Clinical pharmacokinetics of intravenous and oral 9-amino-1,2,3,4-tetrahydroacridine,tacrine

Summary The pharmacokinetics of 9-amino-1,2,3,4-tetrahydroacridine; tacrine, THA, was studied after intravenous administration and following the first and last oral doses of a seven week clinical trial involving 8 patients with amyotrophic lateral sclerosis, ALS. Two surgical patients given intravenous THA for reversal of postoperative sedation were also included. Plasma concentration of THA and in some cases the metabolite, 1-hydroxy-THA, were assayed using a selective and sensitive method with high performance liquid chromatography.After an intravenous dose of 30 mg THA, the plasma concentrations were fitted to a two-compartment model. Plasma clearance showed a threefold interindividual variation with a mean of 2.42 l·h^–1. Volume of distribution, V varied 100–680 l with a mean of 349 l. The plasma half-lives of distribution and elimination were 1.8 and 98.2 min, respectively. Oral bioavailability showed large interindividual differences and ranged 6–36% in the four subjects studied.After seven weeks treatment with oral THA, plasma concentrations immediately prior to medication were below 10 ng/ml in three patients and above 100 ng/ml in two patients. At the same occasion the plasma metabolite concentrations considerably exceeded those of THA. THA medication was associated with side effects in the majority of the patients.     

硬膜外麻醉中用异丙酚镇静目标控制输注系统的性能及测评

目的：研究硬膜外阻滞时异丙酚目标控制输注镇静系统的性能。方法：12例中、低位硬膜外腔阻滞择期手术病人,选用Marsh的药代动力学参数进行异丙酚目标控制输注镇静。目标血药浓度设定范围1．5－3．0mg.L^-1,由麻醉医师根据镇静需要调整目标浓度,笨一病例的目标浓度可调整1－2次,以高效液相色谱法检测异丙酚血药浓度。计算偏离不性、不准确度等性能评价指标,分析系统性能。结果：多数实测血药浓度低于预计浓度,偏离性（MDPE）为－16．14％。偏离性和不准确确度与硬膜外阻滞范围无相关。结论：采用Marsh参数作目标控制镇静,血浆异丙酚目标浓度与实测浓度的偏离性较大,应用时需进行校正。     

Optimizing sedation following major vascular surgery: a double-blind study of midazolam administered by continuous infusion

A randomized, double-blind study was undertaken to determine the dose requirements, recovery characteristics, and pharmacokinetic variables of midazolam given by continuous infusion for sedation in patients following abdominal aortic surgery. Thirty subjects, 50–75 yr, scheduled to undergo aortic reconstructive surgery, entered the study. Following a nitrous oxide-isoflurane-opioid anaesthetic technique, patients were randomly allocated to receive one of three loading doses (0.03, 0.06 or 0.1 mg · kg^?1) and initial infusion rates (0.5, 1.0 or 1.5 μg · kg^?1 · min^?1) of midazolam, corresponding to groups low (L), moderate (M) and high (H). The infusion of midazolam was adjusted to maintain sedation levels of “3, 4 or 5,“ which permitted eye opening in response to either verbal command or a light shoulder tap, using a seven-point scale ranging from “0” (awake, agitated) to “6” (asleep, non-responsive). Additionally, morphine was given in increments of 2.0 mg iv prn for analgesia. On the morning after surgery, midazolam was discontinued, and the tracheas were extubated when patients were awake. Blood samples were taken during, and at increasing intervals for 48 hr following discontinuation of the infusion, and analyzed by gas chromatography. The desired level of sedation was maintained during more than 94% of the infusion period in all three groups, with a maximum of three dose adjustments per patient, for treatment which lasted 16.3 ± 0.6 hr. There was, however, an increase in both the infusion rates and mean plasma concentrations from Group L to Group H (P < 0.05), which corresponded to an inverse relationship of morphine requirements during the period of sedation (P < 0.05, Group H vs Group L). Optimal midazolam infusion rates and resulting plasma concentrations at the times the infusions were discontinued (in parentheses) were as follows — Group L: 0.60 ± 0.18 μg · kg^?1 min^?1 (76 ± 32 ng · mL^?1), Group M: 0.90 ± 0.52 μg · kg^?1 · min^?1 (133 ± 71 ng · mL^?1), and Group H: 1.34 ± 0.69 μg · kg^?1 · min^?1 (206 ± 106 ng · mL^?1). Times to awakening were longer in Group H: 3.1 ± 3.4 hr, than in Group L: 1.1 ± 0.8 h, P < 0.05. Pharmacokinetic variables were found to be dose- independent over the range of infusion rates. Mean values were t_1/2β = 4.4 ± 1.5 hr, CL = 5.94 ± 1.69 mL · min^?1 · kg^?1, Vd = 3.13 ± 1.07 L · kg^?1. It is concluded that midazolam, infused between 0.6–0.9 μg · kg^?1 · min^?1, provides a stable level of sedation, when administered in conjunction with intermittent iv morphine following AAS. This sedation technique, which costs $1.65 ± 0.73 hr^?1 ($Can), is associated with rapid recovery and minimal side effects.     

Pharmacodynamic Analysis of Analgesic Clinical Trials Using Empirical Methods

Data from analgesic clinical trials have characteristics such as ordered categorical longitudinal responses with repeated measures, delay of effect with respect to analgesic plasma concentration, and right-hand censoring of response due to remedication. In order to determine the concentration-effect relationship of such data, we propose convolving an empirical function for plasma concentration, in the form of broken lines which connect each pair of neighboring observations, with a monoexponential function, to generate effect site concentration Effect site concentration and time are used, simultaneously, as independent variables in the fit of the model for the logit of the probability of having a specific pain relief (PR) score at each time point pre-remedication, via maximum likelihood. Using corresponding effect site concentration, the probabilities of having specific PR scores post-remedication are predicted via the concentration-response relationship established. The overall (pre- and post-remedication) predictions and corresponding standard errors for the responses are then estimated. Inference of the PR scoring, using a posterior method, is proposed. An illustration using real data is used to demonstrate these methods.     

三阶梯药物治疗原发性肝癌疼痛

目的:评价三阶梯药物治疗癌痛计划对原发性肝癌疼痛的疗效.方法:对29例中晚期原发性肝癌患者采用三阶梯用药方法按序、按时治疗癌性疼痛.结果:完全缓解(CR)19例(占65.52%),部分缓解(PR)3例(占10.35%),轻度缓解(MR)3例(占10.35%),有效率86.22%,无缓解(NR)4例(占13.78%),疗效优于单用哌替啶组,两组之间有非常显著差异(P相似文献   

The use of chemical restraint in helicopter transport

Introduction: Helicopter transport of the combative patient is a major safety hazard facing air medical teams. Although physical restraints alone are helpful, the addition of chemical restraint (CR) often is necessary to control these patients while in flight.

Methods: A survey was conducted to determine the current practices of using nonparalyzing CR in air medical transport programs nationwide. The survey consisted of 24 questions on the use of CR during transport. Each U.S. program belonging to the Association of Air Medical Services was contacted by telephone, and a flight nurse or paramedic provided answers based on personal experience and statistics compiled by his or her individual program.

Results: Of the 100 programs responding, benzodiazepines were used most commonly to control agitation with 51% using midazolam. Patients with a head injury required CR more frequently than any other condition (73%). Crews flying larger aircraft reported less need for CR. A physician order was required by only 30% of the programs, but delays infrequently endangered the patient (2%). Only 7% of the responding programs had a patient whose condition deteriorated because of CR.

Conclusion: CR is necessary in air medical transport. Most programs use short-acting benzodiazepines. Crews in smaller aircraft use CR more frequently, and head injury is the most common condition requiring such restraint.     

Preliminary UK experience of dexmedetomidine, a novel agent for postoperative sedation in the intensive care unit

Dexmedetomidine, a highly selective and potent alpha2-adrenergic agonist, has a potentially useful role as a sedative agent in patients requiring intensive care. As part of a larger European multicentre trial, a total of 119 postoperative cardiac and general surgical patients requiring ventilation and sedation in an intensive care unit were enrolled in four centres in the United Kingdom. One hundred and five patients were randomly allocated to receive either dexmedetomidine or placebo with rescue sedation and analgesia provided by midazolam and morphine, respectively. Compared with the control group, intubated patients receiving dexmedetomidine required 80% less midazolam [mean 4.9 (5.8) microg.kg-1.h-1 vs. 23.7 (27.5) microg.kg-1.h-1, p < 0.0001], and 50% less morphine [11.2 (13.4) microg.kg-1.h-1 vs. 21.5 (19.4) microg.kg-1.h-1,p = 0.0006]. Cardiovascular effects and adverse events could be predicted from the known properties of alpha-2 agonists. In conclusion, dexmedetomidine is a useful agent for the provision of postoperative analgesia and sedation.     

麻醉性镇痛药使用及依赖性发生的调查

本文调查分析１所大型综合性医院１９８９－１９９４年麻醉性镇痛药使用情况,平均年消耗量为２９６４５±ｓ５５９１ＤＤＤｓ。年开支金额逐年增加,１９９４年为１９９０年的４４０％。内科用量占全院的５５．３％,二氢埃托啡片１９９１年猛增至１０万片以上,卫生部下达文件后下降。门诊麻醉镇痛药用量占４．９％,其处方量占总处方量的０．３５％。主要使用单位是急诊科,占７０．２％。男女患者比为２．４：１;２６－４５ａａ组占４５．６％。药物利用指数０．２９－０．７０,使用不当者主要是二氢埃托啡,发现２人发生依赖性。４３名癌痛患者很少按“三阶梯止痛疗法”给药。根据存在的问题,本文提出相应的建议。     

Incidence of analgesic nephropathy among patients undergoing renal replacement therapy in Czech republic and Slovak republic

BACKGROUND.: The occurrence of analgesic nephropathy (AN) among renal replacementtherapy patients in former Czechoslovakia is not known. Previoussurveys were not based on representative samples and lackeduniform criteria for diagnosing the disease. METHODS.: Incidence of AN in former Czechoslovakia was investigated inpatients commencing renal replacement therapy in 24 (1/3 ofall) dialysis centres from 1 January to 31 December 1992. Patientsshowing an unclear renal diagnosis (n=149) were investigatedwith an interview and renal imaging techniques. The diagnosisof AN was withheld or rejected on the base of recently publisheddiagnostic criteria demonstrating that a decreased renal massof both kidneys combined with bumpy contours and/or papillarycalcifications had a high performance for diagnosing AN (NephrolDial Transplant 1992; 7: 479–486). RESULTS.: Based on the renal imaging criteria, AN was diagnosed in 30of 328 registered patients, resulting in an AN incidence of9.1% while the EDTA data only mentioned an incidence of 4.8%(period 1986–1989). The products most commonly abusedwere analgesic mixtures containing two analgesic substancescombined with caffeine and/or codeine. CONCLUSIONS.: AN was found to be a common disease in the Czech and SlovakRepublics. The disease was diagnosed using reliable renal imagingcriteria.     

Drug use patterns in Northern Territory Aboriginal communities 1986-1987

During April to November 1986 and May to October 1987, a systematic survey of patterns of use of alcohol, kava, tobacco and analgesics by Northern Territory Aboriginal people aged 15 years and older was conducted. The objectives of the study were to ascertain the prevalence of drug use, the frequency of drug use and the quantity of drugs used. In addition, information about Aboriginal people's perceptions of the drugs, their beliefs about drug use and the value of drugs in their culture was collected. This paper describes only the quantitative aspects of drug use of this population. A stratified sampling procedure was used to sample 10 per cent of the target population. Using two survey instruments, an individual questionnaire and a group questionnaire, data were gathered from 1764 Aboriginal people living in the Northern Territory. As a whole, the Northern Territory Aboriginal people have a drug consumption pattern quite distinct from urban Australians.