistent with inhibition of persistent current.

CONCLUSIONS AND IMPLICATIONS

Our findings support the feasibility of using selective suppression of increased persistent current as a potential new therapeutic strategy for familial neurological disorders associated with certain sodium channel mutations.