Ultrasound microbubble contrast and current clinical applications

Ultrasound imaging is widely used worldwide principally because it is cheap, easily available and contains no exposure to ionizing radiation. The advent of microbubble ultrasound contrast has further increased the diagnostic sensitivity and specificity of this technique thus widening its clinical applications. The third generation of ultrasound contrast agents consist of sulphur hexafluoride microbubbles encased in a phospholipid shell. This review will elaborate on the pharmacology, safety profile and method of action of these agents. We also aim to discuss the ever expanding uses for contrast enhanced ultrasound in a number of clinical specialities which include the liver, kidney, prostate, sentinel node detection, vascular tree and endovascular stent surveillance. We will also discuss some of the recent patents regarding the future uses of ultrasound microbubble contrast and recent technological advances in clinical applications.     

Remacemide: current status and clinical applications

Remacemide (RMC) is a non-competitive, low-affinity N-methyl-D-aspartate (NMDA) receptor antagonist that does not cause the behavioural and neuropathological side effects seen with other NMDA receptor antagonists. RMC and its active metabolite, AR-R 12495 AR, which has moderate affinity for the NMDA receptor, also interact with voltage-dependent neuronal sodium channels. Both agents show efficacy in a variety of animal models of epilepsy, parkinsonism and cerebral ischaemia. There is no evidence for teratogenicity or genotoxicity. RMC delays the absorption of L-dopa and elevates the concentrations of drugs metabolised by the hepatic cytochrome P450 3A4 isoform. RMC and AR-R 12495 AR have moderate protein binding and linear pharmacokinetics. Controlled studies show evidence of efficacy in treating epilepsy and Parkinson’s disease. Post-surgical outcomes in RMC-treated patients at risk for intra-operative cerebral ischaemia are also encouraging. Adverse effects are related to the gastrointestinal and central nervous systems. RMC is a promising drug with numerous potential applications for both acute or chronic conditions associated with glutamate-mediated neurotoxicity.     

Remacemide: current status and clinical applications

Remacemide (RMC) is a non-competitive, low-affinity N-methyl-D-aspartate (NMDA) receptor antagonist that does not cause the behavioural and neuropathological side effects seen with other NMDA receptor antagonists. RMC and its active metabolite, AR-R 12495 AR, which has moderate affinity for the NMDA receptor, also interact with voltage-dependent neuronal sodium channels. Both agents show efficacy in a variety of animal models of epilepsy, parkinsonism and cerebral ischaemia. There is no evidence for teratogenicity or genotoxicity. RMC delays the absorption of L-dopa and elevates the concentrations of drugs metabolised by the hepatic cytochrome P450 3A4 isoform. RMC and AR-R 12495 AR have moderate protein binding and linear pharmacokinetics. Controlled studies show evidence of efficacy in treating epilepsy and Parkinson's disease. Post-surgical outcomes in RMC-treated patients at risk for intra-operative cerebral ischaemia are also encouraging. Adverse effects are related to the gastrointestinal and central nervous systems. RMC is a promising drug with numerous potential applications for both acute or chronic conditions associated with glutamate-mediated neurotoxicity.     

Oxcarbazepine: current status and clinical applications

Oxcarbazepine (OXC) was introduced in 1990 and is now registered in 54 countries worldwide as monotherapy, as add-on treatment for partial seizures, with or without secondarily generalised seizures, and primary generalised tonic-clonic seizures. OXC and its active metabolite, monohydroxy derivative (MHD), block voltage-dependent sodium channels and may effect potassium and calcium channels. In animal models of epilepsy, OXC and MHD have efficacy similar to that of CBZ. There is no evidence for clinically important teratogenicity, mutagenicity or carcinogenicity. OXC has no effect on serum concentrations of hepatically metabolised anti-epileptic drugs (AEDs) and no clinically important interactions with common non-AEDs, other than hormonal contraceptives. MHD has low protein binding and linear pharmacokinetics. Adverse effects (AEs) are usually related to the central nervous system. Approximately three-quarters of patients who experience adverse effects with CBZ improve when switched to OXC, without loss of seizure control. The incidence of rash appears to be less than that expected with CBZ. While hyponatraemia may occur more often with OXC than with CBZ, it is rarely symptomatic. OXC is an effective and safe drug for the treatment of partial-onset and primary generalised tonic-clonic seizures. Placebo- and low-dose controlled double-blind monotherapy studies prove that OXC has anticonvulsant activity and that therapeutic dosages may be obtained with a 24 h titration in hospitalised patients, if necessary. Comparative double-blind trials show that OXC has similar efficacy to VPA, CBZ and PHT, but has advantages compared to those agents in terms of pharmacokinetics, side-effects and tolerability.     

Oxcarbazepine: current status and clinical applications

Oxcarbazepine (OXC) was introduced in 1990 and is now registered in 54 countries worldwide as monotherapy, as add-on treatment for partial seizures, with or without secondarily generalised seizures, and primary generalised tonic-clonic seizures. OXC and its active metabolite, monohydroxy derivative (MHD), block voltage-dependent sodium channels and may effect potassium and calcium channels. In animal models of epilepsy, OXC and MHD have efficacy similar to that of CBZ. There is no evidence for clinically important teratogenicity, mutagenicity or carcinogenicity. OXC has no effect on serum concentrations of hepatically metabolised anti-epileptic drugs (AEDs) and no clinically important interactions with common non-AEDs, other than hormonal contraceptives. MHD has low protein binding and linear pharmacokinetics. Adverse effects (AEs) are usually related to the central nervous system. Approximately three-quarters of patients who experience adverse effects with CBZ improve when switched to OXC, without loss of seizure control. The incidence of rash appears to be less than that expected with CBZ. While hyponatraemia may occur more often with OXC than with CBZ, it is rarely symptomatic. OXC is an effective and safe drug for the treatment of partial-onset and primary generalised tonic-clonic seizures. Placebo- and low-dose controlled double-blind monotherapy studies prove that OXC has anticonvulsant activity and that therapeutic dosages may be obtained with a 24 h titration in hospitalised patients, if necessary. Comparative double-blind trials show that OXC has similar efficacy to VPA, CBZ and PHT, but has advantages compared to those agents in terms of pharmacokinetics, side-effects and tolerability.     

Recombinant human granulocyte macrophage colony-stimulating factor: current status of clinical trials and potential future applications.

Recombinant human granulocyte macrophage colony-stimulating factor (rhGM-CSF) was one of the first of the myeloid growth factors to become available for clinical trials. Phase I studies have demonstrated that the optimal administration is by continuous intravenous infusion or subcutaneous injections at doses of 4-5 micrograms/kg/day. Phase II trials in patients with a variety of malignancies who receive rhGM-CSF after standard doses of chemotherapy have demonstrated significant reductions of the duration of leucocytopenia. Use of rhGM-CSF after high-dose chemotherapy (with or without bone marrow rescue) suggest that this agent decreases the time to recovery of a normal blood count and reduces infective complications. Results in myelodysplasia and aplastic anemia have been less encouraging. The potential value of rhGM-CSF in the treatment of a variety of other conditions including AIDS and the leukemias is being tested and the early results are discussed.     

Adaptive clinical trials for new drug applications in Japan

Adaptive design is regarded as an efficient method for clinical trials in order to increase the success rate of a new drug in development, and recently has been actively discussed among regulatory agencies, industry and academia. Since adaptive design involves interim analyses and is more complex than traditional fixed design, some points such as possibility of introducing statistical and operational bias should be considered when planning and implementing such trials. In this article, we share our perspectives in the consideration of adaptive design clinical trials based on our experiences discussing adaptive design in clinical trial consultation meetings in Japan.     

我国儿童注册临床试验现状分析

目的：检索并调查中国临床试验注册中心的儿童临床试验现状。方法：计算机检索中国临床试验注册中心中以儿童为研究对象的临床试验,检索时间截止2014年4月。两名研究者独立筛选检索到的临床试验,并按预先设计的资料提取表提取疾病类型、资助基金和注册时间等内容,并将数据输入Excel,使用SPSS17.0软件进行统计分析。结果：检索获得儿童临床试验133项,儿童临床试验注册数量随着时间推移而不断增加;申请人所在单位为医院的为72项（54.1%）。93（69.9%）项的注册号状态是预注册,85.7%的试验获得伦理委员会的批准,政府经费资助的试验项目最多,占29.6%;干预措施类型中,药物干预最多（62,46.6 %）,干预性研究有78项（58.6 %）,随机平行对照试验占64.7%,仅24.8%的试验说明使用了盲法。试验资料收集、分析、管理单位为医院的试验项目数分别为47（35.1%）,45（33.8%）,33（24.6%）。结论：儿童临床数量在不断增加,且大部分儿童临床试验受政府资助,这将有助于减少部分偏倚,今后研究应该更多的关注注册的临床试验的注册质量问题,推动儿童临床试验的发展。     

Amifostine in clinical oncology: current use and future applications

Amifostine (Ethyol), an inorganic thiophosphate, is a selective broad-spectrum cytoprotector of normal tissues that provides cytoprotection against ionizing radiation and chemotherapeutic agents, thus preserving the efficacy of radiotherapy and chemotherapy. This review summarizes the preclinical data and clinical experience with amifostine, and provides insight into future clinical directions. Amifostine, an inactive pro-drug, is transformed to an active thiol after dephosphorylation by alkaline phosphatase found in the normal endothelium. The absence of alkaline phosphatase in the tumoral endothelium and stromal components, and the hypovascularity and acidity of the tumor environment, may explain its cytoprotective selectivity. The cytoprotective mechanism of amifostine is complicated, involving free radical scavenging, DNA protection and repair acceleration, and induction of cellular hypoxia. Intravenous administration of amifostine 740-900 mg/m(2) before chemotherapy and 250-350 mg/m(2) before each radiotherapy fraction are widely used regimens. The US Food and Drug Administration has approved the use of amifostine as a cytoprotector for cisplatin chemotherapy and for radiation-induced xerostomia. Ongoing trials are being conducted to determine the efficacy of amifostine in reducing radiation-induced mucositis and other toxicities. Novel schedules and routes of administration are under investigation, and may further simplify the use of amifostine and considerably broaden its applications.     

Non-inferiority clinical trials: Practical issues and current regulatory perspective

Non-inferiority clinical trials are being performed with an increasing frequency now-a-days, because it helps in finding a new treatment that have approximately the same efficacy, but may offer other benefits such as better safety profile. Non-inferiority clinical trials aim to demonstrate that the test product is no worse than the comparator by more than a pre-specified small amount. There are several fundamental differences between non-inferiority and superiority trials. Some practical issues concerning the non-inferiority trials are assay sensitivity, choice of the non-inferiority margin, sample size estimation, choice of active-control, and analysis of non-inferiority clinical trials. For serious infections such as hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia, community-acquired bacterial pneumonia, and acute bacterial skin and skin structure infections, the United States Food and Drug Administration (US FDA) has recently recommended that it is possible to define a reliable and consistent estimate of the efficacy of active treatment relative to placebo from available data, which can serve as the basis for defining a new inferiority margin for an active-controlled, non-inferiority trial. But for some indications with a high rate of resolution without antibacterial drug therapy such as acute bacterial sinusitis (ABS), acute bacterial exacerbation of chronic bronchitis (ABECB), and acute bacterial otitis media (ABOM), the US FDA has recommended that the available data will not support the use of a non-inferiority design and other trial designs (i.e., superiority designs) should be used to provide the evidence of effectiveness in these three indications.     

Vagus nerve stimulation: current status and clinical applications

Despite the recent introduction of new anti-epileptic drugs (AEDs), many patients with epilepsy, especially those with partial-onset seizures, continue to have seizures that are refractory to pharmacotherapy. Other patients are unable to tolerate the side-effects of AEDs given singly or in combination. Cerebral resective surgery may be an option for a sub-group of these patients; however, many patients with refractory partial epilepsy are not optimal candidates for epilepsy surgery. Consequently, the introduction of left vagus nerve stimulation (VNS) for those patients who have been afflicted by seizures or medication side-effects has opened up a new, non-pharmacological approach to epilepsy treatment. The mechanism of action of VNS is uncertain. VNS exerts an anticonvulsant effect in a variety of animal seizure models; has no effect on hepatic metabolic processes, serum concentrations of AEDS, or laboratory values; and has no clinically significant effect on vagally-mediated physiological processes. VNS is safe and well-tolerated in patients with long-standing, medically-refractory, partial-onset epilepsy. Adverse effects are usually mild to moderate in severity and related to stimulation, and almost always resolve with adjustment in stimulation settings. Controlled studies of patients on AED therapy show that adjunctive VNS is effective for partial-onset seizures when given every 5 min for 30 s intervals. Results of studies in paediatric patients are encouraging.     

The analysis of small-sample multivariate data with applications in clinical trials

This article discusses statistical methods for the analysis of multivariate data arising in clinical trials involving a small number of subjects randomly assigned to one of several treatment groups. Possible violations of traditional assumptions such as variance homogeneity and normality of errors are often dealt with by carrying out the statistical analysis using strategies such as transforming the data or applying nonparametric procedures. Multivariate nonparametric tests provide a realistic alternative for analyzing such data. We present a permutation procedure for analyzing data arising in randomized experiments     

Treating restless legs syndrome: current pathophysiological concepts and clinical trials

Restless legs syndrome is a distinctive clinical syndrome with a prevalence of about 5% in the general population. One of the outstanding characteristics of restless legs syndrome is its extreme responsiveness to dopaminergic agents. Together with the latest pathophysiological and genetic findings, recent epidemiological and clinical data give a new insight into the classification of restless legs syndrome, thus building the theoretical foundation for the development of new pharmacological methods in its treatment. Current efforts within this area focus on establishing dopaminergic substances for therapy. The hypothesis of a disturbed iron metabolism in restless legs syndrome has been revived by recent theoretical considerations. The present review attempts to explain current strategies of treatment for restless legs syndrome in relation to aetiological, genetic and pathophysiological findings.     

Laboratory and software applications for clinical trials: the global laboratory environment

The Applied Pharmaceutical Software Meeting is held annually. It is sponsored by The Boston Society, a not-for-profit organization that coordinates a series of meetings within the global pharmaceutical industry. The meeting generally focuses on laboratory applications, but in recent years has expanded to include some software applications for clinical trials. The 2011 meeting emphasized the global laboratory environment. Global clinical trials generate massive amounts of data in many locations that must be centralized and processed for efficient analysis. Thus, the meeting had a strong focus on establishing networks and systems for dealing with the computer infrastructure to support such environments. In addition to the globally installed laboratory information management system, electronic laboratory notebook and other traditional laboratory applications, cloud computing is quickly becoming the answer to provide efficient, inexpensive options for managing the large volumes of data and computing power, and thus it served as a central theme for the meeting.     

A review of the current clinical trials for gastroenteropancreatic neuroendocrine tumours

Neuroendocrine tumours of the gastroenteropancreatic axis include carcinoid tumours and islet cell tumours of the pancreas (pancreatic endocrine tumours). Standard medical therapies prescribed for these malignancies include long-acting somatostatin analogues (octreotide and lanreotide) for the palliation of hormonal syndromes; cytotoxic agents (streptozocin, dacarbazine, adriamycin and 5-fluorouracil), which are primarily for the management of advanced islet cell tumours; and hepatic artery embolisation or chemoembolisation for the treatment of liver metastases. Clinical research promises to expand this therapeutic armamentarium. Most of the experimental treatments that are being evaluated in human clinical trials fall into the following categories: angiogenesis inhibitors, novel somatostatin analogues, radiolabelled somatostatin analogues, mTOR inhibitors and novel cytotoxic agents. This review summarises the present scope of clinical research in this field.     

A review of the current clinical trials for gastroenteropancreatic neuroendocrine tumours

Neuroendocrine tumours of the gastroenteropancreatic axis include carcinoid tumours and islet cell tumours of the pancreas (pancreatic endocrine tumours). Standard medical therapies prescribed for these malignancies include long-acting somatostatin analogues (octreotide and lanreotide) for the palliation of hormonal syndromes; cytotoxic agents (streptozocin, dacarbazine, adriamycin and 5-fluorouracil), which are primarily for the management of advanced islet cell tumours; and hepatic artery embolisation or chemoembolisation for the treatment of liver metastases. Clinical research promises to expand this therapeutic armamentarium. Most of the experimental treatments that are being evaluated in human clinical trials fall into the following categories: angiogenesis inhibitors, novel somatostatin analogues, radiolabelled somatostatin analogues, mTOR inhibitors and novel cytotoxic agents. This review summarises the present scope of clinical research in this field.     

Oncolytic viruses for the treatment of cancer: current strategies and clinical trials

Tumor-selective replicating viruses offer appealing advantages over conventional cancer therapy and are a promising new approach for the treatment of human cancer. The development of virotherapeutics is based on several strategies that each provides a different foundation for tumor-selective targeting and replication. Results emerging from clinical trials with oncolytic viruses demonstrate the safety and feasibility of a virotherapeutic approach and provide early indications of efficacy. Strategies to overcome potential obstacles and challenges to virotherapy are currently being explored and are discussed here. Importantly, the successful development of systemic administration of oncolytic viruses will extend the range of tumors that can be treated using this novel treatment modality.     

我国创新性抗菌药物临床试验现状及发展的探讨

在整个药物研发过程中,创新性抗菌药物的临床试验占有非常重要的地位。本文对目前我国创新药临床试验现状进行探讨,并结合负责起草的新版《抗菌药物临床试验技术指导原则》的认知,展望未来发展方向,旨在促进研发与评价。