心房颤动的抗栓治疗

心房颤动（房颤）是临床最常见的心律失常之一,是脑卒中的主要原因,房颤并发的脑卒中有较高的死亡率及致残率.2010年欧洲心脏病学会（ESC）房颤指南指出：抗栓治疗是房颤治疗中永恒的主题[1].而我国的华法林治疗率仅为2.0%,且治疗强度亦达不到要求.这与医师对其治疗的紧迫性及必要性认识不足和高估出血风险不无关系.提高抗栓治疗的认识是亟待解决的问题,为此,将有关问题进行综述.     

心房颤动患者危险分层后抗凝治疗的临床研究

目的根据CHADS2评分对心房颤动（房颤）患者进行危险分层,探讨口服阿司匹林抗凝治疗与口服华法林抗栓治疗预防缺血性脑卒中的临床效果。方法对82例非瓣膜病房颤患者根据CHADS2评分进行分组,抗凝周期均大于6个月,其中40例评分〈2的患者口服阿司匹林（1组）,评分≥2的患者中25例口服阿司匹林（2组）抗凝,17例口服华法林抗栓,分别随访是否有缺血性脑卒中、死亡及主要出血事件的发生。结果1组1例发生缺血性脑卒中,2组发生缺血性脑卒中5例,口服华法林治疗组无缺血性脑卒中发生,1例胃出血。结论根据CHADS2评分进行危险分层后,1组抗凝治疗安全有效,而2组抗凝治疗较口服华法林抗栓治疗不能有效地预防缺血性脑卒中的发生。     

冠心病合并房颤的老年患者PCI术后抗栓治疗的安全性和有效性

目的比较华法林联合阿司匹林、氯吡格雷和华法林联合替格瑞洛在冠心病合并房颤的老年患者PCI术后抗栓治疗中的安全性和有效性。方法 207例符合特定条件的PCI术后冠心病合并房颤的老年患者随机分成两组,对照组(n=103)为华法林+阿司匹林(100 mg/d)+氯吡格雷(75 mg/d)三联抗栓6个月,之后改为华法林+氯吡格雷(75 mg/d)或阿司匹林(100 mg/d)抗栓至12个月,试验组(n=104)为华法林+替格瑞洛(90 mg/d,2次/d)双联抗栓6个月,之后改为华法林+替格瑞洛(60 mg,2次/d)抗栓至12个月,两组均给予其他规范药物治疗方案。比较两组患者12个月内出现的主要心血管不良事件(MACE)及出血事件。结果两组MACE事件、出血事件差异比较均无统计学意义(P>0. 05)。结论对于PCI术后冠心病合并房颤的老年患者12个月华法林联合替格瑞落和华法林联合阿司匹林、氯吡格雷的抗栓效果相似,且出血风险未增加,提示本研究中华法林联合替格瑞洛双联抗栓策略安全有效。     

心房颤动患者脑卒中预防的现状和进展

预防脑卒中是心房颤动(房颤)治疗中的重要问题,应用抗栓治疗能降低脑卒中的发生,但房颤患者中华法林应用不足.近年来房颤患者脑卒中预防有新的药物和技术,如抗血小板药物联合运用、新的抗凝药物ximelagatran、左心耳堵闭技术等.     

心房颤动的抗栓与抗血小板治疗

目的:了解临床实践中心房颤动(房颤)患者抗栓治疗的现状及分析。方法:调查2003年(225例) -2004年(280例)年间有血栓栓塞高危因素的房颤患者接受抗栓治疗的情况。结果:发现2年间高危因素有明显增加(由平均1．4个增加到1．8个),但接受抗栓治疗均以阿司匹林为主(64．8％与72．5％),服用华法林的比例很低(4．0％与6．25％),且剂量均偏低。结论:临床实践中房颤接受抗栓治疗达到标准的比例很低,接受阿司匹林治疗者较多,但剂量偏少,接受华法林治疗者很少,房颤的抗栓治疗尚需进一步规范。     

新型抗凝药物的研究进展

华法林在临床应用有一定局限性,需要有新的抗凝剂来代替。本文主要对新近出现的抗凝药物,如直接Xa因子抑制剂、直接凝血酶抑制剂和新型维生素K拮抗剂作一综述。     

Dabigatran预防心房颤动脑卒中的效果

背景华法林降低心房颤动（简称房颤）病人发生脑卒中的危险，但增加大出血的危险，所以掌握不易。Dabigatran是一种新的口服直接凝血酶抑制剂。     

心房颤动患者脑卒中预防的现状和进

预防脑卒中是心房颤动 (房颤 )治疗中的重要问题 ,应用抗栓治疗能降低脑卒中的发生 ,但房颤患者中华法林应用不足。近年来房颤患者脑卒中预防有新的药物和技术 ,如抗血小板药物联合运用、新的抗凝药物ximelagatran、左心耳堵闭技术等。     

第54届欧洲心脏病年会纪要(续完)

心房颤动:新的口服抗凝药物的出现使心房颤动的抗凝治疗成为本次会议的又一亮点,RELY研究得到达比加群酯(凝血酶抑制剂)在卒中、大出血和死亡方面明显优于华法林,为房颤患者抗凝治疗带来了曙光,今年的ARISTOTLE研究比较了阿哌沙班(Apixapan,口服Xa因子抑制剂)与华法林在至少有一个卒中危险因素的心房颤动患者抗凝治疗的有效性和安全性,入选了18 201例患者,主要终点为卒中和血栓事件,平均随访1.8年,与华法林相比,前者无需经常检查凝血,使卒中降低21％ (P=0.01),大出血降低31％ (P＜0.001),死亡降低11％(P=0.047).     

心房颤动(1)心房颤动抗栓治疗的策略与进展(续前)

缺血性脑卒中是心房颤动(房颤)的主要并发症,抗栓治疗具有重要的临床意义.近年房颤抗栓治疗取得进展,包括对房颤缺血性脑卒中/血栓及出血风险的评估,抗栓策略的选择以及具有循证医学依据的新抗凝药物.房颤缺血性脑卒中危险因子包括老龄,高血压,糖尿病,心力衰竭,以及既往缺血性脑卒中/一过性脑缺血等;女性和血管疾病是目前明确的增加房颤血栓事件的高危因子.2010年欧洲心脏病协会(European Society of Cardiology,ESC)房颤管理指南以及2012年美国胸科医师协会(ACCP 9)推荐CHADS2以及CHA2DS2-VASc作为房颤缺血性脑卒中风险评分工具.CHA2DS2-VASc比CHADS2更能准确辨认真正低危的房颤患者.真正低危患者(CHA2DS2-VASc=0)可不抗栓治疗.CHA2DS2-VASc≥1的患者均应抗凝治疗,无论华法林或新的口服抗凝药物.达比加群,Rivaroxaban(利伐沙班),Apixaban(阿哌沙班)是有循证医学依据的新一代抗凝药物.     

Emerging therapies for the treatment of relapsed or refractory multiple myeloma

Encouraging progress has been made in the treatment of patients with relapsed/refractory multiple myeloma (MM). The rapidly evolving understanding of key pathways responsible for tumor growth and survival has led to the development of novel agents (including immunomodulatory drugs, proteasome inhibitors, histone deacetylase inhibitors, and other targeted agents) with the potential to provide significant improvements in response and survival, and influence treatment guidelines. This review summarizes recent advances in understanding of the biology of relapsed/refractory MM and clinical trials with novel targeted agents that are currently under investigation for patients with this disease.     

No Evidence on Significant Roles of the Prostaglandin-Thromboxane and Kallikrein-Kinin System in the Antihypertensive Effect of MK 421 in Rats Made Hypertensive by Norepinephrine or Vasopressin

Inhibition of angiotensin converting enzyme by MK 4–21 (6 mg/kg/day ip) induced a significant increase in urinary kinin excretion in norepinephrine-infused rats (1.8 mg/kg/day ip), whereas it had no effect on urinary prostaglandin E₂ excretion. In contrast, MK 421 did not induce any significant changes in urinary kinin and prostaglandin E₂ excretion in vasopressininfused rats (7.2 U/kg/day ip). The simultaneous administration of indomethacin (10 mg/kg/day sc), OKY 046 (12 mg/kg/day sc) or aprotinin (100, 000 units/kg/day sc) did not affect the antihypertensive effect of MK 4–21 in rats made hypertensive by chronic infusion of norepinephrine or vasopressin. The present results suggest that the hypotensive effect of MK 421 may depend on a reduced sensitivity of the vasculature to vasoconstrictor substances. In addition, it is also suggested that neither the prostaglandin-thromboxane or kallikrein-kinin systems are essential for the antihypertensive effect of MK 421 in these models of hypertension.     

A very potent factor V inhibitor interferes with the levels of all coagulation factors and causes a fatal hemorrhagic syndrome

We report a very high factor V inhibitor affecting the measurement of all coagulation factors besides fibrinogen, all these factors being dramatically decreased. This inhibitor could be linked to antibiotic use. The patient died of massive hemorrhage before a plasma exchange could be initiated.     

The therapeutic approaches for hepatitis C virus: protease inhibitors and polymerase inhibitors

The current standard of care for hepatitis C infection is peginterferon/ribavirin (PegIFN/RBV). We are entering the era where direct-acting antiviral agents (DAAs) will be added to PegIFN/RBV, leading to higher sustained response rates in genotype 1 infected individuals. Currently DAAs are directed toward specific proteins involved in hepatitis C replication with NS3/NS4A protease inhibitors furthest in development. Telaprevir and boceprevir are both NS3/NS4a inhibitors that significantly improve sustained response when added to PegIFN and RBV. The hepatitis C virus (HCV) polymerase inhibitors are another promising DAA class. These molecules are divided into nucleoside/nucleotide polymerase inhibitors and nonnucleotide/nucleoside polymerase inhibitors. Nucleoside/nucleotide polymerase inhibitors have a high barrier to resistance and appear to be effective across a broad range of genotypes. Nonnucleoside polymerase inhibitors have a lower barrier of resistance and appear to be genotype specific. Preliminary data with these compounds are also promising. A third class, NS5A inhibitors, has also shown potent HCV RNA suppression in preliminary studies as monotherapy and with PegIFN and RBV. Combinations of these agents are also entering clinical trials and indeed a preliminary report has demonstrated that the combination of an NS3/4A protease inhibitor and NS5B polymerase inhibitor can effectively suppress virus in genotype 1 individuals. Future studies will concentrate on combinations of direct-acting antiviral agents without and with PegIFN and RBV. Clinicians will need to be familiar with managing side effects as well as resistance as we enter this new era.     

Remote loading of preencapsulated drugs into stealth liposomes

Loading drugs into carriers such as liposomes can increase the therapeutic ratio by reducing drug concentrations in normal tissues and raising their concentrations in tumors. Although this strategy has proven advantageous in certain circumstances, many drugs are highly hydrophobic and nonionizable and cannot be loaded into liposomes through conventional means. We hypothesized that such drugs could be actively loaded into liposomes by encapsulating them into specially designed cyclodextrins. To test this hypothesis, two hydrophobic drugs that had failed phase II clinical trials because of excess toxicity at deliverable doses were evaluated. In both cases, the drugs could be remotely loaded into liposomes after their encapsulation (preloading) into cyclodextrins and administered to mice at higher doses and with greater efficacy than possible with the free drugs.There is currently wide interest in the development of nanoparticles for drug delivery (1–7). This area of research is particularly relevant to cancer drugs, wherein the therapeutic ratio (dose required for effectiveness to dose causing toxicity) is often low. Nanoparticles carrying drugs can increase this therapeutic ratio over that achieved with the free drug through several mechanisms. In particular, drugs delivered by nanoparticles are thought to selectively enhance the concentration of the drugs in tumors as a result of the enhanced permeability and retention (EPR) effect (8–18). The enhanced permeability results from a leaky tumor vascular system, whereas the enhanced retention results from the disorganized lymphatic system that is characteristic of malignant tumors.Much current work in this field is devoted to designing novel materials for nanoparticle generation. This new generation of nanoparticles can carry drugs—particularly those that are insoluble in aqueous medium—that are difficult to incorporate into conventional nanoparticles such as liposomes. However, the older generation of nanoparticles has a major practical advantage in that they have been extensively tested in humans and approved by regulatory agencies such as the Food and Drug Administration in the United States and the European Medicines Agency in Europe. Unfortunately, many drugs cannot be easily or effectively loaded into liposomes, thereby compromising their general use.In general, liposomal drug loading is achieved by either passive or active methods (9, 19–22). Passive loading involves dissolution of dried lipid films in aqueous solutions containing the drug of interest. This approach can only be used for water-soluble drugs, and the efficiency of loading is often low. In contrast, active loading can be extremely efficient, resulting in high intraliposomal concentrations and minimal wastage of precious chemotherapeutic agents (9, 23, 24). In active loading, drug internalization into preformed liposomes is typically driven by a transmembrane pH gradient. The pH outside the liposome allows some of the drug to exist in an unionized form, able to migrate across the lipid bilayer. Once inside the liposome, the drug becomes ionized due to the differing pH and becomes trapped there (Fig. 1A). Many reports have emphasized the dependence of liposome loading on the nature of the transmembrane pH gradient, membrane–water partitioning, internal buffering capacity, aqueous solubility of the drug, lipid composition, and other factors (25–28). As described in a recent model (28), the aqueous solubility of the drug is one of the requirements for efficient active loading. Another key element for the success of remote loading is the presence of weakly basic functional groups on the small molecule.Open in a separate windowFig. 1.Schematic representation of active loading of a liposome. (A) Remote loading of an ionizable hydrophilic drug using a transmembrane pH results in efficient incorporation. (B) A poorly soluble hydrophobic drug results in meager incorporation into preformed liposomes under similar conditions. (C) Encapsulation of a poorly soluble drug into an ionizable cyclodextrin (R = H, ionizable alkyl or aryl groups) enhances its water solubility and permits efficient liposomal loading via a pH gradient.Only a small fraction of chemotherapeutic agents possesses the features required for active loading with established techniques. Attempts at active loading of such nonionizable drugs into preformed liposomes result in poor loading efficiencies (Fig. 1B). One potential solution to this problem is the addition of weakly basic functional groups to otherwise unloadable drugs, an addition that would provide the charge necessary to drive these drugs across the pH gradient. However, covalent modification of drugs often alters their biological and chemical properties, and is not desirable in many circumstances. We therefore attempted to develop a general strategy that would allow loading of unmodified hydrophobic chemotherapeutics devoid of weakly basic functional groups. For this purpose, we used modified β-cyclodextrins to facilitate the loading of such drugs into liposomes (Fig. 1C).Cyclodextrins are a family of cyclic sugars that are commonly used to solubilize hydrophobic drugs (29–32). They possess a hydrophobic cavity and a hydrophilic surface and are known to stably encapsulate a large variety of hydrophobic organic molecules in aqueous media. Cyclodextrins bind to their cargos strongly enough to form relatively stable complexes, but allow a slow efflux of the entrapped drug and consequent steady concentrations of free drug once administered in vivo (33, 34). Cyclodextrins are nontoxic and biologically inert, and several have been approved for use in humans (35–38).In this work, we synthesized cyclodextrins with multiple weakly basic or weakly acidic functional groups on their solvent-exposed surfaces. We hypothesized that these modified cyclodextrins would still be able to encapsulate chemotherapeutic agents and that the cyclodextrin–drug complexes could then be remotely loaded into liposomes using pH gradients that exploited ionizable groups on the cyclodextrins rather than on the drugs themselves.     

Biologic therapy in familial Mediterranean fever

Familial Mediterranean fever (FMF) is the most common autoinflammatory hereditary disease characterized by self-limited attacks of fever and serositis. Although colchicine is the gold standard treatment for the attacks ～10% of cases of FMF are resistant or intolerant to effective doses of colchicine. In such cases, however, there are increasing numbers of case reports or clinical trials treated by biologic agents which directly target the proinflammatory cytokines. Anti-interleukin-1 (IL-1) treatment has proven beneficial in improving the inflammation in terms of clinical manifestations and laboratory findings in clinical trials. Furthermore, anti-tumor necrosis factor treatment has also revealed the efficacy and safety in patients with colchicine-resistant FMF. More recently, cases of successful treatment with IL-6 inhibitor, tocilizumab (TCZ), has been reported from Japan and Turkey. Of note, TCZ may be preferable in the treatment as well as the prevention of secondary amyloidosis of FMF patients since it significantly suppresses acute inflammatory response. In the present review, we summarize the literatures regarding the efficacy of biologic therapy in colchicine-resistant or -intolerant patients with FMF.