Newer neuromuscular blocking agents: how do they compare with established agents?

Rapacuronium bromide (rapacuronium; ORG-9487) is a nondepolarising muscle relaxant (NMBA) with a low potency [90% effective dose (ED90) 1 mg/kg], which to some extent is responsible for its rapid onset of action. Because of the high plasma clearance (5.3 to 11.1 mg/kg/min) of rapacuronium, its clinical duration of action following single bolus doses up to 2 mg/kg in adults is short (i.e. <20 minutes). Rapacuronium forms a pharmacologically active 3-desacetyl metabolite, ORG-9488, which may contribute to a delay in spontaneous recovery after repeat bolus doses or infusions. After rapacuronium 1.5 mg/kg clinically acceptable intubating conditions are achieved within 60 to 90 seconds in the majority of adult and elderly patients undergoing elective anaesthesia. However, in a rapid-sequence setting. intubating conditions are less favourable after rapacuronium 1.5 to 2.5 mg/kg than after succinylcholine. The most prominent adverse effects of rapacuronium (tachycardia, hypotension and bronchospasm) are dose-related, and in particular pulmonary adverse effects are observed more frequently under conditions of a rapid-sequence induction in adults. Therefore, it seems worthwhile to consider only doses of rapacuronium < or = 1.5 mg/kg to facilitate rapid tracheal intubation, and to use succinylcholine or rocuronium rather than rapacuronium in a rapid-sequence setting. Rapacuronium, however, is a suitable alternative to mivacurium chloride (mivacurium) and succinylcholine for short procedures (e.g. ambulatory anaesthesia). Rocuronium bromide (rocuronium) is a relatively low-potent, intermediateacting NMBA. Its main advantage is the rapid onset of neuromuscular block whereby good or excellent intubating conditions are achieved within 60 to 90 seconds after rocuronium 0.6 mg/kg (2 x ED95), and within 60 to 180 seconds after smaller doses (1 to 1.5 x ED95). Larger doses of rocuronium (> or = 1 mg/kg) seem to be suitable for rapid-sequence induction under relatively light anaesthesia. However, it is still a matter of controversy whether, in the case of an unanticipated difficult intubation, the long duration of rocuronium administered in such large doses outweighs the many adverse effects of succinylcholine. Rocuronium has mild vagolytic effects and does not release histamine, even when administered in large doses. Rocuronium is primarily eliminated via the liver and its pharmacokinetic profile is similar to that of vecuronium bromide (vecuronium). Unlike vecuronium, rocuronium has no metabolite. Cisatracurium besilate (cisatracurium), the IR-cis, 1'R-cis isomer of atracurium besilate (atracurium) is approximately 4 times more potent than atracurium. The onset time of cisatracurium is significantly slower than after equipotent doses of atracurium. The recommended intubating dose is 0.15 to 0.2 mg/kg (3 to 4 times ED95). Over a wide range of clinically relevant doses the recovery properties of cisatracurium are affected by neither the size of the bolus dose nor by the duration of infusion. Unlike atracurium, cisatracurium does not trigger histamine release. Like atracurium, cisatracurium undergoes Hofmann elimination. In contrast to atracurium, cisatracurium does not undergo hydrolysis by nonspecific plasma esterases. Moreover, about 77% of the drug is cleared by organ-dependent mechanisms.     

Neuromuscular blocking activity and therapeutic potential of mixed-tetrahydroisoquinolinium halofumarates and halosuccinates in rhesus monkeys

Structure-activity relationships in rhesus monkeys for a novel mixed-onium class of ultra-short-acting nondepolarizing tetrahydroisoquinolinium neuromuscular blockers (NMBs) are described. Bis-onium chlorofumarate 20a with (1R,2S)-benzyltetrahydroisoquinolinium groups was a potent lead compound (ED(95) = 0.079 mg/kg) with an ultra-short duration of NMB effect (7.1 min) and a selectivity index (SI: defined as a ratio of the cardiovascular threshold dose to the ED(95)) similar to that of mivacurium (3). The mean threshold dose for cardiovascular effects with 20a was ca. 20 times its ED(95) value (SI = 20). A novel mixed-onium analogue of 20a was prepared by replacing the benzyltetrahydroisoquinolinium group distal to the fumarate chlorine atom with a (1S,2R)-phenyltetrahydroisoquinolinium moiety. The resulting mixed-onium chlorofumarate 24a displayed good NMB potency (ED(95) = 0.063 mg/kg), ultra-short duration of action (5.6 min) and an improved selectivity index (SI = 57). Several other mixed-onium derivatives containing octanedioate (25a; ED(95) = 0.103 mg/kg), difluorosuccinate (27c; ED(95) = 0.056 mg/kg), and fluorofumarate (28a; ED(95) = 0.137 mg/kg) linkers were also potent, ultra-short-acting NMBs with good to excellent selectivity index values (SI = 37-96). Octanedioate 25a was longer acting at higher doses compared to difluorosuccinate 27c and chlorofumarate 24a. Durations of NMB effect following a 0.4 mg/kg bolus dose (100% block) of 25a, 27c, and 24a were 16.9, 13.0, and 10.0 min, respectively. Recovery time for mixed-onium chlorofumarate 24a following a 1 h continuous infusion at 10-20 microg/kg/min (95-100% block) was ca. 5 min which is similar to that observed following a 0.2 mg/kg bolus dose of this compound and indicates a lack of cummulative effects. Preliminary studies with chlorofumarate 24a in whole human blood revealed that mixed-onium thiazolidine 29 was the major metabolite and that plasma cholinesterases do not play the primary role in duration of NMB effect. The NMB properties of 24a in rhesus monkeys led to its clinical evaluation as a possible alternative to succinylcholine.     

维库溴铵和阿曲库铵预处理对琥珀胆碱的肌震颤及肌松效应的影响

目的 观察维库溴铵和阿曲库铵预处理对琥珀胆碱肌震颤的预防及对其肌松效应的影响。方法 ３０例全麻病人根据不同预处理药分成３组,即０．９％生理盐水（对照组）;０．０１ｍｇ／ｋｇ维库溴铵组和０．０５ｍｇ／ｋｇ阿中铵组,每组１０例。预处理４分后静注琥珀胆囊１．５ｍｇ／ｋｇ。采用ＰａｒａＧｒａｐｈ监测肌松。结果 阿曲库铵预处理能基本消除琥珀胆碱引起的肌震颤,维库溴铵只能减轻或部分消除琥珀胆碱引起的肌震颤。但     

阿曲库铵恢复期应用琥珀胆碱对其肌松恢复的影响

目的：观察在阿曲库铵阻滞恢复期应用琥珀胆碱是否影响其肌松恢复时间。方法：４０例择期眼科手术病人随机分为２组,即对照组和试验组分别为１７和２３例。ＴＯＦ监测肌松,两组病人诱导过程中均用琥珀胆碱协助插管（ＴＯＦ＝０）。气管插管后Ｔ１恢复至对照值７５％时两组病人均静注阿曲库铵０．５ｍｇ／ｋｇ维持肌松,组Ⅰ对照,组Ⅱ当Ｔ１恢复至对照的５０％时静注琥珀胆碱１～１．５ｍｇ／ｋｇ,监测起效时间、临床肌松维持时间     

Concert-1闭环肌松注射系统输注不同剂量米库氯铵在耳鼻喉手术中的疗效及安全性比较

目的 探究Concert-1闭环肌松注射系统输注不同剂量米库氯铵在耳鼻喉手术中的疗效及安全性差异.方法 回顾分析2018年1月至2019年6月在保定市第二医院行全麻下耳鼻喉手术的病人临床资料,根据治疗剂量分为高剂量组(0.25 mg/kg)、常规剂量组(0.20 mg/kg)及低剂量组(0.15 mg/kg),各40例,并应用Concert-1闭环肌松注射系统进行对应剂量米库氯铵注射.记录两组病人肌松起效时间、恢复时间,米库氯铵注射前后血流动力学变化、血液组胺浓度变化及两组病人不良反应发生情况.结果 三组病人肌松起效时间比较具有显著差异,其中高剂量组肌颤搐抑制达75％(ThD75)(135.25±15.61)s、肌颤搐抑制达90％(ThD90)(150.25±21.54)s及肌颤搐抑制达最大阻滞程度时间(ThDmax)(168.16±19.78)s均最快,低剂量组ThD75(158.71±17.24)s、ThD90(179.67±24.67)s及ThDmax(190.18±21.13)s最慢,比较差异有统计学意义(F=26.513、18.692、36.425,均P<0.001);三组病人肌松恢复时间ThR25、RI及TOFr90比较差异无统计学意义(P>0.05);米库氯铵注射后5 min,高剂量组收缩压(SBP)(113.79±23.31)mmHg出现明显降低,心率(HR)(96.47±11.97)次/分明显升高,与常规剂量组SBP(126.67±23.97)mmHg、HR(84.36±10.59)次/分和低剂量组SBP(98.72±0.84)mmHg、HR(82.49±10.54)次/分比较差异有统计学意义(F=5.818、18.804,均P<0.05);米库氯铵注射后5 min,三组病人血液组胺浓度均显著升高,其中高剂量组(1.57±0.26)ng/mL>常规剂量组(1.34±0.25)ng/mL>低剂量组(1.07±0.21)ng/mL,组间比较差异有统计学意义(P<0.05),三组米库氯铵用量、手术时间总时间及不良发应总发生率比较差异无统计学意义(P>0.05).结论 Concert-1闭环肌松注射系统输注0.20 mg/kg、0.25 mg/kg米库氯铵均能提供耳鼻喉手术中满意的肌松效果,且安全性相当,临床可根据病人机体耐受情况选择合适剂量.     

Interaction between mivacurium and pancuronium: impact of the order of administration

Introduction Potentiation of mivacurium by low-dose pancuronium is mostly due to an inhibition of plasma butyryl cholinesterase (BchE) resulting in a decreased rate of hydrolysis of mivacurium. Nevertheless, an interaction at the receptor site could not be ruled out. By changing the order of the muscle relaxant injections, we may lessen the pharmacokinetic interaction and assess the impact at the acetylcholine receptor level.Methods Twenty patients scheduled for general anesthesia with propofol and fentanyl, and isoflurane were randomized into two groups receiving, mivacurium 100 g kg^–1 followed by pancuronium 15 g kg^–1 (group 1) or pancuronium 15 g kg^–1 followed by mivacurium 100 g kg^–1 (group 2). BchE before and after injection of each relaxant was measured. Neuromuscular block was assessed with a force transducer at the adductor pollicis measuring the elicited twitch to ulnar nerve stimulation.Results The neuromuscular block was greater when pancuronium was administered before mivacurium (100% versus 96±3%; P<0.05). Times to recovery of the elicited twitch response to 25% and 75% of control value were increased by 100% (P<0.05). After pancuronium, decreases in BchE of 11% and 14% in groups 1 and 2 were observed, respectivelyConclusion Interaction between mivacurium and low dose pancuronium is significant only when mivacurium is injected after pancuronium.     

Rapacuronium bromide: a review of its use in anaesthetic practice

Rapacuronium bromide (rapacuronium) is an aminosteroid, nondepolarising neuromuscular blocking agent (NMBA). At the recommended dose for endotracheal intubation (1.5 mg/kg), an intravenous bolus of rapacuronium has a rapid onset (approximately 1.2 to 1.8 minutes) and short duration of action (10.2 to 16.5 minutes) in adults undergoing elective surgery. Rapacuronium 1.5 mg/kg produced clinically acceptable intubating conditions in 68 to 89% of these patients at about 1 minute after administration. The onset, extent and duration of action and clinical efficacy of an intubating dose of rapacuronium appeared to be similar in the general adult population, adult patients with renal or hepatic dysfunction, patients undergoing Caesarean section, and elderly, paediatric or obese adult patients. Onset time with rapacuronium 1.3 to 2.5 mg/kg (0.9 to 1.8 minutes) was similar to or slower than that with a 1 mg/kg dose of the depolarising NMBA suxamethonium chloride (0.8 to 1.2 minutes). Intubating conditions were clinically acceptable about I minute after administration in 86 to 100% of patients with rapacuronium 1.3 to 2.5 mg/kg compared with in 88 to 97% of patients with suxamethonium chloride 1 or 1.5 mg/kg. Spontaneous recovery was slower with rapacuronium than with suxamethonium chloride, but neostigmine 0.04 or 0.05 mg/kg administered 2 or 5 minutes after rapacuronium 1.3 or 1.5 mg/kg accelerated recovery. In the few available comparative clinical trials, rapacuronium 1.5 mg/kg appeared to have a more rapid onset of action than the nondepolarising NMBAs mivacurium chloride 0.25 mg/kg, rocuronium bromide 0.45 or 0.6 mg/kg or vecuronium bromide 0.07 mg/kg, and a shorter duration of action than rocuronium bromide 0.45 or 0.6 mg/kg or vecuronium bromide 0.07 mg/kg. Additional boluses (< or =3) of rapacuronium 0.5 or 0.55 mg/kg after an intubating bolus of 1.5 mg/kg provided continued skeletal muscle relaxation during short surgical procedures in adult patients. However, these patients may recover more slowly than those who receive a single bolus of the drug. Bronchospasm was the most common treatment-related adverse event with rapacuronium 0.3 to 3 mg/kg (3.4% of adult patients). Tachycardia, injection site reaction and hypotension were also reported in small proportions of patients (1.6, 1.1 and 0.9%). The overall incidence of drug-related adverse events was similar with rapacuronium 1.5 or 2.5 mg/kg or suxamethonium chloride 1 mg/kg (8 vs. 6%) but bronchospasm, tachycardia and injection site reaction tended to occur more often with rapacuronium. Conclusions: At the recommended dose of 1.5 mg/kg, the nondepolarising NMBA rapacuronium has a rapid onset and short duration of action. It may provide a nondepolarising alternative to suxamethonium chloride for endotracheal intubation. Rapacuronium may be preferred over rocuronium bromide, vecuronium bromide or mivacurium chloride in this indication.     

New intravenous anaesthetics and neuromuscular blocking drugs. A review of their properties and clinical use

The newer neuromuscular blocking drugs include vecuronium and atracurium. Vecuronium is a competitive neuromuscular blocking drug with a steroid nucleus. A dose of 0.1 mg/kg has an onset time of 2 minutes and provides surgical paralysis for 20 minutes. Recovery to 90% twitch height occurs in 40 to 50 minutes. Vecuronium has few adverse effects and its use is associated with cardiovascular stability. Atracurium is a competitive neuromuscular blocking drug which undergoes Hofmann degradation and ester hydrolysis in plasma. A dose of 0.6 mg/kg has an onset time of around 2 minutes and provides surgical paralysis for 20 to 30 minutes. Recovery to 90% twitch height occurs in 60 to 80 minutes. Histamine release, usually only localised, has been reported in association with the use of atracurium. The organ-independent metabolism of atracurium allows its use in standard dosage in patients with renal or hepatic disease. Edrophonium, although not a new drug, has recently been re-evaluated for reversal of neuromuscular blockade. In a dose of 0.5 mg/kg it has been shown to be as effective as neostigmine at reversing neuromuscular blockade after recovery has started (greater than 25% twitch height recovery). However, if blockade is profound (less than 10% recovery), edrophonium is less effective. Among the newer intravenous anaesthetics are propofol (disoprofol) and midazolam. In a dose of 1.5 to 2.5 mg/kg, propofol produces sleep rapidly with a prompt recovery in 4 to 6 minutes. Induction of anaesthesia may be associated with a transient apnoea and a fall in systolic pressure. The rapid recovery has led to its use for maintenance of anaesthesia. Midazolam is a water-soluble benzodiazepine which has been used as an anaesthetic agent. The dose needed to induce sleep varies widely (0.15 to 0.5 mg/kg); onset is slow (1.5 to 5 minutes), and recovery may be prolonged. Midazolam is also used in lower doses as a sedative. Ketamine, an intravenous induction agent, has recently been used intrathecally and extradurally to provide analgesia.     

2型糖尿病患者罗库溴铵的肌松效应

目的 观察2型糖尿病(T2DM)患者罗库溴铵的肌松效应.方法 60例择期手术全麻病人等分为基本资料相仿的T2DM(D组)和非糖尿病(C组)两组.全麻诱导时,快速静注罗库溴铵0.6 mg/kg,记录两组的肌松起效时间、临床时效、恢复时间和恢复指数.结果 与C组比较,D组肌松起效时间略长于对照组(P>0.05),临床时效、恢复时间和恢复指数均明显延长(P<0.05).结论 与非糖尿病患者比较,T2DM患者罗库溴铵的临床维持时间延长,恢复时间亦延迟.     

Control of haemodynamic response to tracheal intubation in cigarette smokers compared with non-smokers

Some authors have demonstrated that a bolus dose of 1 microg/kg followed by an infusion rate of 0.5 microg/kg/min is adequate to attenuate the haemodynamic response to laringoscopy and tracheal intubation. In this study we have evaluated the efficacy of Remifentanil in controlling haemodynamic and some neuroendocrine responses to tracheal intubation in smokers compared with non-smokers. We studied 126 patients, ASA I-II, aged 20-49 yr, submitted laparoscopic cholecystectomy (66 male, 60 female); sixty-three patients were non-smokers and 63 patients smoked 10 or more cigarettes per day. Anaesthesia was induced with thiopental 3-5 mg/kg and remifentanil 1 microg/kg. Vecuronium 0.1 mg/kg was administrated to facilitate tracheal intubation. Immediately after intubation heart rate of smokers (mean 101.2 +/- 17 beat/min) was significantly higher (p < 0.001) than non-smokers (mean 90.2 +/- 14 beat/min) and also the neuroendocrine responses of smokers (epinephrine value 155 +/- 173 pcg/ml; norepinephrine value 276 +/- 164 pcg/ml) was significantly higher (p < 0.01) than non-smokers (epinephrine 95 +/- 75, norepinephrine 154 +/- 76). These findings may be clinically important to evaluate the risk of ischaemic heart diseases.     

Effect of glucagon on amitriptyline-induced cardiovascular toxicity in rats

The aim of this study was to investigate the effect of glucagon on cardiovascular parameters in anesthetized rat model of tricyclic antidepressant overdose. Toxicity was induced by infusion of amitriptyline 0.94 mg/kg/min until a 40-45% of reduction in mean arterial pressure was observed. Amitriptyline infusion rats were then randomized into three groups. Control group of rats (group 1) received a bolus of 5% dextrose followed by the continuous infusion of dextrose, whereas treatment groups received 1 mg/kg (group 2) or 2 mg/kg (group 3) bolus doses of glucagon followed by continuous infusion (0.1 mg/kg/min) of glucagons for 60 min. Mean arterial pressure, heart rate, and electrocardiogram were recorded. Amitriptyline caused a significant decrease in mean arterial pressure and a prolongation in QRS, yet it did not change the heart rate. High-bolus dose of glucagon (2 mg/kg) followed by glucagon infusion significantly increased mean arterial pressure at 40, 50, and 60 min (P < 0.05) and shortened the prolonged QRS at 50 and 60 min (P < 0.05) when compared with control group. There was also a significant increase in heart rate. In conclusion, bolus doses followed by a continuous infusion of glucagon were found to be effective in reversing the hypotension and QRS prolongation in the rat model of amitriptyline toxicity. Further studies are needed to reveal the exact mechanism of the proposed effect.     

Effect of glucagon-like peptide-1(7-36) and exendin-4 on the vascular reactivity in streptozotocin/nicotinamide-induced diabetic rats

We investigated the vascular effects of glucagon-like peptide-1 (GLP-1) and Exendin-4 in type 2 diabetic rat aortae. Studies were performed in a normal control group (NC) (0.2 ml i.p. saline, n = 10), streptozotocin (STZ)/nicotinamide diabetic control group (DC) (a single dose of 80 mg/kg STZ i.p. injection 15 min after administration of 230 mg/kg nicotinamide i.p.), GLP-1 (GLPC) control group (1 microg/kg twice daily i.p. for 1 month, n = 10), Exendin-4 control group (EXC) (0.1 microg/kg twice daily i.p. for 1 month, n = 10), GLP-1-treated diabetic group (GLPT) (1 microg/kg twice daily i.p. for 1 month, n = 10), and Exendin-4-treated diabetic group (EXT) (0.1 microg/kg twice daily i.p. for 1 month, n = 10). One month of GLP-1 and Exendin-4 treatment significantly decreased the blood glucose levels of diabetic rats (113 +/- 2 mg/dl, p < 0.001, and 117 +/- 1 mg/dl, p < 0.001, respectively versus 181 +/- 9 mg/dl in the DC group). Sensitivity (pD2) and maximum response (% Max. Relax) of acetylcholine-stimulated relaxations in the DC group (pD2: 6.73 +/- 0.12 and 55 +/- 6, respectively) were decreased compared with the non-diabetic NC group (pD2: 7.41 +/- 0.25, p < 0.05, and 87 +/- 4, p < 0.01). Treating diabetic rats with GLP-1, pD2 values and with Exendin-4, Max. Relax %values of aortic strips to acetylcholine returned to near non-diabetic NC values (pD2: 7.47 +/- 0.15, p < 0.05, and 87 +/- 3, p < 0.01, respectively). Maximal contractile responses (Emax) to noradrenaline in aortic strips from the diabetic DC group (341 +/- 27 mg tension/mg wet weight) were significantly decreased compared with the non-diabetic NC (540 +/- 66 mg tension/mg wet weight, p < 0.001) and the GLPT group (490 +/- 25 mg tension/mg wet weight, p < 0.05). There were no significant differences in pD2 values of aortic strips to noradrenaline from all groups. Emax to KCl in aortic strips from the DC group (247 +/- 10 mg tension/mg wet weight, p < 0.01) was significantly decreased compared with non-diabetic NC group (327 +/- 26 mg tension/mg wet weight). Treating diabetic rats with GLP-1 (GLPT), Emax values of aortic strips to KCl returned to near non-diabetic NC values (271 +/- 12 mg tension/mg wet weight). GLP-1 and (partially) Exendin-4 treatment could improve the increased blood glucose level and normalize the altered vascular tone in type 2 diabetic rats.     

Newer neuromuscular blocking drugs. An overview of their clinical pharmacology and therapeutic use.

Four new nondepolarising muscle relaxants, pipecuronium bromide, doxacurium chloride, mivacurium chloride and Org 9426 (rocuronium) offer alternatives to the established agents atracurium besilate and vecuronium bromide. Pipecuronium and Org 9426 are steroidal compounds, the latter being a monoquaternary agent, whereas doxacurium and mivacurium are bisquaternary benzylisoquinolinium compounds. Pipecuronium and doxacurium have a relatively slow onset and a long duration of action. Pipecuronium produces maximum block in 3 to 6 min when given in a dose of 45 to 80 micrograms/kg, and a duration of clinical relaxation of between 40 and 110 min. Doxacurium is more potent, but is the least rapid and the longest acting relaxant currently available. When administered in doses of 37 to 80 micrograms/kg, it produces maximum block within 3.5 to 10 min, with a duration of clinical relaxation of 77 to 164 min. The advantage of both pipecuronium and doxacurium is their cardiovascular stability. Both agents are primarily eliminated via the kidneys and both have now been licensed for use in the US. Mivacurium is a muscle relaxant with a short duration of action. When administered in doses of 0.1 to 0.25 mg/kg it produces maximum block in 2 to 4 min, but the duration of clinical relaxation is less than 20 min. Higher doses which could induce a faster neuromuscular block are unfortunately associated with some histamine liberation. The drug is metabolised by plasma cholinesterase. Mivacurium has also been licensed for use in the US. Org 9426 is an agent with a rapid onset but an intermediate duration of action. A dose of 0.5 to 0.6 mg/kg induces maximum block in about 1.5 min and has a duration of clinical relaxation of about 30 min. The rapid onset of effect could be useful for early intubation as an alternative to suxamethonium chloride. However, much more clinical experience is needed with this agent, particularly with regard to duration of action of larger doses and occurrence of side effects. The drug is mainly eliminated via the liver.     

Lepirudin dosing in dialysis-dependent renal failure

Lepirudin is a direct thrombin inhibitor indicated for parenteral anticoagulation in patients with heparin-induced thrombocytopenia. In patients with normal renal function, a bolus dose of 0.4 mg/kg is injected over 15-20 seconds, followed by a continuous infusion of 0.15 mg/kg/hour adjusted to prolong the activated partial thromboplastin time (aPTT) to 1.5-2.5 times the patient's baseline. Because renal function directly influences lepirudin elimination, patients with renal impairment require significant adjustments in the initial infusion rate. Current recommendations suggest that patients with dialysis-dependent renal failure should receive an initial bolus of 0.2 mg/kg, followed by 0.1 mg/kg every other day if the aPTT falls below the lower limit of the therapeutic range; however, this dosing may result in significant and prolonged overanticoagulation. A review of available literature regarding pharmacokinetics of lepirudin in renal failure suggests considerable variability in patient response over a narrow creatinine clearance range. Because there is no antidote for lepirudin if significant bleeding occurs, lower and less frequent dosing, guided by aPTT results, is recommended.     

Quinpirole, 8-OH-DPAT and ketanserin modulate catalepsy induced by high doses of atypical antipsychotics

The effect of the selective dopamine D2 receptor agonist quinpirole, the selective 5-HT1A receptor agonist 8-OH-DPAT and the selective 5-HT2A receptor antagonist ketanserin on catalepsy induced by atypical antipsychotics clozapine, risperidone, olanzapine and sertindole at higher doses was studied in rats. Haloperidol (0.5, 1 and 2 mg/kg), clozapine (50 and 75 mg/kg) and olanzapine (15 and 30 mg/kg) produced catalepsy dose-dependently while sertindole at doses up to 40 mg/kg failed to produce catalepsy in rats. However, sertindole (15, 30 and 45 mg/kg) produced a cataleptic effect in mice in a dose-dependent manner. At a high dose (5 mg/kg), risperidone produced catalepsy in rats. Quinpirole (0.05 and 0.1 mg/kg) reversed the cataleptic effect of haloperidol (2 mg/kg), risperidone (5 mg/kg), olanzapine (30 mg/kg) and sertindole (45 mg/kg). Quinpirole (0.05 and 0.1 mg/kg) reversed clozapine (75 mg/kg)-induced catalepsy. 8-OH-DPAT (0.15 and 0.3 mg/kg) dose-dependently reversed catalepsy induced by haloperidol (2 mg/kg) and risperidone (5 mg/kg) without affecting the cataleptic effect of olanzapine. However, the higher dose (0.45 mg/kg) of 8-OH-DPAT reversed it significantly. 8-OH-DPAT (0.3 mg/kg) reversed clozapine (75 mg/kg)-induced catalepsy. 8-OH-DPAT (0.15, 0.3 and 0.45 mg/kg) failed to reverse sertindole-induced catalepsy. Ketanserin (0.75 and 1.5 mg/kg) completely reversed catalepsy induced by haloperidol (2 mg/kg) and risperidone (5 mg/kg). Ketanserin (0.75 and 1.5 mg/kg) dose-dependently reversed olanzapine (30 mg/kg) and sertindole (45 mg/kg)-induced catalepsy without any effect on clozapine (75 mg/kg)-induced catalepsy. A higher dose (3 mg/kg) of ketanserin reversed clozapine-induced catalepsy. The present study suggests that atypical antipsychotics show fewer extrapyramidal symptoms (EPS) due to greater modulation of the serotonergic system. Therefore, an antipsychotic with dopamine D2/5-HT2A antagonistic action and 5-HT1A agonistic action may prove to be superior to the existing antipsychotics.     

Effect of succinylcholine on the neuromuscular junction of hypoglycemic rats

The aim of the present study was to investigate the effect of neuromuscular blocking drugs on the neuromuscular junction in hypoglycemic rats. Three groups of 6 white adult Wistar albino rats were used. Group A consisted of the control animals with normal blood glucose levels ranging between 80-120 mg/dl. Groups B and C consisted of animals which were made hypoglycemic by intravenous injection of insulin at a dose of 1 iU/100 g b.w. In this way, their blood glucose levels were reduced to 50% of the blood glucose levels of the control animals. The test animals (groups B and C) were sacrificed 40 min after the injection of insulin and the preparations of the phrenic nerve-hemidiaphragm were placed into a 100 ml_bath containing Paradelis-Zaimis solution. The bath was aerized with O2/CO2:95/5%, it's temperature was maintained at 37 degrees C and it's pH at 7.2. After the stabilization of the system and the recording of neuromuscular activity, succinylcholine was administered (1.5 x 10(-8) M in groups A and B and 3.0 x 10(-8) M in group C). For the statistical analysis of the results, student's t-test was used. According to our results, there is a statistically significant difference (with p < 0.02 being considered significant) between the n.bl/t% (magnitude of final neuromuscular blockage) values of the animals of groups B and C and those of the animals of group A. We also observed a statistically significant difference (with p < 0.001 being considered significant) between the t (time required for complete blockage in groups A and C or time required for stabilization of blockage in group B) values of the animals of groups B and C and those of the animals of group A. On the other hand, there was a statistically significant difference (p < 0.02 being considered significant) in the n.bl/5'% (magnitude of neuromuscular blockage 5 min after the administration of succinylcholine) values only between the animals of group A and B. Our results indicate that under hypoglycemic conditions, the amount of succinylcholine required for final neuromuscular blockage is two times greater than that needed under normal glucose blood levels. This finding suggests that the integrity of the neuromuscular junction is altered during hypoglycemia.     

The effect of ketamine upon depolarizing and non-depolarizing neuromuscular blockade in rabbit

Summary The interaction between ketamine and various neuromuscular blocking drugs is presently unclear. Therefore, experiments were carried out on rabbits to determine ketamine's effect upon the neuromuscular blockade produced by succinylcholine (SCh), d-tubocurarine (d-TC), pancuronium and a new short-acting drug, AH 8165, an azobis-arylimidazo-(1,2-a) pyridinium dihalide. The results of these experiments indicate that ketamine at a dose of 15 mg/kg, i.v. had no muscle blocking action of its own, but did cause a 10% increase in the muscle twitch height. When ketamine was given prior to SCh, the depth of SCh blockade was significantly increased compared to the SCh blockade alone. Ketamine was without effect upon the depth of the pancuronium, d-TC and AH 8165 neuromuscular block. p Recovery slopes of the SCh, pancuronium, d-TC and AH 8165 blocks were unaffected by the ketamine administration. These results support the concept that ketamine facilitates the action of depolarizing blocking drugs and has no effect upon the non-depolarizing neuromuscular blocking drugs.     

Cardiac vagolytic action of some neuromuscular blockers

Cardiac vagolytic effect of four commonly used neuromuscular blockers, (viz. D-tubocurarine, decamethonium, pancuronium and gallamine) was compared in mid-collicular decerebrate rats. The intravenous doses of neuromuscular blockers used (d-tubocurarine: 0.1 mg/kg; decamethonium: 2 mg/kg; pancuronium: 0.1 mg/kg; gallamine: 20 mg/kg) were sufficient to produce the paralysis of respiratory muscles. Bradycardia was induced by electrical stimulation of the vagus or by injecting dimethyl-phenyl-piperazinium (DMPP; a ganglionic stimulant). It was observed that d-tubocurarine and decamethonium were devoid of cardiac vagolytic action. On the other hand, pancuronium and gallamine inhibited significantly the bradycardia induced by electrical stimulation of the vagus or injection of DMPP; gallamine was found to have greater vagolytic action. The pressor responses to DMPP were not attenuated by pancuronium and gallamine indicating that in the dose administered, these agents did not block the ganllia. Bradycardia induced by the administration of acetylcholine in the left atrium was also attenuated by pancuronium and gallamine suggesting that the drugs produce cardiac vagolytic action by acting on the post-synaptic cholinergic receptors of the heart.     

Kinetics of d-tubocurarine disposition and pharmacologic response in rats

After bolus intravenous dosing of d-tubocurarine (d-TC) to rats, the twitch heights of the tibialis anterior muscle indirectly stimulated were followed, and its decrease was defined as pharmacologic response of d-TC. The relation between dose and response intensity was found to be well described with Hill's equation. According to a theory proposed by Smolen, Hill's equation was also applicable to the biophase d-TC concentration-response relation; the time courses of the relative biophase d-TC concentration indicated linear kinetics with dose levels 0.15 mg/kg and the occurrence of dose-dependent disposition with 0.30 mg/kg. After bolus i.v. dosing of³H-d-TC, plasma d-TC concentration obeyed a dose-independent two compartment model with doses 0.15mg/kg, but not with 0.30 mg/kg. This finding matched the above estimated with pharmacologic data. The active metabolite was not found in plasma and urine. The extent of d-TC plasma protein binding was independent of the wide range of plasma levels and its mean (±SD) value was 30.5 (±3.8). Plasma d-TC levels and pharmacologie response intensity were well correlated by Hill's equation and a three compartment model (the general two and the biophase compartments) in the dose range 0.15 mg/kg.This work was presented at the First Japanese-American Symposium on Pharmacokinetics and Biopharmaceutics, Tokyo, July 1981, which was held in memory of Dr. Sidney Riegelman.     

顺式阿曲库铵对79例全麻患者肌松效应及血流动力学观察

目的观察3倍95%有效药物剂量的顺式阿曲库铵对全麻患者的肌松效应及血流动力学指标。方法选取79例全麻患者,采用TOF-Guard肌松监测仪监测拇内收肌的肌松程度。经麻醉诱导意识丧失后,静注顺式阿曲库铵0.15mg/kg。经口气管插管,观察肌松作用起效的时间、恢复时相,以及血流动力学指标。结果麻醉效果91.1%的患者达到气管插管1级水平,7.6%的患者达到2级水平,且全部患者均完成气管插管。肌松恢复时相:25%为(39.1±7.9)min,75%为(47.8±8.1)min,100%为(61.9±10.2)min。所有患者均未出现皮肤潮红、支气管痉挛以及肝肾功能损害等不良反应。结论 3倍95%有效药物剂量的顺式阿曲库铵具有肌松效应良好,血流动力学稳定,不良反应发生少等特性,临床价值较高。