Utilizing experimental design and desirability function in optimizing RP-HPLC method for simultaneous determination of some skeletal muscle relaxants and analgesics.

An experimental design and response surface methodologies using Plackett-Burman and Box-Behnken designs were applied for selecting and optimizing the most appropriate parameters which significantly affect the separation and quantitative estimation of five skeletal muscle relaxants and four analgesic drugs (baclofen, methocarbamol, dantrolene sodium, orphenadrine citrate, cyclobenzaprine hydrochloride, ketoprofen, etoricoxib, ibuprofen, and mefenamic acid) with a relatively short duration of analysis in a single run. For the separation of the nine drugs, an INERTSIL ODS-V3-5 µm C18 column (250 × 4.6 mm I.D.) was used with the optimum mobile phase conditions (45.15 mM ammonium acetate buffer pH 5.56 adjusted with acetic acid, acetonitrile, and methanol in a ratio of 30.5:29.5:40, v/v/v with a flow rate of 1.5 mL/min) and UV-detection at 220 nm. The optimized method was successfully subjected to the validation steps as described in ICH guidelines for linearity, precision, accuracy, robustness, and sensitivity. The optimized and validated method was effectively applied to determine the content of the studied drugs in their pharmaceutical preparations and to expand its applicability to the counterfeit estimation of etoricoxib in different brands of tablet dosage forms.

Tizanidine: Advances in Pharmacology & Therapeutics and Drug Formulations.

Background: Skeletal muscle relaxants (SMRs) are widely used in treating musculoskeletal conditions. All SMRs, with the exception of baclofen and tizanidine, are on the list of 2023 American Geriatrics Society Beers Criteria® for potentially inappropriate medication use in older adults. In our geriatric practice, off-label use of tizanidine as preemptive analgesia drove us to find recent advances in its pharmacology and therapeutics. An update review of tizanidine was thus presented, aiming to bring the latest knowledge to clinicians and promote further research and practical exploration. Methods: Relevant literature up to December 2023 was identified through searches of PubMed, Web of Science, and Embase. Results: Tizanidine, a centrally acting alpha-2 adrenoceptor agonist with both antispastic and antispasmodic activity, shows efficacy in the common indications for all SMRs. From the perspective of drug safety, tizanidine has lower incidences of adverse events (injury, delirium, encephalopathy, falls, and opioid overdose) compared to baclofen, no association with risk of Alzheimer's disease as with orphenadrine, no risk of serotonin syndrome like metaxalone when comedicated with serotonergic drugs, no significant pharmacokinetic changes in CYP2C19 poor metabolizers unlike diazepam and carisoprodol, and no physically addictive or abuse properties like carisoprodol and diazepam. From the perspective of new and potential therapeutic uses, tizanidine has additional benefits (eg, gastroprotection that can improve patient tolerance to nonsteroidal anti-inflammatory agents, anti-neuropathic pain, a key component of multimodal analgesia strategy to reduce early postoperative pain, and anti-tumor effects). New delivery systems of tizanidine are developing to improve the pharmacokinetics of oral products, including buccal patches, transdermal delivery systems, nasal spray, and in situ rectal gel. Conclusion: Tizanidine is an SMR with unique features and may be an optimal initial choice for older adults. There would be more scientific studies, wider therapeutic applications, and new drug formulations in the future.

Feasibility and Safety of Remazolam versus Propofol When Inserting Laryngeal Masks Without Muscle Relaxants During Hysteroscopy.

Purpose: This study aimed to evaluate the efficacy and safety of remazolam compared with propofol in patients who underwent laryngeal mask airway (LMA) insertion without the use of muscle relaxant agents during hysteroscopic surgery. Patients and Methods: A total of 72 patients undergoing hysteroscopy with LMA insertion were assigned to two groups. The patients in the remazolam group received 0.3 µg/kg sufentanil, 0.3 mg/kg remazolam and 1.2 mg/kg remifentanil, whereas the patients in the propofol group received 0.3 µg/kg sufentanil, 2.0 mg/kg propofol and 1.2 mg/kg remifentanil for insertion of the LMA. The primary endpoint was the summed score of the insertion conditions. The secondary endpoints included hemodynamics, the duration of induction, the duration of insertion, tidal volume, plateau pressure and adverse events. Results: No difference was identified between the propofol group and remazolam group in the median summed score [18.0 (18.0, 18.0), 18.0 (17.0, 18.0), respectively, P > 0.05]. The induction duration was significantly longer (P < 0.05) in the remazolam group than propofol group. The cost of dopamine (P < 0.05) was significantly lower in the remazolam group compared with the patients in the propofol group, while the plateau pressure (P < 0.05) and the incidence of transient mild laryngospasm (P < 0.05) were significantly higher in the remazolam group. No differences were identified between the two groups in terms of heart rate, tidal volume, injection pain or hiccups (P > 0.05). Conclusion: Remazolam provided similar insertion conditions and better hemodynamic stability than propofol during LMA insertion without the use of muscle relaxant agents. However, a higher incidence of transient mild laryngospasm was found in the remazolam group, which should be considered.

Factors Associated With Prolonged Ventilation in Patients Receiving Prone Positioning Protocol With Muscle Relaxants for Severe COVID-19 Pneumonia.

BACKGROUND: Prone positioning and neuromuscular blocking agents (NMBAs) are frequently used to treat severe respiratory failure from COVID-19 pneumonia. Prone positioning has shown to improve mortality, whereas NMBAs are used to prevent ventilator asynchrony and reduce patient self-inflicted lung injury. However, despite the use of lung-protective strategies, high death rates in this patient population have been reported. METHODS: We retrospectively examined the factors affecting prolonged mechanical ventilation in subjects receiving prone positioning plus muscle relaxants. The medical records of 170 patients were reviewed. Subjects were divided into 2 groups according to ventilator-free days (VFDs) at day 28. Whereas subjects with VFDs < 18 d were defined as prolonged mechanical ventilation, subjects with VFDs ≥18 d were defined as short-term mechanical ventilation. Subjects' baseline status, status at ICU admission, therapy before ICU admission, and treatment in the ICU were studied. RESULTS: Under the proning protocol for COVID-19, the mortality rate in our facility was 11.2%. The prognosis may be improved by avoiding lung injury in the early stages of mechanical ventilation. According to multifactorial logistic regression analysis, persistent SARS-CoV-2 viral shedding in blood (P = .03), higher daily corticosteroid use before ICU admission (P = .007), delayed recovery of lymphocyte count (P < .001), and higher maximal fibrinogen degradation products (P = .039) were associated with prolonged mechanical ventilation. A significant relationship was found between daily corticosteroid use before admission and VFDs by squared regression analysis (y = -0.00008522x2 + 0.01338x + 12.8; x: daily corticosteroids dosage before admission [prednisolone mg/d]; y: VFDs/28 d, R2 = 0.047, P = .02). The peak point of the regression curve was 13.4 d at 78.5 mg/d of the equivalent prednisolone dose, which corresponded to the longest VFDs. CONCLUSIONS: Persistent SARS-CoV-2 viral shedding in blood, high corticosteroid dose from the onset of symptoms to ICU admission, slow recovery of lymphocyte counts, and high levels of fibrinogen degradation products after admission were associated with prolonged mechanical ventilation in subjects with severe COVID-19 pneumonia.

Difficult airway due to cervical haemorrhage caused by spontaneous rupture of a parathyroid adenoma: A case report.

BACKGROUND: Cervical haemorrhage due to spontaneous rupture of a parathyroid adenoma is a rare complication that may cause life-threatening acute airway compromise. CASE SUMMARY: A 64-year-old woman was admitted to the hospital 1 day after the onset of right neck enlargement, local tenderness, head-turning difficulty, pharyngeal pain, and mild dyspnoea. Repeat routine blood testing showed a rapid decrease in the haemoglobin concentration, indicating active bleeding. Enhanced computed tomography images showed neck haemorrhage and a ruptured right parathyroid adenoma. The plan was to perform emergency neck exploration, haemorrhage removal, and right inferior parathyroidectomy under general anaesthesia. The patient was administered 50 mg of intravenous propofol, and the glottis was successfully visualised on video laryngoscopy. However, after the administration of a muscle relaxant, the glottis was no longer visible and the patient had a difficult airway that prevented mask ventilation and endotracheal intubation. Fortunately, an experienced anaesthesiologist successfully intubated the patient under video laryngoscopy after an emergency laryngeal mask placement. Postoperative pathology showed a parathyroid adenoma with marked bleeding and cystic changes. The patient recovered well without complications. CONCLUSION: Airway management is very important in patients with cervical haemorrhage. After the administration of muscle relaxants, the loss of oropharyngeal support can cause acute airway obstruction. Therefore, muscle relaxants should be administered with caution. Anaesthesiologists should pay careful attention to airway management and have alternative airway devices and tracheotomy equipment available.

Maternal cyclobenzaprine exposure and risk of birth defects in the National Birth Defects Prevention Study (1997-2011) and Birth Defects Study to Evaluate Pregnancy exposureS (2014-2018).

PURPOSE: Cyclobenzaprine is a muscle relaxant indicated for acute pain. Little is known about cyclobenzaprine's safety during pregnancy. We explored the association between maternal cyclobenzaprine exposure and risk of birth defects among offspring. METHODS: We combined data from two large, multi-site, population-based case-control studies in the United States. Cases were identified from birth defects registries across 10 states; controls were liveborn infants without birth defects randomly selected from the same catchment areas. Participants reported cyclobenzaprine use during the month before conception through the third month of pregnancy ("periconception") via computer-assisted telephone interview. We used logistic regression to assess associations between periconceptional cyclobenzaprine exposure and selected structural birth defects. We calculated crude odds ratios (OR) with corresponding 95% confidence intervals (CI). RESULTS: Our study included 33 615 cases and 13 110 controls. Overall, 51 case (0.15%) and 9 control (0.07%) participants reported periconceptional cyclobenzaprine use. We observed increased risk for all seven defects with ≥3 exposed cases: cleft palate (OR = 4.79, 95% CI 1.71-13.44), cleft lip (OR = 2.50, 95% CI 0.89-7.02), anorectal atresia/stenosis (OR = 6.91, 95% CI 1.67, 28.65), d-transposition of the great arteries (OR = 6.97, 95% CI 2.17-22.36), coarctation of the aorta (OR = 5.58, 95% CI 1.88-16.58), pulmonary valve stenosis (OR = 4.55, 95% CI 1.10-18.87), and secundum atrial septal defect (OR = 3.08, 95% CI 0.83-11.45). CONCLUSIONS: Even in our large sample, cyclobenzaprine use was rare. Our estimates are unadjusted and imprecise so should be interpreted cautiously. These hypothesis-generating results warrant confirmation and further research to explore possible mechanisms.

[Possible changes in the electroencephalogram and electrocardiogram after the introduction of peripheral muscle relaxants]. / Vozmozhnye izmeneniya elektroentsefalogrammy i elektrokardiogrammy pri ispol'zovanii miorelaksantov perifericheskogo deistviya.

OBJECTIVE: To evaluate the changes in the electroencephalogram (EEG) parameters in time, coinciding with the changes recorded by the electrocardiogram (ECG) channel in patients after the introduction of peripheral muscle relaxants. MATERIAL AND METHODS: Twenty-four patients were examined in intensive care units on artificial lung ventilation (ALV). During the study, myographic artifacts were recorded in all patients in the EEG, the elimination of which was impossible without the use of pharmacological agents leading to relaxation of muscles - muscle relaxants of peripheral action. RESULTS: Complete suppression of myographic artifacts on the EEG was noted in all patients after the introduction of peripheral muscle relaxants. However, in 4 of them, EEG changes were noted in the period 2 to 3 minutes after the introduction of muscle relaxants and the disappearance of myographic artifacts on the EEG. These changes coincided in time with the changes recorded by the ECG channel. CONCLUSIONS: The EEG changes in time, coinciding with the changes in ECG indicators, suggest the presence of short-term disturbances of the functional state of the basic brain systems, probably due to changes in hemodynamics due to cardiac rhythm and conduction disturbances. It is advisable to record the EEG with the inclusion of an ECG channel in the wiring diagram for synchronous recording.

Design of Multitarget Inhibitors as Tracheal Smooth Muscle Relaxants.

INTRODUCTION: Asthma complications and adverse effects associated with steroidal therapy highlight the need for non-steroidal compounds intercepting asthmatic pathophysiology at multiple targets. The present investigation was carried out to evaluate the tracheal smooth muscle relaxant effect of virtually designed, combinatorially synthesized polyfunctional N-heteroarylamides. METHODS: Virtual screening and molecular docking studies of designed compounds were performed using PyRx and AUTODOCK 4.2 software against molecular targets viz. FLAP, LTB4, and H1 receptor. Cross-validation of virtual screening results and active site, confirmation was performedusingVlife MDS software version 3.5. The combinatorial approach was used to synthesize designed compounds in which heterocyclic amines were reacted with substituted aromatic acid chlorides by nucleophilic substitution reaction to obtain a 5x5 mini-library. The structures of synthesized leads were confirmed by infrared and proton magnetic resonance spectroscopic analysis. Synthesized compounds were evaluated for their smooth muscle relaxation effect on isolated goat tracheal smooth muscle. RESULTS: Results were calculated as a percent decrease in contraction response observed using histamine and LTB4. The tested compounds produced anticipated tracheal smooth muscle relaxant activity. Based on the results of screening the structure-activity relationships (SAR) have been reported. CONCLUSION: Present study concluded that synthesized polyfunctional N-heteroarylamides have a tracheal smooth muscle relaxant effect. The mode of action is predicted from the analysis of virtual screening results. A good correlation was observed between virtual screenings and biological activities of lead molecules suggesting the rationale used to optimize the structural requirements of a ligand for selected targets is appropriate.

Perioperative neuromuscular blockade. 2020 update of the SEDAR (Sociedad Española de Anestesiología y Reanimación) recommendations.

We present an update of the 2020 Recommendations on neuromuscular blockade of the SEDAR. The previous ones dated 2009. A modified Delphi consensus analysis (experts, working group, and previous extensive bibliographic revision) 10 recommendations were produced1: neuromuscular blocking agents were recommended for endotracheal intubation and to avoid faringo-laryngeal and tracheal lesions, including critical care patients.2 We recommend not to use neuromuscular blocking agents for routine insertion of supraglotic airway devices, and to use it only in cases of airway obstruction or endotracheal intubation through the device.3 We recommend to use a rapid action neuromuscular blocking agent with an hypnotic in rapid sequence induction of anesthesia.4 We recommend profound neuromuscular block in laparoscopic surgery.5 We recommend quantitative monitoring of neuromuscular blockade during the whole surgical procedure, provided neuromuscular blocking agents have been used.6 We recommend quantitative monitoring through ulnar nerve stimulation and response evaluation of the adductor pollicis brevis, acceleromyography being the clinical standard.7 We recommend a recovery of neuromuscular block of at least TOFr ≥ 0.9 to avoid postoperative residual neuromuscular blockade.8 We recommend drug reversal of neuromuscular block at the end of general anesthetic, before extubation, provided a TOFr ≥ 0.9 has not been reached.9 We recommend to choose anticholinesterases for neuromuscular block reversal only if TOF≥2 and a TOFr ≥ 0.9 has not been attained.10 We recommend to choose sugammadex instead of anticholinesterases for reversal of neuromuscular blockade induced with rocuronium.

Bloqueo neuromuscular perioperatorio. Actualización 2020 de las Recomendaciones de la Sociedad Española de Anestesiología, Reanimación y Terapéutica del Dolor (SEDAR) / Perioperative neuromuscular blockade. 2020 update of the SEDAR (Sociedad Española de Anestesiología y Reanimación) recommendations

Se presenta la actualización 2020 de las Recomendaciones de bloqueo neuromuscular de la Sociedad Española de Anestesiología, Reanimación y Terapéutica del Dolor (SEDAR). Las anteriores databan de 2009. Tras un análisis de consenso Delphi (expertos, grupo de trabajo y revisión bibliográfica previa) se generaron 10 recomendaciones: 1) Se recomienda el uso de fármacos bloqueantes neuromusculares (fbnm) para facilitar la intubación traqueal y evitar lesiones faringo-laringo-traqueales en cualquier paciente, incluidos pacientes críticos. 2) Se recomienda no utilizar fbnm para la inserción rutinaria de dispositivos supraglóticos y utilizar solo en caso de obstrucción de la vía aérea o intubación traqueal a través de este. 3) Se recomienda utilizar un fármaco bloqueante neuromuscular de inicio de acción rápido asociado al agente hipnótico en la inducción de secuencia rápida. 4) Se recomienda utilizar un nivel de bloqueo neuromuscular profundo en cirugía laparoscópica. 5) Se recomienda el uso de monitorización cuantitativa del bloqueo neuromuscular durante todo el procedimiento quirúrgico, siempre que se utilicen fbnm. 6) Se recomienda la monitorización cuantitativa mediante estimulación del nervio cubital y evaluación de la respuesta en el músculo aductor corto del pulgar, siendo el estándar clínico la aceleromiografía (AMG). 7) Se recomienda una recuperación del bloqueo neuromuscular al menos hasta alcanzar un TOFr ≥ 0,9 para evitar el bloqueo neuromuscular residual postoperatorio. 8) Se recomienda la reversión farmacológica del bloqueo neuromuscular al finalizar la anestesia general, previo a la extubación traqueal siempre que no se haya alcanzado un TOFr ≥ 0,9. 9) Se recomienda utilizar fármacos anticolinesterásicos para la reversión del bloqueo neuromuscular solo cuando el tren de cuatro estímulos (TOF) es ≥ 2 y no se haya alcanzado un TOFr ≥ 0,9. 10)...(AU)

We present an update of the 2020 Recommendations on neuromuscular blockade of the SEDAR. The previous ones dated 2009. A modified Delphi consensus analyisis (experts, working group, and previous extensive bibliographic revision) 10 recommendations were produced: (1) neuromuscular blocking agents were recommended for endotracheal intubation and to avoid faringo-laryngeal and tracheal lesions, including critical care patients. (2) We recommend not to use neuromuscular blocking agents for routine insertion of supraglotic airway devices, and to use it only in cases of airway obstruction or endotracheal intubation through the device. (3) SWe recommend to use a rapid action neuromuscular blocking agent with an hypnotic in rapid sequence induction of anesthesia. (4) We recommed profound neuromuscular block in laparoscopic surgery. (5) We recommend quantitative monitoring Sof neuromuscular blockade during the whole surgical procedure, provided neuromuscular blocking agents have been used. (6) We recommend quantitative monitoring through ulnar nerve stimulation and response evaluation of the adductor pollicis brevis, acceleromyography being the clinical standard. (7) We recommned a recovery of neuromuscular block of at least TOFr ≥ 0.9 to avoid postoperative residual neuromuscular blockade. (8) We recommend drug reversal of neuromuscular block at the end of general anesthetic, before extubation, provided a TOFr ≥ 0.9 has not been reached. (9) We recommend to choose anticholinesterases for neuromuscular block reversal only if TOF ≥ 2 and a TOFr ≥ 0.9 has not been atained. (10) We recommend to choose sugammadex instead of anticholinesterases for reversal of neuromuscular blockade induced with rocuronium.(AU)

Comparison of the onset and offset times of two available formulations of rocuronium bromide in an animal model.

Rocuronium bromide is a neuromuscular blocker in widespread use in anaesthesia, emergency and intensive care. Reports of reduced efficacy of a new different formulation of rocuronium bromide were submitted to Medsafe, the New Zealand Medicines and Medical Devices Safety Authority, in 2020. Given the requirement for rapid and predictable paralysis for patient safety the efficacy of the two available formulations of rocuronium bromide was investigated in an animal model. After ethics committee approval, 19 rats were anaesthetised and paralysis, defined as loss of tibialis anterior flexion on direct electrical stimulation of the sciatic nerve, was assessed by mechanomyography in response to ED90 doses of rocuronium.Paralysis was observed at a median of 12 seconds for the new different formulation: A, Hameln Pharma (interquartile range (IQR) 6-106 seconds) and 28 seconds for formulation B: Pfizer (IQR 12-68 seconds) P = 0.48. Offset of paralysis was observed after 293 seconds for formulation A (IQR 250-372 seconds) and 241 seconds for formulation B (IQR 220-263 seconds). While the differences observed were substantial, they were not statistically significant. Moreover, the direction of observed difference was towards a shorter median onset and longer offset for the newer formulation, a finding in the opposite direction to the initial clinical concern.Relevance to the clinical situation is indeterminate given the study was stopped at low numbers for futility and limitations around the clinical applicability of animal pharmacokinetics and dynamics. Nevertheless our findings provide some reassurance that the newly available different formulation of this critical use medication does not exhibit a substantial increase in time to onset.

Muscle relaxants as adjunctive analgesics in the perioperative setting: A review of the literature.

Patients undergoing surgical procedures are one of the few populations that still require substantial doses of opioid medications to provide analgesia, despite the best efforts of clinicians to integrate non-opioid adjunctive analgesics into practice. While many options exist with varying degrees of evidence, one drug class that deserves renewed consideration are muscle relaxants. Although these medications have differing mechanisms of action and require a more thorough evaluation of patient parameters prior to administration as opposed to other adjunctive analgesics, it is readily apparent by the results of this review that these agents may be able to mitigate pain and limit opioid usage. The objective of this review was to determine the efficacy and safety of adjunctive muscle relaxers for the purposes of analgesia in the perioperative setting.

Prescription medication use of United States military service members by therapeutic classification.

Background: This cross-sectional study investigated the prevalence of, and factors associated with, filled prescription medications (FPMs) among United States (US) service members (SMs). Methods: A stratified random sample of active duty SMs from the Air Force, Army, Marine Corps, and Navy was obtained from military workforce records. Participants (n = 26,680) completed a questionnaire on demographics, physical characteristics, and lifestyle factors and approved access to their FPM for the previous 6 months. FPMs were obtained from the military Pharmacy Data Transaction Service that included all prescription medications dispensed at military medical treatment facilities, abroad, at retail pharmacies in the US, and/or through mail-order programs. Results: About two-thirds (65%) of SMs had ≥1 FPM in the 6 months surveillance period. Central nervous system (CNS) agents had the highest prevalence (41%), followed by anti-infective agents (20%), eye/ear/nose/throat preparations (20%), gastrointestinal drugs (18%), autonomic drugs (17%), skin and mucous membrane agents (13%), antihistamine drugs (12%), respiratory tract agents (12%) and cardiovascular drugs (9%). Among CNS agents, overall prevalence of dispensed non-steroidal anti-inflammatory drug (NSAIDs) was 30%. The odds of any FPM was independently associated with female gender, older age, higher body mass index, former tobacco use (smoking and smokeless tobacco), lower alcohol consumption, and was highest among Army, lowest among Marine Corps personnel. Conclusion: In this sample of SMs, dispensing of prescription medication was high, especially NSAIDs, but dispensing of cardiovascular drugs was much lower compared to the general US population, likely because of the younger age and higher level of physical activity of SMs.

Thromboembolic Events in Users of Warfarin Treated with Different Skeletal Muscle Relaxants.

Background and Objectives: Warfarin and a skeletal muscle relaxant are co-treatments in nearly a quarter-million annual United States (US) office visits. Despite international calls to minimize patient harm arising from anticoagulant drug interactions, scant data exist on clinical outcomes in real-world populations. We examined effects of concomitant use of warfarin and individual muscle relaxants on rates of hospitalization for thromboembolism among economically disadvantaged persons. Materials and Methods: Using 1999−2012 administrative data of four US state Medicaid programs, we conducted 16 retrospective self-controlled case series studies: half included concomitant users of warfarin + one of eight muscle relaxants; half included concomitant users of an inhaled corticosteroid (ICS) + one of eight muscle relaxants. The ICS analyses served as negative control comparisons. In each study, we calculated incidence rate ratios (IRRs) comparing thromboembolism rates in the co-exposed versus warfarin/ICS-only exposed person-time, adjusting for time-varying confounders. Results: Among ~70 million persons, we identified 8693 warfarin-treated subjects who concomitantly used a muscle relaxant, were hospitalized for thromboembolism, and met all other inclusion criteria. Time-varying confounder-adjusted IRRs ranged from 0.31 (95% confidence interval: 0.13−0.77) for metaxalone to 3.44 (95% confidence interval: 1.53−7.78) for tizanidine. The tizanidine finding was robust after quantitatively adjusting for negative control ICS findings, and in numerous prespecified secondary analyses. Conclusions: We identified a potential >3-fold increase in the rate of hospitalized thromboembolism in concomitant users of warfarin + tizanidine vs. warfarin alone. Alternative explanations for this finding include confounding by indication, a native effect of tizanidine, or chance.

Skeletal muscle relaxant drug-drug-drug interactions and unintentional traumatic injury: Screening to detect three-way drug interaction signals.

AIM: The aim of this study was to identify skeletal muscle relaxant (SMR) drug-drug-drug interaction (3DI) signals associated with increased rates of unintentional traumatic injury. METHODS: We conducted automated high-throughput pharmacoepidemiologic screening of 2000-2019 healthcare data for members of United States commercial and Medicare Advantage health plans. We performed a self-controlled case series study for each drug triad consisting of an SMR base-pair (i.e., concomitant use of an SMR with another medication), and a co-dispensed medication (i.e., candidate interacting precipitant) taken during ongoing use of the base-pair. We included patients aged ≥16 years with an injury occurring during base-pair-exposed observation time. We used conditional Poisson regression to calculate adjusted rate ratios (RRs) with 95% confidence intervals (CIs) for injury with each SMR base-pair + candidate interacting precipitant (i.e., triad) versus the SMR-containing base-pair alone. RESULTS: Among 58 478 triads, 29 were significantly positively associated with injury; confounder-adjusted RRs ranged from 1.39 (95% CI = 1.01-1.91) for tizanidine + omeprazole with gabapentin to 2.23 (95% CI = 1.02-4.87) for tizanidine + diclofenac with alprazolam. Most identified 3DI signals are new and have not been formally investigated. CONCLUSION: We identified 29 SMR 3DI signals associated with increased rates of injury. Future aetiologic studies should confirm or refute these SMR 3DI signals.

The Use of Muscle Relaxants and Reversal Agents in a Setting Without Cost Restrictions: Experience from a Tertiary Academic Hospital in the Netherlands.

Introduction: Muscle relaxants are often given during general anesthesia to facilitate endotracheal intubation. However lingering effects after anesthesia-end may lead to respiratory compromise in the PACU. Strategies to reduce these adverse events include monitoring neuromuscular block, the use of short-acting agents and active pharmacological reversal before extubation. At Leiden University Medical Center (LUMC), a tertiary care academic hospital in the Netherlands, various muscle relaxants and reversal agents are freely available to all clinicians without restrictions. In this setting, we intended to evaluate how patient and surgical characteristics impacted the use of these agents for a variety of non-cardiac surgeries. Material and Methods: This is a retrospective database study of adult patients that had received elective, non-cardiac surgery and general anesthesia with endotracheal intubation between 2016 and 2020 at LUMC in the Netherlands. Exclusion criteria consisted of patients pharmacologically reversed with both sugammadex and neostigmine during the same procedure, diagnosed with myasthenia gravis, receiving pyridostigmine therapy, or with renal failure (eGFR <30 mL.min.1.73m2). Results: We retrieved 23,373 patient records of which 9742 were excluded because one or more exclusion criteria were met. The final cohort consisted of 13,631 cases. Rocuronium was the most commonly used muscle relaxant (88.5%); sugammadex was the most commonly used reversal agent (99.9% of those pharmacologically reversed). Of all cases that received rocuronium as muscle relaxant, 76.9% of patients were not reversed, while 23.1% were reversed with sugammadex. The odds of reversal increased with age, BMI, ASA class (1-3) and shorter duration of surgery. Conclusion: In an unrestricted clinical environment, rocuronium and sugammadex are the preferred agents for muscle relaxation and reversal. Pharmacologic reversal of neuromuscular block was uncommon overall, but more likely in older and obese patients, higher ASA classification and shorter lasting procedures. Sugammadex has largely replaced neostigmine for this purpose.

The use of sugammadex in critical events in anaesthesia: A retrospective review of the webAIRS database.

Sugammadex has been used for more than ten years in Australia and New Zealand and has been implicated as an effective treatment, and in some cases a potential cause, of a critical incident. We aimed to identify and analyse critical incidents involving sugammadex reported to webAIRS, a de-identified voluntary online critical incident reporting system in Australia and New Zealand. We identified 116 incidents where the reporter implicated sugammadex as either a cause (23 cases) or a treatment (93 cases) during anaesthesia. There were 17 incidents suggestive of sugammadex anaphylaxis, although not all were confirmed by skin testing. There were six incidents when bradycardia was temporally related to sugammadex administration, although it was not possible to exclude other causes or contributory factors. There were nine incidents in which sugammadex was used to reverse aminosteroid-related neuromuscular blockade successfully in a 'can't intubate, can't oxygenate' (CICO) situation, and a further 67 incidents in which sugammadex was used to reverse aminosteroid neuromuscular blockade as part of the management of other critical incidents. While sugammadex was used during the management of 16 cases of anaphylaxis, there was no clear indication that this altered the course of the anaphylaxis in any of the cases. These reports indicate that sugammadex can be a potential trigger for anaphylaxis and that its use may be associated with the development of significant bradycardia. However, it is not possible to estimate or even speculate on the incidence of these sugammadex-related incidents on the basis of voluntary reporting to a database such as webAIRS. The reports also indicate that sugammadex has been used successfully to reverse residual or deep aminosteroid neuromuscular blockade in critical incident situations and to help rescue CICO scenarios. These findings provide further support for ensuring the ready availability of sugammadex wherever aminosteroid muscle relaxants are used.

Single and Multiple Dose PK-PD Characterization for Carisoprodol. Part I: Pharmacokinetics, Metabolites, and 2C19 Phenotype Influence. Double-Blind, Placebo-Controlled Clinical Trial in Healthy Volunteers.

Carisoprodol was authorised in 1959 without a full pharmacokinetic-pharmacodynamic (PK-PD) characterisation. We designed a crossover, double-blind, placebo-controlled, randomized clinical trial to characterize the PKs of carisoprodol and its main active metabolite, meprobamate, after single (350 mg), multiple (350 mg/8 h, 14 days), and double (700 mg) doses of carisoprodol. Thirteen healthy volunteers were enrolled. After a single (350 mg) dose, the main carisoprodol parameters were (mean ± SD) Cmax: 2580 ± 1214 ng/mL, AUC0-∞: 8072 ± 6303 h·ng/mL, and half-life (T1/2): 2 ± 0.8 h. For meprobamate, the parameters were Cmax: 2181 ± 605 ng/mL and 34,529 ± 7747 h·ng/mL y 9 ± 1.9 h. Different profiles were found for extensive and poor 2C19 metabolizers. After 14 days of treatment (350 mg/8 h) the results for carisoprodol were (mean ± SD) Cmax: 2504 ± 730 ng/mL, AUC0-∞: 7451 ± 3615 h·ng/mL, and T1/2: 2 ± 0.7 h. For meprobamate (a steady state was reached), the parameters were Cmax: 5758 ± 1255 ng/mL and 79,699 ± 17,978 h·ng/mL y 8.7 ± 1.4 h. The study allowed for the full characterization of the pharmacokinetic profile of carisoprodol and meprobamate. Accumulation of meprobamate but not of carisoprodol was evident after 14 days of treatment.

The associations between central serous chorioretinopathy and muscle relaxants: A case-control study.

PURPOSE: To evaluate the role of muscle-relaxants as risk factors for the development of central serous chorioretinopathy (CSC) - the second most common retinopathy in our settings; despite multiple risk factors seen in our patients, 21% were initially labelled as idiopathic. MATERIALS AND METHODS: Retrospective case-control study at a tertiary hospital in the United Arab Emirates, where we reviewed the medical records of 273 patients with CSC examined between 2010 and 2019 for use of muscle-relaxants including tolperisone/eperisone, carisoprodol and gabapentin/pregabalin within a year of onset/recurrence of the disease. Intake of drugs with known association with CSC (including corticosteroids/sympathomimetics) was also recorded. Two hundred eighty-six subjects with adverse events seen at the same institute during the same study period served as controls. Odds ratios, Chi-Square tests and multivariate logistic regression were carried out to determine any associations with the muscle-relaxants and other pharmacological confounders - corticosteroids/sympathomimetics. RESULTS: Muscle relaxants may increase the risk of CSC as evident on multivariate regression analysis (OR: 2.55; confidence interval [CI]: 1.208-5.413); the significance was retained on removing the 6 subjects who had corticosteroids/sympathomimetics (OR: 2.30; CI: 1.073-4.939). Univariate analysis yielded an OR of 2.52 for muscle relaxants (CI: 1.2149-5.2276), 2.96 for eperisone/tolperisone (CI: 1.3531-6.5038), and 6.26 for eperisone as an individual agent (CI: 1.8146-21.6252). CONCLUSION: We found muscle relaxants to be associated factors of CSC regardless of inclusion of corticosteroids/sympathomimetics (P < 0.05). Among individual classes of muscle relaxants in this study, only eperisone/tolperisone posed a significant risk (P < 0.05). The vascular smooth muscle relaxation could be the possible mechanism that affects the choroidal blood flow and indirectly predisposes to CSC.