The plasma coagulation cascade: potential targets for novel anticoagulants in major lower limb surgery

Strategies for prevention of venous thromboembolism in orthopaedic patients undergoing major lower limb surgery include pharmacological prophylaxis. Over the last three decades, the search for new safe and effective approaches for the prevention of venous thromboembolism in these patients has continued. Increased understanding of the haemostatic process has led to a clearer appreciation of the mechanisms of action of antithrombotic drugs already in use as well as the identification of new targets for novel drug development. As a result, the development of new anticoagulants has advanced rapidly over recent years. The molecular targets of several novel anticoagulants, and their effectiveness in early Phase II and Phase III trials are reviewed.     

Novel and emerging drugs for acute myeloid leukemia

Acute myeloid leukemia (AML) is a challenging disease to treat with the majority of patients dying from their illness. While overall survival has been markedly prolonged in acute promyelocytic leukemia (APL), survival in younger adults with other subtypes of AML has only modestly improved over the last twenty years. Physicians who treat AML eagerly await drugs like Imatinib for chronic myeloid leukemia, Cladribine for hairy cell leukemia, and Rituximab for non-Hodgkin Lymphoma which have had an important impact on improving outcome. Recent research efforts have focused on refining traditional chemotherapeutic agents to make them more active in AML, targeting specific genetic mutations in myeloid leukemia cells, and utilizing novel agents such as Lenalidomide that have shown activity in other hematologic malignancies. Here, we focus on reviewing the recent literature on agents that may assume a role in clinical practice for patients with AML over the next five years.     

Novel and emerging drugs for chronic lymphocytic leukemia

During the last decades advanced treatment options for chronic lymphocytic leukemia have enabled the shift from rather ineffective palliative treatment to therapies that are aiming for long lasting complete remission and prolongation of survival. This remarkable progress was achieved by combining conventional chemotherapy with monoclonal antibodies such as rituximab and alemtuzumab. Despite this improvement, CLL remains an incurable disease and all patients will eventually relapse and become refractory to treatment. Allogeneic stem cell transplantation is the only curative option but is feasible only in a minority of patients due to the comorbidity and impaired physical fitness of many patients, since the mean age at first diagnosis lies between 70 and 75 years. Therefore, novel less-toxic therapeutic agents are needed, particularly for patients with comorbidities or high-risk cytogenetic abnormalities. Research in the field of CLL and growing understanding of the pathogenesis of B-cell lymphomas has produced a wide variety of new substances for different targets, e.g. different novel monoclonal antibodies, immunomodulatory agents and inhibitors targeting different kinases of B-cell receptor signalling cascade, such as Bruton tyrosine kinase (BTK) and phosphatidylinositol-3-kinase (PI3K). This article reviews novel drugs that were recently developed for the use in CLL. The agents discussed in this article were selected for having already shown preliminary evidence of clinical activity.     

Novel and emerging drugs for acute lymphoblastic leukemia

Over the past several decades the important progress has been made in the management of acute lymphoblastic leukemia (ALL), especially among children. However, in adult patients reported cure rates seldom exceeded 40%, despite the use of hematopoietic stem-cell transplantation in many cases. Conventional chemotherapy is toxic and ineffective. Therefore, new treatment options and risk-adapted therapies are needed to improve the outcome of ALL patients. This review is focused on new systemic treatment modalities, such as nucleoside analogues, purine synthetase inhibitors, monoclonal antibodies, tyrosine kinase inhibitors and other agents targeting molecular pathways that are aimed to benefit patients and improve the outcome of their treatment.     

新型口服抗凝药物的药动学特性及其临床应用案例

近年来,新型口服抗凝药物成为治疗血栓栓塞性疾病的主要抗凝方案,较维生素K拮抗剂,其具有较高的抗凝效果,使抗凝抗栓方法获得较多新选择。目前,新型口服抗凝药物种类较多、半衰期短,不同药物之间的药物作用不同,治疗效果也不同。因此,本文对希美加群（已撤市）、达比加群酯、利伐沙班、阿哌沙班的药动力学进行分析,并对不同抗凝药物临床应用现状进行阐明,以此在最大程度上保障新型口服抗凝药物在临床实践中的应用合理性。     

Novel and emerging drugs for rarer chronic lymphoid leukaemias

Rarer chronic lymphoid leukaemias represent a challenge to the clinicians due to the limited information on their pathogenesis, difficulties on setting up prospective clinical trials and to their refractoriness to drugs used in the most common form of chronic lymphocytic leukaemia (CLL). In this review all these issues are addressed in three B-cell leukaemias: B-cell prolymphocytic leukaemia (B-PLL), hairy cell leukaemia (HCL) and HCL-variant and three T-cell leukaemias: T-cell prolymphocytic leukaemia (T-PLL), T-cell large granular lymphocytic leukaemia (T-cell LGLL) and adult T-cell leukaemia lymphoma (ATLL). Data will be presented on the natural history, current therapies and emerging drugs potentially useful in the treatment of patients with these leukaemias. Emphasis is made on: 1- the novel agents targeting a variety of B and T-cell antigens expressed on the surface of the leukaemic cells; these are either unconjugated monoclonal antibodies (McAb) such as Rituximab (anti-CD20), the second and third generation of anti-CD20 McAbs, Alemtuzumab (anti-CD52), Siplizumab (anti-CD2), Daclizumab (anti-CD25) and KW-0761, an anti-chemokine receptor 4 (CCR4) or McAbs conjugated to toxins such as CD22 linked to the pseudomonas exotoxin or radiolabelled McAb; 2- the use of new purine nucleosides such as nelarabine and 3- agents targeting deregulated genes in the leukaemic cells from these diseases such as the Poly (ADP-ribose) polymerase (PARP) Olarapib in T-PLL with deregulation of the ataxia telangiectasia mutated (ATM) gene. Data of phase I and II clinical studies with these agents as well as the potential and current use of other drugs are outlined.     

Novel oral anticoagulants and their role in clinical practice

The complexities of oral anticoagulation with warfarin have led to the search for more practical alternative agents. Novel direct factor IIa inhibitors and direct factor Xa inhibitors currently in development can be administered at a fixed dose and do not require routine coagulation monitoring and ongoing dosage adjustment to ensure their effectiveness and safety. A number of phase III trials of these agents for the prevention of venous thromboembolism associated with orthopedic surgery and acute medical illness, for the treatment of venous thromboembolism, and for stroke prevention in patients with atrial fibrillation have been completed, with almost universally positive results. If these novel agents are approved for use in the United States, the future of oral anticoagulant therapy will allow a more nuanced approach to drug selection than has been available in the past. Attention to drug interactions and renal function will be required, as methods to measure the presence of these agents are not precise, cannot quantify the degree of anticoagulant present, and are influenced by the changes in serum drug concentrations during the dosing interval. In the future, patient preferences and the pharmacokinetic and pharmacodynamic characteristics of individual drugs will be able to be matched to optimize therapy. These new agents represent a new paradigm for anticoagulation that promises to improve patient care in the long term.     

Novel and emerging drugs for acute myeloid leukemia: pharmacology and therapeutic activity

For the last twenty years, significant progress in Molecular and Cellular Biology has resulted in a better characterization and understanding of the biology and prognosis of acute myeloid leukemia (AML). These achievements have provided new opportunities for the development of innovative, more effective therapies. Novel agents potentially useful in the treatment of patients with AML include new formulations of established drugs, newer nucleoside analogs, molecular target drugs, monoclonal antibodies and other agents. Three newer nucleoside analogs, clofarabine, troxacitabine and sapacitabine have been recently investigated in patients with AML. Two methylation inhibitors, 5-azacyticline and decitabine are pyrimidine nucleoside analogs of cytidine which can be incorporated into RNA and/or DNA. Lower doses of these agents are active in AML and have been extensively investigated, especially in secondary AML and AML in elderly patients. Tipifarnib and lonafarnib are orally available farnesyltransferase inhibitors with in vitro and in vivo activity against AML. In recent years, FLT3 inhibitors, lestaurinib, tandutinib and PKC 412 have been developed and tested in AML. The preclinical observations and clinical studies indicate that FLT3 inhibitors are promising agents in the treatment of FLT3 mutated AML patients, especially when used in combinations with chemotherapy. Several newer MDR inhibitors, including valspodar (PSC-833) and zosuquidar trihydrochloride have been also tested for the treatment of relapsed AML. This article reviews the various classes of AML targets and drugs that are under early phase clinical evaluation, especially those that are likely to enter clinical practice in the near future.     

Inflammation and beyond: new directions and emerging drugs for treating atherosclerosis

Introduction: Cardiovascular (CV) atherosclerotic disease remains the leading cause of morbidity and mortality worldwide, despite the advances in contemporary therapies. Inflammation is an important process in atherosclerosis, leading to plaque rupture and acute coronary syndrome. Although statin therapy has substantially reduced CV events in primary and secondary prevention, many treated patients will have recurrent adverse CV events despite the standard of care. Thus, drug development aiming to target inflammatory pathways seems a promising avenue for novel therapies in atherosclerosis.

Areas covered: Statins have been extensively studied and are the most effective lipid-lowering drugs available for CV prevention. Novel anti-inflammatory drugs are being tested in Phase II and III trials, targeting pathways like interleukin-1, leukotrienes, TNF-α, P-selectin, CCL2-CCR2 and MAP Kinase.

Expert opinion: Novel anti-inflammatory therapies seem promising additions to address the residual CV risk present despite the current standard of care, but large clinical trials have not yet shown beneficial effects on clinical events. PCSK9 inhibitors have been shown to substantially reduce LDL-C, however their long-term safety and effects on CV risk are currently being investigated. Pharmacogenomics holds great potential in future lipid trials, enabling the identification of patients who will respond with greater benefits and smaller risk to therapies and to decrease failure rates in drug development, as genotype-dependent effects of the CETP inhibitor dalcetrapib were shown in the dal-OUTCOMES and dal-PLAQUE-2 trials.     

Opioids: old drugs for potential new applications

Opioids are commonly used analgesics in clinical practice. Three opioid receptors (mu, delta and kappa) that mediate opioid effects have been identified by molecular cloning. Each type of opioid receptors consists of subtypes of receptors as suggested by pharmacological studies. Although mu opioid receptors are the major receptor to mediate the analgesic effects of opioids, delta and kappa receptors are also important in anti-nociception (for example, delta and kappa receptors can mediate spinal analgesia). Recently, the cytoprotective effects of opioids have been recognized. The presence of opioids during harmful events such as ischemia reduces cell injury in multiple organs including heart and brain. These effects appear to be mediated by delta receptors in most studies. A new form of cytoprotection in which a prior exposure to opioids renders protection against cell ischemia (opioid preconditioning) has been identified. In the heart, this opioid preconditioning-induced protection has been well documented by multiple studies and may be mediated by delta receptors, G(i/o) proteins, protein kinase C, ATP-sensitive potassium channels and free radicals. Our initial study suggests that opioid preconditioning also induces neuroprotection. This neuroprotection involves delta(1) receptors, mitochondrial ATP-sensitive potassium channels and free radical production. In this review, we will briefly describe the analgesic effects of opioids. We will focus our discussion on opioid preconditioning-induced protection and its mechanisms. Opioids and agents that specifically work on the signaling molecules for opioid preconditioning-induced protection may prove to be useful in inducing protection against ischemia in clinical practice.     

舒芬太尼复合左布比卡因蛛网膜下腔麻醉在下腹部或下肢手术中的应用

目的：评估舒芬太尼复合左布比卡因蛛网膜下腔麻醉在下腹部或下肢手术中的临床效果。方法：将120例ASAⅠ—Ⅱ择期行下腹部或下肢手术患者随机分为4组,每组30例。Ⅰ组：0.75%左布比卡因12㎎＋舒芬太尼2 μg;Ⅱ组：0.75%左布比卡因12㎎＋舒芬太尼4 μg;Ⅲ组：0.75%左布比卡因12㎎＋舒芬太尼6 μg;Ⅳ组：0.75%左布比卡因15㎎行蛛网膜下腔麻醉。观察感觉阻滞起效时间、感觉阻滞平面上界、运动阻滞起效时间、运动阻滞程度、镇痛维持时间（T10）、运动阻滞恢复时间、血液动力学影响及不良反应情况。结果：Ⅰ组感觉阻滞起效时间、运动阻滞起效时间长于Ⅱ组、Ⅲ组、Ⅳ组(P＜0.05),镇痛维持时间（T10）短于其它组(P＜0.05);Ⅰ组、Ⅱ组、Ⅲ组用药后血液动力学影响小,运动阻滞恢复时间短于Ⅳ组(P＜0.05);Ⅱ和Ⅲ组麻醉效果相当;4组恶心、头痛、呼吸抑制等不良反应无明显差异。结论：舒芬太尼4 μg复合左布比卡因12㎎蛛网膜下腔麻醉可提供良好的麻醉效果,安全性高。     

Novel and emerging drugs for systemic lupus erythematosus: mechanism of action and therapeutic activity

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by B cell hyperactivity and defective T-cell function, and several cytokine aberrations, with high titer production of autoantibodies and clinical involvement in multiple organ systems. It can present with a wide variety of symptoms, most commonly involving the skin, joints, kidneys, and blood vessels. Patients with mild SLE can be treated with non-steroidal antiinflammatory drugs and antimalarials. Corticosteroids, azathioprine and cyclophosphamide, remain important for long term management of most patients with active disease. In recent years, significant progress in molecular and cellular biology of SLE has resulted in a better characterization and understanding of the biology and prognosis of this disease. These achievements have provided new opportunities for the development of innovative, more effective, therapies. Novel agents potentially useful in the treatment of patients with SLE include tolerogens, monoclonal antibodies and other agents. Tolerogens are synthetic molecules that can bind and cross-link autoantibodies on reactive B-cell surface, promoting B-cell depletion or inactivity. An anti-DNA antibody based peptide, pCons, might have also therapeutic efficacy in SLE patients who are positive for anti-DNA antibodies. In addition, prasterone, a proprietary synthetic dehydroepiandrosterone product is under investigation for the treatment of SLE. Blockade of TLR9 with specific G-rich DNAoligonucleotids also suppresses lupus activity. Several newer mAbs have been developed and are being evaluated in phase I/II clinical trials. These include newer anti-CD20 mAbs, anti-cytokine therapies, anti-BLys mAbs and anti-C5 mAbs. Most of the new agents which could be potentially useful in the treatment of patients with SLE need further laboratory investigations and clinical trials. In this review, promising new agents, potentially useful in SLE, are presented.     

Safety and efficacy of rivaroxaban for thromboprophylaxis following lower limb surgery: an update

Introduction: Thromboprophylaxis in orthopedic surgery remains a controversial issue despite recent changes to NICE guidelines, particularly with the addition of oral factor Xa inhibitors. The healthcare burden of venous thromboembolism is substantial and needs frequent academic and clinical appraisal.

Areas covered: The authors review the available relevant literature on the use of rivaroxaban in orthopedic surgery, identified using an EMBASE (1980 – 2010) and Ovid MEDLINE (1950 – 2010) search of published articles up to August 2010. This includes clinical studies, case reports and experimental studies where applicable. Search terms include: ‘rivaroxaban’, ‘safety’, ‘efficacy’, ‘bleeding’, ‘toxicity’, ‘tolerability’ and ‘complication’.

Expert opinion: Rivaroxaban is a safe and effective choice of thromboprophylactic agent following lower limb arthroplasty surgery. More research is required to expand the application of this novel agent to other areas of orthopedic surgery.     

Safety and efficacy of rivaroxaban for thromboprophylaxis following lower limb surgery: an update

INTRODUCTION: Thromboprophylaxis in orthopedic surgery remains a controversial issue despite recent changes to NICE guidelines, particularly with the addition of oral factor Xa inhibitors. The healthcare burden of venous thromboembolism is substantial and needs frequent academic and clinical appraisal. AREAS COVERED: The authors review the available relevant literature on the use of rivaroxaban in orthopedic surgery, identified using an EMBASE (1980 - 2010) and Ovid MEDLINE (1950 - 2010) search of published articles up to August 2010. This includes clinical studies, case reports and experimental studies where applicable. Search terms include: 'rivaroxaban', 'safety', 'efficacy', 'bleeding', 'toxicity', 'tolerability' and 'complication'. EXPERT OPINION: Rivaroxaban is a safe and effective choice of thromboprophylactic agent following lower limb arthroplasty surgery. More research is required to expand the application of this novel agent to other areas of orthopedic surgery.     

单侧腰麻在高龄患者下肢手术中的应用

目的 探讨单侧腰麻在高龄患者髋及下肢手术的可行性和安全性.方法 择期高龄患者髋及下肢手术30例,年龄71～85岁,男性20例,女性10例,体重45～65 kg,ASAⅢ～Ⅳ级,随机分为单侧腰麻USA组(U组)和硬膜外CEA组(C组),每组15例.穿刺点选择L3～4或L2～3椎间隙,U组取患侧卧位,抽取0.75%布比卡因1.8 ml加50%GS 0.2 ml以0.1 ml/秒速度注入,注药后取原体位卧10 min.C组常规硬膜外麻醉,以2%利多卡因2 ml为试验量,根据麻醉平面及患者反应追加全量0.5%布比卡因12～15 ml.记录麻醉起效时间,阻滞完全时间和辅助用药例数、腰麻后头痛、马尾综合症、恶心呕吐和布比卡因用量.结果 两组患者年龄、体重、性别比、手术时间和输液量差异无显著性,两组血流动力学比较,差异无显著性,两组麻醉效果比较:腰麻组麻醉起效时间1.06±0.58 min,硬膜外组5.07±1.23 min;阻滞完善时间腰麻组6.71±2.27 min,硬膜外组18.74±4.83 min;辅助用药腰麻组2例,硬膜外组13例;布比卡因用量U组9.21±0.42 mg,C组69.48±4.52 mg,以上结果硬膜外组与腰麻组比较(P＜0.05),差异均有显著性.两组术后均无头痛、恶心呕吐、尿潴留、马尾综合症等并发症.结论 只要掌握好适应症,麻醉中精心管理,单侧腰麻用于高龄患者也是安全可靠的麻醉方法之一.     

Novel antimalarial drug targets: hope for new antimalarial drugs

Malaria is a major global threat, that results in more than 2 million deaths each year. The treatment of malaria is becoming extremely difficult due to the emergence of drug-resistant parasites, the absence of an effective vaccine, and the spread of insecticide-resistant vectors. Thus, malarial therapy needs new chemotherapeutic approaches leading to the search for new drug targets. Here, we discuss different approaches to identifying novel antimalarial drug targets. We have also given due attention to the existing validated targets with a view to develop novel, rationally designed lead molecules. Some of the important parasite proteins are claimed to be the targets; however, further in vitro or in vivo structure–function studies of such proteins are crucial to validate these proteins as suitable targets. The interactome analysis among apicoplast, mitochondrion and genomic DNA will also be useful in identifying vital pathways or proteins regulating critical pathways for parasite growth and survival, and could be attractive targets. Molecules responsible for parasite invasion to host erythrocytes and ion channels of infected erythrocytes, essential for intra-erythrocyte survival and stage progression of parasites are also becoming attractive targets. This review will discuss and highlight the current understanding regarding the potential antimalarial drug targets, which could be utilized to develop novel antimalarials.     

Novel avenues for treating diabetic nephropathy: new investigational drugs

Introduction: At present, treatment of diabetic kidney disease (DKD) is still mainly based on drugs acting on glycemic and blood pressure control, as there is no validated therapy able to halt the progression of renal failure. Because of the high incidence of DKD, due to the increase of diabetes mellitus in general population, new therapeutic strategies are needed.

Areas covered: We analysed ongoing and already completed clinical trials, from clinicaltrials.gov and PubMed, dealing with new therapies for DKD.

Expert opinion: Among the drugs currently being explored, the most promising molecules are those that interfere with glucose-dependent pathways, in particular polyol, protein kinase, hexosamine and AGEs metabolic pathways, and impaired renal vascular regulation. One of the recent goals achieved by molecular biology is the development of monoclonal antibodies able to interfere with extracellular matrix accumulation and fibrosis. Other interesting therapies are under investigation and further studies with a greater number of patients will establish a better approach for diabetic nephropathy.     

Novel antimalarial drug targets: hope for new antimalarial drugs

Malaria is a major global threat, that results in more than 2 million deaths each year. The treatment of malaria is becoming extremely difficult due to the emergence of drug-resistant parasites, the absence of an effective vaccine, and the spread of insecticide-resistant vectors. Thus, malarial therapy needs new chemotherapeutic approaches leading to the search for new drug targets. Here, we discuss different approaches to identifying novel antimalarial drug targets. We have also given due attention to the existing validated targets with a view to develop novel, rationally designed lead molecules. Some of the important parasite proteins are claimed to be the targets; however, further in vitro or in vivo structure-function studies of such proteins are crucial to validate these proteins as suitable targets. The interactome analysis among apicoplast, mitochondrion and genomic DNA will also be useful in identifying vital pathways or proteins regulating critical pathways for parasite growth and survival, and could be attractive targets. Molecules responsible for parasite invasion to host erythrocytes and ion channels of infected erythrocytes, essential for intra-erythrocyte survival and stage progression of parasites are also becoming attractive targets. This review will discuss and highlight the current understanding regarding the potential antimalarial drug targets, which could be utilized to develop novel antimalarials.     

Editorial : novel and emerging drugs for leukemias

For the last twenty years, significant progress in molecular and cellular biology has resulted in a better characterization and understanding of the molecular abnormalities in leukemias. These achievements have provided new opportunities for the development of innovative, more effective drugs. Novel therapies are being evaluated both in preclinical studies and in early clinical trials. In this editorial, we demonstrate a brief review of the present insights into new therapeutic strategies for acute and chronic leukemias.