Design, synthesis, and biological evaluation of new bis-benzylisoquinoline-based analogues as potential neuromuscular blocking agents.

Neuromuscular blocking agents (NMBAs) are widely used in anesthesia for intubation and surgical muscle relaxation. Novel atracurium and mivacurium derivatives were developed, with compounds 18c, 18d, and 29a showing mivacurium-like relaxation at 27.27 nmol/kg, and 15b, 15c, 15e, and 15h having a shorter duration at 272.7 nmol/kg. The structure-activity and configuration-activity relationships of these derivatives and 29a's binding to nicotinic acetylcholine receptors were analyzed through molecular docking. Rabbit trials showed 29a has a shorter duration compared to mivacurium. This suggests that linker properties, ammonium group substituents, and configuration are crucial for NMBA activity and duration, with compound 29a emerging as a potential ultra-short-acting NMBA.

First derivative synchronous spectrofluorimetric method for the simultaneous determination of propofol and cisatracurium besylate in biological fluids.

Propofol and cisatracurium besylate have been simultaneously determined using a highly sensitive first derivative synchronous spectrofluorometric method. The method is based on measuring first derivative synchronous spectrofluorimetric amplitude at Δλ = 40 nm with a scanning rate of 600 nm/min. The different experimental parameters affecting the fluorescence intensity of the two drugs were carefully studied and optimized. The amplitude-concentration plots were rectilinear over the range 40.0-400.0 ng/mL and 20.0-280.0 ng/mL for propofol and cisatracurium, respectively with lower detection limits of 4.0 and 2.35 ng/mL and quantification limits of 12.1 and 7.1 ng/mL for propofol and cisatracurium, respectively. The proposed method was successfully applied for the determination of the two compounds in synthetic mixtures and in commercial ampoules. The high sensitivity attained using the proposed method allowed the simultaneous determination of both drugs in spiked plasma samples. The mean % recoveries in spiked human plasma (n = 3) were 96.53 ± 0.90 and 96.20 ± 1.64 for each of propofol and cisatracurium, respectively. The method was validated in compliance with International Council of Harmonization (ICH) Guidelines.

Simultaneous HPLC Determination of Cisatracurium and Propofol in Human Plasma via Fluorometric Detection.

The proposed method describes a high performance liquid chromatographic method with fluoremetric detection for the determination of cisatracurium (CIS) and propofol (PRP) simultaneously, which are co-administered as a pre-operative injection mixture. The separation of the two drugs was achieved using monolithic column (100 mm and 4.6 mm internal diameter) and mixture of methanol and 0.1 M phosphate buffer in the ratio of 80:20 (v/v) at pH 4.5 as a mobile phase. The fluorescence detection was carried out at 230/324 nm. The procedure showed good linearity through the concentration ranges of 0.01-1.00 µg/mL and 0.1-3.0 µg/mL with limits of detection of 0.002, 0.030 µg/mL and limits of quantification of 0.006, 0.100 µg/mL for CIS and PRP, respectively. Simultaneous determination of CIS and PRP in spiked human plasma samples was additionally executed and the results were satisfactory precise and accurate.

Real-time potentiometric sensor; an innovative tool for monitoring hydrolysis of chemo/bio-degradable drugs in pharmaceutical sciences.

In recent years, the whole field of ion-selective electrodes(ISEs) in pharmaceutical sciences has expanded far beyond its original roots. The diverse range of opportunities offered by ISEs was broadly used in a number of pharmaceutical applications, with topics presented ranging from bioanalysis of drugs and metabolites, to protein binding studies, green analytical chemistry, impurity profiling, and drug dissolution in biorelevant media. Inspired from these advances and with the aim of extending the functional capabilities of ISEs, the primary focus of the present paper is the utilization of ISE as a tool in personalized medicine. Given the opportunity to explore biological events in real-time (such as drug metabolism) could be central to personalized medicine. (ATR) is a chemo-degradable and bio-degradable pharmaceutically active drug. Laudanosine (LDS) is the major degradation product and metabolite of ATR and is potentially toxic and reported to possess epileptogenic activity which increases the risk of convulsive effects. In this work, ATR have been subjected to both chemical and biological hydrolysis, and the course of the reactions is monitored by means of a ISE. In this study, we have designed an efficient real-time tracking strategy which substantially resolve the challenges of the ATR chemical and biological degradation kinetics. By utilizing a potentiometric sensor, tracking of ATR chemical and biological degradation kinetics can be performed in a very short time with excellent accuracy. The LOD was calculated to be 0.23 µmol L-1, the potential drift was investigated over a period of 60 min and the value was 0.25 mV h-1. Real serum samples for measurement the rate of in vitro metabolism of ATR was performed. Furthermore, a full description of the fabricated screen-printed sensor was presented.

Stability of Drugs Used in Helicopter Air Medical Emergency Services: An Exploratory Study.

OBJECTIVE: Transportation by air exposes drugs used in emergency medical services to vibrations. The aim of the study was to determine whether or not vibrations caused by a helicopter induce the degradation of 5 drugs used in this setting. METHODS: A longitudinal study in an operating medical helicopter along with a worst case was conducted. The studied drugs were 3 drugs labeled for refrigeration (cisatracurium, lorazepam, and succinylcholine) and 2 albumin solutions (human albumin 4% and 20%). These drugs were stored for 4 months according to the following conditions: inside a helicopter, worst case with exposure to extreme vibrations, at room temperature, and according to manufacturers' recommendations. Samples were analyzed with validated high-performance liquid chromatography assay methods. A drug was considered stable if the remaining drug content was above 90% of the label claim. Except for the albumin solutions, visual inspection was used to determine instability by the formation of aggregates. RESULTS: Only the samples stored at room temperature became unstable after 4 months. No difference in extreme foaming was observed in the albumin solutions. CONCLUSIONS: These data suggest that the effect of degradation of drugs caused by vibrations is negligible. Temperature was observed as the main cause of drug degradation.

Capillary electrophoresis with electrochemiluminescence detection for the simultaneous determination of cisatracurium besylate and its degradation products in pharmaceutical preparations.

Capillary electrophoresis with electrochemiluminescence detection for the simultaneous analysis of cisatracurium besylate and its degradation products (laudanosine, quaternary monoacrylate) in pharmaceutical preparation was developed and fully validated. The significant parameters that influence capillary electrophoresis separation and electrochemiluminescence detection were optimized. The total analysis time of the analytes was 15 min. The linearities of the method were 0.1∼40.0 µg/mL for cisatracurium besylate and 0.04∼8.00 µg/mL for laudanosine, with correlation coefficients (r) of 0.999 and 0.998, respectively. The detection limits (S/N = 3) were 83.0 ng/mL for cisatracurium besylate and 32.0 ng/mL for laudanosine. The intraday relative standard deviations of the analytes were <3.0%, and the interday relative standard deviations were <8.0%. The developed method was cost-effective, sensitive, fast, and resource-saving, which was suitable for the ingredient analysis in pharmaceutical preparation.

Physical compatibility of cisatracurium with selected drugs during simulated Y-site administration.

PURPOSE: The physical compatibility of cisatracurium with selected drugs during simulated Y-site administration was studied. METHODS: Study drugs were selected based on the lack of physical compatibility data with cisatracurium and their use in intensive care units. Test admixtures were prepared by mixing 2.5-mL samples of varying concentrations of calcium gluconate, diltiazem, esomeprazole, regular insulin, nicardipine, pantoprazole, and vasopressin with either 2.5 mL of normal saline 0.9% (control) or 2.5 mL of cisatracurium (experimental) to simulate a 1:1 Y-site ratio. Drug infusions were prepared at the maximum concentrations used clinically. Physical compatibility of the admixtures was determined by visual and turbidimetric assessments performed in triplicate immediately after mixing and at 15, 30, and 60 minutes. Visual incompatibility was defined as a change in color, the formation of haze or precipitate, the presence of particles, or the formation of gas in the experimental groups compared with the controls. Disturbances invisible to the naked eye were determined by assessing changes in turbidity of experimental admixtures compared with the controls. RESULTS: None of the admixtures exhibited visual changes when mixed with cisatracurium. Six of the seven admixtures exhibited turbidimetric compatibility with cisatracurium. Pantoprazole admixtures demonstrated a significant difference in turbidimetric assessment between the control and experimental groups when mixed with cisatracurium (p < 0.001). CONCLUSION: Calcium gluconate, diltiazem hydrochloride, esomeprazole, regular insulin, nicardipine hydrochloride, and vasopressin demonstrated physical compatibility with cisatracurium over 60 minutes during simulated Y-site administration. Cisatracurium and pantoprazole should not be coadministered due to a significant difference in turbidity between control and experimental samples.

[Physicochemical stability study of injectable solutions of cisatracurium besilate in clinical conditions]. / 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 0.1mg/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, 48hours 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 24hours at 5°C and 25°C for concentrations between 0.1 and 5mg/mL. Beyond 24hours, the solutions at 2 and 5mg/mL remained stable for seven days at 5°C. At 25°C, potentially toxic degradation products appear in solutions of 0.1mg/mL between 24 and 48hours. No racemization was detected, the drug remains in its active form cis. CONCLUSION: Cisatracurium solutions at 2 and 5mg/mL may be stored at 5°C or 25°C for seven days. It's advisable to keep the solutions in a dilution of 0.1mg/mL in 0.9 % sodium chloride or 5 % glucose in the refrigerator. No diluted solution should be stored at room temperature beyond 24hours.

High-performance liquid chromatography assay with programmed flow elution for cisatracurium in human plasma: application to pharmacokinetics in infants and children.

A high-performance liquid chromatography (HPLC) assay with fluorescence detection (FLD) for quantification of cisatracurium in human plasma was developed and fully validated. Liquid-liquid extraction was employed for sample preparation. The separation was carried out on a C18 column with ternary mobile phase composed of 30mmolL(-1) phosphate buffer (pH 3.0), acetonitrile and methanol (60:35:5, v/v/v). Verapamil was used as the internal standard. The isocratic elution with programmed flow rate was employed by setting at 0.8mLmin(-1) from 0 to 3.5min, 0.5mLmin(-1) from 3.5 to 6min, and 1.0mLmin(-1) from 6 to 10min. The fluorescence detection was performed at 236nm for excitation and 324nm for emission. The assay was linear from 50 to 2800ngmL(-1), with a detection limit of 12ngmL(-1). The correlation coefficient (r) for linear regression was 0.9997. The intra-day coefficients of variation (CVs) were less than 2.0%, and the inter-day CVs were less than 4.0%. The mean recoveries were in the range of 92.1-100.4%. The total HPLC run time was less than 10min. The developed HPLC method was fast, simple, sensitive, accurate and suitable for studying the pharmacokinetics of cisatracurium in infants and children after intravenous administration.

An enriched simulation environment for evaluation of closed-loop anesthesia.

To simulate and evaluate the administration of anesthetic agents in the clinical setting, many pharmacology models have been proposed and validated, which play important roles for in silico testing of closed-loop control methods. However, to the authors' best knowledge, there is no anesthesia simulator incorporating closed-loop feedback control of anesthetic agent administration freely available and accessible to the public. Consequently, many necessary but time consuming procedures, such as selecting models from the available literatures and establishing new simulator algorithms, will be repeated by different researchers who intend to explore a novel control algorithm for closed-loop anesthesia. To address this issue, an enriched anesthesia simulator was devised in our laboratory and made freely available to the anesthesia community. This simulator was built by using MATLAB(®) (The MathWorks, Natick, MA). The GUI technology embedded in MATLAB was chosen as the tool to develop a human-machine interface. This simulator includes four types of anesthetic models, and all have been wildly used in closed-loop anesthesia studies. For each type of model, 24 virtual patients were created with significant diversity. In addition, the platform also provides a model identification module and a control method library. For the model identification module, the least square method and particle swarm optimization were presented. In the control method library, a proportional-integral-derivative control and a model predictive control were provided. Both the model identification module and the control method library are extensive and readily accessible for users to add user-defined functions. This simulator could be a benchmark-testing platform for closed-loop control of anesthesia, which is of great value and has significant development potential. For convenience, this simulator is termed as Wang's Simulator, which can be downloaded from http://www.AutomMed.org .

[Storage at room temperature does not change cisatracurium onset time: a prospective, randomized, double-blind controlled study]. / La température de conservation du cisatracurium ne modifie pas le délai d'action: étude randomisée, en double insu

OBJECTIVE: Storage of cisatracurium at room temperature seems to have no effect on its degradation in vitro contrary to the recommendations of storage at +4°C. The purpose of this study was to evaluate the influence of cisatracurium' s storage temperature on its onset time. STUDY DESIGN: Prospective, randomized, double-blind trial study. PATIENTS AND METHODS: Thirty patients were enrolled. The control group consisted of 15 patients receiving cisatracurium (0.15mg/kg) stored at room temperature and the intervention consisted of 15 patients receiving cisatracurium (0.15mg/kg) stored at +4°C. The primary endpoint was to compare cisatracurium onset time depending on the storage temperature. RESULTS: Cisatracurium onset time was 235 (180-292) seconds in the "room temperature" group vs. 240 (210-292) seconds in the "refrigerated" group. There was no difference between the onset of cisatracurium depending on the temperature of storage (p=0.51). Subgroups analysis in the "room temperature" group did not show any difference in cisatracurium onset depending on whether it was stored at room temperature for one, two or three weeks. Excellent intubation score was obtained for 100% of the patients. CONCLUSION: This study demonstrated that cisatracurium's storage at room temperature had no influence on its onset time. It provides an argument for the preservation of cisatracurium at room temperature for a period not exceeding 21 days. Monitoring the onset of curarization may increase the quality score of intubation.

[Cis-atracurium--an equivalent substitution for atracurium in pediatric anesthesia?]. / Cis-Atracurium--Ein gleichwertiger Ersatz für Atracurium in der Kinderanästhesie?

Cis-atracurium is a stereoisomer of atracurium, about five times more potent than the racemate. Whereas cis-atracurium is routinely used in adults, its effects on children are still poorly defined. We compared equipotent doses of atracurium and cis-atracurium in children aged between 2 and 12 years regarding the quality of neuromuscular blockade, the intubation conditions and the occurrence of side-effects. After approval by the ethics committee and with informed parental consent, 84 children (ASA I or ASA II) were randomly allocated to receive either 0.5 mg/kg atracurium (group A, n = 42) or 0.1 mg/kg cis-atracurium (group C, n = 42). In both groups anaesthesia was induced with 15 micrograms/kg alfentanil and 5-7 mg/kg thiopentone. We assessed the intubation conditions according to the Krieg Scale. Anaesthesia was maintained with a nitrous oxide/oxygen mixture of 2:1 and isoflurane in an endexpiratory concentration of approximately 0.6 Vol.%. Neuromuscular blockade was controlled acceleromyographically in response to supramaximal stimulation of the ulnar nerve. We measured the onset time (T1 = 5%), duration of effect (T1 = 25%), recovery index (T1 = 25%-75%) and the recovery time at a train-of-four-ratio (T4/T1) of 0.7. These parameters did not show any significant differences between group A and group C: onset time: 3.1 +/- 1.5 min (group A) versus 3.4 +/- 1.1 min (group C), duration of effect: 34.1 +/- 5.5 min (group A) versus 34.1 +/- 6.5 min (group C), recovery index: 9.3 +/- 3.3 min (group A) versus 9.6 +/- 2.5 min (group C), recovery time at a TOF-ratio of 0.7:49.3 +/- 8.4 min (group A) versus 52.3 +/- 6.6 min (group C). In group A, the intubation conditions were "excellent" or "good" in 98% of the patients, whereas in group C the figure was only 69%. Regarding side-effects, we found significantly more frequent urticaria in group A (6 of the 42 patients) (p < or = 0.05) than in group C, in which no patient showed urticaria. Flush and tachycardia occurred much less frequently and there were no significant differences in the two groups: two patients in group A and only one in group C. The authors conclude that atracurium and cis-atracurium lead to comparable neuromuscular effects in children aged between 2 and 12 years. Only the intubation conditions were better after atracurium, but atracurium was followed by urticaria more often than cis-atracurium.

Does ester hydrolysis change the in vitro degradation rate of cisatracurium and atracurium?

BACKGROUND: We assessed the role of ester hydrolysis as an additional degradation mechanism to Hofmann elimination in the breakdown of cisatracurium and atracurium. METHODS: Cisatracurium and atracurium were incubated in phosphate buffer (pH 7.4, 37 degrees C) with and without the addition of carboxylesterase. Control measurements with an added esterase inhibitor were performed separately. Cisatracurium/atracurium and their degradation products, laudanosine and monoquaternary acid, were analysed using high-pressure liquid chromatography. RESULTS: Degradation of cisatracurium and atracurium proceeded exponentially, and after addition of carboxylesterase, no significant differences in the degradation rates were found. Neither an increase in carboxylesterase activity nor the addition of esterase inhibitor showed any effect. However, areas under the peaks of the chromatogram representing monoquaternary acid increased during incubation with esterase. CONCLUSION: The rate-limiting step in the degradation of cisatracurium/atracurium is Hofmann elimination. Ester hydrolysis is involved in the second degradation step that forms monoquaternary acid, but its contribution to the total elimination rate is negligible.

The distribution of laudanosine in tissues after death from atracurium injection.

A case is presented involving an acute fatality resulting from self-administration of atracurium, a muscle relaxant by a 45-year-old nurse. In the body, atracurium undergoes a spontaneous non-enzymatic degradation to laudanosine and an acrylate moiety. Laudanosine was quantified using gas chromatography coupled to mass spectrometry after extraction with chloroform-isopropanol-n-heptane (50:17:33 v/v) at pH 9.5 and separation on a HP5-MS capillary column. Laudanosine was subject to postmortem redistribution due to release from drug-rich tissues such as the lung and heart. The heart blood (917 ng/ml) to peripheral blood (390 ng/ml) ratio was 2.4. No other drugs, including ethanol were detected.

Molar potency is not predictive of the speed of onset of atracurium.

UNLABELLED: In an effort to determine the extent to which atracurium may represent an exception to the rule that molar potency predicts onset time, we studied the onset profile of atracurium after a dose selected to produce approximately 95% twitch depression. We compared these results with data obtained in a previous study after the administration of vecuronium, rocuronium, and cisatracurium. Eighteen ASA physical status I and II patients were studied. After the induction of anesthesia, tracheal intubation was accomplished without relaxants. The evoked electromyographic response to 0.10-Hz single stimuli was continuously recorded. After baseline stabilization, a single bolus of atracurium, averaging 0.21 mg/kg, was administered. If peak twitch depression did not fall within the range of 90%-98%, the patient was excluded. The time to 50% and 90% of peak effect was recorded. The time to 90% of maximal effect (192 +/- 23 s) was not different from that previously observed for vecuronium (201 +/- 20 s). The time to 50% of peak effect (110 +/- 15 s) was shorter (P < 0.05) after atracurium administration than after vecuronium (125 +/- 9 s). The onset times recorded for atracurium were slower than previously observed after rocuronium and more rapid than that which was seen after cisatracurium (P < 0.001). The observed onset profile of atracurium was considerably slower than anticipated, based on the drug's molar potency. The 95% effective dose (microM/kg) may not be a reliable predictor of a muscle relaxant's onset time, when the drug administered is a mixture isomers of varying potency. IMPLICATIONS: The speed of onset of atracurium is slower than predicted, based on its molar potency. Potency of a relaxant may not be a reliable predictor of its time to peak effect, when the drug administered is a mixture of isomers with widely different neuromuscular activities.