Novel Lipid and Preservative-free Propofol Formulation: Properties and Pharmacodynamics

Purpose

Propofol is a water-insoluble intravenous anesthetic agent that is actually formulated as a water-in-oil emulsion with known drawbacks such as pain on injection, microorganism growth support and stability. We report on the properties of formulations of propofol in poly (N-vinyl-2-pyrrolidone)-block-poly(d,l-lactide), PVP–PLA, polymeric micelles (Propofol-PM).

Methods

Microbial growth in these formulations was evaluated with Pseudomonas aeruginosa (ATCC 9027), Staphylococcus aureus (ATCC 6538), Escherichia coli (ATCC 25922) and Candida albicans (ATCC 10231). Sleep-recovery studies in female Sprague–Dawley rats, at a dose of 10mg/kg were performed to compare pharmacodynamic profiles of the new Propofol-PM formulations with those of Diprivan®, a commercially available lipid based propofol formulation.

Results

Growth of microorganisms was not supported in the Propofol-PM formulations tested. No significant differences in times to unconsciousness, awakening, recovery of righting reflex and full recovery were observed between Propofol-PM formulations and Diprivan®.

Conclusions

Propofol loaded in PVP–PLA micelles (Propofol-PM) is not significantly different in terms of pharmacodynamic but demonstrates no microorganism growth support and improved stability that opens up the door to pain on injection reduction strategy.

     

不同丙泊酚载药体系中游离药物浓度与体外溶血性的关系

考察了静脉注射用丙泊酚脂肪乳、聚氧乙烯蓖麻油胶束、微乳、混合胶束体系中游离药物浓度与体外溶血性的关联.用HPLC法测定游离丙泊酚的浓度,建立了UV法测定溶血百分率的方法.结果表明,载药脂肪乳、聚氧乙烯蓖麻油胶束、微乳、混合胶束体系透析后游离药物浓度(μg/ml)分别为19.54±0.6、33.5±2.8、107.3±3.9、151.1±13.1,溶血百分率(%)分别为4.6±0.4、20.0±0.4、55.7±4.0、89.O±O.8,而四者空白组的溶血百分率(%)则分别为1.5、6.1、0、31.在各载药体系中,由丙泊酚引起的溶血百分率在3.1%～58%范围内与游离药物浓度具有良好的线性关系(r=0.9650).     

The Misuse and Abuse of Propofol

Media attention on the misuse of propofol increased significantly when the drug was implicated in the death of pop music superstar Michael Jackson in 2010. The misuse and abuse of propofol among healthcare providers has been reported worldwide, with some misuse resulting in death. Propofol policies guiding healthcare worker re-entry into the workplace after misusing propofol have received rare attention in the research literature. The paucity of information regarding propofol-specific re-entry policies suggests that little research has addressed this problem and the lack of research and policy guidance can contribute to unsafe re-entry and even death. This paper focuses on healthcare providers because they have an easy access to propofol and therefore are vulnerable to misusing or abusing the drug. To accomplish this, the pharmacology and misuse/abuse potential of propofol and the influence of the 12-step recovery paradigm in the re-entry literature are reviewed. In conclusion, existing research and policy are drawn upon to suggest employment re-entry guidelines for healthcare workers.     

In Vitro Evaluation of the Plasma and Blood Compatibility of a Parenteral Formulation for Ditekiren,a Novel Renin Inhibitor Pseudopeptide

Ditekiren (U-71038; Boc-Pro-Phe-N-MeHis-Leu-[CHOHCH₂]-Val-Ile-aminomethyl)pyridine) is a potent renin inhibitor peptide and was formulated for clinical intravenous administration in acidified dextrose. This formulation of ditekiren was evaluated in vitro with human and monkey plasma as to its potential for forming a precipitate either of drug or of plasma proteins. Analysis by centrifugation showed that no drug precipitation occurred in plasma from either species at concentrations 25 times higher than anticipated in clinical studies. Results obtained by turbidimetry indicated that formulated ditekiren did not cause aggregation of human platelets or flocculation of proteins at concentrations approaching the solubility limit of the drug in plasma. Ditekiren or vehicle also caused no detectable lysis of red cells at concentrations representing 10 times the maximum clinical level. Therefore, ditekiren solutions as formulated are judged completely compatible with blood and plasma upon clinical intravenous administration.     

新型麻醉药异丙酚的氧化动力学

采用高效液相色谱法测定了异丙酚在不同温度下及其甲醇 水（Ｖ∶Ｖ＝７０∶３０）混合溶液在不同ｐＨ值下的反应速率常数，并求出了异丙酚氧化反应的活化能，结果表明ｐＨ值与温度对异丙酚的氧化动力学均有影响     

丙泊酚单用与联合芬太尼用于无痛人流术中麻醉的效果对比

目的比较丙泊酚单用与联合芬太尼在无痛人流术中麻醉的效果。方法选择医院2011年1月到2012年6月行人工流产术的早孕妇女681例,分为两组,对照组325例,观察组356例。对照组患者均缓慢静脉注射丙泊酚注射液2.5 mg/kg,观察组患者先给予枸橼酸芬太尼注射液1μg/kg静脉滴注,再静脉注射丙泊酚注射液1.5 mg/kg。观察两组患者镇痛效果、术毕苏醒时间、麻醉效果以及不良反应。结果对照组镇痛总有效率为80.31%,明显低于观察组的100.00%(P<0.05);对照组术毕苏醒时间为(6.8±2.2)min,明显长于观察组的(5.4±2.1)min(P<0.05);对照组丙泊酚用量为(2.92±0.81)mg/kg,显著多于观察组的(2.22±0.42)mg/kg(P<0.05);对照组麻醉总有效率为92.62%,明显低于观察组的100.00%(P<0.05)。对照组6例患者出现轻微恶心、呕吐,观察组3例患者出现轻微恶心、呕吐等不良反应。结论丙泊酚联合芬太尼用于无痛人流术的麻醉及镇痛效果好,安全可靠,值得临床推广。     

辣椒素固体分散体的处方工艺优化及表征

目的:制备辣椒素固体分散体,优化其处方工艺,并进行表征。方法:采用熔融法,以泊洛沙姆188(P188)或聚乙二醇4000(PEG4000)为载体制备辣椒素固体分散体。以60 min的累积释放度为指标,采用正交试验设计优化载体种类、药载比及搅拌时间,并进行验证;考察所制辣椒素固体分散体在温度40℃、相对湿度75%条件下0、30、180 d内的稳定性及X射线衍射法(XRD)分析是否有新峰出现;利用差示扫描量热法(DSC)、XRD对其进行物相表征。结果:以P188-PEG4000为载体,辣椒素-P188-PEG4000的质量比为1∶5∶3,搅拌20 min,所制辣椒素固体分散体体外60 min的累积释放度为84.6%(n=3),180 d内稳定性良好[含量RSD为3%(n=3),XRD显示未出现新峰];物相表征证明,辣椒素以无定型状态或分子状态高度分散于载体中。结论:通过此工艺制备了辣椒素固体分散体并且在60 min可体外溶出80%以上,稳定性好,工艺简便可行。     

A Compartmental Analysis of the Pharmacokinetics of Propofol in Sheep

Conventional compartmental pharmacokinetic analysis may provide inaccurate prediction of drug concentrations after rapid iv administration. To examine this, compartment and effect compartment analysis was applied to measured arterial and brain concentrations of propofol in sheep after iv administration at a range of doses and dose rates. Although arterial and brain concentrations were reasonably well fitted to compartmental and effect compartment models for individual doses and dose rates, the structure and parameters of all models differed with changes in both dose and rate of administration. There were large discrepancies between predicted and measured arterial and brain concentrations when these models were used to predict drug concentrations across doses and dose rates. These data support the limitations of this type of modeling in the setting of rapid propofol administration.     

舒芬太尼与丙泊酚在妇科腹腔麻醉术中的应用效果探究

目的:探讨妇科腹腔镜麻醉术中采用舒芬太尼与丙泊酚的应用效果。方法:将2016年1月~2018年2月接收的80例采取妇科腹腔麻醉术者随机分为两组,A组采用芬太尼与丙泊酚麻醉,B组采用舒芬太尼与丙泊酚麻醉,比较两组的麻醉效果。结果:两组麻醉前DBP、SBP、HR指标对比差异不明显(P>0.05);B组诱导后、气管插管后上述指标改善程度明显优于A组,且B组患者麻醉时间、拔管时间明显多于A组,呼吸恢复时间、镇痛药物使用率明显少于A组,差异有统计学意义(P<0.05)。结论:妇科腹腔麻醉术中采用舒芬太尼与丙泊酚麻醉,能稳定患者血流动力学指标,且麻醉安全性更高,适合临床应用。     

Propofol for Treatment of Refractory Alcohol Withdrawal Syndrome: A Review of the Literature

The authors evaluated all available evidence on the use of propofol as an adjuvant for the treatment of resistant alcohol withdrawal syndrome (AWS) in comparison to other therapies. A comprehensive PubMed search (1966–December 2015) was conducted using the search terms propofol, alcohol withdrawal, and drug therapy. Articles were cross‐referenced for other citations. Clinical studies, case series, and case reports published in the English language assessing the use of propofol in adult patients for treatment of AWS were reviewed for inclusion. Propofol is a sedative‐hypnotic that exerts its actions through agonism of GABA_A receptors at a different binding site than benzodiazepines and reduces glutamatergic activity through N‐methyl‐d ‐aspartase (NMDA) receptor blockade. Dosages from 5 to 100 μg/kg/minute reduced AWS symptoms with frequent development of hypotension and requirement for mechanical ventilation. Patients on propofol often experienced longer durations of mechanical ventilation and length of stay, which may be attributed to more‐resistant cases of AWS. When propofol was compared with dexmedetomidine as adjuncts in AWS, both agents showed similar benzodiazepine‐ and haloperidol‐sparing effects. Dexmedetomidine was associated with more numerical rates of bradycardia, while propofol was associated with more numerical instances of hypotension. Dexmedetomidine was used more frequently in nonintubated patients. The available data assessing the utility of propofol for AWS exhibited significant heterogeneity. Propofol may be useful in a specific population of patients with AWS, limited to those who are not clinically responding to first‐line therapy with benzodiazepines. Specifically, propofol should be considered in patients who are refractory to or not candidates for other adjuvant therapies, patients already requiring mechanical ventilation, or those with seizure activity or refractory delirium tremens. In severe, refractory AWS, adjuvant therapy with propofol may be considered but requires further research to recommend its use either preferentially or as monotherapy.     

丙泊酚后处理对大鼠脑缺血再灌注损伤的长时程保护作用

目的:观察丙泊酚后处理对大鼠脑缺血再灌注损伤是否具有长时程保护作用。方法:采用Longa法加以改良建立局灶性脑缺血再灌注模型,健康成年SD雄性大鼠144只,体质量250~280g,随机分为假手术组(S组)、缺血再灌注组(IR组)、脂质溶剂对照组(I组)和丙泊酚后处理组(P组),每组36只,各组各取6只在术后1、3、7、14、21和28d分别进行改良神经功能缺损程度评分(modified neurological severity score,mNSS),在术后1、7、14和28d每个时间点每组取6只进行脑梗死体积百分比测定,余每组6只于术后8和22d进行Morris水迷宫测试。结果:经长时程观察,IR组较S组mNSS评分明显增高,脑梗死体积百分比明显增大,水迷宫定位航行测试逃避潜伏期明显延长;P组与IR组比较,mNSS评分减小,脑梗死体积百分比缩小,逃避潜伏期缩短;IR组与I组比较差异无统计学意义。结论:丙泊酚后处理具有长时程脑保护作用,且此作用时效可维持28d,与丙泊酚脂质溶剂成分无关。     

丙泊酚和七氟烷应用于小儿腹股沟疝腹腔镜手术的效果及安全性探讨

[摘要]目的：比较丙泊酚与七氟烷对小儿腹股沟疝腹腔镜手术的效果及安全性。方法：选择2014年1月至2016年12月在该院行腹股沟疝腹腔镜手术的小儿104例,采用随机数字表法分为丙泊酚静脉注射麻醉组与七氟烷吸入麻醉组各52例,比较两组患儿手术期不同时点的呼吸（R）、心率（HR）以及两组患儿的麻醉诱导时间、苏醒时间、自主呼吸恢复时间、拔管时间、定向力恢复时间、术后躁动例数、躁动评分和不良反应。结果：观察组切皮时（T2）、麻醉后5 min（T3）的HR、RR均低于对照组,差异有统计学意义（P<0.05）;丙泊酚组的苏醒时间、自主呼吸恢复时间、拔管时间与定向力恢复时间均长于七氟烷组（P<0.05）,两组患儿的术后躁动发生率与躁动评分比较差异均无统计学意义（P>0.05）;两组不良反应比较差异无统计学意义（P>0.05）。结论：丙泊酚与七氟烷均能用于小儿腹股沟疝腹腔镜手术,但七氟烷对患儿的血液动力学影响较小,苏醒质量更高。     

In Vivo Assessment of Intestinal,Hepatic, and Pulmonary First Pass Metabolism of Propofol in the Rat

Purpose. The relative contribution of the intestinal mucosa, liver and lung to the in vivo disposition of propofol in the rat was investigated. Methods. Propofol (4.9–5.1 mg · kg^–l) was administered to groups of rats (n = 4) via the intra-arterial, intravenous, hepatic portal venous and oral routes. The AUC's of propofol were estimated and the fractions of the administered dose escaping first pass metabolism by the gut wall (f_G), liver (f_H) and lung (f_L) were calculated. In addition, transport experiments were carried out using Caco-2 cell monolayers to rule out the possibility that intestinal permeability is limiting the oral absorption of propofol. Results. Values for f_G, f_H and f_L were the following: 0.21 ± 0.07, 0.61 ± 0.13, and 0.82 ± 0.09, respectively. The apparent permeability coefficient of propofol across Caco-2 cell monolayers was 24.2 ± 0.3 × 10^–6 cm · sec^–1, which is similar to the apparent permeability coefficient obtained for propranolol (30.7 ± 1.7 × 10^–6 cm · sec^–1), a compound known to easily cross the intestinal epithelial membranes. The formation of propofol glucuronide, a major metabolite of propofol, could not be demonstrated during the flux experiments across the Caco-2 cell monolayers. Conclusions. The intestinal mucosa is the main site of first pass metabolism following oral administration of propofol in the rat. Intestinal metabolism could therefore also contribute to the systemic clearance of propofol.     

Propofol and arrhythmias: two sides of the coin

The hypnotic agent propofol is effective for the induction and maintenance of anesthesia. However, recent studies have shown that propofol administration is related to arrhythmias. Propofol displays both pro- and anti-arrhythmic effects in a concentration-dependent manner. Data indicate that propofol can convert supraventricular tachycardia and ventricular tachycardia and may inhibit the conduction system of the heart. The mechanism of the cardiac effects remains poorly defined and may involve ion channels, the autonomic nervous system and cardiac gap junctions. Specifically, sodium, calcium and potassium currents in cardiac cells are suppressed by clinically relevant concentrations of propofol. Propofol shortens the action potential duration (APD) but lessens the ischemia-induced decrease in the APD. Furthermore, propofol suppresses both sympathetic and parasympathetic tone and preserves gap junctions during ischemia. All of these effects cumulatively contribute to the antiarrhythmic and proarrhythmic properties of propofol.     

地佐辛复合丙泊酚用于无痛肠镜诊治100例

目的 观察地佐辛复合丙泊酚用于无痛肠镜检查麻醉效果的有效性、安全性及可行性.方法 选择拟进行肠镜检查的患者200例,美国麻醉医师协会（ASA）分级Ⅰ～Ⅱ级,随机分为两组,各100例,分别为丙泊酚组（Ⅰ组）和地佐辛复合丙泊酚组（Ⅱ组）.观察两组患者麻醉药物起效时间、清醒时间、肠镜检查时间和丙泊酚用量,记录所有患者检查前、中、后的血压（BP）、心率（HR）、指脉血氧饱和度（Sp02）、相对危险度值及不良反应发生的例数.结果 Ⅰ组与Ⅱ组相比,两组术中与术前BP,SpO2的差值比较,差异有统计学意义（P＜0.05）,Ⅰ组有2例出现收缩压（SBP）＜ 80 mmHg,16例患者出现SpO2低于95％,Ⅱ组发生例数低于Ⅰ组（P＜0.05）,两组患者麻醉药物起效时间、肠镜检查时间比较,差异无统计学意义（P＞0.05）,Ⅱ组术毕清醒时间和全程丙泊酚用量均少于Ⅰ组（P＜0.05）,术中呼吸暂停和术后恶心呕吐发生率Ⅰ组明显高于Ⅱ组（P＜0.05）,苏醒期兴奋躁动发生率Ⅱ组明显低于Ⅰ组（P＜0.05）.结论 地佐辛联合丙泊酚麻醉效果好,安全性高,是一种安全、有效、可行的无痛肠镜麻醉方法.     

新型麻醉药异丙酚静注乳剂的制备及其物理性质的测定

用国产原料制备了异丙酚静注乳剂，并对其一些物理性质进行了测定．结果表明该制剂的粒度分布、ｐＨ值、渗透压等项均符合静脉注射制剂的要求     

2%和1%丙泊酚用于腹腔镜子宫肌瘤剔除术患者的药效学比较

目的 比较2%与1%丙泊酚的实际药效关系,减少丙泊酚麻醉患者脂质输入过多引起的相关不良反应。方法 择期行腹腔镜子宫肌瘤剔除术患者82例,采用随机数字表法分为1%丙泊酚组和2%丙泊酚组,每组41例;2组丙泊酚诱导靶控血浆浓度为4 μg·mL^-1,术中靶控输注丙泊酚维持麻醉,根据脑电双频指数（bispectral index,BIS）值调整丙泊酚的靶控血浆浓度,使BIS值维持在50左右（45~55）;记录意识开始消失所需时间、意识消失时丙泊酚用量、苏醒时间和丙泊酚输注总量。结果 2%丙泊酚组意识开始消失所需时间、意识消失时丙泊酚用量和丙泊酚输注总量>1%丙泊酚组,苏醒时间<1%丙泊酚组,差异均有统计学意义（P<0.05）;2%丙泊酚组脂剂的输入量为1%丙泊酚组的59%。结论 使用2%丙泊酚靶控输注麻醉,可减少丙泊酚麻醉患者的脂质输入量,减少脂质输入过多引起的相关不良反应;2%丙泊酚的实际药效约等于1%丙泊酚的1.7倍。     

静脉滴注丙泊酚复合骶管阻滞麻醉用于痔上黏膜环切吻合术30例

目的观察3种椎管内麻醉方式用于痔上黏膜环切吻合术(procedure for prolapse and hemorrhoids,PPH)的镇痛效果和不良反应。方法选取2008年1月至2009年1月实施痔上黏膜环切吻合术患者90例,随机分为持续硬膜外麻醉(A)组、脊椎麻醉(B)组、骶管阻滞复合静脉滴注丙泊酚(C)组,每组30例。分别记录每组术前、术中、术后的血压、心率、血氧饱和度;将麻醉效果进行分级,观察并记录麻醉镇痛效果;观察术后12 h内患者不良反应发生情况。结果 B组和C组镇痛效果明显优于A组(P<0.05),而B组和C组之间镇痛效果比较无明显差异(P>0.05)。此外,B组不良反应出现最多,共20例(66.67%),A组和C组不良反应均为9例(30.00%),B组不良反应发生率明显高于A组和C组(P<0.05)。结论骶管阻滞复合丙泊酚静脉滴注麻醉操作简单、安全有效、麻醉质量高且不良反应相对较少,可作为痔上黏膜环切吻合术患者的首选麻醉方式。     

Structural and charge requirements for antimicrobial and hemolytic activity in the peptide PKLLETFLSKWIG,corresponding to the hydrophobic region of the antimicrobial protein bovine seminalplasmin

Several analogs of the 13-residue antimicrobial and hemolytic peptide PKLLETFLSKWIG (SPF), which is the most hydrophobic region of the 47-residue antimicrobial protein seminalplasmin [Sitaram, N. & Nagaraj, R. (1990) J. Biol. Chem. 265, 10438-104423 have been synthesized. The antimicrobial and hemolytic properties of the peptides were investigated with a view to gain an insight into the structural and charge requirements for these activities of SPF. Peptides in which E was replaced by K exhibited considerably improved antimicrobial activity with no concomitant increase in hemolytic activity. A peptide in which the aromatic amino acids were replaced by leucine exhibited antimicrobial activity like those of the peptides which had aromatic amino acids. Interchange in the positions of E and K and total replacement of K by E resulted in complete loss of activity. The peptides having antimicrobial activities showed appreciable helical content in a hydrophobic environment, whereas inactive peptides did not. Thus, by suitable‘engineering’ the biological activity of a short 13-residue peptide can be altered to yield peptides specifically having only antimicrobial activity with increased potency. © Munksgaard 1995.     

右美托咪定与丙泊酚用于子痫前期产妇剖宫产手术术中镇静的比较

目的 比较右美托咪定与丙泊酚用于子痫前期患者剖宫产手术术中镇静的有效性和安全性。方法 腰硬联合麻醉下行择期剖宫产手术的子痫前期患者90例,随机均分为右美托咪定组、丙泊酚组及对照组,各组按预定方法分别给予药物。记录患者入室时(T₀)、CSEA给药前(T₁)、切皮时(T₂)、清理腹腔时(T₃)及手术结束时(T₄)的平均动脉压(mean arterial pressure,MAP)、心率(heart rate,HR)、脉搏血氧饱和度(oxygen saturation,SpO₂)、警觉-镇静(observer’s assessment of alertness/sedation,OAA/S)评分,记录新生儿Apgar评分及各组不良反应发生情况。结果 MAP、HR及OAA/S T_1-4右美托咪定组及丙泊酚组均低于对照组,MAP T_1-4,HR T₁、T₃及T₄及OAA/S T₄右美托咪定组低于丙泊酚组(P<0.05)。新生儿Apgar 评分,3组组间比较差异无统计学意义。恶心呕吐、牵拉痛及寒战发生率右美托咪定组及丙泊酚组均低于对照组(P<0.05);低血压及心动过缓发生率右美托咪定组及丙泊酚组略高于对照组,呼吸抑制及躁动发生率右美托咪定组低于丙泊酚组,但差异均无统计学意义。结论 右美托咪定和丙泊酚均可安全有效地应用于子痫前期患者剖宫产术中镇静,比较而言,右美托咪定镇静后可唤醒,血流动力学更平稳,呼吸抑制等不良反应更少。