Limits and perspective of oral therapy with statins and aspirin for the prevention of symptomatic cholesterol gallstone disease

The prevalence of gallstones disease in Western countries is 10 – 15%. Gallstones can be one of two types – cholesterol or pigment – with cholesterol gallstones representing nearly the 80% of the total. Cholesterol and pigment gallstones have different predisposing factors: cholesterol gallstones are related to supersaturated bile in cholesterol, whereas black pigment gallstones are related to hyperbilirubinbilia factors (hemolysis, etc.); these are necessary, but not sufficient, factors to produce gallstones in vivo. Gall bladder mucosa factors (gall bladder secretion of mucin, local bile stasis and production of endogenous biliary β-glucuronidase) may coexist with the aforementioned factors and facilitate gallstone nucleation and growth. The gold-standard treatment for symptomatic gallstones is laparoscopic cholecystectomy. Several studies have reported a significant reduction in the onset of symptomatic gallstones disease in patients undergoing chronic therapy with statins, which can reduce bile cholesterol saturation. Aspirin, which has been shown to reduce the local production of gall bladder mucins (mucosal or parietal factors of gallstone formation) in animal experimental models, does not appear to reduce the risk of symptomatic gallstones disease when tested alone. The new horizon of oral therapy for the prevention of symptomatic gallstone disease needs to evaluate the long-term effect of statins and chronic aspirin administration in patients with dyslipidemia and/or atherosclerosis.     

New targets in and potential treatments for cholesterol gallstone disease

Gallstone disease is very common among American Indians and Hispanics, and approximately 20 million patients are treated for this disease annually in the US. Bile acid receptor (nuclear farnesoid X receptor; FXR) knockout mice fed a lithogenic diet are more susceptible to gallstone disease than wild-type mice. The C57L mouse is also susceptible to gallstone formation when fed a lithogenic diet, and in this model, the small-molecule FXR agonist GW-4064 prevents the precipitation of cholesterol. Bile acids (eg, P-muricholic acid) and their derivatives are also being developed as FXR agonists. Fatty acid bile acid conjugates have the potential to prevent and reverse cholesterol crystallization. Furthermore, agents that increase the expression of selected hepatocyte bile acid transporters may also be useful in the treatment of gall bladder disease.     

Modulation of cholesterol crystallization in bile. Implications for non-surgical treatment of cholesterol gallstone disease

The first step in cholesterol gallstone disease is precipitation of cholesterol crystals in bile. In gallbladder bile. cholesterol is normally solubilized together with bile salts and phospholipids to form mixed micellar structures. When cholesterol in bile is in excess, vesicles (i.e. phospholipid-cholesterol globular structures: liquid crystals) form which become supersaturated in cholesterol. Early aggregation and precipitation of cholesterol molecules into submicroscopic nuclei occurs from these supersaturated vesicles. This crucial step is followed by precipitation and agglomeration of cholesterol crystals which then become visible at light microscopy. Here we describe the mechanism of cholesterol crystallization and its modulation in vivo and in vitro. Recent advances on the role of ursodeoxycholate as an agent preventing the precipitation of cholesterol crystals in bile will be highligthed.     

阿嗪米特对豚鼠胆囊胆固醇结石的治疗作用

目的:研究阿嗪米特(azintamide)对豚鼠胆囊胆固醇结石的治疗作用。方法:用高胆固醇饮食诱发豚鼠胆囊胆固醇结石模型,进行胆囊结石计数;测定胆囊体积和胆囊胆汁量;测定血清总胆汁酸(TBA)、总胆红素(TBIL)、胆固醇(TCHO)、三酰甘油(TG)、高密度脂蛋白胆固醇(HDL-c)、低密度脂蛋白胆固醇(LDL-C)、碱性磷酸酶(ALP);测定胆汁TCHO,TBA和TBIL。观察阿嗪米特(20和80mg·kg~(-1))对胆囊胆固醇结石的治疗作用。为探讨阿嗪米特抗胆囊胆固醇结石的作用机制,对胆囊壁组织进行了黏液素(mucin)的免疫组化实验。结果:与模型组比较,阿嗪米特20和80mg·kg~(-1)组成石率明显下降;胆囊体积和胆囊胆汁量显著减少;血清TCHO及LDL-C明显降低(P＜0．05);胆汁TBA升高(P＜0．05),胆汁TCHO及TBIL降低(P＜0．05)。黏液素免疫组化实验中可观察到,模型组黏液素表达水平较高,而阿嗪米特组黏液素表达水平较低。已知利胆药熊去氧胆酸(UDCA)亦有显著效果。结论:阿嗪米特对高胆固醇饮食诱发的豚鼠胆囊胆固醇结石模型具有明显的治疗作用。     

胆固醇结石患者肝脏核受体基因蛋白的表达

目的 探讨胆囊胆固醇结石(CGs)患者肝脏的核受体基因的蛋白表达.方法 对20例CGS(胆石组)和10例无胆石症的胆囊息肉患者(对照组)测定了胆石胆固醇成分及血清脂类成分:总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白胆固醇(HDL-C)和胆汁脂类成分(胆固醇、磷脂和胆汁酸),并计算胆汁总脂和胆汁胆固醇饱和指数.Western blot法测定肝脏肝受体同类物1(LRH-1)、法尼醇受体(FXR)、人类固醇异生物受体(SXR)及肝脏X受体a(LXRa)基因的蛋白表达量.结果 胆石组血清HDL-C浓度明显低于对照组[(0.91±0.05)mmol/L vs.(1.31±0.09)mmol/L](P<0.01);胆汁胆固醇摩尔百分比浓度较对照组高[(7.89±0.39)mol%vs.(5.15±0.89)mol%](P<0.01);胆汁总脂较对照组明显下降[(105.62±10.51)g/L vs.(153.50±13.20)g/L](P<0.05);胆石组LRH-1蛋白表达高于对照组[(0.88±0.05)vs.(0.69±0.03)3(P<0.05),LXRa、FXR和SXR表达两组差异无统计学意义(P>0.05).结论 人肝脏LRH-1的蛋白表达增高与胆囊胆固醇结石形成有关.     

整体护理在胆石症手术治疗过程中的评价

目的:评价整体护理在胆石症手术治疗过程中的作用.方法:回顾性分析88例胆石症病人的护理资料.结果:整体护理组病人在24小时内下床活动例数、24～48小时内肛门排气的例数和24小时内自行排尿的例数明显多于常规护理组(P<0.01).整体护理组病人对护理满意度明显好于常规护理组(P<0.01).结论:整体护理能够缓解焦虑,提高病人术后康复质量,有效地改善医患关系.     

阿司匹林联合辛伐他汀防治缺血性脑血管病临床研究

目的：探讨缺血性脑血管病应用阿司匹林联合辛伐他汀治疗的效果,以丰富临床治疗经验。方法：选择2012年6月～2013年6月在我院接收并确诊的缺血性脑血管病患者100例,根据入院治疗顺序随机分为对照组与观察组各50例,对照组通过给予阿司匹林进行治疗,观察组则通过给予阿司匹林以及辛伐他汀同时治疗,治疗后8周,统计两组患者的治疗总有效率,将结果进行对比。一年以后对所有患者进行随访,了解患者的长期病情。结果：治疗后,患者的临床症状均有明显的改善与缓解,观察组治疗的总有效率为84.00%,优于对照组的68.00%,差异显著（P<0.05）;在治疗一年后,对患者进行随访,观察组心肌梗死、短暂性脑缺血发作以及再发性脑梗死等疾病的发生率为16.00%,远远低于对照组的36.00%,差异显著（P<0.05）。结论：缺血性脑血管病应用阿司匹林联合辛伐他汀治疗,具有疗效确切、安全可靠等优点,值得临床推广。     

Protective and symptomatic strategies for therapy of Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of the capacity to execute voluntary movements appropriately. PD develops as a consequence of the degeneration of dopamine-containing neurons in the substantia nigra pars compacta (SNc). SNc is a component of the basal ganglia nuclei, the network that controls the neural signaling underlying voluntary movements. The nigral cell loss triggers a cascade of functional modifications in the basal ganglia circuit, the most important of which is hyperactivity of another component of the circuit, the subthalamic nucleus (STN). Subthalamic hyperactivity represents a major neural substrate of PD motor symptoms. The etiopathogenesis of PD is probably multifactorial. Various mechanisms - including mitochondrial defects, oxidative stress, glutamate toxicity and genetic factors - are likely to contribute to the degenerative process. Current therapy for PD is essentially symptomatic. L-dopa, the direct precursor of dopamine, is still the "gold standard". However, long-term therapy with L-dopa is associated with significant side effects. Therefore, there is a need for new therapeutic strategies aimed at relieving motor symptoms and slowing the progression of neuronal degeneration. The excitatory amino acid glutamate plays a central role in the functional modifications that affect the basal ganglia in PD. In particular, it mediates the enhanced excitatory drive of the STN to the output nuclei of the basal ganglia, which leads to the expression of PD symptoms. Furthermore, since the STN projects to the SNc, the excessive glutamatergic stimulation on residual nigral neurons may sustain the degenerative process, generating a self-maintaining vicious circle. From these considerations, it ensues that the use of drugs capable of antagonizing the effects of glutamate may provide new symptomatic and neuroprotective strategies for therapy of PD.     

Dietary implications for patients receiving long-term oral anticoagulation therapy for treatment and prevention of thromboembolic disease

Introduction: The effectiveness of oral anticoagulation therapy with warfarin (a vitamin K antagonist) in the treatment of thromboembolic disease, including stroke prophylaxis in patients with atrial fibrillation is well recognised. However, warfarin has a narrow therapeutic window and an unpredictable anticoagulation response, which make it difficult to achieve and maintain optimal anticoagulation. Various dietary factors, including sudden changes in eating patterns, can significantly alter anticoagulation control, thereby potentially exposing patients to the risk of bleeding or thromboembolic complications. Dietary vitamin K intake is a particularly important factor, given the mechanism of action of warfarin.

Areas covered: In this article, we cover the sources of vitamin K and their potential effect of dietary vitamin K on anticoagulation response to warfarin. We also discuss the results of studies on the effect of vitamin K supplementation on anticoagulation stability.

Expert commentary: A stable dietary vitamin K, promoted by daily oral vitamin K supplementation, can improve anticoagulation stability in patients on warfarin therapy. There is experimental evidence in animals that dietary vitamin K affects anticoagulation response to the direct thrombin inhibitor, ximelagatran. Whether dietary vitamin K affects anticoagulation response to the currently licensed direct oral anticoagulants (DOACs) in man remains to be investigated.     

A new method of estimating cost effectiveness of cholesterol reduction therapy for prevention of heart disease

The purpose of this study was to demonstrate a new method of estimating the cost effectiveness of interventions that lower blood cholesterol levels in the prevention of coronary heart disease (CHD) at the community level. The participants in the study were 67 651 men aged 35 to 64 years in the Lower Hunter region of New South Wales, Australia. Census data, risk factor profiles and CHD event rates from community surveillance, plus costs in 1988-1989 Australian dollars, were used as inputs to a computer program that used a logistic equation. The output estimated the CHD events avoided and the cost effectiveness of an intervention that identified and treated men with cholesterol levels greater than 6.5 mmol/L with dietary modification and cholestyramine. The cost of implementation of the intervention was $A50.1 million to prevent 104 CHD events. The cost-effectiveness ratio was $A482 224 per CHD event avoided (SD = $A24 761) and the direct medical costs avoided were approximately $A500 000 over a 5-year period ($A4535.07 per CHD event avoided). Drug acquisition costs contributed substantially (88%) to the total costs of interventions that rely on screening to identify individuals with high cholesterol for intensive treatment.     

他汀类药物联合依折麦布用于冠心病患者治疗的有效性和安全性评价

目的:研究中强度他汀联用依折麦布在冠状动脉粥样硬化性心脏病患者中与中、高强度他汀单用的有效性与安全性差异。方法:检索北京安贞医院HIS系统中2018年1月至2019年4月门诊及住院数据库,筛选出住院就诊记录后3~5周有门诊复查记录的病例。根据病例所使用的他汀类药物分为中强度他汀组、中强度他汀联用依折麦布组及高强度他汀组。比较门诊记录与住院记录血脂指标变化及变化率,并以门诊记录的低密度脂蛋白胆固醇(LDL-C)值,评估病例降脂目标达成率,对比各组降脂疗效的差距。以门诊记录病例中谷草转氨酶(AST)、谷丙转氨酶(ALT)以及肌酸激酶(CK)值超过正常上限2倍及3倍的人数,评估各组安全性差异。结果:共有371例患者纳入研究。联用组降脂目标达成率显著高于中、高强度他汀组;联用组LDL-C绝对变化、相对变化均显著优于中、高强度他汀组(P＞0.05);安全性无显著差异(P＜0.05)。结论:对于冠状动脉粥样硬化性心脏病患者的降脂治疗,中强度他汀联用依折麦布治疗方案降脂效果优于中、高强度他汀单用,且安全性无显著差异。