Model Features of a Cardiac lontophoretic Drug Delivery Implant

Pharmaceutical Research -     

国产注射用盐酸瑞芬太尼有效性和安全性的评价

目的 采用随机、对照、双盲、多中心的Ⅱ期临床试验,评价国产注射用盐酸瑞芬太尼的有效性和安全性。方法201名受试者分成两组:对照组使用静脉芬太尼(2.5μkg诱导,0.03μg·kg-1·min-1维持)复合吸入66％氧化亚氮麻醉,试验组使用静脉瑞芬太尼(2μg/kg诱导,0.2μ·kg-1·min-1维持)复合吸入66％氧化亚氮麻醉。药物有效性的观察指标有:手术刺激时的应激反应,如血压、心率、流泪、麻醉质量。安全性的观察指标有:血压和心率、麻黄碱、阿托品、纳洛酮、乌拉地尔的使用量、手术失血量、心电图变化、术前和术后48 h内血中ALT、AST、肌酐、尿素氮、停止麻醉到可以拔除气管导管的时间、拔除气管导管前的PETCO2或PaCO2、停止麻醉(关闭氧化亚氮)后呼唤名字可以睁眼时间、术后送往麻醉恢复室或ICU情况以及不良事件。结果 瑞芬太尼与芬太尼在本试验剂量下,药效作用相似,但镇痛作用瑞芬太尼强于芬太尼,停止输注后其作用消退快于芬太尼。结论 国产瑞芬太尼用于全麻可产生良好的镇痛作用,且具有与芬太尼相同的安全性。     

Sampling Patients Within and Across Health Care Providers: Multi-Stage Non-Nested Samples in Health Services Research

In order to better inform study design decisions when sampling patients within and across health care providers we develop a simulation-based approach for designing complex multi-stage samples. The approach explores the tradeoff between competing design goals such as precision of estimates, coverage of the target population and cost.We elicit a number of sensible candidate designs, evaluate these designs with respect to multiple sampling goals, investigate their tradeoffs, and identify the design that is the best compromise among all goals. This approach recognizes that, in the practice of sampling, precision of the estimates is not the only important goal, and that there are tradeoffs with coverage and cost that should be explicitly considered. One can easily add other goals. We construct a sample frame with all phase III clinical cancer treatment trials that are conducted by cooperative oncology groups of the National Cancer Institute from October 1, 1998 through December 31, 1999. Simulation results for our study suggest sampling a different number of trials and institutions than initially considered.Simulations of different study designs can uncover efficiency gains both in terms of improved precision of the estimates and in terms of improved coverage of the target population. Simulations enable us to explore the tradeoffs between competing sampling goals and to quantify these efficiency gains. This is true even for complex designs where the stages are not strictly nested in one another.     

异丙酚及氯胺酮靶控输注全静脉麻醉临床应用

目的　研究异丙酚复合不同镇痛剂量氯胺酮靶控输注全静脉麻醉临床应用的可行性及对血流动力学、麻醉恢复的影响。方法　择期手术患者 80例 ,分别采用异丙酚 (P组 ,n =16)及复合氯胺酮血药浓度 0 2 0mg/L(PK1组 ,n =16) ,0 40mg/L(PK2 组 ,n =16) ,0 60mg/L(PK3 组 ,n =16)和 0 80mg/L(PK4组 ,n =16)全静脉麻醉 ,采用微机控制Graseby 3 5 0 0输液泵靶控输注异丙酚或氯胺酮 ,连接Aspect-A10 0 0型脑电监护仪监测脑电变化 ,观察两组患者血流动力学改变及麻醉恢复情况。结果　单用异丙酚患者随着异丙酚血药浓度升高脑电双频指数 (BIS)值降低 ,呈明显负相关 (P <0 0 5 ) ,氯胺酮血药浓度从 0 2 0mg/L增至 0 80mg/L ,BIS值无明显变化 (P >0 0 5 )。与P组相比 ,PK1,PK2 ,PK3 ,PK4组异丙酚用量减少约 15 %～ 40 % ,PK4组停药至睁眼时间明显延长 ,其余各组无明显差异 (P >0 0 5 )。术中P ,PK1组收缩压、舒张压升高 ,PK2 ,PK3 ,PK4组无明显改变。术后无躁动、不良回忆等并发症。结论　异丙酚复合镇痛剂量的氯胺酮 (0 40～ 0 60mg/L)靶控输注全静脉麻醉具有血流动力学稳定、减少异丙酚用量、无明显术后并发症等优点。     

Reports of Large Immunosuppression Trials in Kidney Transplantation: Room for Improvement

The reporting quality of publications of clinical trials can affect the quality of clinical decision-making. We systematically assessed the quality of publications of large multicenter trials evaluating immunosuppressive regimens in de novo kidney transplantation. Study quality, reporting quality and accessibility of the results of 63 publications were assessed independently by three blinded investigators using an instrument combining the Jadad scale with a list of reporting quality items. Study quality was rated with an average of only 2.3 (range 1-5) on the Jadad scale. Unblinded studies were reported in 68.3% of publications and follow-up longer than 12 months was reported for only 13 out of 50 studies. The reviewed publications fulfilled an average of 69.1% of the reporting quality criteria. Fifty-four percent of publications did not report both treated and biopsy-proven rejections. Whether reported graft survival was censored for death could not be determined for 27% of publications. Only a few publications gave confidence intervals (CIs) or stated whether additional analyses were pre-specified. Even the largest trials of immunosuppression in kidney transplantation show considerable quality deficits in their design and publication. Additional efforts are required of investigators, editors and sponsors to achieve maximum study and reporting quality.     

Post-polio syndrome patients treated with intravenous immunoglobulin: a double-blinded randomized controlled pilot study

Post-polio syndrome (PPS) is characterized by new muscle weakness, atrophy, fatigue and pain developing several years after the acute polio. Some studies suggest an ongoing inflammation in the spinal cord in these patients. From this perspective, intravenous immunoglobulin (IvIg) could be a therapeutic option. We performed a double-blinded randomized controlled pilot study with 20 patients to investigate the possible clinical effects of IvIg in PPS. Twenty patients were randomized to either IvIg 2 g/kg body weight or placebo. Primary endpoints were changes in pain, fatigue and muscle strength 3 months after treatment. Surrogate endpoints were changes in cerebrospinal fluid (CSF) cytokine levels. Secondary endpoints were pain, fatigue and isometric muscle strength after 6 months. Patients receiving IvIg reported a significant improvement in pain during the first 3 months, but no change was noted for subjective fatigue and muscle strength. CSF levels of tumour necrosis factor- α (TNF- α ) were increased compared with patients with non-inflammatory neurological disorders. In conclusion, in this small pilot study no effect was seen with IvIg treatment on muscle strength and fatigue, however IvIg treated PPS patients reported significantly less pain 3 months after treatment. TNF- α was increased in the CSF from PPS patients. The results are promising, but not conclusive because of the low number of patients studied.     

Improving clinical trial design for hepatocellular carcinoma treatments

Despite its place as the third leading cause of cancer deaths worldwide, there are currently no approved chemotherapeutic agents, devices or techniques to treat hepatocellular carcinoma. Importantly, there have been no phase III studies demonstrating survival benefit, nor any randomized studies of treatment except for transarterial chemoembolization and most recently sorafenib. The importance of well-designed clinical trials of agents to treat HCC has never been greater. However, general clinical study design issues, combined with HCC-specific issues pose significant challenges in structuring such studies. HCC-related challenges include the heterogeneity of this cancer and the fact that it is frequently accompanied by significant comorbidities at diagnosis, such as active hepatitis B or C virus replication, substantial past or on-going alcohol use, and cirrhosis, itself often a fatal disease. The recently published comparison of a newer treatment, nolatrexed to doxorubicin, and comments about this study’s initial HCC diagnostic criteria, staging system, comparator therapy and choice of endpoints have provided a platform to discuss the challenges unique to the design of HCC clinical trials. The difficulty in accurately framing study results obtained from the constantly changing HCC clinical landscape and approaches to meet these challenges will be reviewed.     

Cholesterol reduction and death from noncoronary causes: evidence from randomised controlled trials*

An overview of randomised trials of cholesterol reduction (26 trials, 50,000 patients, net cholesterol reduction ?10%) provides clear evidence of a reduction in the incidence of coronary heart disease (CHD) after just a few years of treatment. Overall, the observed reduction in CHD death (9%± 3) was only half as large as the reduction in non-fatal myocardial infarction (19%±4), although both were statistically significant (2p <0.005). In these trials, 60% of all deaths were from CHD, and since treatment reduced these by about 9%, the expected reduction in total deaths was about 5–6%. This expected reduction falls within the 95% confidence interval of the observed effect of cholesterol reduction on total mortality in these trials. There were small excesses of deaths from cancer and deaths from trauma among patients allocated active treatment. However, in no single trial, nor in the trials collectively, were these increases individually statistically significant. Furthermore, the increases did not appear to be specific to any one agent nor were the increases consistent between trials of the same agent. These observations suggest that the small excesses of noncoronary deaths observed in the cholesterol reduction trials may have occurred by chance. Evidence from ongoing longer-term studies of treatments producing larger cholesterol reductions will be useful in further delineating the effects, if any, of such treatments on non-coronary mortality.     

Evaluation of hypothesis testing for comparing two populations using NONMEM analysis

In a simulation study of inference on population pharmacokinetic parameters, two methods of performing tests of hypotheses comparing two populations using NONMEM were evaluated. These two methods are the test based upon 95% confidence intervals and the likelihood ratio test. Data were simulated according to a monoexponential model and, in that context, power curves for each test were generated for (i)the ratio of mean clearance and (ii)the ratio of the population standard deviations of clearance. To generate the power curves, a range of these parameters was employed; other pharmacokinetic parameters were selected to reflect the variability typically present in a Phase II clinical trial. For tests comparing the means, the confidence interval tests had approximately the same power as the likelihood ratio tests and were consistently more faithful to the nominal level of significance. For comparison of the standard deviations, and when the volume of information available was relatively small, however, the likelihood ratio test was more able to detect differences between the two groups. These results were then compared to results on parameter estimation in order to gain insight into the question of power. As an example, the nonnormality of estimates of the ratio of standard deviations plays an important role in explaining the low power for the confidence interval tests. We conclude that, except for the situation of modeling standard deviations with only sparse information, NONMEM produces tests of significance that are effective at detecting clinically significant differences between two populations.Partial support from the Upjohn Company, NIH-BRSG SO RR 07066, and the Burroughs Wellcome Foundation.     

Simultaneous noninvasive evaluation of gastric emptying and orocaecal transit times

Summary The aim of the study was to use a novel combination of two methods for the simultaneous evaluation of two effects of oral cisapride in 10 diabetic patients with autonomic neuropathy; gastric emptying time was measured by following radio-opaque markers and orocaecal transit time by the sulphasalazine-sulphapridine method. The study was of double-blind, randomized, placebo-controlled, cross-over design.It was possible to evaluate the effect of a prokinetic drug on gastric emptying and orocaecal transit times using these two noninvasive techniques at the same time. Cisapride significantly reduced both the gastric emptying (1.2 h versus 2.1 h) and orocaecal tansit (5.9 h versus 7.7 h) times.