Pharmacokinetics and pharmacodynamics of propofol 6% SAZN versus propofol 1% SAZN and Diprivan-10 for short-term sedation following coronary artery bypass surgery

Objective: A new formulation of propofol 6% in Lipofundin MCT/LCT 10% (propofol 6% SAZN) has been developed in order to reduce the fat, emulsifier and volume load that is given during prolonged infusions of propofol. The pharmacokinetics, pharmacodynamics and safety characteristics of propofol 6% SAZN were investigated during a short-term infusion and compared with the commercially available product propofol 1% in Intralipid 10% (Diprivan-10) and propofol 1% in Lipofundin MCT/LCT 10% (propofol 1% SAZN). Methods: In a randomised double-blind study, 24 male patients received a 5-h infusion of propofol at the rate of 1 mg/kg/h for sedation in the immediate postoperative period following coronary artery bypass surgery. Results: The average pharmacokinetic parameter estimates of clearance (Cl), volume of distribution at steady state (V_d,ss), elimination half-life (t _1/2,β) and distribution half-life (t _1/2,α) observed in the three groups were 28 ± 1.1 ml/kg/min, 1.8 ± 0.12 l/kg, 94 ± 4.1 min and 3.1 ± 0.26 min, respectively (mean ± SEM, n=24) and no significant differences were noted between the three formulations (P > 0.05). In one patient receiving propofol 6% SAZN, in two patients receiving propofol 1% SAZN and in three patients receiving Diprivan-10, the level of sedation was inadequate and additional sedative medication had to be given. In all other 18 patients, the level of sedation was adequate. The mean propofol concentration in these six inadequately sedated patients was lower than the adequately sedated patients (P=0.015). The serum triglyceride concentrations were not significantly different between the groups studied. No adverse events occurred in any of the patients. Conclusions: The pharmacokinetics, pharmacodynamics and safety characteristics of propofol 6% SAZN are in good agreement with those of the 1% formulations. Propofol 6% SAZN therefore provides a useful alternative to the commercially available 1% formulation for short-term sedation in the intensive care unit. Expected advantages in long-term sedation of the 6% over 1% formulation are the subject of an ongoing study. Received: 11 June 1999 / Accepted in revised form: 23 December 1999     

Pilot study in humans on the pharmacokinetics and safety of propofol 6% SAZN

In a pilot study on the first application of Propofol 6% SAZN in humans, the pharmacokinetics and safety of the new product seem to be similar to those of Propofol 1% SAZN and Diprivan®10 after bolus injection. The results will have to be confirmed in a larger clinical study in order to develop Propofol 6% SAZN as an alternative for Diprivan®10.     

Influence of Different Fat Emulsion-Based Intravenous Formulations on the Pharmacokinetics and Pharmacodynamics of Propofol

Purpose. The influence of different intravenous formulations on the pharmacokinetics and pharmacodynamics of propofol was investigated using the effect on the EEG (11.5-30 Hz) as pharmacodynamic endpoint. Methods. Propofol was administered as an intravenous bolus infusion (30 mg/kg in 5 min) or as a continuous infusion (150 mg/kg in 5 hours) in chronically instrumented male rats. Propofol was formulated as a 1% emulsion in an Intralipid 10%^®-like fat emulsion (Diprivan-10^®, D) or as a 1%- or 6% emulsion in Lipofundin^® MCT/LCT-10% (Pl% and P6%, respectively). EEG was recorded continuously and arterial blood samples were collected serially for the determination of propofol concentrations using HPLC. Results. Following bolus infusion, the pharmacokinetics of the various propofol emulsions could adequately be described by a two-compart-mental pharmacokinetic model. The average values for clearance (Cl), volume of distribution at steady-state (V_d,ss) and terminal half-life (t_{1/2, 2}) were 107 ± 4 ml/min/kg, 1.38 ± 0.06 l/kg and 16 ± 1 min, respectively (mean ± S.E., n = 22). No significant differences were observed between the three propofol formulations. After continuous infusion these values were 112 ± 11 ml/min/kg, 5.19 ± 0.41 l/kg and 45 ± 3 min, respectively (mean±S.E., n = 20) with again no statistically significant differences between the three propofol formulations. Comparison between the bolus- and the continuous infusion revealed a statistically significant difference for both V_d,ss and t_{1/2, 2} (p < 0.05), whereas Cl remained unchanged. In all treatment groups infusion of propofol resulted in a burst-suppression type of EEG. A profound hysteresis loop was observed between blood concentrations and EEG effect for all formulations. The hysteresis was minimized by a semi-parametric method and resulted in a biphasic concentration-effect relationship of propofol that was described non-parametrically. For P6% a larger rate constant onset of drug effect (t,_{1/2, keo}) was observed compared to the other propofol formulations (p<0.05). Conclusions. The pharmacokinetics and pharmacodynamics of propofol are not affected by to a large extent the type of emulsion nor by the concentration of propofol in the intravenous formulation.     

Pharmacokinetics and effects of propofol 6% for short-term sedation in paediatric patients following cardiac surgery

AIMS: This paper describes the pharmacokinetics and effects of propofol in short-term sedated paediatric patients. METHODS: Six mechanically ventilated children aged 1-5 years received a 6 h continuous infusion of propofol 6% at the rate of 2 or 3 mg kg-1 h-1 for sedation following cardiac surgery. A total of seven arterial blood samples was collected at various time points during and after the infusion in each patient. Pharmacokinetic modelling was performed using NONMEM. Effects were assessed on the basis of the Ramsay sedation score as well as a subjective sedation scale. RESULTS: The data were best described by a two-compartment pharmacokinetic model. In the model, body weight was a significant covariate for clearance. Pharmacokinetic parameters in the weight-proportional model were clearance (CL) = 35 ml kg-1 min-1, volume of central compartment (V1) = 12 l, intercompartmental clearance (Q) = 0.35 l min-1 and volume of peripheral compartment (V2) = 24 l. The interindividual variabilities for these parameters were 8%, < 1%, 11% and 35%, respectively. Compared with the population pharmacokinetics in adults following cardiac surgery and when normalized for body weight, statistically significant differences were observed the parameters CL and V1 (35 vs 29 ml kg-1 min-1 and 0.78 vs 0.26 l kg-1P < 0.05), whereas the values for Q and V2 were similar (23 vs 18 ml kg-1 min-1 and 1.6 vs 1.8 l kg-1, P > 0.05). In children, the percentage of adequately sedated patients was similar compared with adults (50% vs 67%) despite considerably higher propofol concentrations (1.3 +/- 0.10 vs 0.51 +/- 0.035 mg l-1, mean +/- s.e. mean), suggesting a lower pharmacodynamic sensitivity to propofol in children. CONCLUSIONS: In children aged 1-5 years, a pharmacokinetic model for propofol was described using sparse data. In contrast to adults, body weight was a significant covariate for clearance in children. The model may serve as a useful basis to study the role of covariates in the pharmacokinetics and pharmacodynamics of propofol in paediatric patients of different ages.     

丙泊酚长链脂肪乳和中／长链脂肪乳注射液对肝脏能量代谢的影响

目的：观察丙泊酚长链脂肪乳注射液（LCT ）和丙泊酚中／长链脂肪乳注射液（MCT／LCT ）短时间恒速输注对肝脏能量代谢的影响。方法选择年龄为18～50岁,术前 ASA分级Ⅰ～Ⅱ级的20例择期手术病人,随机分为2组,每组10例,分别行丙泊酚长链脂肪乳注射液4 mg · kg-1· h-1维持麻醉（L组）、丙泊酚中／长链脂肪乳注射液4 mg · kg-1· h-1维持麻醉（M组）。在气管插管后（T1）、维持输注丙泊酚麻醉2 h后（T 2）,各取静脉血检测乙酰乙酸、β-羟丁酸值,计算血酮体比率（乙酰乙酸／β-羟丁酸）。结果 T1、T2时点两组乙酰乙酸、β-羟丁酸和血酮体比率之间比较,差异均无统计学意义（P＞0．05）。结论丙泊酚长链脂肪乳注射液和丙泊酚中／长链脂肪乳注射液短时间持续输注对肝脏能量代谢没有明显的影响。     

氯胺酮对丙泊酚药动学与药效学的影响研究

目的:研究氯胺酮对丙泊酚静脉麻醉后药动学、药效学的影响。方法:24例门诊无痛人流术患者随机分为2.5mg·kg-1丙泊酚静脉麻醉组(A组,n=8)、复合0.25mg·kg-1氯胺酮组(B组,n=8)及复合0.75mg·kg-1氯胺酮组(C组,n=8)。分别在停止注射丙泊酚后0、2、4、6、8、10、15、30、45min与1、2、3h及唤醒、清醒时采集未注药侧肘静脉血,用高效液相色谱法测定单次给药后各时点丙泊酚血药浓度,并由3p97软件处理计算出药动学参数,同时监测相应时间点收缩压(SBP)、舒张压(DBP)、心率(HR)、血氧饱和度(SpO2)。结果:与A组比较,B、C组的t1/2α、Vd呈减少趋势(A、C组比较:P<0.05);B、C组的K12、CL呈增加趋势(A、C组比较:P<0.05)。3组间t1/2β、K21、K10差异无统计学意义。停止注射丙泊酚后1～4min血压、HR、SpO2变化明显,SBP、DBPA、C组比较:P<0.05或B、C组比较:P<0.05;HRA、C组比较:P<0.05;SpO2A、C组比较:P<0.05。结论:单次静脉注射氯胺酮0.75mg·kg-1可促进丙泊酚的分布或再分布,而氯胺酮0.25mg·kg-1对丙泊酚分布或再分布无明显影响。2.5mg·kg-1丙泊酚复合0.25mg·kg-1氯胺酮用于无痛人流术安全、有效。     

Propofol in cesarean section. A pharmacokinetic and pharmacodynamic study

The induction properties and pharmacokinetics of propofol, 2.5 mg/kg i.v., were studied in twelve unpremedicated healthy pregnant patients at term. The onset of anesthesia was rapid (27.7 +/- 7.3 sec) and the quality of induction, maintenance of and rapid recovery from anesthesia were clinically very acceptable. On the basis of Apgar scores and blood gas analyses of the feto-placental unit, propofol appears to be a safe alternative to other available induction agents. The pharmacokinetics of propofol in pregnant women (n = 8) were described by a high value for total body clearance (mean 2189.6 ml/min) and a short elimination half-life (mean 24.1 min). There was no correlation between the pharmacokinetic parameters determined for propofol and some pharmacodynamic observations during the induction of anesthesia (n = 8), nor was there any correlation between drug levels of propofol in the feto-placental unit and blood-gas tensions and pH values or Apgar scores (n = 12).     

异丙酚咪唑安定依托咪酯对小儿全麻诱导比较

目的比较异丙酚、咪唑安定和依托咪酯用于小儿全麻诱导作用。方法患儿60例,ASAⅠ～Ⅱ级,随机分三组,分别给异丙酚(P组)2.5mg·kg     

丙泊酚对大鼠空间学习记忆能力影响的实验研究

目的研究丙泊酚对于大鼠空间学习记忆能力的影响。方法给予大鼠丙泊酚(10、30和75mg·kg-1)腹腔注射,给予脂肪乳腹腔注射作为对照,然后应用Morris水迷宫评价其对于大鼠空间学习记忆的影响。结果30和75mg·kg-1的丙泊酚腹腔注射可以损害大鼠的空间学习记忆能力,而10mg·kg-1的丙泊酚腹腔注射不影响大鼠的空间学习记忆能力。结论多次给大鼠腹腔注射丙泊酚重复实施麻醉或镇静可以损害其空间学习记忆能力。     

Propofol: therapeutic indications and side-effects

Propofol (2, 6-diisopropylphenol) is a potent intravenous hypnotic agent which is widely used for the induction and maintenance of anesthesia and for sedation in the intensive care unit. Propofol is an oil at room temperature and insoluble in aqueous solution. Present formulations consists of 1% or 2% (w/v) propofol, 10% soybean oil, 2.25% glycerol, and 1.2% egg phosphatide. Disodium edetate (EDTA) or metabisulfite is added to retard bacterial and fungal growth. Propofol is a global central nervous system depressant. It directly activates GABA(A) receptors. In addition, propofol inhibits the NMDA receptor and modulates calcium influx through slow calcium ion channels. Propofol has a rapid onset of action with a dose-related hypnotic effect. Recovery is rapid even after prolonged use. Propofol decreases cerebral oxygen consumption, reduces intracranial pressure and has potent anti-convulsant properties. It is a potent antioxidant, has anti-inflammatory properties and is a bronchodilator. As a consequence of these properties propofol is being increasingly used in the management of traumatic head injury, status epilepticus, delirium tremens, status asthmaticus and in critically ill septic patients. Propofol has a remarkable safety profile. Dose dependent hypotension is the commonest complication; particularly in volume depleted patients. Hypertriglyceridemia and pancreatitis are uncommon complications. Allergic complications, which may include bronchospasm, have been reported with the formulation containing metabisulfite. In addition, this formulation has been demonstrated to result in the generation of oxygen free radicals. High dose propofol infusions have been associated with the "propofol syndrome"; this is a potentially fatal complication characterized by severe metabolic acidosis and circulatory collapse. This is a rare complication first reported in pediatric patients and believed to be due to decreased transmembrane electrical potential and alteration of electron transport across the inner mitochondrial membrane.     

Effect of container on the physicochemical stability of propofol injectable emulsion after being diluted with 0.9% NaCl for intravenous infusion

Effects of glass and plastic containers on the physicochemical properties of propofol injectable emulsion consisting of medium-chain triglycerides (MCTs) and long-chain triglycerides (LCTs) after being diluted with 0.9% NaCl were evaluated. Propofol MCT/LCT reconstituted with normal saline to 2.0 mg/mL, 2.5 mg/mL, 3.0 mg/mL, 4.0 mg/mL, and 5.0 mg/mL were packaged into glass (type II soda-lime-silica), polyvinyl chloride (PVC) soft bag, and non-PVC soft bag (Cryovac^® polyolefin soft bag container), and then stored at ambient temperature/humidity (25 ± 2 °C/50 ± 5% RH) for 3 days to test its stability. We found that the pH and osmolarity of propofol injectable emulsions were consistent among different formulations. All formulations packaged in glass and plastic containers were stable for 6 hours; the globule size distribution of these emulsions met the requirements described in Chapter 729 of the United States Pharmacopeia. However, propofol formulations of higher concentrations (3.0 mg/mL, 4.0 mg/mL, and 5.0 mg/mL) stored in plastic containers were found to have abnormal globule size distribution profiles compared with those stored in glass containers after 24 hours. We therefore recommend that the propofol MCT/LCT emulsions should be packaged into glass containers and used within 6 hours after reconstitution with diluents.     

Biopharmaceutics: Formulation-dependent Pharmacokinetics and Pharmacodynamics of Propofol in Rats

Propofol, a highly lipophilic anaesthetic, is commercially formulated as a lipid emulsion (diprivan) for intravenous use. This formulation is characterized by rapid onset and offset of effect after rapid intravenous administration and an effect-site equilibration half-life (t 1/2 k_E0) of 1.7min in rats. Paradoxically these characteristics are usually associated with relatively water-soluble anaesthetics. To test the influence of the formulation on propofol pharmacokinetics, effect-site equilibration kinetics and pharmacodynamics we performed a pharmacokinetic-pharmacodynamic study of propofol in chronically instrumented rats after administration in a lipid-free formulation. In this report we present the results of this study and compare these results with previous data obtained with rats receiving propofol in the emulsion formulation. Compared with the emulsion formulation the distribution volumes (Vd_c and Vd_ss) were significantly higher but the t 1/2 k_E0 (2.0 min) was similar for the lipid-free formulation. The concentration-effect relationship was biphasic. Propofol effect-site concentrations required to achieve 50% activation, peak activation, 50% inhibition of peak activation effect and maximum inhibition were significantly lower, indicating a higher apparent steady-state potency for the lipid-free formulation compared with the emulsion formulation. The evanescent characteristics of propofol's effect-time-course disappeared when the anaesthetic was administered in the lipid-free formulation. These results suggest that the nature of the formulation can profoundly influence the clinical characteristics of intravenously administered drugs by modifying the pharmacokinetics or pharmacodynamics or both.     

Propofol. A review of its pharmacodynamic and pharmacokinetic properties and use as an intravenous anaesthetic

Propofol is an intravenous anaesthetic which is chemically unrelated to other anaesthetics. Induction of anaesthesia with propofol is rapid, and maintenance can be achieved by either continuous infusion or intermittent bolus injections, with either nitrous oxide or opioids used to provide analgesia. Comparative studies have shown propofol to be at least as effective as thiopentone, methohexitone or etomidate for anaesthesia during general surgery. The incidence of excitatory effects is lower with propofol than with methohexitone, but apnoea on induction occurs more frequently with propofol than with other anaesthetics. Additionally, a small number of studies of induction and maintenance of anaesthesia have found propofol to be a suitable alternative to induction with thiopentone and maintenance with halothane, isoflurane or enflurane. Propofol is particularly suitable for outpatient surgery since it provides superior operating conditions to methohexitone (particularly less movement), and rapid recovery in the postoperative period associated with a low incidence of nausea and vomiting. When used in combination with fentanyl or alfentanil, propofol is suitable for the provision of total intravenous anaesthesia, and comparative studies found it to be superior to methohexitone or etomidate in this setting. Infusions of subanaesthetic doses of propofol have been used to sedate patients for surgery under regional anaesthesia, and also to provide sedation of patients in intensive care. In the latter situation it is particularly encouraging that propofol did not suppress adrenal responsiveness during short term studies. If this is confirmed during longer term administration this would offer an important advantage over etomidate. Thus, propofol is clearly an effective addition to the limited range of intravenous anaesthetics. While certain areas of its use need further study, as would be expected at this stage of its development, propofol should find a useful role in anaesthetic practice.     

不同剂量丙泊酚微乳注射液在Beagle犬体内的药动学参数比较

目的:比较3种不同剂量丙泊酚微乳注射液在Beagle犬体内的药动学参数,并了解其相关性。方法:取Beagle犬12只随机均分为丙泊酚微乳注射液高、中、低剂量组(6、4、2mg·kg-1),静脉注射相应药物,采用高效液相色谱-荧光法检测各组犬给药前及给药后480min内血药浓度,1周和2周后3组犬交叉给药,给药剂量、方法一致,并计算其药动学参数。结果:高、中、低剂量组丙泊酚微乳注射液在犬体内的药-时曲线均符合静注二室模型,其t1/2β分别为(33.02±10.00)、(31.25±23.27)、(53.64±21.78)min,AUC0～480min分别为(60.00±12.50)、(26.90±11.61)、(19.61±3.39)μg·min·mL-1。结论:不同剂量丙泊酚微乳注射液体内消除率和消除方式类似,AUC0～480min与剂量呈正相关。     

Propofol attenuation of renal ischemia/reperfusion injury involves heme oxygenase-1

Aim： To examine the protective effect of propofol in renal ischemia/reperfusion （I/R） injury and the role of heme oxygenase-1 （HO-1） in this process. Methods： Sprague-Dawley rats were randomly divided into 3 groups： （i） sham-operated group; （ii） I/R group; and （iii） propofol group. Bilateral renal warm ischemia for 45 min was performed. After 2, 6, and 24 h reperfusion, blood samples and kidneys were collected for assessment of renal injury, and HO-1 expressions were analyzed by immunohistochemical analysis, RT-PCR and Western blotting. Results： Blood urea nitrogen and serum creatinine levels in the propofol group were significantly lower than that in the I/R group at 24 h after reperfusion. The mean histological score by Paller＇s standard showed that propofol significantly attenuated renal I/R injury after 6 h reperfusion. Propofol increased HO-1 mRNA and protein levels 2 h after reperfusion, whereas HO-1 expressions were present at exceedingly low levels in the I/R group and the sham-operated group at same time point. Propofol also markedly increased HO-1 mRNA and protein levels than I/R at 6 and 24 h after reperfusion. Conclusion： These results suggest that propofol mitigates renal I/R injury in rats. This protection may be partly through the induction of the HO- 1 expression.     

Remoxipride: pharmacokinetics and effect on plasma prolactin.

1. The pharmacokinetics of remoxipride, a new neuroleptic, were investigated in 15 healthy subjects after an intravenous infusion of 50 mg, an intramuscular injection of 100 mg and after administration of two immediate release capsules (A and B), each of 100 mg, in a cross-over study. The effect of the different remoxipride formulations on plasma prolactin concentrations was also studied. 2. The volume of distribution of remoxipride was 0.65 +/- 0.11 kg-1 (mean +/- s.d.). Total plasma clearance was 119 +/- 39 ml min-1, of which 31 +/- 13 ml min-1 was due to renal clearance. The absolute bioavailability after the i.m. and oral formulations was greater than 90%, indicating a small extent of first-pass metabolism. The mean elimination half-life was 4.8 +/- 1.4 h. The unbound fraction of remoxipride and the blood/plasma ratio were 0.19 +/- 0.03 and 0.64 +/- 0.06, respectively. 3. The transient increase in plasma prolactin was similar after all four remoxipride administrations and independent of the given dose.     

右美托咪定对妇科腹腔镜手术患者Narcotrend指数与丙泊酚用量的影响

摘要 目的观察右美托咪定（Dex）对全麻下妇科腹腔镜手术患者Narcotrend指数（NTI）及丙泊酚用量的影响。方法择期全麻下行妇科腹腔镜探查术的患者40例,随机分成Dex 组（D组） 和对照组（C组）,每组20例。D组以0.5 μg·kg－1Dex稀释成10 mL静脉泵注10 min,再维持0.4 μg·kg－1·h－1持续泵注;C 组以0.9%氯化钠溶液用相同方法输注。给药后15 min丙泊酚靶控输注（TCI）,使丙泊酚靶控效应室浓度（Ce）以1.0 μg·mL－1递增,直至Ce为4.0 μg·mL－1,手术中以丙泊酚和瑞芬太尼维持。记录用药前（t0）、用药后5 min（t1）、10 min（t2）、15 min（t3）时的NTI、改良清醒镇静评分（MOAA/S）,记录诱导时Ce值分别为1.0,2.0,3.0,4.0 μg·mL－1下的NTI,记录手术开始时、手术开始后15,30,45 min,缝皮时的Ce值及丙泊酚总用量,记录术毕患者睁眼时间,拔管时间和麻醉后监测治疗室（PACU）停留时间。结果 ①D组NTI在t0～t3时为（98.5±0.6）,（94.0±4.5）,（87.5±5.0）,（86.8±7.1）,C组NTI在对应时点为（98.8±0.8）,（98.4±0.7）,（98.5±0.6）,（98.6±0.4）;与C组相比,D组NTI 在t1～t3时显著降低（P＜0.01）。②诱导过程Ce值为1.0,2.0,3.0,4.0 μg·mL－1时,D组NTI分别为（76.4±3.4）,（64.5±7.2）,（46.8±7.6）,（34.3±6.7）,C组为（83.7±5.4）,（69.4±8.1）,（52.2±7.5）,（38.0±6.6）;不同Ce值时,D组NTI均显著低于C组（P＜0.05）。③D组手术中丙泊酚用量（9.1±1.2） mg·kg－1·h－1,显著少于C组的（11.1±1.5） mg·kg－1·h－1（P＜0.05）。④术毕两组睁眼时间、拔管时间、PACU停留时间差异无统计学意义（P＞0.05）。结论Dex可明显降低NTI,能增强丙泊酚的麻醉作用,减少手术中丙泊酚用量,对麻醉苏醒无明显影响。     

Pharmacogenetics,Plasma Concentrations,Clinical Signs and EEG During Propofol Treatment

A variety of techniques have been developed to monitor the depth of anaesthesia. Propofol's pharmacokinetics and response vary greatly, which might be explained by genetic polymorphisms. We investigated the impact of genetic variations on dosage, anaesthetic depth and recovery after total intravenous anaesthesia with propofol. A total of 101 patients were enrolled in the study. The plasma concentration of propofol during anaesthesia was measured using high‐performance liquid chromatography. EEG was monitored during the surgical procedure as a measure of anaesthetic depth. Pyrosequencing was used to determine genetic polymorphisms in CYP2B6, CYP2C9, the UGTIA9‐promotor and the GABRE gene. The correlation between genotype and to plasma concentration at the time of loss of consciousness (LOC), the total induction dose, the time to anaesthesia, eye opening and clearance were investigated. EEG monitoring showed that the majority of the patients had not reached a sufficient level of anaesthetic depth (subdelta) at the time of loss of consciousness despite a high induction dose of propofol. Patients with UGT1A9‐331C/T had a higher propofol clearance than those without (p = 0.03) and required a higher induction dose (p = 0.03). The patients with UGT1A9‐1818T/C required a longer time to LOC (p = 0.03). The patients with CYP2C9*2 had a higher concentration of propofol at the time of LOC (p = 0.02). The polymorphisms in the metabolizing enzymes and the receptor could not explain the large variation seen in the pharmacokinetics of propofol and the clinical response seen. At LOC, the patients showed a large difference in EEG pattern.     

Spline functions in convolutional modeling of verapamil bioavailability and bioequivalence. II: study in healthy volunteers.

The pharmacokinetics of a new verapamil retard tablet formulation have been investigated in a randomized cross-over bioequivalence study on 12 healthy subjects. The drug was given orally at a single new or standard retard tablet dose of 240mg and at a single intravenous dose of 5mg. Plasma verapamil concentrations were determined by HPLC. New retard tablets produced peak plasma verapamil concentrations of 81.34+/-5.69microg/l, time to peak plasma concentrations of 4.91+/-0.89h and an AUC (0-24h) of 1291+/-103.4h x microg/l, with a terminal phase half-life of 55.1+/-14.9h. After intravenous administration verapamil exhibited biphasic elimination kinetics with a terminal plasma half-life of 2.36+/-0.42h and systemic clearance of 34.32+/-5.81 l/h. Bioavailability of the new peroral retard formulation ranged from 19.49+/-4.41% to 67.69+/-11.70%. Absorption rates and amounts were evaluated by means of the spline-convolutional method. Input rates for the new verapamil retard formulation ranged from 0.77+/-0.20mg/h to 5.57+/-1.58mg/h. The cumulative amount of verapamil input was 39.17+/-9.71% for the new retard tablets. All pharmacokinetic parameters for the new verapamil retard tablet formulation, were in reasonable agreement with the data obtained on already registered verapamil retard formulations, indicating their bioequivalence.     

Propofol in anesthesia. Mechanism of action, structure-activity relationships, and drug delivery

Propofol (2,6-diisopropylphenol) is becoming the intravenous anesthetic of choice for ambulatory surgery in outpatients. It is extensively metabolized, with most of the administered dose appearing in the urine as glucuronide conjugates. Favorable operating conditions and rapid recovery are claimed as the main advantages in using propofol, whereas disadvantages include a relatively high incidence of apnea, and blood pressure reductions. Besides a literature summary of the pharmacodynamics, pharmacokinetics, toxicology, and clinical use, this review provides a deeper discussion on the current understanding of mechanism of action and structure-activity relationships, and recent findings on drug delivery technologies as applied to the improvement of propofol formulations. The action of propofol involves a positive modulation of the inhibitory function of the neurotransmitter gama-aminobutyric acid (GABA) through GABAA receptors. Recent results from recombinant human GABAA receptor experiments and findings from the work exploring the effects at other receptors (e.g., glycine, nicotinic, and M1 muscarinic receptors) are reviewed. Studies showing its antiepileptic and anxiolytic properties are also discussed. The structure-activity relationships (SAR) of series of alkylphenols and p-X-substituted congeners have been reinvestigated. Interestingly, unlike the other congeners tested sofar, p-iodo-2,6-diisopropylphenol displayed anticonvulsant and anticonflict effects, but not sedative-hypnotic and anesthetic properties. Due to its high lipid-solubility, propofol was initially formulated as a solution with the surfactant Cremophor EL, but the occurrence of pain on injection and anaphylactoid reactions prompted to search for alternative formulations. Results from using cyclodextrins, water-soluble prodrugs, and adopting Bodor's approach to the site-specific chemical delivery system (CDS), as well as the advantages provided by computer-controlled infusion systems, are examined in some detail.