Pharmacodynamic and pharmacokinetic effects of the intravenously administered CB1 receptor agonist Org 28611 in healthy male volunteers

CB1/CB2 agonists are reported to have sedative, amnestic, analgesic and anti-emetic properties, which would make them ideal drugs for outpatient treatments under conscious sedation. The main objective of this in human study was to assess the sedative properties of Org 28611, a potent water-soluble CB1 agonist. Single ascending doses were administered during a slow 25 min infusion and after a 1 min bolus administration to healthy male volunteers. In addition, the pharmacokinetics, amnestic properties, postural stability, electro-encephalography, behavioural and cardiovascular effects were studied. Midazolam 0.1 mg/kg was used as a positive control. The pharmacokinetic parameters were proportional to dose. No effects were observed after intravenous administration of doses up to Org 28611 1 microg/kg. Dose-related effects were observed at higher doses. Although subjects reported subjective sedation after administration of Org 28611 3-10 microg/kg, the observed sedation was considerably less than after midazolam. Org 28611 is, therefore, not suitable for providing sedation for outpatient surgical procedures and doses above the maximum tolerated dose of 3 microg/kg (either administered as a slow infusion or a bolus dose) can cause untoward psychotropic effects.     

Impact of the CYP3A5 genotype on midazolam pharmacokinetics and pharmacodynamics during intensive care sedation

Objective Information is lacking on whether the CYP3A5 genotype affects the disposition and effects of midazolam during the long-term intensive care sedation of patients. This study was undertaken to estimate whether the CYP3A5 genotype can explain a relevant portion of pharmacokinetic interindividual variability. Methods We determined the CYP3A5 genotype in 71 Caucasian patients who underwent long-term sedation during intensive care treatment. We then assessed the relation between the genotype and both the plasma concentrations of midazolam and 1′-OH-midazolam in 645 plasma samples and the simultaneously estimated Ramsay sedation score, both of which were recorded during routine midazolam drug monitoring. Results Eight patients had the CYP3A5*1/*3 genotype and 63 patients the CYP3A5*3/*3 genotype. The concentration–dose ratio [C/D; plasma concentration of midazolam (ng/ml) divided by the rate of infusion (mg/h); expressed as the mean (95% confidence interval)] was 87.4 (70.8, 108.9) for the *3/*3 patients and 79.0 (48.9, 129.0) for *1/*3 patients. The corresponding data for infusion rate (IR; in mg/h), Ramsay score (RS) and the ratio 1′-OH-midazolam concentration/midazolam concentration (ROH) for *3/*3 and *1/*3 patients were IR 7.4 (6.2, 8.6) vs. 11.4 (4.9, 17.9), RS 5.4 (5.2, 5.6) vs. 5.3 (4.2, 6.0) and ROH 0.11 (0.09, 0.13) vs. 0.17 (0.11, 0.26), respectively. Conclusions The CYP3A5*1/*3 genotype did not lead to an apparently lower midazolam concentration/dose ratio or Ramsay score values. As the present sedation procedure during intensive care therapy may be described as a physician closed-loop titration towards Ramsay scores of 4 ± 1, our data do not indicate that prior determination of the genotype will result in better care or economic savings.     

Effect of route of administration of fluconazole on the interaction between fluconazole and midazolam

Objective: Midazolam is a short-acting benzodiazepine hypnotic extensively metabolized by CYP3A4 enzyme. Orally ingested azole antimycotics, including fluconazole, interfere with the metabolism of oral midazolam during its absorption and elimination phases. We compared the effect of oral and intravenous fluconazole on the pharmacokinetics and pharmacodynamics of orally ingested midazolam. Methods: A double-dummy, randomized, cross-over study in three phases was performed in 9 healthy volunteers. The subjects were given orally fluconazole 400 mg and intravenously saline within 60 min; orally placebo and intravenously fluconazole 400 mg; and orally placebo and intravenously saline. An oral dose of 7.5 mg midazolam was ingested 60 min after oral intake of fluconazole/placebo, i.e. at the end of the corresponding infusion. Plasma concentrations of midazolam, α-hydroxymidazolam and fluconazole were determined and pharmacodynamic effects were measured up to 17 h. Results: Both oral and intravenous fluconazole significantly increased the area under the midazolam plasma concentration-time curve (AUC_0–3, AUC_0–17) 2- to 3-fold, the elimination half-life of midazolam 2.5-fold and its peak concentration (C_max) 2- to 2.5-fold compared with placebo. The AUC_0–3 and the C_max of midazolam were significantly higher after oral than after intravenous administration of fluconazole. Both oral and intravenous fluconazole increased the pharmacodynamic effects of midazolam but no differences were detected between the fluconazole phases. Conclusion: We conclude that the metabolism of orally␣administered midazolam was more strongly inhibited by oral than by intravenous administration of fluconazole. Received: 1 July 1996 / Accepted in revised form: 4 September 1996     

Dose-finding and pharmacokinetic study of intramuscular midazolam

Ten healthy male volunteers received intramuscular (IM) doses of 0.050, 0.075, and 0.100 mg/kg midazolam hydrochloride or its vehicle (placebo) in a double-blind manner until a dose producing adequate preanesthetic sedation was administered. Level of sedation, degree of impairment of psychomotor function, existence of antegrade amnesia, and incidence of side effects were evaluated after each dose. An adequate level of sedation (awake/drowsy or asleep/easily responds to verbal command for at least one hour after drug administration) was produced, beginning shortly after drug administration, in eight of the volunteers by 0.075 mg/kg; the dose producing the same effect (the optimal dose) was 0.050 mg/kg for the oldest volunteer, and the other volunteer required 0.100 mg/kg. Sedation lasted no more than four hours after administration of the optimal dose. The optimal dose in each volunteer produced an impairment of psychomotor function that lasted no more than six hours and antegrade amnesia that lasted no more than two hours. Mild erythema at the injection site occurred infrequently. The pharmacokinetic variables describing the absorption and disposition of midazolam were determined in five of the volunteers. Pharmacokinetic studies indicated that midazolam hydrochloride is absorbed rapidly from IM injection sites; this consistent with the observation of a rapid onset of sedation. The relatively high elimination clearance of midazolam after IM administration is similar to that reported after intravenous administration. The results of this study suggest that midazolam hydrochloride 0.075 mg/kg IM provides sedation and amnesia that is satisfactory for preanesthetic medication but does not last too long into the recovery period.     

咪达唑仑与芬太尼联合用于ICU机械通气患者镇静的临床观察

目的观察咪达唑仑与芬太尼联合用于ICU患者镇静的作用。方法对30例ICU机械通气患者给予咪达唑仑和芬太尼联合镇静,维持理想的镇静深度3～4级,观察各项镇静指标。结果镇静效率为(87±8.8)%,镇静期间咪达唑仑的平均输注速度为(0.14±0.02)mg/(kg.h)。镇静期间血压、心率平稳,且明显低于镇静前;镇静期间的血氧饱和度则明显高于镇静前。停药后完全清醒时间为(90±24.8)min,拔除气管插管时间为(140±36.6)min。拔管后1h血气正常。结论咪达唑仑与芬太尼联合用于ICU机械通气患者可获得满意的镇静效果。     

Comparative evaluation of benzodiazepines for control of soman-induced seizures

This study evaluated the ability of six benzodiazepines to stop seizures produced by exposure to the nerve agent soman. Guinea pigs, previously prepared with electrodes to record electroencephalographic (EEG) activity, were pretreated with pyridostigmine (0.026 mg/kg, i.m.) 30 min before challenge with soman (56 μg/kg, s.c.) and then treated 1 min after soman exposure with atropine (2.0 mg/kg, i.m.) and pralidoxime chloride (2-PAM Cl; 25 mg/kg, i.m.). All animals developed seizures following this treatment. Benzodiazepines (avizafone, clonazepam, diazepam, loprazolam, lorazepam, and midazolam) were given i.m. 5 or 40 min after seizure onset. All benzodiazepines were effective in stopping soman-induced seizures, but there were marked differences between drugs in the rapidity of seizure control. The 50% effective dose (ED₅₀) values and latencies for anticonvulsant effect for a given benzodiazepine were the same at the two times of treatment delay. Midazolam was the most potent and rapidly acting compound at both treatment times. Since rapid seizure control minimizes the chance of brain damage, use of midazolam as an anticonvulsant may lead to improved clinical outcome in the treatment of nerve agent seizures. Received: 6 July 1999 / Accepted: 20 September 1999     

The pharmacokinetics,toxicities, and biologic effects of FK866, a nicotinamide adenine dinucleotide biosynthesis inhibitor

Summary Background FK866 is a potent inhibitor or NAD synthesis. This first-in-human study was performed to determine the maximum-tolerated dose, toxicity profile, and pharmacokinetics on a 96-h continuous infusion schedule. Materials and methods Twenty four patients with advanced solid tumor malignancies refractory to standard therapies were treated with escalating doses of FK866 as a continuous, 96-h infusion given every 28 days. Serial plasma samples were collected to characterize the pharmacokinetics of FK866. Further blood samples were collected for the measurement of plasma VEGF levels. Results There were 12 women and 12 men with a median age of 61 (range 34-78) and a median KPS of 80%, received a 4-day of infusion of FK866 at dose levels of 0.018 mg/m²/h (n = 3), 0.036 mg/m²/h (n = 3), 0.072 mg/m²/h (n = 3), 0.108 mg/m²/h (n = 4), 0.126 mg/m²/h (n = 6), and 0.144 mg/m²/h (n = 5). Thrombocytopenia was the dose limiting toxicity, observed in two patients at the highest dose level and one patient at the recommended phase II dose of 0.126 mg/m2/h No other hematologic toxicities were noted other than mild lymphopenia and anemia. There was mild fatigue and grade 3 nausea; the latter was controlled with antiemetics and was not a DLT. C_ss (the mean of the 72 and 96 h plasma concentrations) increased in relation to the dose escalation. The study drug did not significantly affect plasma concentrations of VEGF. There were no objective responses, although four patients had stable disease (on treatment for 3 months or greater). Conclusions The recommended phase II dose is 0.126 mg/m²/h given as a continuous 96-h infusion every 28 days. The dose limiting toxicity of FK866 is thrombocytopenia. Pharmacokinetic data suggest an increase in the plasma C_ss in relation to the escalation of FK866.     

Population pharmacodynamic modelling of lorazepam- and midazolam-induced sedation upon long-term continuous infusion in critically ill patients

Objective The objective of the present investigation was to develop a population pharmacodynamic model for midazolam- and lorazepam-induced sedation upon long-term continuous infusion in critically ill patients. Methods The study was conducted in 59 patients receiving lorazepam and 54 patients receiving midazolam by continuous infusion for at least 24 h. Repeated blood samples were obtained for determination of the concentrations of lorazepam and midazolam. The level of sedation was assessed using a 5-point sedation scale. Results The pharmacokinetics of lorazepam and midazolam was described with previously proposed pharmacokinetic models. For the pharmacodynamics, the probability that the sedation was equal to or more than a specific score was described using a sigmoid E_max model. The EC₅₀ values of lorazepam for the sedation scores equal or larger than 2–5 were 6.1, 57, 184 and 529 ng/ml, respectively. The corresponding values for midazolam were 216, 483, 1100 and 2200 ng/ml. Inter-individual variability in the EC₅₀ values was relatively high with a CV of 68% for lorazepam and 86% for midazolam (p=0.035). No covariates explaining part of the observed inter-individual variability were identified. Conclusion The population pharmacodynamic model shows a similarly wide intra- and inter-individual variability in the pharmacodynamics of both lorazepam and midazolam. Thus, the previously observed differences in “ease of titration” between lorazepam and midazolam are unrelated to pharmacodynamic factors.     

The effect of Y-25510 injection on the serum levels of some cytokines in healthy adult volunteers

Objective: Y-25510 was administered by means of an intravenous drip infusion to healthy adult male volunteers at a dose of 40, 80 or 160 mg in a single-dose study, and at a dose of 160 mg once a day for 7 days in a multiple-dose study. Results: Serum levels of interleukin (IL)-1β, IL-6 and IL-10 were significantly increased, but there was no change in leukocyte and platelet counts. The peak serum concentration of IL-1β was nearly maximum at the single doses of 40 and 80 mg, and at the multiple dose of 160 mg per day. The peak serum concentration of IL-6 increased in a dose-dependent manner at a dose of 40 mg or more. For the multiple-dose study, the serum level of IL-10, which remained unchanged in the placebo group, began to increase in the Y-25510 group following the maximum serum level of IL-1β and IL-6. There were no clinically relevant differences in body temperature and blood pressure after the administration of Y-25510. Conclusion: These findings that leukocyte and platelet counts never increased, despite the increment of the IL-1β and IL-6 production after the administration of Y-25510, may be explained in part by the negative feedback mechanism induced by IL-10. Received: 28 April 1997 / Accepted in revised form: 25 September 1997     

异丙酚、咪达唑仑在纤维支气管镜检查中的镇静作用比较

目的比较异丙酚和咪达唑仑在纤维支气管镜检查中实施镇静的效果以及患者的满意程度。方法 68例支气管镜检患者随机分为异丙酚组（P组）和咪达唑仑组（M组）。在利多卡因局麻后,P组首次静脉缓慢注入异丙酚1.5mg·kg-1,速度为40～60s,然后以5～10mg/（kg·h）输注;M组首次静脉注入咪达唑仑2mg,2min后根据镇静情况追加,每次追加0.5mg,间隔2min。维持用药均根据镇静分级调整,使患者镇静程度位于闭眼入睡和大声指令可唤醒之间。观察镇静诱导时间、意识恢复时间、低氧血症发生率、咳嗽程度、局麻药物追加量以及患者的满意度。结果两组患者的镇静诱导时间分别为48±16s（P组）、210±49s（M组）,意识恢复时间分别为4.9±1.8min（P组）、15.1±5.7min（M组）,镇静诱导时间和意识恢复时间P组均明显短于M组,差异具有统计学意义（P〈0.05）。两组患者低氧血症发生率、咳嗽程度、局麻药物追加量以及患者满意度比较,均无明显差异（P〉0.05）。结论异丙酚、咪达唑仑均可安全用于纤维支气管镜检查镇静,但异丙酚镇静诱导时间短,意识恢复迅速。     

Analgesia for pediatric patients. Standards and special aspects

In this paper we describe the assessment and medical treatment of pain in children according to the concept of the Centre of Pediatrics and Adolescent Medicine at the university of Freiburg, Germany. Opiate therapy in children as well as novel data about the association of paracetamol (acetaminophen) and wheezing/asthma bronchiale in children are discussed. Special aspects of analgesia for painful procedures and a nitrous oxide/oxygen mixture which has been recently introduced in Germany are described. The second part of the paper presents results of our prospective study about continuous infusion of fentanyl and midazolam in a fixed combination in 19 critically ill patients with a median age of 46 months, 40% of these patients had an ARDS. The mortality rate was 21%. A median dose of fentanyl of 3.9 microg/kg/h (midazolam 0.26 mg/kg/h) was infused. The fentanyl serum level (median 4.2 ng/ml, range 1.7-17.8 ng/ml) correlated significantly with the administered dose while the midazolam serum levels (median 911 ng/ml, range 234-4 651 ng/ml) correlated neither with the administered dose nor with any of the analysed parameters. Conclusion: A standard protocol for the assessment and treatment of pain should be established in every pediatric hospital. The data about the association of asthma bronchiale and paracetamol cannot be interpreted conclusively, but show that even for well known substances clinical trials may lead to new awareness. The study data about continuous infusion of fentanyl and midazolam show a good correlation of the fentanyl application to serum levels, while midazolam appears to be not the optimal substance for continuous sedation in this setting.     

咪达唑仑联合芬太尼对重症机械通气患者镇静效果的研究

目的探讨咪达唑仑联合应用芬太尼对重症机械通气患者镇静效果的影响。方法将40例使用机械通气的重症患者,随机分为咪达唑仑组（对照组,n=20）和咪达唑仑加芬太尼组（实验组,n=20）,记录镇静前2组呼吸循环指标。镇静开始前2组均给予咪达唑仑0.05mg/kg静注,直至患者镇静达Ramsay3～4级（采用Ramsay镇静评分）,对照组给予咪达唑仑（咪达唑仑50mg＋生理盐水至50ml）,以0.1mg/kg/h微量注射泵持续泵入;实验组选用咪达唑仑和芬太尼（咪达唑仑50mg＋芬太尼0.5mg＋生理盐水至50ml）,以0.1ml/kgh微量注射泵持续泵入,观察2组患者镇静1、6、12、24h呼吸频率、脉搏、平均血压、末梢血氧饱和度、氧合指数及镇静评分。结果镇静后2组呼吸频率、血氧饱和度、氧合指数均较镇静前明显改善（P〈0.01）;镇静后实验组各时点脉搏均低于对照组（P〈0.05）,RS评分均高于对照组（P〈0.05）,各组镇静后平均血压、脉搏、RS评分均较镇静前明显改善（P〈0.01）。结论对重症机械通气的患者,咪达唑仑联合应用芬太尼能显著提高患者的镇静效果,增加人机顺应性。     

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     

Phase I trial of oblimersen (Genasense®) and gemcitabine in refractory and advanced malignancies

Background: Overexpression of Bcl-2 is associated with worse prognosis for a number of cancer types. The present study was designed to determine the maximum tolerated dose (MTD) of oblimersen (antisense Bcl-2) and gemcitabine when administered to patients with refractory malignancies. Materials and methods: Sixteen patients with advanced solid tumors refractory to standard therapies were treated with escalating doses of oblimersen continuous, 120-h intravenous infusion given every 14 days, with a fixed-dose-rate intravenous infusion of gemcitabine administered on day 5 of each cycle. Serial plasma samples were collected to calculate the pharmacokinetics of oblimersen and gemcitabine, and also to measure the effect of oblimersen on Bcl-2 expression. Results: 7 women and 9 men, median age 55 years (range 35–74 years), received a 5-day infusion of oblimersen at dose levels of 5 mg/kg/day (n = 4) or 7 mg/kg/day (n = 12). On the 5th day of the infusion, gemcitabine was given at 10 mg/m²/h for a total dose of 1,000 mg/m² (n = 7; cohorts I and II), 1,200 mg/m² (n = 3; cohort III), or 1,500 mg/m² (n = 6; cohort IV). Edema was the dose-limiting toxicity (DLT), necessitating expansion of cohort IV. No subsequent DLTs were noted. Thus, the maximum planned doses were well tolerated, and a formal MTD was not determined. Most hematologic toxicities were grade 1 or 2. There was low-grade fatigue, nausea/vomiting, and myalgias/arthralgias. Oblimersen C_ss and AUC increased in relation to the dose escalation, but gemcitabine triphosphate levels did not correlate well with dose. There were no objective responses, though 5 patients had stable disease. A >75% reduction in Bcl-2 expression in peripheral blood mononuclear leucocytes was seen more frequently in patients who achieved stable disease than in progressing patients. Conclusions: The maximal planned dose levels of oblimersen and gemcitabine in combination were well tolerated. Only one DLT (edema) occurred. There was a correlation between Bcl-2 reduction and stable disease. The recommended doses of the drugs for future studies are 7 mg/kg/day of oblimersen on days 1–5, and gemcitabine 1,500 mg/m² on day 5, every two weeks.     

Stable low-rate midazolam self-injection with concurrent physical dependence under conditions of long-term continuous availability in baboons

 The current research was undertaken to characterize intravenous midazolam self-injection and the concurrent development of physical dependence under conditions of continuous drug availability. Baboons (n=6) IV self-injected midazolam under conditions of continuous availability under a fixed-ratio 30 schedule of lever-pull responses with a 5-min time-out after each injection. Midazolam (1.0 mg/kg) maintained an orderly spaced within-day pattern of injections and low, but stable, daily rates of self-injection over 30 or more days (e.g. <20 injections/day). Sequential substitution of saline and then midazolam produced rapid extinction and then reinstatement of responding at the same stable rate. In subsequent manipulations, a range of lower doses of midazolam (0.0156–0.25 mg/kg) were also shown to reinstate self-injection responding after extinction on saline; however, both chronic and acute dose manipulations indicated that dose-regulation was poor. Chronic self-injection of the high dose (1.0 mg/kg) but not lower doses produced a suppression in responding maintained by food pellet delivery. Chronic self-injection of 1.0 and 0.25 mg/kg midazolam produced physical dependence as reflected in classic benzodiazepine spontaneous and flumazenil-precipitated withdrawal syndromes, including tremor, vomiting and, in one instance, seizure. The stable, low-rate self-injection of midazolam, with concurrent development of physical dependence, demonstrated in the present study may provide a useful model system for investigating factors which contribute to long-term inappropriate use of benzodiazepines by physically dependent patients. Received: 6 March 1997 / Final version: 29 June 1997     

Assessment of micafungin loading dosage regimens against Candida spp. in ICU patients by Monte Carlo simulations

To assess the efficacy of loading dose on micafungin by simulating different dosage regimens. A published study of micafungin in ICU patients was employed to simulate nine different dosage regimens which were sorted out three groups in terms of three maintenance doses. Using pharmacokinetic parameters and pharmacodynamic data, 5000-subject Monte Carlo simulations were conducted to simulate concentration-time profiles of micafungin, calculate probabilities of target attainment (PTAs), and cumulative fractions of response (CFRs) in terms of AUC/MIC targets. PTAs were calculated using AUC/MIC cut-offs: 285 (Candida parapsilosis), 3000 (all Candida spp.), and 5000 (non-parapsilosis Candida spp.). PTA or CFR > 90% was considered optimal for a dosage regimen. The concentration-time profiles of micafungin-simulated dosage regimens were obtained. PTA values were over 90% while applying the loading dose in each group of regimens: for Candida albicans and Candida glabrata (AUC/MIC = 5000), all regimens with loading dose provided PTAs of ≥ 90% for MIC ≤ 0.008 mg/L. The PTAs (AUC/MIC = 3000) were over 90% for MIC ≤ 0.008 mg/L in any regimen. However, for MIC inferior to 0.016 mg/L, only loading dosage regimens provided PTAs exceeding 90%. For C. parapsilosis (AUC/MIC = 285), the maximum MIC of achieving a PTA ≥ 90% was 0.25 mg/L both in the regimens of B (150 mg maintenance dose) and C (200 mg maintenance dose) with loading dose. In addition, CFR of any regimen with loading dose was ≥ 90% against C. albicans and C. glabrata. None of the dosage regimens achieved an expected CFR against C. parapsilosis. The dosage regimen of micafungin which had a loading dose of 1.5 times was more suitable for ICU patients infected by Candida spp.     

右美托咪定复合小剂量咪唑安定在慢诱导麻醉中对镇静程度的影响

目的比较右美托咪定(DEX)复合小剂量咪唑安定与单纯咪唑安定(MDZ)在慢诱导气管插管时对镇静程度的影响。方法 40例择期行气管插管全麻手术患者随机分为右美托咪定复合小剂量咪唑安定组(DEX-MDZ)和单用咪唑安定组(MDZ),每组20例。MDZ组静脉注射MDZ 0.05 mg/kg,增加量0.05 mg/kg,至警觉/镇静(OAA/S)评分2～4分;MDZ-DEX组静脉注射MDZ 0.02 mg/kg,然后于10 min内静注DEX负荷量1μg/kg,再持续泵注0.1μg/(kg.h)逐渐增量至0.7μg/(kg.h),直至镇静评分2～4分。记录重要时间点患者的血压(BP)、心率(HR)、OAA/S评分及反应;记录术后患者对慢诱导气管插管过程的记忆程度及满意度。结果两组患者BP、HR比较差异无统计学意义;DEX-MDZ患者在慢诱导气管插管期间较MDZ组更安静更配合,不良反应少;DEX-MDZ组患者慢诱导气管插管更舒适。结论右美托咪定复合小剂量咪唑安定较单用咪唑安定更适合于慢诱导气管插管。     

瑞马唑仑在内镜检查中镇静效应有效性和安全性的Meta分析

目的 系统性评价瑞马唑仑在内镜检查中镇静效应的有效性和安全性,并与丙泊酚和咪达唑仑进行比较。方法 在PubMed、Embase、Cochrane图书馆、万方数据库、CNKI等数据库进行了检索,收集了内镜检查中瑞马唑仑用于镇静的随机对照试验文献。检索时间从2018年起瑞马唑仑获批准于临床试验开始到2022年4月。搜索策略包括以下变量关键字：瑞马唑仑、胃镜检查、支气管镜检查和结肠镜检查。通过Rev Man5.4软件对纳入文献质量进行评估和对收集的资料进行Meta分析。结果 共有10项瑞马唑仑与丙泊酚和咪达唑仑的随机对照研究,共有2076 名患者纳入分析。结果表明,瑞马唑仑镇静效应优于咪达唑仑[OR = 0.03, 95% CI: (0.02, 0.05),?I2?= 0%,?p?< 0.00001];逊于丙泊酚[OR = 11.32, 95% CI: (2.12, 60.56),??I2= 0%,?p= 0.005]。瑞马唑仑起效时间较丙泊酚慢,较咪达唑仑快;但苏醒时间快于丙泊酚和咪达唑仑。与咪达唑仑相比,其不良反应发生风险无明显差异。与丙泊酚相比,瑞马唑仑的低血压、心率减慢、低氧血症和注射痛发生风险更低,但恶心发生风险升高,二者呕吐发生风险无差异。结论 瑞马唑仑用于内镜检查时,其镇静效应和起效时间优于咪达唑仑,但不及丙泊酚。苏醒时间快于丙泊酚和咪达唑仑。瑞马唑仑对呼吸瑞马唑仑对呼吸、循环抑制发生率低于丙泊酚,与咪达唑仑相比不良反应无明显差异。     

Efficacy of biperiden and atropine as anticonvulsant treatment for organophosphorus nerve agent intoxication

The ability of the nerve agents tabun, sarin, soman, GF, VR, and VX to produce brain seizures and the effectiveness of the anticholinergics biperiden HCl or atropine SO₄ as an anticonvulsant treatment were studied in a guinea-pig model. All animals were implanted a week prior to the experiment with cortical electrodes for electroencephalogram (EEG) recordings. On the day of exposure, the animals were pretreated with pyridostigmine (0.026 mg/kg, i.m.) 30 min prior to challenge with a 2 × LD₅₀ dose (s.c.) of a given agent. In separate experiments, animals were challenged with 5 × LD₅₀ (sc) of soman. One minute after agent challenge, the animals were treated intramuscularly (i.m.) with 2 mg/kg atropine SO₄ admixed with 25 mg/kg 2-PAM Cl and then observed for the onset of seizure activity. Five minutes after the start of nerve agent-induced EEG seizures, animals were treated i.m. with different doses of biperiden HCl or atropine SO₄ and observed for seizure termination. The anticonvulsant ED₅₀ of biperiden HCl and atropine SO₄ for termination of seizures induced by each nerve agent was calculated and compared. With equally toxic doses (2 × LD₅₀) of these agents, continuous EEG seizures (status epilepticus) developed in all animals challenged with soman, tabun, or VR, and in more than 90% of the animals challenged with GF or sarin. In contrast, only 50% of the animals developed seizures when challenged with VX. The times to onset of seizures for soman, tabun, GF, and sarin were very similar (5–8 min) while for VR, it was about 10 min. In the case of VX, not only was the time to seizure development longer (20.7 min), but the seizure activity in 19% of the animals terminated spontaneously within 5 min after onset and did not return. Under these conditions, the anticonvulsant ED₅₀s of biperiden HCl for soman, GF, VR, tabun, sarin, and VX were 0.57, 0.51, 0.41, 0.2, 0.1, and 0.09 mg/kg, respectively, while those of atropine SO₄ for soman, VR, tabun, GF, sarin, and VX were 12.2, 11.9, 10.4, 10.3, 5.1, and 4.1 mg/kg, respectively. In separate experiments, the anticonvulsant ED₅₀ doses of biperiden for animals challenged with 2 or 5 × LD₅₀ of soman were 0.48 (95% confidence limits 0.25–0.73) or 0.57 (95% CI 0.38–0.84) mg/kg, respectively, while the anticonvulsant ED₅₀s for atropine (12.2 mg/kg, i.m.) were identical under these same two challenge conditions. The present study demonstrates that all nerve agents can produce status epilepticus and that the therapeutic effectiveness of atropine and biperiden roughly paralleled the seizurogenic potential of these agents. Received: 16 November 1999 / Accepted: 9 February 2000     

A Pilot Pharmacokinetic-Pharmacodynamic Study of Benzodiazepine Antagonism by Flumazenil and Aminophylline

Study Objectives . To develop a pharmacokinetic-pharmacodynamic model using quantitative electroencephalographic (EEG) analysis to compare two separate benzodiazepine antagonists and generate data concerning response variability. Design . A pilot study using a randomized, blinded, crossover design. Setting . The Neurology Laboratory at the Akron City Hospital campus of SUMMA Health System. Patients . Four healthy volunteers completed the protocol. Interventions . Subjects received midazolam 0.1–0.2 mg/kg by intravenous bolus on 3 study days, separated by a minimum washout period of 1 week. Subjects participated in an initial open-label response phase followed by a randomized, crossover trial of each benzodiazepine antagonist. Measurements and Main Results . Venous blood samples were obtained to characterize the pharmacokinetics of all study compounds. The EEG parameter of total number of waves/second (recorded from FP1-F3 and FP2-F4 electrodes) in the frequency of 12–30 Hz was used to quantify effect. Flumazenil appeared to prolong the elimination half-life of midazolam significantly (p < 0.05). Theophylline (aminophylline) also appeared to prolong the half-life of flumazenil (p < 0.05). Despite considerable variability, flumazenil resulted in reversal of sedation at concentrations achieved by routine dosing. Resedation was apparent for all subjects following flumazenil reversal. Only partial reversal of sedation by theophylline was achieved by an aminophylline dose of 1–2 mg/kg. Conclusions . Flumazenil was consistently effective in reversing sedation by midazolam at routinely recommended dosing. Further investigation of aminophylline as a reversal agent should use an estimated dose of 6–8 mg/kg aminophylline. To achieve adequate reversal, some patients may require aminophylline dosages that exceed safe clinical administration.