Vecuronium bromide and its advanced intermediates: A crystallographic and spectroscopic study.

Vecuronium bromide (Piperidinium, 1-[(2ß,3α,5α,16ß,17ß)-3,17-bis(acetyloxy)-2-(1-piperidinyl)androstan-16-yl]-1-methyl-, bromide; Norcuron®) has been extensively used in anesthesiology practice as neuromuscular blocking agent since its launch on the market in 1982. However, a detailed crystallographic and NMR analysis of its advanced synthetic intermediates is still lacking. Hence, with the aim of filling this literature gap, vecuronium bromide was prepared starting from the commercially available 3ß-hydroxy-5α-androstan-17-one (epiandrosterone), implementing some modifications to a traditional synthetic procedure. A careful NMR study allowed the complete assignment of the 1H, 13C, and 15N NMR signals of vecuronium bromide and its synthetic intermediates. The structural and stereochemical characterization of 2ß,16ß-bispiperidino-5α-androstane-3α,17ß-diol, the first advanced synthetic intermediate carrying all the stereocenters in the final configuration, was described by means of single-crystal X-ray diffraction and Hirshfeld surface analysis, allowing a detailed conformational investigation.

Quantitative Structure-Activity Relationship (QSAR) Model for the Severity Prediction of Drug-Induced Rhabdomyolysis by Using Random Forest.

Drug-induced rhabdomyolysis (DIR) is a rare and potentially life-threatening muscle injury that is characterized by low incidence and high risk. To our best knowledge, the performance of the current predictive models for the early detection of DIR is suboptimal because of the scarcity and dispersion of DIR cases. Therefore, on the basis of the curated drug information from the Drug-Induced Rhabdomyolysis Atlas (DIRA) database, we proposed a random forest (RF) model to predict the DIR severity of the marketed drugs. Compared with the state-of-art methods, our proposed model outperformed extreme gradient boosting, support vector machine, and logistic regression in distinguishing the Most-DIR concern drugs from the No-DIR concern drugs (Matthews correlation coefficient (MCC) and recall rate of our model were 0.46 and 0.81, respectively). Our model was subsequently applied to predicting the potentially serious DIR for 1402 drugs, which were reported to cause DIR by the postmarketing DIR surveillance data in the FDA Spontaneous Adverse Events Reporting System (FAERS). As a result, 62.7% (94) of drugs ranked in the top 150 drugs with the Most-DIR concerns in FAERS can be identified by our model. The top four drugs (odds ratio >30) including acepromazine, rapacuronium, oxyphenbutazone, and naringenin were correctly predicted by our model. In conclusion, the RF model can well predict the Most-DIR concern drug only based on the chemical structure information and can be a facilitated tool for early DIR detection.

[Indications and clinical use of sugammadex]. / Indications et utilisation clinique du sugammadex.

Sugammadex, a cyclodextrin, is a novel agent designed to encapsulate selectively steroidal neuromuscular blocking agents such as rocuronium and vecuronium as well. One molecule of sugammadex is able to encapsulate only one molecule of muscle relaxant. This original pharmacological property allows a very rapid reversal of muscle paralysis. After sugammadex injection, a train of four ratio higher than 0.9 is obtained in less than 5 minutes in all the patients whatever the degree of muscle paralysis at the time of reversal and even when anesthesia is maintained with halogenated agents. However, in order to preserve this efficacy, the dose of sugammadex needs to be adjusted to the degree of muscle paralysis at the time of reversal : 2 mg/kg after obtaining 2 responses at the adductor pollicis muscle after a train of four stimulation, 4 mg/kg with a post-tetanic count between 1 and 3 responses, and 12 to 16 mg/kg in case of rescue reversal (3 to 15 minutes after 0.6 to 1.2 mg/kg rocuronium). Even if the original property of sugammadex lets us think that per-operative neuromuscular transmission monitoring would not be furthermore useful, the assessment of the exact degree of muscle paralysis before reversal is mandatory for choosing the right dose of sugammadex.

Stability of vecuronium in sterile water for injection stored in polypropylene syringes for 21 days.

PURPOSE: The stability of vecuronium bromide 1 mg/mL in preservative-free sterile water for injection for up to 21 days was studied. METHODS: A vecuronium bromide 1-mg/mL solution was prepared by diluting 15 vials of 10-mg Vecuronium Bromide for Injection, USP, powder with preservative-free sterile water for injection and adding the solution to an evacuated i.v. bag. Identical 10-mL volumes of the solution were prepared and stored at 23-25 or 3-5 degrees C in polypropylene syringes. The stability of vecuronium was analyzed in triplicate with stability-indicating high-performance liquid chromatography immediately after preparation of solutions and at 3, 7, 14, and 21 days. The samples were also inspected for volume and color change and for visible precipitation and microbial growth. RESULTS: The percentage of the initial vecuronium bromide concentration remaining at each time point was greater than 100% at both 23-25 and 3-5 degrees C. There were no detectable changes in volume or color and no precipitation or visible microbial growth. CONCLUSION: Vecuronium bromide in an extemporaneously prepared solution in preservative-free sterile water for injection was stable for at least 21 days at 23-25 or 3-5 degrees C.

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.

Increased tolerance to vecuronium in a patient with testicular feminization.

Muscle relaxant pharmacophysiology can be altered in various clinical situations. We report increased requirement of vecuronium in a patient diagnosed with testicular feminization. Increased level of endogenous testosterone and steroidal-core structure of vecuronium may explain the increased tolerance to vecuronium in this patient.

The precipitate formed by thiopentone and vecuronium.

PURPOSE: To determine the composition and solubility of the precipitate formed by thiopentone and vecuronium in vitro. METHODS: The precipitate formed by mixing thiopentone 2.5% and vecuronium 0.1% at room temperature was analyzed by ultraviolet spectrophotometry and high performance liquid chromatography (HPLC). The solubility of the precipitate in human plasma was measured by HPLC. RESULTS: The UV absorption spectrum of the precipitate resembled that of thiopentone. HPLC analysis produced a single peak with the same retention time as thiopentone (4.6 min). In human plasma the solubility of the precipitate was not different from that of thiopentone acid. The solubility of thiopentone was greater than that of the precipitate. CONCLUSION: The precipitate formed by thiopentone and vecuronium in vitro consisted of thiopentone acid, which was insoluble in human plasma.

Lipid solubility of pancuronium and vecuronium determined by n-octanol/water partitioning.

We have measured the n-octanol/water distribution coefficients at 37 degrees C of two steroidal myoneural blockers (pancuronium and vecuronium) and of their 3-hydroxy metabolites over a pH range from 1.5 to 11. Pancuronium was found not to be lipid soluble. The mean distribution coefficient of 3-hydroxy vecuronium at pH = 7.4 was 0 and that of vecuronium 0.12 (SD 0.1). Distribution coefficients of the parent drug showed a slightly greater lipid solubility than the metabolite (11.37 (2.91) and 9.53 (3.44), respectively (mean t0.05 x SE)). Because of its lipid solubility, vecuronium may penetrate into lipid structures.

Liquid chromatography-mass spectrometry with ionspray and electrospray interfaces in pharmaceutical and biomedical research.

Electrospray and ionspray techniques use samples that exist as ions or ion-molecule complexes in solution. After the dispersion of the solution into an electrically charged aerosol, the sample ions may escape from the solution into the gas phase in a region that is at atmospheric pressure. The sample ions are transported into the mass analyser which is operated under a high vacuum. Liquid chromatographs can be coupled to electrospray and ionspray interfaces. Flow injection or continuous infusion of a sample solution (both without the use of a separating column) may be preferred over on-line liquid chromatography-mass spectometry in certain applications. Electrospray or ionspray is applicable to polar or ionic samples. Weakly polar and apolar samples are not ionized under electrospray or ionspray conditions. Applications of the techniques are in the fields of drug metabolism, natural product analysis and the determination of high molecular weights through the observation of multiply charged ions.