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.     

Soft Drugs. XX. Design,Synthesis, and Evaluation of Ultra-Short Acting Beta-Blockers

A new type of ultra-short acting -blocker which might prove advantageous in treating acute arrhythmias was designed, synthesized and investigated. Based on the soft drug inactive metabolite approach, the inactive phenylacetic acid metabolite of both metoprolol and atenolol was reactivated by esterification with sulfur-containing aliphatic alcohols. Since the sulfur-containing moieties are labile to the ubiquitous esterases, the new compounds should be inactivated by a one step enzymatic cleavage back to the inactive phenylacetic acid derivative. Pharmacological and pharmacokinetic profiles of the new compounds were evaluated in rats and rabbits. Isoproterenol-induced tachycardia was inhibited with short-term infusion of each compound. This tachycardia blocking effect rapidly disappeared upon termination of infusion, while -blocking activity was 2–4-fold longer after comparable doses of the short-acting -blocker, esmolol. The rapid recovery from the -receptor blockade is believed due to fast hydrolysis of the soft drugs in the body. This is supported from in vitro results showing the t_l/2 of esmolol is about 10-fold longer than the new soft drugs in rat, rabbit, dog and human blood. Hydrolysis studies in phosphate buffered solutions indicated that the esters are labile to base-catalyzed hydrolysis. However, the relative t_1/2 values measured in biological media compared to phosphate buffered solution clearly support rapid enzymatic cleavage of the soft drugs. Interestingly, one of the soft -blockers, the sulfonyl ester derivative, showed a unique property of exhibiting good -receptor blocking activity without significant hypotensive action.     

小腿前外侧群肌的应用解剖

目的　为小腿下 1 /3的骨髓炎和其它创伤性修复提供满意的肌瓣。方法　用 30具成人的尸体 ,采用连续层次解剖法 ,调查了小腿前群和外侧群各肌 ,并用游标卡尺测量了有关的数据。结果　转动小腿前、外侧群各肌肌腹 ,均可不同程度地覆盖小腿下 1 /3的前内侧面。结论　除胫骨前肌和腓骨长肌因受功能的限制外 ,其它各肌均可移植。     

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   

Ventricular fibrillation related to reversal of the neuromuscular blockade in a patient with long QT syndrome

The long QT syndrome (LQTS) is associated with syncopal attacks or even sudden death at a young age due to ventricular fibrillation. We report a patient with an undiagnosed LQTS who had an episode of cardiac arrest during the final part of general anesthesia, immediately after the drugs for reversal of the neuromuscular blockade were given. We suggest that the administration of glycopyrronium might have been the provoking factor in this patient.     

Preparing Older People to Cope after a Fall

Clinical experience and previous research show that older people at risk of falling can become anxious at the thought of being on the floor, therefore physiotherapists and occupational therapists may be reluctant to teach them how to get up.Old people's reactions to two different methods of teaching them this skill are compared (three groups, mean age 84 years). The conventional method requires people to be helped down to the floor and then to learn how to get on to their knees prior to getting up with the help of furniture. An alternative method, based on backward-chaining principles, does not require that people start from the floor and reduces the likelihood of them experiencing failure. The activity is broken down into small steps — the last step in the chain being taught first.It is concluded that:

1 The backward-chaining method of teaching elderly people how to get up from the floor is much less stressful to older people and to staff than the conventional method.

2 Older people are slightly more likely to learn successfully how to get up from the floor by the backward-chaining method which, even if they are not successful, provides them with functionally relevant exercise.

3 Older people who cannot learn to get up from the floor should be helped to develop alternative strategies for summoning help and for preventing the consequences of the long lie.

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.     

Plasma level monitoring of mitotane (o,p'-DDD) and its metabolite (o,p'-DDE) during long-term treatment of cushing's disease with low doses

Summary. Mitotane (o,p'-DDD) can be used for the treatment of various adrenocortical diseases such as Cushing's syndrome, but the usual doses of 6–8 g per day are often associated with severe adverse effects.This paper reports the results of much lower doses of o,p'-DDD (0.5–2 g per day) in two patients with Cushing's disease over periods of 8 and 5 years, respectively, under concomitant monitoring of the plasma levels of the parent drug and its major metabolite, o,p'-DDE.It became apparent that o,p'-DDD and o,p'-DDE have a strong tendency to accumulate in the body due to their high lipophilicity. As a consequence, changes in dose regimens had long lag times before they were reflected in plasma levels and once an increase or decrease had started one had to be careful not to cause overshoot.Steady state plasma levels of o,p'-DDD between 5–10 g/ml appeared sufficient to induce and to maintain remission of the disease, which was accompanied with normal cortisol levels in plasma and urine. DDD-levels below 5 g/ml for several weeks may lead to relapses, whereas DDD-levels over 10 g/ml gave rise to side effects. On the other hand, o,p'-DDE seemed inactive at levels up to 4 g/ml in plasma.