Hemodynamic profile in rabbits of fospropofol disodium injection relative to propofol emulsion following rapid bolus injection

The effects of aqueous fospropofol disodium (FP) and propofol emulsion (PE) on hemodynamics and sympathetic nerve activity in rabbits following bolus injection were evaluated. Barodenervated and neuraxis-intact rabbits received PE at 4 mg/kg (PE(4)) or FP equal to 4 or 8 mg/kg propofol equivalents (FP(4) and FP(8), respectively) intravenously as a rapid bolus injection, and mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) were recorded for 20 min. The plasma propofol pharmacokinetic behavior from FP and PE was evaluated to support the pharmacodynamic observations. In barodenervated animals, MAP and RSNA decreased significantly in all groups (PE(4) > FP(8) > FP(4)). HR decreased only in the PE(4) group. The time for the maximum reduction of MAP was significantly longer with FP(8) compared with PE(4). MAP decreased, and RSNA and HR increased significantly in the neuraxis-intact animals (PE(4) > FP(8) > FP(4)). The time for maximum reduction of MAP was essentially the same in all neuraxis-intact groups. Plasma propofol levels from FP were lower than those from PE in the first 4 min following administration. The results suggest that the tachycardia observed in humans following injection of FP is not a direct physiological effect of the agent.     

磷丙泊福钠的药理及临床评价

磷丙泊福钠是丙泊酚的水溶性前体药物，是一种应用于诊断及治疗阶段的镇静催眠新药。临床研究表明磷丙泊福钠在支气管镜检查及结肠镜检查镇静麻醉疗效及安全性很好。文中就其药理作用、药动学、临床评价、不良反应和药物相互作用作一综述。     

磷丙泊福钠的药理及临床评价

磷丙泊福钠是丙泊酚的水溶性前体药物,是一种应用于诊断及治疗阶段的镇静催眠新药。临床研究表明磷丙泊福钠在支气管镜检查及结肠镜检查镇静麻醉疗效及安全性很好。文中就其药理作用、药动学、临床评价、不良反应和药物相互作用作一综述。     

磷丙泊福钠的药理及临床评价

磷丙泊福钠是丙泊酚的水溶性前体药物，是一种应用于诊断及治疗阶段的镇静催眠新药。临床研究表明磷丙泊福钠在支气管镜检查及结肠镜检查镇静麻醉疗效及安全性很好。文中就其药理作用、药动学、临床评价、不良反应和药物相互作用作一综述。     

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。     

Pharmacokinetics and pharmacodynamics of GPI 15715 or fospropofol (Aquavan injection) - a water-soluble propofol prodrug

Propofol (2,6-diisopropylphenol) is inadequably soluble in water and is therefore formulated as a lipid emulsion. This may have disadvantages when propofol is used to provide total intravenous anaesthesia or especially during long-term sedation. There has been considerable interest in the development of new propofol formulations or propofol prodrugs. GPI 15715 or fospropofol (Aquavan injection; Guilford Pharmaceutical, Baltimore, MD) is the first water-soluble prodrug that has been thoroughly studied in human volunteers and patients. GPI 15751 or fospropofol is cleaved by alkaline phosphatase to phosphate, formaldehyde and propofol. Formaldehyde is rapidly metabolised to formate. Although a formate accumulation is the principal pathomechanism responsible for the toxicity of methanol ingestion, so far there has been no report of toxicity due to the administration of fospropofol or other phosphate ester prodrugs, such as fosphenytoin. Fosphenytoin has been successfully introduced into the market for the treatment of status epilepticus in 1996. The main side-effects were a feeling of paraesthesia after rapid i.v. administration of GPI 15715 or fospropofol, which has also been described for fosphenytoin. The pharmacokinetics of GPI 15715 or fospropofol could be described by a combined pharmacokinetic model with a submodel of two compartments for GPI 15715 and of three compartments for propofol(G). The liberated propofol(G) compared to lipid-formulated propofol showed unexpected pharmacokinetic and pharmacodynamic differences. We found a significantly greater V(c), V(dss), significantly shorter alpha- and beta-half-life and a longer MRT (mean residence time) for propofol(G). The pharmacodynamic potency of propofol(G) appears to be higher than propofol when measured by EEG and clinical signs of hypnosis. In summary, GPI 15715 or fospropofol was well suited to provide anaesthesia or conscious sedation.     

Pharmacokinetics of eltanolone following bolus injection and constant rate infusion

Disposition of intravenous anaesthetic eltanolone was studied when administered as a bolus injection (B) of 0.75 mg/kg and constant rate intravenous infusion at 2 mg/kg/hr (I2) and 3.5 mg/kg/hr (I3.5) for 2 hr in healthy male volunteers. Venous blood samples were collected for 12 hr and 20 hr following bolus injection and intravenous infusion, respectively. Serum eltanolone concentrations were determined by a specific gas chromatographic mass spectrometric assay. Using a nonlinear regression analysis, the individual data sets were best fitted by a three-compartment mamillary model with central elimination. Derived pharmacokinetic parameters expressed as median and 95% confidence intervals indicated an initial fast distribution with a half-life of 1.80 (0.23–5.47) min (B), 1.44 (0.97–2.06) min (I2) and 1.44 (0.95–2.39) min (I3.5), an intermediate phase with a half-life of 35.4 (28.7–45.2) min (B), 39.6 (31.0–47.9) min (I2) and 35.4 (33.3–44.9) min (I3.5) and a moderately short terminal phase with a half-life of 3.8 (2.7–5.9) hr (B), 5.0 (4.2–6.1) hr (I2) and 4.6 (4.0–4.8) hr (I3.5). The serum clearance after bolus injection was 1.37 (1.23–1.67) L/hr/kg and after infusion was 1.36 (1.25–1.52) L/hr/kg (I2) and 1.17 (1.11–1.31) L/hr/kg (I3.5). The pharmacokinetics of eltanolone appear to be linear over the dosage range studied. Pharmacokinetic parameters obtained after bolus injection were very much similar to the parameters obtained after infusion with the exception of t_1/2β which was longer after the infusion (significant) and the volume of central compartment which was lower after infusion (not significant). Context sensitive times were estimated for a 30%, 50% and 80% drop in the concentration of eltanolone after different infusion times. A 30% drop in concentration is estimated to take about 2 to 3 min. A 50% drop in concentration, is estimated to take about 8 min when duration of infusion is 3 hr and reaches a value of about 10 min by a duration of infusion of 10 hr. A 80% drop in concentration is estimated to take about 55 min following an infusion of 1 hr and it reaches a value of 70–80 min following an infusion of 10 hr.     

Pharmacokinetics of GM1 ganglioside following parenteral administration

The pharmacokinetic parameters of monosialotetrahexosylganglioside (GM1) have been determined in healthy volunteers at 3 dose levels: 100, 200, 300 mg. Each dose was administered to separate groups of 12 volunteers. GM1 levels were determined in plasma, urine, and faeces by a method based on the property of the cholera toxin beta subunit to react specifically with GM1 ganglioside. A non-compartmental model was applied to determine standard pharmacokinetic parameters. The average AUC increased with dose (1002 +/- 121.2, 1306 +/- 146.1, 3155 +/- 121.6 micrograms mL-1 h after 100, 200, 300 mg, respectively). Plasma clearance was less than 3 mL min-1 and the distribution volume was close to the plasma volume (on average between 4.3 and 7.2 L). Mean residence time was about 43 h for all doses. GM1 was not detected in urine, while in faeces the amount of GM1 determined was similar to the baseline values obtained before dosing.     

Cognitive and EEG recovery following bolus intravenous administration of anesthetic agents

Bolus intravenous (IV) administration of commonly used IV anesthetic agents such as fentanyl and the fentanyl analogues, alfentanil, remifentanil, and sufentanil, etomidate and propofol, produced anesthesia in rats as measured by the loss of righting (LOR) with calculated ED₁₅₀ doses of 0.06, 0.09, 0.037, 0.007, 2.51 and 6.12 mg/kg, respectively. Animals trained in an eight arm radial maze (RAM) were assessed for cognitive recovery, as measured by response efficiency (percentage of correct arm entries within 10 min), immediately, 15 min and 30 min following IV administration of the calculated ED₁₅₀ dose of each of these agents, and the subsequent return of righting (ROR). Animals administered fentanyl or sufentanil were unable to successfully complete the maze throughout the testing periods. Animals receiving remifentanil showed cognitive recovery within the first testing interval (immediately following the return of righting), while animals receiving alfentanil, etomidate or propofol showed recovery at the 15-min testing interval following ROR. In a separate experiment, bolus IV administration of the ED₁₅₀ dose of these agents was evaluated in an acute rat EEG model. Following ROR, return to baseline EEG levels occurred at 0.30, 2.88, 5.06, 16.25, 31.29 and 43.98 min for remifentanil, propofol, alfentanil, etomidate, fentanyl and sufentanil, respectively. These data show that the return to efficient cognitive functioning corresponds to the return to normal baseline EEG waveforms.     

Stability of propofol with parenteral nutrient solutions during simulated Y-site injection.

The stability of propofol in three parenteral nutrient (PN) solutions was studied. Nine combinations of three PN solutions (with amino acid concentrations of 1.5, 2.5, and 5.0%) and three propofol concentrations (0.5, 2.0, and 3.0 mg/mL) were prepared in triplicate and stored at 22 degrees C under fluorescent light. Duplicate samples were visually inspected for color changes, precipitation, or gas formation, and the pH of the samples was determined. These samples were evaluated for propofol content by high-performance liquid chromatography at zero, one, three, and five hours. The stability of the vehicle for propofol injection (similar in composition to fat emulsion) was evaluated by visual inspection, pH determination, and particle-size measurements at zero, one, three, and five hours. The concentration of propofol in all of the propofol-PN combinations remained greater than 90% of the initial concentration except for the combination of propofol 0.5 mg/mL and the 1.5% amino acid PN solution, which contained only 72% of the initial propofol concentration five hours after the start of the study. Visual examination revealed no evidence of color change, precipitation, gas formation, creaming, or streaking in any of the propofol-PN solution combinations. No substantial changes in pH occurred. The particle size of the vehicle for propofol remained relatively constant throughout the study period. Propofol 2 and 3 mg/mL was stable for five hours during simulated Y-site injection with PN solutions containing 1.5, 2.5, and 5% amino acids. Propofol 0.5 mg/mL was stable during simulated Y-site injection with the same PN nutrition solutions for five hours, except for the solution containing 1.5% amino acid.     

Modelling of initial distribution of drugs following intravenous bolus injection

Based on a recirculatory pharmacokinetic model, a physiologically realistic definition of the initial distribution volume has been developed to characterize the overall distribution process occurring shortly after rapid bolus injection of a drug. This apparent volume of distribution, which refers to the peak right atrial blood concentration, depends on the cardiac output and basic pharmacokinetic parameters usually derived from the whole blood concentration vs time curve. The initial distribution process appears to be affected by changes in the variance of the distribution of residence times of the drug in the body. The influence of the site and time of early blood sampling on the estimated initial distribution volume is discussed. This relatively simple a priori model should prove useful in predicting to a first approximation the principal characteristics of the initial distribution process.     

丙泊酚甲磷酸钠盐的含量测定及其杂质检查

目的 建立测定原料药丙泊酚甲磷酸钠的含量及检查杂质的方法.方法 采用HPLC法和酸碱滴定法.结果 丙泊酚甲磷酸钠盐在0.82～4.04 μg范围内,线性关系良好(r=0.9998),日内及日间精密度分别为0.26%、0.32%;丙泊酚检查的定量限为0.016 ng(S/N=10),在6.73～323.4 ng范围内,线性关系良好(r=0.9991).结论 所建立的方法简便、灵敏、准确,可用于丙泊酚甲磷酸钠的含量测定及杂质丙泊酚的检查.     

Absorption of diazepam in man following rectal and parenteral administration.

Serum concentrations of diazepam and N-desmethyldiazepam were measured in six adult patients following administration of 10 mg diazepam in solution by the rectal, intravenous, and intramuscular routes. Maximum serum concentrations of 121--200 ng/ml were recorded from 10 to 20 min. after the rectal instillation, whereas following intramuscular injection the levels rose slowly and irregularly, reaching a maximum (62--186 ng/ml) in 1 to 24 hours. The bioavailability of diazepam given by rectal instillation was found to be 50 +/- 17 per cent (mean +/- S. D.) as compared with the intravenous administration. The possible reasons for the low bioavailability are discussed. It is concluded that administration by rectal tube provides a useful alternative to the tablets (and intramuscular injections) when a rapid onset of effect of the drug is wanted, and when intravenous administration is not applicable or practical.     

丙泊酚中/长链脂肪乳预充注射液与注射液的经济性评价

目的:评价丙泊酚中/长链脂肪乳预充注射液与注射液的经济性以及配置药师的满意度.方法:采用现场模拟试验法,由5名配置药师在静脉用药调配中心分别对2种注射液模拟手术室环境进行配置准备.比较2种注射液的配置时间,采用最小成本分析方法评价2种注射液配置的经济性,采用问卷调查方法调查配置药师的满意度,评分1～5分依次表示非常不满...     

丙泊酚脂肪乳注射液生物等效性研究实施和管理的专家共识

丙泊酚脂肪乳注射液是临床上广泛使用的静脉用麻醉药.近年来国内丙泊酚临床需求不断增加,丙泊酚生物等效性研究数量持续攀升,然而其设计、实施、管理尚缺乏共识和指南.本专家组共同研讨,达成此共识,旨在为国内开展丙泊酚生物等效性研究提供参考和指导.     

密盖息联合帕米磷酸二钠治疗多发性骨转移癌患者的舒适护理

目的探讨密盖息联合帕米磷酸二钠治疗多发性骨转移癌患者的护理方法。方法密盖息联合帕米磷酸二钠治疗多发性骨转移癌患者69例,随机分为两组。对照组36例按常规护理,实验组33例给予舒适护理。结果两组止痛有效率对比无统计学意义（84．8％对比83．3％,x2=0．029,P〉0．05）。实验组治疗后生命质量Kamofsky评分明显提高,与对照组比较有统计学意义[（81．9±13．6）对比（74．6±11．3）,t=2．413,P〈0．05]。实验组较对照组患者满意度提高（93.3％对比75．0％,x2=4．609,P〈0．05）。结论人性化的舒适护理措施配合药物治疗肯定的止痛效果,提高了多发性骨转移癌患者的生活质量。     

Effect of syringe filter and i.v. administration set on delivery of propofol emulsion.

Propofol emulsion was studied to determine the effects of filtration and of passage through an i.v. administration set on drug concentration. To study syringe filter effects, propofol emulsion samples (Diprivan Injection, 10 mg/mL) were discharged through either a 5-mm filtering needle or a standard needle. To determine the effects of the i.v. administration set on propofol delivery, a diluted dispersion containing approximately 2 mg/mL was prepared from propofol emulsion and 5% dextrose injection. This formulation was siphoned into a 6-foot length of administration set tubing, from which samples were withdrawn at 0, 30, 60, and 120 minutes. Another 2-mg/mL diluted dispersion of propofol and 5% dextrose injection was placed in a glass reservoir and delivered through a 6-foot i.v. set at a rate of 1.75 mL/min, which corresponds to a low dosage rate of 0.05 mg.kg-1.min-1. Samples of the effluent were collected at 0, 5, 10, 15, 30, 60, 90, and 120 minutes. Samples collected from all three tests were assayed by using high-performance liquid chromatography. The mean propofol concentrations in the filtered and unfiltered samples were 96.05% and 96.09% of label claim, respectively, after discharge through needles; the difference was not significant. In the static study of the i.v. tubing effects, a 31.54-34.74% loss of propofol occurred after 120 min. In the study of propofol flowing through the i.v. tubing, the concentration dropped slightly in the initial sample, which was taken after the propofol was placed in the tubing. The concentration remained essentially constant for the first hour and then declined, with an overall average loss of 7.70%.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of epirubicin emulsion and solution in rabbits after intrahepato-arterial and intravenous injection.

The study reports pharmacokinetic findings on the disposition of a formulated emulsion of epirubicin in rabbits as compared to plain epirubicin solution after intrahepato-arterial and intravenous administration. The dose of epirubicin used was 1 mg/kg body weight. Blood samples were collected at several time points up to 6 h after administration. Serum concentrations of epirubicin were measured by liquid chromatography with fluorometric detection. The area under serum concentration-time curve (AUC infinity 0) is smallest after intrahepato injection of epirubicin emulsion. This, together with the highest apparent volume of distribution (Vss) suggest a possible targetting effect. Although the mean residence times are similar, intrahepato injection of emulsion apparently has the largest clearance. Difference in bioavailability in the general circulation between the 2 routes of administration also suggests a certain degree of liver first-pass metabolism of the drug. In view of these findings, further investigation and assessment are worthwhile for future application in human subjects.