创新药物的药代动学研究策略

在新药临床试验中，药代动力学研究占有非常重要的地位。为此，本文对临床药理学研究范畴、药代动力学策略、临床试验开发策略等进行了分析与讨论。     

1619例婴幼儿心脏直视手术的围手术期处理

目的 探讨婴幼儿心脏直视手术围手术期的处理方法。方法统计分析1619例婴幼儿围手术期治疗的临床资料。结果该组死亡68例，死亡率4．2％，术后发生并发症190例，发生率11．7％。结论婴幼儿心脏直视手术围手术期的治疗重点在于输液成分和量的控制、呼吸道的管理以及心功能维护、防止多器官衰竭的发生。     

Evaluation of pharmacological treatment strategies in traumatic brain injury

Traumatic brain injury (TBI) is a devastating disease, predominately affecting young people. Although the prognosis for TBI victims has improved in recent years, many survivors of TBI suffer from emotional, cognitive and motor disturbances and a decreased quality of life. In recent years, there has been a rapid increase in the number of pharmacological targets evaluated in clinically-relevant experimental TBI models, showing improved cognitive and motor outcome and decreased loss of brain tissue. Despite the completion of several recent clinical trials using compounds showing neuroprotection in preclinical studies, pharmaceutical treatment strategies with proven clinical benefit are still lacking. This paper reviews the preclinical pharmacological treatment studies evaluated to date in experimental models of TBI. Although human TBI is a complex and multifaceted disease, these studies provide encouraging translational data suggesting that pharmacological compounds, delivered in a clinically-relevant time window, may improve the outcome of TBI patients.     

Antibiotic prophylaxis in open-heart surgery patients: comparison of cefamandole and cefuroxime

The efficacy of cefamandole and cefuroxime in preventing postoperative wound infections was compared in 3037 patients undergoing open-heart surgery. Antibiotic prophylaxis in 1467 patients having coronary artery bypass and valve replacement surgery was cefamandole 2 g iv preoperatively followed by 2 g q6h for five days postoperatively; 1570 patients received cefuroxime 1.5 g iv preoperatively then 1.5 g iv q 12h for three days postoperatively. Postoperative wound infections (sternal and leg wounds) were studied in each treatment group. In the cefamandole study group, 27 patients (1.8 percent) developed postoperative wound infections (9 sternal and 18 leg wounds). In the cefuroxime treatment group, 19 patients (1.2 percent) developed postoperative wound infections (9 sternal and 10 leg wounds). Overall, no statistical difference was found between the two antibiotics in preventing postoperative wound infections. However, in patients having valve replacement surgery, cefuroxime was found statistically more effective than cefamandole prophylaxis in preventing sternal wound infections (no infections in 284 patients compared with five infections in 205 patients, respectively, p = 0.01). The most common organism isolated from infected wounds with cefamandole was Staphylococcus aureus followed by S. epidermidis compared with cefuroxime which had S. epidermidis followed by S. aureus. Cefuroxime was found to be as effective as cefamandole and considerably less expensive in preventing postoperative wound infections in patients undergoing open-heart surgery.     

Cost considerations in the pharmacological prevention and treatment of stroke

Stroke remains the leading cause of neurological disability and the third leading cause of death worldwide, consuming a large share of total healthcare expenditures. In this review, we discuss the cost effectiveness of stroke prevention for various risk factor-modification programmes and pharmacological interventions with aspirin (acetylsalicylic acid), ticlopidine and warfarin. Cost considerations and potential cost savings resulting from acute treatment are discussed for parenterally administered anticoagulants, such as heparin and nadroparin, and for intravenous thrombolysis with alteplase (recombinant tissue plasminogen activator; r-tPA). Patients with multiple risk factors for stroke require more aggressive prevention strategies which are associated with a greater risk of complications. The rates of complications, particularly intracerebral haemorrhage, should be kept low to achieve cost benefits for warfarin and alteplase. Reduced hospital length of stay is the key factor in the implementation of cost-effective stroke therapies. The analysis of future clinical trials of new stroke therapies should also include economic parameters, such as length of hospital stay and intensity of resource usage, to help guide formulary and therapeutic decision.     

快通道麻醉应用于小儿心内直视手术中的临床价值研究

目的探讨快通道麻醉应用于小儿心内直视手术的临床应用价值。方法将本院2010年1月至2011年12月行心内直视手术的72例先天性心脏病患儿随机分成2组：实验组36例;对照组36例。对照组采用常规麻醉;实验组采用快通道麻醉。观察和比较两组患儿麻醉围手术期的血流动力学参数变化情况、术后拔管时间、CICU留观时间、住院时间、住院费用、不良反应发生情况。结果实验组患儿麻醉围手术期的MAP、CVP、HR指标水平与对照组相比差异无统计学意义（P〉0.05）;实验组的术后拔管时间、CICU留观时间、住院时间、住院费用均明显少于对照组（P〈0.05）;实验组的总不良反应发生率为13.89%,对照组的总不良反应发生率为36.11%,实验组的不良反应发生率明显低于对照组（P〈0.05）。结论快通道麻醉应用于小儿心内直视手术的临床效果显著。     

Emerging pharmacological strategies in the fight against cocaine addiction

Cocaine addiction continues to be an important public health problem worldwide. At present, there are no proven pharmacotherapies for cocaine addiction. The studies reviewed here revealed a number of emerging targets for cocaine pharmacotherapy. First, disulfiram, a medication with dopaminergic effects, reduced cocaine use in a number of clinical trials. Second, GABA medications, tiagabine and topiramate, were found promising in clinical trials. Third, a beta-adrenergic blocker, propranolol, may be effective especially among cocaine-addicted individuals with high withdrawal severity. Fourth, treatment with a stimulant medication, modafinil, has reduced cocaine use. Last, a cocaine vaccine that slows entry of cocaine into the brain holds promise. These promising findings need to be further tested in controlled clinical trials.     

Emerging pharmacological strategies in the fight against cocaine addiction

Cocaine addiction continues to be an important public health problem worldwide. At present, there are no proven pharmacotherapies for cocaine addiction. The studies reviewed here revealed a number of emerging targets for cocaine pharmacotherapy. First, disulfiram, a medication with dopaminergic effects, reduced cocaine use in a number of clinical trials. Second, GABA medications, tiagabine and topiramate, were found promising in clinical trials. Third, a β-adrenergic blocker, propranolol, may be effective especially among cocaine-addicted individuals with high withdrawal severity. Fourth, treatment with a stimulant medication, modafinil, has reduced cocaine use. Last, a cocaine vaccine that slows entry of cocaine into the brain holds promise. These promising findings need to be further tested in controlled clinical trials.     

Novel pharmacological strategies for motor complications in Parkinson's disease

In advanced Parkinson's disease, the combination of disease progression and levodopa therapy leads to the development of motor problems complicating the therapeutic response, known as motor response complications. The nonphysiological, pulsatile stimulation produced by most currently available dopaminergic therapies triggers a complicated series of responses resulting in the dysregulation of glutamate receptors and many other neurotransmitter systems on striatal neurons. Although a number of novel compounds that provide a more continuous dopaminergic stimulation are becoming available, no practical way to accomplish this in a truly physiological manner currently exists. Novel strategies for pharmacological intervention with the use of nondopaminergic treatments, with drugs targeting selected transmitter receptors expressed on striatal neurons appear more promising. These include NMDA or AMPA antagonists, or drugs acting on 5-hydroxytryptamine subtype 2A, alpha2-adrenergic, adenosine A2A and cannabinoid CB1 receptors. Future strategies may also target pre- and postsynaptic components that regulate firing pattern, like synaptic vesicle proteins, or nonsynaptic gap junction communication mechanisms, or drugs with actions at the signal transduction systems that modulate the phosphorylation state of NMDA receptors. These new therapeutic strategies, alone or in combination, hold the promise of providing effective control or reversal of motor response complications.     

Alternative strategies in drug development: clinical pharmacological aspects

Due to the continuous increase in time and cost of drug development and the considerable amount of resources required by the traditional approach, companies can no longer afford to continue to late phase 3 with drugs which are unlikely to be therapeutically effective. The future challenge must be for the pharmaceutical industry to slash its research and development costs by achieving a significant cut in the attrition rate for drugs entering preclinical and clinical development, and to reduce the development time and to increase the probability of success in later clinical trials by streamlining the development processes. In the 100 years to 1995, the pharmaceutical industry worked on about 500 targets with a limited number of compounds, whereas now, using new technologies like genomics, high throughput screening and combinatorial chemistry, drug companies will see an explosion in the number of targets and leads it can explore. Therefore, a tough selection process for picking candidate compounds out of research and a quick kill process for the candidate, which does not measure up in advanced trials, is mandatory to avoid wasting time, energy and money. To improve the transition from research to development it is necessary to validate new targets, define success criteria for research, integrate bioinformation at every stage in drug discovery, define prerequisites for development, identify the "losers" and select the "winners" early and concentrate efforts on them, and to automate the research and development (R&D) process to optimize resource requirements versus time lines and to ensure effective flow of information from drug discovery to late phase of development. In drug development a deeper understanding of a drugs' action is necessary from animal models and phase I, IIa studies prior to taking the drug further in development. Instead of moving from discovery thorough development phases in sequential steps, drug development should be streamlined combining preclinical and early clinical development as an exploratory stage and phases IIb, III as a confirmatory stage. Preclinical and clinical-pharmacological studies in the exploratory stage of drug development should be designed for decision making in contrast to later clinical trials that require power for proof-of-safety and efficacy. Strategies to improve the quality of decisions in drug development are: the use and integration of new tools and technologies such as pharmacogenomics to improve our knowledge about the origin of the disease and to identify new therapeutic strategies; modelling and simulation of preclinical and clinical trials to bridge the gap between the early stages of the development of a new drug and its potential effects in humans; more sophisticated clinical pharmacokinetics to answer the question if the drug is present at the disease site for a sufficient time and to provide information on concentration-effect-relationships; selecting and evaluating surrogates/biomarkers for safety and efficacy; involvement of the target population as soon as possible; using information technologies to make better use of existing data. The more thorough and profound studies have been carried out during this exploratory stage of development, the earlier a decision can be made on the continuation or discontinuation of further development, thus saving development time and money and assessing and considerably reducing the risk for the patients and increasing the success-rate of the project in the later confirmatory effectiveness trial. Taking responsibility as the link between research and development gives clinical pharmacology a major opportunity to assume a pivotal role in research and development of new drugs. To reach this goal, clinical pharmacology must be fully integrated in the whole process from the candidate selection to its approval.     

Behavioral and pharmacological treatment of cigarette smoking: end of treatment comparisons

Success in a stop-smoking treatment program was compared in patients who received behavioral treatment alone (BT) or behavioral treatment plus Nicorette gum (NT). The proportion of nonsmokers at the end of the 10-week program was higher with the groups receiving BT (82%) than in those receiving NT (50%). While the groups differed in their initial tolerance levels and number of previous quit attempts, the data suggest that the addition of Nicorette gum did not confer a substantial advantage over BT alone.     

Immunomodulation and pharmacological strategies in the treatment of graft-versus-host disease

Background: Allogeneic hematopoietic stem cell transplantation offers great promise for the treatment of a variety of diseases including malignancies and other diseases of hematopoietic origin. However, morbidity and mortality due to graft-versus-host disease (GVHD) remain a major barrier to its application. Objective: This review will provide an overview of the pathophysiology of GVHD and discuss the recent advances in GVHD management in both preclinical and clinical studies. Methods: An extensive literature search on PubMed from 1995 to 2008 was performed. Results/conclusion: There has been much progress in our understanding of GVHD and finding new means to control acute GVHD. While these approaches hold promise, as yet none has been able to replace the standard methods we may use routinely to decrease the incidence of the condition.