Ester und Stereoisomere

This review discusses concepts of isomers, stereoisomers, chirality, and enantiomers as applied to drugs used in anaesthesia. The inhalational anaesthetics enflurane and isoflurane are examples of stereoisomers. A chiral centre is formed when a carbon or quaternary nitrogen atom is connected to four different atoms. A molecule with one chiral centre is then present in one of two possible configurations termed enantiomers. A racemate is a mixture of both enantiomers in equal proportions. Many of the drugs used in anaesthesia are racemic mixtures (the inhalational anaesthestics, local anaesthetics, ketamine, and others). The shape of the atracurium molecule is comparable to that of a dumb-bell: the two isoquinoline groups representing the two bulky ends connected by an aliphatic chain. In each isoquinoline group there are two chiral centres, one formed by a carbon and the other by a quaternary nitrogen atom. From a geometric point of view, the connections from the carbon atom to a substituted benzene ring and from the quaternary nitrogen to the aliphatic chain may point in the same direction (cis configuration) or in opposite directions (trans configuration). The two isoquinoline groups in atracurium are paired in three geometric configurations: cis-cis, trans-trans, or cis-trans. However, the two chiral centres allow each isoquinoline group to exist in one of four stereoisomeric configurations. In the symmetrical atracurium molecule, the number of possible stereoisomers is limited to ten. Among these, 1 R-cis, 1′ R-cis atracurium was isolated and its pharmacologic properties studied. This isomer, named cis-atracurium, offers clinical advantages over the atracurium mixture, principally due to the lack of histamine-releasing propensity and the higher neuromuscular blocking potency. The ester groups appear in one of two steric configurations true and reverse esters. In the true esters, oxygen is positioned between the nitrogen atom and the carbonyl group, while in the reverse esters it is positioned on the other side of the carbonyl group. True esters, suxamethonium and mivacurium, are hydrolysed by the enzyme plasma cholinesterase (butyrylcholinesterase), albeit at different rates. The more rapid degradation of suxamethonium is responsible for its fast onset and short duration of action in comparison with mivacurium. The reverse esters, atracurium, cisatracurium, and remifentanil, are hydrolysed by nonspecific esterases in plasma (carboxyesterases). Remifentanil is hydrolysed rapidly; the degradation leads to its inactivation and short duration of action. Cis-atracurium is preferentially degraded and inactivated by a process known as Hofmann elimination. In a second step, one of the degradation products, the monoester acrylate, is hydrolysed by a nonspecific esterase.     

LC-QQQ-MS/MS分析苯磺酸氨氯地平中痕量苯磺酸酯类基因毒性杂质

摘要：目的 建立LC-QQQ-MS/MS分析测定苯磺酸氨氯地平中痕量苯磺酸酯类基因毒性杂质苯磺酸甲酯、苯磺酸乙酯、苯磺酸丙酯和苯磺酸异丙酯的检测方法。方法 采用Agilent Zorbax SB-C18（3.0mm×100mm,1.8μm）色谱柱,以水（含 5mMol?L-1甲酸铵和0.1%甲酸）和甲醇（含5mMol?L-1甲酸铵和0.1%甲酸）为流动相,梯度洗脱,流速0.4 mL?min-1,电喷雾离子化（ESI）,正离子模式下MRM采集。结果 苯磺酸甲酯定量限为20 ng?mL-1,苯磺酸乙酯、苯磺酸丙酯和苯磺酸异丙酯定量限为1 ng·mL-1;方法精密度良好,保留时间和峰面积RSD%均小于5%（n=10）;苯磺酸甲酯在20~1000ng·mL-1,苯磺酸乙酯、苯磺酸丙酯和苯磺酸异丙酯在1~1000ng?mL-1的浓度范围内呈良好的线性关系,r≥0.998;方法准确度良好,平均加标回收率（n=10）分别为99.77%、100.19%、94.21%和92.43%。5个不同厂家生产的苯磺酸氨氯地平中苯磺酸甲酯的含量均小于LOQ（8μg?g-1）,苯磺酸乙酯、苯磺酸丙酯和苯磺酸异丙酯的含量均小于LOQ（0.4μg?g-1）。结论 该方法可用于苯磺酸氨氯地平中痕量基因毒性杂质苯磺酸甲酯、苯磺酸乙酯、苯磺酸丙酯和苯磺酸异丙酯含量的检测分析。     

苯磺顺阿曲库铵合成工艺的优化

目的 对苯磺顺阿曲库铵合成工艺的优化 方法 以3,4-二甲氧基苯乙胺和3,4-二甲氧基苯乙酸为原料,依次经酰化、脱水环化及还原制得四氢罂粟碱。采用半量拆分法,以D-(+)-二对甲基苯甲酰酒石酸为拆分剂,进行拆分,得到R-四氢罂粟碱,经过麦克加成,氮甲基化反应得苯磺酸阿曲库铵。 结果 目标产物结构通过质谱法、核磁共振氢谱、碳谱和DEPT谱对结构进行了确证,产物的纯度经 HPLC检测为99.18 %,总产率为24.79%。结论 优化后的工艺反应条件温和、操作简便,反应产率高,为工业化生产提供了信息和依据。     

Lipid based nanocarriers: a translational perspective

Over the recent couple of decades, pharmaceutical field has embarked most phenomenal noteworthy achievements in the field of medications as well as drug delivery. The rise of Nanotechnology in this field has reformed the existing drug delivery for targeting, diagnostic, remedial applications and patient monitoring. The convincing usage of nanotechnology in the conveyance of medications that prompts an extension of novel lipid-based nanocarriers and non-liposomal systems has been discussed. Present review deals with the late advances and updates in lipidic nanocarriers, their formulation strategies, challenging aspects, stability profile, clinical applications alongside commercially available products and products under clinical trials. This exploration may give a complete idea viewing the lipid based nanocarriers as a promising choice for the formulation of pharmaceutical products, the challenges looked by the translational process of lipid-based nanocarriers and the combating methodologies to guarantee the headway of these nanocarriers from bench to bedside.     

预注法联合限时法缩短顺苯磺酸阿曲库铵起效时间疗效观察

目的：研究预注法联合限时法缩短顺苯磺酸阿曲库铵起效时间的效果。方法：成年择期手术全麻患者112例按入院先后顺序分为甲乙丙3组,3组患者均使用芬太尼4μg·kg-1和丙泊酚2 mg·kg^-1作为诱导药。甲组采用预注法联合限时法,患者先静注顺苯磺酸阿曲库铵20μg·kg-1,3 min后再先后注射诱导药和顺苯磺酸阿曲库铵80μg·kg-1;乙组采用预注法,患者先静注顺苯磺酸阿曲库铵100μg·kg-1,1.5 min后注入诱导药;丙组采用限时法,患者先后注入诱导药与顺苯磺酸阿曲库铵l00μg·kg-1。观察比较各组诱导前T1百分比,肌肉颤搐抑制90%和100%的时间、气管插管评级以及药品不良反应。结果：3组患者气管插管优秀率比较,差异无统计学意义（P〉0.05）。与甲、乙组比较,丙组诱导前不存在T1抑制,乙组（9.8±2.6）多于甲组（3.2±1.5）（P〈0.01）;达肌肉颤搐抑制90%与100%时间,丙组明显长于甲、乙两组（P〈0.01）。丙组不良反应发生率明显高于甲、乙两组（P〈0.05）。结论：应用预注法以及限时法,均可有效缩短顺苯磺酸阿曲库铵的起效时间,效果显著,且安全性高。     

Stabilité physico-chimique des solutions injectables de bésilate de cisatracurium dans les conditions cliniques d’utilisation

Objectives

To assess the stability of cisatracurium besilate solution stored at 5 °C and 25 °C.

Materials and methods

Cisatracurium solutions at 2, 5 and 0.1 mg/mL in 0.9 % sodium chloride or 5 % glucose were exposed to 5 °C and 25 °C under 60 % relative humidity for seven days. The physicochemical stability was assessed at 24, 48 hours and seven days with dosage of the active substance, detection of degradation products and a possible racemization, measuring pH, osmolality and turbidity, assessment of coloration, visible particles and invisible particles count.

Results

Cisatracurium besilate present good stability for 24 hours at 5 °C and 25 °C for concentrations between 0.1 and 5 mg/mL. Beyond 24 hours, the solutions at 2 and 5 mg/mL remained stable for seven days at 5 °C. At 25 °C, potentially toxic degradation products appear in solutions of 0.1 mg/mL between 24 and 48 hours. No racemization was detected, the drug remains in its active form cis.

Conclusion

Cisatracurium solutions at 2 and 5 mg/mL may be stored at 5 °C or 25 °C for seven days. It's advisable to keep the solutions in a dilution of 0.1 mg/mL in 0.9 % sodium chloride or 5 % glucose in the refrigerator. No diluted solution should be stored at room temperature beyond 24 hours.     

联合应用顺阿曲库铵与维库溴铵后ED50和ED95的改变

目的：观察顺式阿曲库铵联合维库溴铵用药后ED50和ED95的变化。方法将75例择期手术患者（ASAⅠ~Ⅱ级）随机分为3组：顺式阿曲库铵组、维库溴铵组和顺式阿曲库铵＋维库溴铵组,每组各25例。麻醉诱导后,以单次给药法观察起效时间和T1达到最大抑制的时间,描绘3组患者的量-效曲线,求得各自的ED50和ED95值,并运用等效图法和代数法对两药相互作用进行分析。结果单用顺式阿曲库铵组、维库溴铵组ED50值分别为32.35、28.78μg/kg,ED95值分别为52.67、51.20μg/kg。联合用药时ED50值为16.81、12.17μg/kg,ED95值为23.49、22.16μg/kg,与单独用药相比,差异均有统计学意义。联合用药时ED50和ED95的合用代数值分别为0.942、0.879。结论联合使用顺式阿曲库铵和维库溴铵具有协同作用,且量-效曲线产生左移。     

气相色谱法测定苯磺阿曲库铵原料中的残留溶剂

目的:用毛细管柱气相色谱法建立苯磺阿曲库铵中残留溶剂(乙醚、丙酮、甲醇、二氯甲烷、乙腈、甲苯)的测定方法。方法:采用DM-Wax(30 m×0.53 mm,1.00μm)毛细管柱(固定相为键合交联聚乙二醇),以氮气为载气,FID检测器,采用程序升温,分流直接进样,外标法计算残留溶剂的含量。结果:在考察的浓度范围内呈现良好的线性关系(乙醚r=0.9997,丙酮r=0.9997,甲醇r=0.9996,二氯甲烷r=0.9996,乙腈r=0.9991,甲苯r=0.9997),平均回收率范围为97.4%～99.7%,理论塔板数均>7000,相邻的峰之间的分离度均>2,精密度、重复性RSD均<3%。结论:本方-法简单、结果准确、重现性好,可用于苯磺阿曲库铵中乙醚、丙酮、甲醇、二氯甲烷、乙腈、甲苯6种残留溶剂的同时测定。     

Neuromuscular blockade with cisatracurium in infants andchildren. Its course under sevoflurane anesthesia

Zusammenfassung Fragestellung. Die Wirkung von nichtdepolarisierenden Muskelrelaxanzien unterscheidet sich bei Kindern unterschiedlichen Alters erheblich. Bisher liegen nur wenige Daten zur Pharmakodynamik von Cisatracurium bei S?uglingen vor. Ziel dieser Untersuchung war, den Verlauf der neuromuskul?ren Blockade von Cisatracurium 0,1 mg/kg unter Sevoflurananaesthesie bei S?uglingen und Kleinkindern zu vergleichen. Methoden. Der Verlauf der neuromuskul?ren Blockade wurde mittels Elektromyographie an jeweils 15 S?uglingen und 15 Kindern gemessen. Die An?sthesie wurde mit Propofol und Remifentanil eingeleitet und mit Sevofluran (konstant 2 Vol% endtidal) sowie Remifentanil nach klinischem Bedarf aufrechterhalten. Nach Injektion von 0,1 mg/kg Cisatracurium wurden folgende Zeitintervalle bestimmt: Anschlagszeit: Zeit von Beginn der Cisatracurium-Injektion bis zur max. Muskelblockade; klinische Wirkdauer: Zeit von der Injektion des Muskelrelaxans bis zur 25%igen T₁-Erholung; Erholungsindex: Zeit von 25- bis 75%igen T₁-Erholung; Erholung TOFR 0,9: Zeit von der Injektion von Cisatracurium bis zur Erholung der Train-of-four-Ratio (TOFR) auf 90%. Zus?tzlich wurde in beiden Gruppen die maximale neuromuskul?re Blockade (Tmax) nach 0,1 mg/kg Cisatracurium bestimmt. Ergebnisse. Beide Gruppen unterschieden sich signifikant hinsichtlich der Anschlagszeit und der klinischen Wirkdauer. Verglichen mit den ?lteren Kindern war die Anschlagszeit bei den S?uglingen kürzer (74 s vs. 198 s) und die klinische Wirkdauer verl?ngert (55 vs. 41 min). Die TOFR 0,9 betrug 73 min (56–86 min) bei den S?uglingen und 59 min (43–72 min) bei den Kindern; p <0,001. Tmax war 100% (97–100%) in der S?uglingsgruppe und 98% (92–100%) in der Gruppe der ?lteren Kinder; p <0,01. Der Erholungsindex war hingegen mit 21 vs. 16 min vergleichbar. Schlussfolgerungen. Unter Sevofluranan?sthesie reagieren S?uglinge wesentlich sensibler auf die Gabe von Cisatracurium als Kinder. Dies zeigt sich sowohl in einer kürzeren Anschlagszeit als auch in einer verl?ngerten Wirkungsdauer und einer verz?gerten neuromuskul?ren Erholung. In der klinischen Praxis empfiehlt es sich daher, auch bei S?uglingen und Kindern nicht auf neuromuskul?res Monitoring zu verzichten.      

Comparison of the variability of the onset and recovery from neuromuscular blockade with cisatracurium versus rocuronium in elderly patients under total intravenous anesthesia

This study was designed to compare the variability of the onset and offset of the effect of two neuromuscular blocking drugs with different elimination pathways in adult and elderly patients during total intravenous anesthesia (TIVA). After Ethics Committee approval and patients'' informed consent, the drugs were compared in 40 adult and 40 elderly patients scheduled for elective surgery under TIVA with tracheal intubation who were randomized to receive a single bolus dose of 0.15 mg/kg cisatracurium or 0.9 mg/kg rocuronium. The time of onset of maximum depression, duration of action, and recovery index time were measured and recorded for each patient and variability is reported as means ± standard deviation. Time of onset was significantly shorter for rocuronium than cisatracurium for the adult and elderly groups (P = 0.000), but the variability of cisatracurium was significantly greater compared with rocuronium for the same age groups (93.25 vs 37.01 s in the adult group and 64.56 vs 33.75 s in the elderly group; P = 0.000). The duration of the effect in the elderly group receiving rocuronium was significantly longer than in the elderly group receiving cisatracurium, and the variability of the duration was significantly greater in the rocuronium group than in the cisatracurium group. Mean time of recovery was significantly longer for the elderly group receiving rocuronium than for the elderly group receiving cisatracurium (P = 0.022), and variability was also greater (P = 0.002). Both drugs favored good intubating conditions. In conclusion, cisatracurium showed less variability in these parameters than rocuronium, especially in the elderly, a fact that may be of particular clinical interest.