Calcium channel blockers and Alzheimer's disease

Alzheimer＇s disease is characterized by two pathological hallmarks： amyloid plaques and neurofibrillary tangles. In addition, calcium homeostasis is disrupted in the course of human aging Recent research shows that dense plaques can cause functional alteration of calcium signals in mice with Alzheimer＇s disease. Calcium channel blockers are effective therapeutics for treating Alzheimer＇s disease. This review provides an overview of the current research of calcium channel blockers involved in Alzheimer＇s disease theraov.

Effect of Calcium Ionophore and Calcium Channel Blockers on Immediate Hypersensitivity Reactions

The release of mediators from mast cells is a model for cell secretion and is an in-vitro index for immediate hypersensitivity reactions. Calcium influx is generally accepted to be the primary biochemicalevent in mast cell activation.We studied the effect of the calcium ionophore A 23187 and calcium channelblockers,nifedipine and verapamil, in triggering the activation of rat peritoneal mast cells.At suitableconcentration nifedipine and verapamil have had the inhibition effect in the IgE-dependent roaction.

Antineoplastic Effect of Calcium Channel Blocker-Verapamil and 5-Fluorouracil Intraperitoneal Chemotherapy on Hepatocarcinoma-Bearing Rats

Objective To study the antineoplastic effect of the calcium channel blocker verapamil and 5-fluorouracil intraperitoneal chemotherapy onhepatocarcinoma-bearing rats, and examine the action between calcium channel blockers and cytotoxic drugs.Methods We adopted the method of subcapsular implantation of carcinoma tissues of walker-256 in the left liver lobe as a model of livercarcinoma-bearing rats. All experimental animals were divided into four groups. On the sixth day post implantation, in group A (controlgroup) 6 ml of saline was injected intraperitoneally once a day for 3 days. In group B (single chemotherapy group) 6 ml of 5-Fu 75 mg/kg was injected intraperitoneally once a day for 3 days. In group C (combination of treatment group) both 5-Fu (75 mg/kg) and verapamil(25 mg/kg) were administered simultaneously as in A and B. In group D (simple verapamil group) only 6 ml of verapamil (25 mg/kg)was administered as above.Results Compared with groups A, B and D, The volume of cancer and the contents of liver cancer DNA and protein were significantlyreduced. The rates of inhibiting cancer (89.9% in group C and 35.4% in group B) were significantly increased in group C. Group C hadsignificantly long survival time compared to groups A, B and D ( P < 0.05) . By light microscopy, a number of focal necroses were foundin cancer tissue in group C.Conclusion Calcium channel blockers can enhance the antineoplastic effect of 5-Fu intraperitoneal chemotherapy to liver cancer ; Theuse of verapamil can not increase the toxicity of 5-Fu.

Calcium channel blocker monotherapy versus combination with reninangiotensin system inhibitors on the development of new-onset diabetes mellitus in hypertensive Korean patients

Background In real practice, two or more antihypertensive drugs are needed to achieve target blood pressure. We investigated the comparative beneficial actions of combination therapy of renin-angiotensin system inhibitors (RASI), with calcium channel blockers (CCB) over CCB monotherapy on the development of new-onset diabetes mellitus (NODM) in Korean patients during four-year follow-up periods. Methods A total of 3208 consecutive hypertensive patients without a history of diabetes mellitus who had been prescribed CCB were retrospectively enrolled from January 2004 to December 2012. These patients were divided into the two groups according to the additional use of RASI (the RASI group, n = 1221 and the no RASI group, n = 1987). Primary endpoint was NODM, defined as a fasting blood glucose ≥ 126 mg/dL or hemoglobin A1c ≥ 6.5%. Secondary endpoint was major adverse cardiac events (MACE) defined as total death, myocardial infarction (MI) and percutaneous coronary intervention (PCI). Results After propensity score-matched (PSM) analysis, two propensity- matched groups (939 pairs, n = 1878, C-statistic = 0.743) were generated. The incidences of NODM (HR = 1.009, 95% CI: 0.700–1.452, P = 0.962), MACE (HR = 0.877, 95% CI: 0.544–1.413, P = 0.589), total death, MI, PCI were similar between the two groups after PSM during four years. Conclusions The use of RASI in addition to CCB showed comparable incidences of NODM and MACE compared to CCB monotherapy in non-diabetic hypertensive Korean patients during four-year follow-up period. However, large-scaled randomized controlled clinical trials will be required for a more definitive conclusion.

Argemone mexicana extract alleviates gastrointestinal disorders by stimulating muscarinic receptors and blocking voltage-gated L-type calcium channels

Objective:To investigate the pharmacological potential of Argemone mexicana in treating constipation and emesis by using in vitro and in vivo models.Methods:The spasmogenic and spasmolytic effects were evaluated on isolated rabbit jejunum fragments loaded in a tissue organ bath.The response was recorded with an isotonic transducer attached with Power Lab Data Acquisition System.The laxative and antiemetic activities were assessed in BALB-c mice and poultry chicks challenged with carbamylcholine and copper sulphate stimulated emesis,respectively.Results:The total phenolic and total flavonoids contents of the extract were(267.75±5.77)mg GAE/g and(73.86±6.01)mg QE/g,respectively.Argemone mexicana extract exerted spasmogenic effect on isolated rabbit jejunum segments with an EC_(50)value of 0.016 mg/m L,which was blocked by atropine(0.3μM).Argemone mexicana extract exerted spasmolytic effect in atropine treated jejunum fragments with an EC_(50)value of 2.185 mg/mL.Furthermore,Argemone mexicana extract relaxed potassium(80 mM)-induced contractions(EC_(50):9.07 mg/mL),similar to a standard drug verapamil.The calcium channel blocker activity was confirmed by a rightward shift of concentration-response curve of calcium in the presence of Argemone mexicana extract(1-5 mg/mL)and verapamil(0.1-1μM).In addition,the extract increased the distance travelled by a charcoal in the gastrointestinal tract and exhibited antiemetic effect on copper sulphate induced emesis in chicks.Conclusions:Argemone mexicana shows cholinergic agonist and calcium channel blocker activities,as well as antiemetic effect.It may be used as a potential agent for treating gastrointestinal disorders.

CCB及RAAS抑制剂降压治疗预防脑血管事件差异的真实世界研究

目的研究钙通道阻滞剂(CCB)及肾素-血管紧张素-醛固酮系统(RAAS)抑制剂降压治疗预防脑血管事件差异的真实世界。方法对915例高血压患者进行资料查看、筛选、分析,观察患者血压控制及终点事件发生情况,比较用药CCB、RAAS抑制剂对减少心脑血管事件效果的真实世界情况。结果随访时间2.0~6.5年,平均随访时间4.5年。915例高血压患者中,482例患者采用单一CCB治疗,433例患者采用单一RAAS抑制剂治疗。用药CCB患者收缩压降低幅度略大于用药RAAS抑制剂患者,舒张压降低幅度略小于用药RAAS抑制剂患者,但差异无统计学意义(P>0.05);随访至终点时,用药CCB患者脑卒中发生率为5.60%(27/482),低于用药RAAS抑制剂患者的6.47%(28/433),经R语言生存分析差异具有统计学意义(P=0.016<0.05)。用药CCB患者心肌梗死发生率为2.90%(14/482),高于用药RAAS抑制剂患者的2.31%(10/433),经R语言生存分析差异无统计学意义(P=0.920>0.05)。用药CCB患者总死亡率为4.56%(22/482),用药RAAS抑制剂患者总死亡率为4.62%(20/433),经R语言生存分析差异无统计学意义(P=0.872>0.05)。结论CCB降压治疗预防脑卒中的效果优于RAAS抑制剂,显示CCB对脑卒中的一级预防具有更多的优势。

ACEI/ARB与CCB防治高血压病伴慢性肾功能不全患者发生造影剂肾病的效果比较

目的 比较血管紧张素转换酶抑制剂（ACEI）/血管紧张素受体阻断剂（ARB）和钙离子通道阻断剂（CCB）对高血压病伴慢性肾功能不全（CKD）患者在介入术后发生造影剂肾病（CIN）的防治效果。方法 回顾分析近6年南方医院内科病房180例高血压病伴CKD 2-3期患者，所有患者均接受了冠脉介入术，并在术前术后使用了水化治疗，术前至少使用了7 d的ACEI/ARB或CCB药物，另设单纯水化对照组；观察3组患者发生CIN的例数，以及术后24、48、72 h及 7d的血清肌酐（SCr）、肌酐清除率（CCr）的变化水平，并记录肾功能恢复的时间。结果 ACEI/ARB组术后发生CIN 20例（占37%），CCB组术后发生CIN 16例（占20%），单纯水化组发生28例（占61%）；与单纯水化组比较，两组术后CIN发生率均较低（P〈0.05，P〈0.01）；CCB组和ACEI/ARB组比较，CCB组的CIN发生率较低（P〈0.05）。3组患者介入术后24、48、72 h及7 d的SCr、CCr水平均有明显升高，差异有显著性；与单纯水化组相比，ACEI/ARB组和CCB组的血清SCr、CCr水平在24、48、72 h及7 d的时间点均有所降低，差异有显著性；CCB组与ACEI/ARB组相比，48、72 h及7 d的SCr降低较明显（均P〈0.05）。术后14 d，ACEI/ARB组有14例（占70%）CIN患者肾功能恢复至术前水平，CCB组有12例（占75%），单纯水化组有16例（占62%），ACEI/ARB组和CCB比较差异无统计学意义。结论 使用ACEI/ARB 和CCB类药物均可对高血压病并发CKD患者发生CIN有预防作用；CCB类药物优于ACEI/ARB类药物。

硝苯地平控释片联合盐酸贝那普利片治疗老年高血压临床效果的研究进展

随着社会与生活环境的不断改变,老年高血压的发病率也逐年攀升。硝苯地平控释片联合盐酸贝那普利片在老年高血压治疗方面受到普遍的关注以及重视,二者分别属于钙离子通道阻滞剂和血管紧张素转化酶抑制剂,发挥降压效果的机制也各不相同。对老年高血压患者联合应用上述两种药物进行治疗,可以发挥互相协同的降压效果,使患者的血压控制率得到明显提升,同时还能够有效地降低单一药物应用所导致的不良反应。本文综述近年在老年高血压患者的临床治疗过程中,联合应用硝苯地平控释片以及盐酸贝那普利片临床效果的研究进展。

钙通道阻滞剂1,4-二氢吡啶类药物的绿色合成

心脏及心脑血管疾病是发达国家人群的第一死因,也是中国人死亡的首位原因.L-型钙通道是目前临床上主要使用选择性钙通道阻滞剂1,4-二氢吡啶类药物.文章研究了在非均相催化剂离子交换树脂Amberlyst 15的催化以及无溶剂条件下,高效的合成了钙通道阻滞剂1,4-二氢吡啶类药物.该反应体系具有原料便宜、反应时间短、操作及后处理简单、催化剂可回收利用、反应可放大等优良特点.

钙通道阻滞剂对未破裂颅内动脉瘤影响的研究进展

未破裂的颅内动脉瘤是一颗埋在患者体内的定时炸弹,这类患者往往伴有高血压病。除去多数研究已证实的促破裂危险因素以外,复杂的血流动力学、炎症因素以及未控制的高血压也增加了其破裂风险。作为临床常用的抗高血压药物,钙通道阻滞剂被发现在促破裂进程中可以发挥保护作用,但也有研究发现了不同甚至矛盾的结果。本文就动脉瘤破裂的危险因素、钙通道阻滞剂使用对瘤体破裂的影响以及发挥的双重效应作一综述。

钙离子通道阻滞剂在慢性疼痛患者中临床应用的研究进展

现代医学将疼痛列为继呼吸、脉搏、血压、体温后的第五生命体征,足见其在人体健康中的重要性。慢性疼痛是指超过正常愈合时间(一般指3个月)持续存在的自觉疼痛感,相对于急性疼痛而言,慢性疼痛一般会涉及生理或神经系统,并可能会影响身体的多个方面。由于受到发病机制复杂、个体差异大以及神经可塑性等因素的影响,慢性疼痛的治疗难度相对较大。药物治疗是慢性疼痛管理中的常用手段,关于药物的选择或配伍也一直是临床研究的热点。本文综述了钙离子通道阻滞剂在慢性疼痛中的应用,旨在为疾病的治疗提供参考。

Effects of Tetrandrine on Cytosolic Free Calcium in Cultured Bovine Aortic Smooth Muscle Cells

\ The effects of tetrandrine (Tet) on cytosolic free calcium ([Ca2+]i) in subcultured bovine aortic smooth muscle cells (SMC) were studied by Fura2 and ARCMMIC cation measurement system. Tet (1～100 μmol·L-1) had no effect on the resting [Ca2+]i, but had inhibitory effects on [Ca2+]i elevation induced by high K+, 5HT, ATP, Ang II and NE in the presence of extracellular Ca2+. High concentration of Tet also inhibited Pheinduced [Ca2+]i elevation in absence of extracellular Ca2+. Tet (1～100 μmol·L-1) inhibited KCl (60 mmol·L-1) induced [Ca2+]i elevation in dosedependent manner, the IC50 value was 9.2 (95% confidence limits: 5.7～14.9) mmol·L-1. The results suggested that Tet had blocking effects on both VOC and ROC in bovine aortic SMC. It appears that the mechanisms of blocking effect of Tet on ROC might be primarily due to its Ca2+ entry blocking effects.

缬沙坦/氨氯地平复方制剂与ARB+CCB联用治疗高血压的药物经济学比较

目的:比较缬沙坦/氨氯地平复方制剂与血管紧张素Ⅱ受体阻滞药(ARB)+钙通道阻滞药(CCB)联用治疗高血压的有效性和经济性。方法:检索Medline、Pub Med、Cochrane Library等3个英文期刊数据库,以及中国知网、维普网、万方数据等3个中文期刊数据库,检索范围设定为"题目/摘要(Title/Abstract)",检索词为"缬沙坦/氨氯地平(Valsartan/Amlodipine)""高血压(Hypertension)",检索时限均为建库起至2018年5月。运用Markov模型,基于中国2017年的药品价格与医疗费用,对纳入文献中缬沙坦/氨氯地平复方制剂组与ARB+CCB组患者的有效性和经济性进行对比分析。结果:从医疗卫生系统角度分析,缬沙坦/氨氯地平复方制剂组在Markov模型中非致死性心肌梗死和非致死性卒中状态的人均治疗成本低于ARB+CCB组。与ARB+CCB组比较,缬沙坦/氨氯地平复方制剂组患者治疗的增量效用是质量调整生命年(QALY)每增加0.067 8个单位所需的增量成本为2 916.63元,其增量成本-效果比为42 988.44元/QALY。结论:与ARB+CCB联用相比,缬沙坦/氨氯地平复方制剂治疗高血压可显著降低患者非致死性心肌梗死和非致死性卒中等不良事件的发生,且可为患者节省医疗费用,更具经济性。

Calcium Signaling is Involved in Negative Phototropism of Rice Seminal Roots

Calcium ions （Ca2＋） act as an intracellular second messenger and affect nearly all aspects of cellular life. They are functioned by interacting with polar auxin transport, and the negative phototropism of plant roots is caused by the transport of auxin from the irradiated side to the shaded side of the roots. To clarify the role of calcium signaling in the modulation of rice root negative phototropism, as well as the relationship between polar auxin transport and calcium signaling, calcium signaling reagents were used to treat rice seminal roots which were cultivated in hydroculture and unilaterally illuminated at an intensity of 100-200 pmol/（m2.s） for 24 h. Negative phototropism curvature and growth rate of rice roots were both promoted by exogenous CaCI2 lower than 100 pmol/L, but inhibited by calcium channel blockers （verapamil and LaCI3）, calcineurin inhibitor （chlorpromazine, CPZ）, and polar auxin transport inhibitor （N-l-naphthylphthalamic acid, NPA）. Roots stopped growing and negative phototropism disappeared when the concentrations increased to 100 pmol/L verapamil, 12.500 ~Jmol/L LaCI3, 60 pmol/L CPZ, and 6 pmol/L NPA. Moreover, 100 pmol/L CaCI2 could relieve the inhibition of LaCI3, verapamil and NPA. The enhanced negative phototropism curvature was caused by the transportation of more auxin from the irradiated side to the shaded side in the presence of exogenous Ca2＋. Calcium signaling plays a key role as a second messenger in the process of light signal regulation of rice root growth and negative phototropism.

ORIGINAL ARTICLES CALCIUM CHANNEL BLOCKERS IN CIRRHOTIC PATIENTS WITH PORTAL HYPERTENSION

Four calcium channel blockers, i.e. nifedipine, verapamil, cinnarizine and tetrandrine are currently available and used widely in treating cardiovascular diseases. To confirm the effects, if any, of calcium channel blockers on cirrhotic patients with portal hypertension, a study was performed on esophageal variceal pressure and rebleeding rate of esophageal varices after 2 years by using calcium channel blocker in 321 patients from some 23 hospitals. The results demonstrated that the calcium channel blockers could significantly reduce the esophageal variceal pressure and the portal blood flow in cirrhotic patients with portal hypertension. The proportion of patients with no recurrent gastrointestinal bleeding after 2 years medication of tetrandrine was 87.9% in tetrandrine group, significantly higher than those in the other 4 groups (P<0.05). It is suggested that tetrandrine should be more effective for cirrhotic patients with portal hypertension in preventing recurrent variceal bleeding.

The effect of calcium-antagonist on Bcl-2 and Bax mRNA expression following ischemic brain injury

AIM:In order to explore whether the member of Bcl-2 gene family,for example,B cl-2 and Bax,are induced after cerebral ischemia,and whether expression of gene s can be modulated by calcium-antagonist.METHODS:The rat cerebral ischemic mode ls were made by Nagasawa and Zea Longa improvement method,by occluding left midd le cerebral artery;the expression of Bcl-2 and Bax mRNA were measured by RT-PC R method.RESULTS:After administration of nimodipine, Bcl-2 mRNA was up-regulat ed in the hippocampus at 6 and 24 h after ischemia,while Bax mRNA was down-regu lated at 6 and 24h after ischemia.CONCLUSION:Calcium-antagonist can up-regulat e Bcl-2 mRNA and down-regulate Bax mRNA.Increasing the ratio of Bcl-2 and Bax mRNA may contribute to the anti-apoptic effect of nimodipine.

ACEI与长效CCB对高血压脑卒中二级预防的效果分析

目的：探讨ACEI与长效CCB对高血压合并脑卒中二级预防的效果。方法回顾性分析2009年6月~2014年6月社区健康档案中高血压合并脑卒中存活跃2个月的患者863例，以ACEI为降压基础治疗的408例，长效CCB为降压基础治疗的455例，主要观察脑卒中的复发、脑卒中死亡、心肌梗死发生及死亡、总死亡等，观察时间6~70个月，平均39个月。结果两组患者血压下降幅度比较差异无统计学意义（P〉0.05）；两组危险因素干预情况比较差异无统计学意义（P〉0.05）；ACEI组联合利尿剂的患者多于CCB组，差异有统计学意义（P〈0.05）；两组≥2种联合用药率相比，差异无统计学意义（P〉0.05）；ACEI组与CCB组所有脑卒中复发分别为111例（27.2%）、107例（23.5%），差异有统计学意义（P〈0.05）；两组其他心血管事件发生率比较，差异无统计学意义（P〉0.05）。结论降压药对高血压合并脑卒中二级预防的效果与脑卒中一级预防相同，长效CCB优于ACEI。

Effects of 2-APB on Store-operated Ca^(2+) Channel Currents of Hepatocytes after Hepatic Ischemia/Reperfusion Injury in Rats

The effects of hepatic ischemia/reperfusion (I/R) injuries on hepatocellular viability and store-operated calcium current (Isoc) in isolated rat hepatocytes and the effects of 2-APB on store-operated calcium current (Isoc) in isolated rat hepatocytes after hepatic ischemia/reperfusion injuries were studied. Hepatic ischemia and reperfusion injury model was established and whole cell patch-clamp techniques were used to investigate the effects of 2-APB on Isoc. The results showed that ischemia/reperfusion injuries could significantly reduce hepatocellular viability and further increase Isoc in hepatocytes and 2-APB (20, 40, 60, 80, 100 μmol/L) produced a concentration-dependent decrease of Isoc with IC 50 value of 64.63±10.56 μmol/L (n=8). It was concluded that ischemia/reperfusion injuries could reduce hepatocellular viability, probably through increased Isoc in hepatocytes and 2-APB had a protective effect on ischemia/reperfusion-induced liver injury, probably though inhibiting Isoc.

Pharmacological Investigation of Voltage-dependent Ca^(2+) Channels in Human Ejaculatory Sperm in vitro

The types of the voltage-dependent calcium channels （VDCCs） in human ejaculatory sperm and the effects of calcium channel blocker （CCB） on human sperm motility parameters in vitro were investigated. The human sperm motility parameters in vitro in response to the pharmacological agents nifedipine （NIF, inhibitor of L-type VDCC） and ω-conotoxin （GVIA, inhibitor of N-type VDCC） were compared and analyzed statistically. The results showed that NIF （1, 5, 10 μmol/L） could not only significantly affect human sperm＇s shape but also spermatozoa motility after incubated at least 10 rain in vitro （P〈0.001）. GVIA （0.1, 0.5 and 1 μmol/L） could just only significantly affect human sperm＇s progressive motility （a %＋b %） after incubated for 20 min in vitro （P〈0.01）, but they both could not significantly affect spermic abnormality rate. It is suggested that L-type VDCC, non L-type VDCCs and isoform of L-type VDCC exist in the cell membrane of human sperm solely or together, and they participate in the spermic physiological processes especially the spermic motility.