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Pharmaceutics May 2022The present study aimed to investigate methods for accelerating autoxidation of crystalline drugs in the solid-state that can potentially predict real-time stability....
The present study aimed to investigate methods for accelerating autoxidation of crystalline drugs in the solid-state that can potentially predict real-time stability. Solid droperidol (DPD) was selected as the model drug. A common free-radical initiator, 2,2'-azobisisobutyronitrile (AIBN), was used to induce autoxidation in solutions. AIBN decomposes at elevated temperatures to yield carbon-centred cyano-isopropyl free radicals that can auto-oxidize neighboring drug molecules. Although the reaction of AIBN is relatively straightforward in solution, it is less so in solids. In this study, we used solid AIBN mixed with DPD powder in the presence and absence of pressurized oxygen headspace. Samples were prepared directly in the form of binary mixtures with DPD and additionally in the form of powder compact/pellet with DPD. The main challenge in carrying out the reaction was related to the preservation of AIBN at elevated temperatures due to the disintegration of the pellet containing the latter. A commercially available free-radical coated silica particle (i.e., 2,2,6,6-tetramethyl-1-piperinyloxy (TEMPO) or (SiliaCAT TEMPO)) was tested as a potential stressor, but with limited success to induce autoxidation. The most valuable results were obtained when a physical mixture of pre-milled PVP K-60 containing free radicals and DPD was exposed to elevated oxygen-temperature conditions, which yielded significant degradation of DPD. The study highlights the practical challenges for conducting accelerated solid-state stress studies to assess the autoxidation susceptibility of drugs using traditional free-radical initiators and presents a proof of application of milled PVP with free-radical as a potential alternative.
PubMed: 35745687
DOI: 10.3390/pharmaceutics14061114 -
Academic Emergency Medicine : Official... Dec 2022Agitation in children in acute care settings poses significant patient and staff safety concerns. While behavioral approaches are central to reducing agitation and oral... (Review)
Review
OBJECTIVE
Agitation in children in acute care settings poses significant patient and staff safety concerns. While behavioral approaches are central to reducing agitation and oral medications are preferred, parenteral medications are used when necessary to promote safety. The goal of this systematic review was to evaluate the effectiveness and safety of an ultra-short-acting parenteral medication, droperidol, for the management of acute, severe agitation in children in acute care settings.
METHODS
A systematic review of randomized controlled trials, observational studies, and case series/reports examined the effectiveness and safety of parenteral droperidol for management of acute agitation in patients ≤21 years old in acute care settings. Effectiveness outcomes included time to sedation and need for a subsequent dose of medication. Safety outcomes were adverse effects such as QTc prolongation, hypotension, respiratory depression, and dystonic reactions.
RESULTS
A total of 431 unique articles were identified. Six articles met inclusion criteria: two in the prehospital setting, one in the emergency department, and three in the inpatient hospital setting. The articles included a prospective observational study, three retrospective observational studies, and two case reports. The largest study reported a median time to sedation of 14 min (interquartile range 10-20 min); other studies reported a time to sedation of 15 min or less. Across studies, 8%-22% of patients required a second dose of medication for ongoing agitation. The most frequent adverse effects were dystonic reactions and transient hypotension. One patient had QTc prolongation and another developed respiratory depression, but both had significant comorbidities that may have contributed. The risk of bias in included studies ranged from moderate to critical.
CONCLUSIONS
Existing data on droperidol for management of acute agitation in children suggest that droperidol is both effective and safe for acute, severe agitation in children. Data are limited by study designs that may introduce bias.
Topics: Humans; Child; Young Adult; Adult; Droperidol; Retrospective Studies; Emergency Service, Hospital; Prospective Studies; Respiratory Insufficiency; Psychomotor Agitation; Observational Studies as Topic
PubMed: 35490341
DOI: 10.1111/acem.14515 -
Parecoxib Reduced Postsurgical Pain and Facilitated Movement More Than Patient Controlled Analgesia.Frontiers in Surgery 2022Postoperative pain management is an imperative issue for patients undergoing lumbar spinal fusion surgery. Delayed pain relief is associated with poor clinical outcomes....
BACKGROUND
Postoperative pain management is an imperative issue for patients undergoing lumbar spinal fusion surgery. Delayed pain relief is associated with poor clinical outcomes. This study compared the effects of intravenously administered patient-controlled analgesia (PCA) with intravenous parecoxib, both commonly used methods for analgesic pain control after surgery.
METHODS
A non-randomized study was used to recruit 68 patients who were scheduled to receive lumbar spinal fusion surgery at a hospital in Taiwan from April through December of 2020. The group treated with parecoxib received an initial perioperative dose of parecoxib 40 mg during a 30-min period and then postoperative intravenous parecoxib at 40 mg per 12-h period, for 72 h. Those with PCA received morphine (0.4 mg/ml), droperidol (0.02 mg/ml), diphenhydramine (0.48 mg/ml), midazolam (0.02 mg/ml) and saline solution during the 3-day study course. Major outcomes, including visual scale pain score and Barthel index of activities of daily living, were collected via review of medical records at 4 times: 12, 24, 48 and 72 h after surgery. Comparative effects between two groups were assessed by the generalized estimating equations.
RESULTS
After adjusting for potential confounders, the administration of parecoxib was associated with a significant decrease in pain scores and an increase in the Barthel Index, when compared with the PCA group (all < 0.05). Notably, both effects would maintain for 72 h after surgery.
DISCUSSION
This is the first trial of which the authors are aware, that supports intravenous parecoxib as significantly enhancing patient mobility, in addition to having pain control efficacy, when compared with PCA. This study could be used as a reference when instituting interventions to improve the adaptation process and clinical prognoses after lumbar spinal fusion surgery.
PubMed: 35465430
DOI: 10.3389/fsurg.2022.799795 -
BMC Anesthesiology Mar 2022Patients with inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, might present difficulties in achieving postoperative analgesia. Prior...
BACKGROUND
Patients with inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, might present difficulties in achieving postoperative analgesia. Prior studies have suggested that patients with IBD undergoing major abdominal surgery require higher doses of perioperative opioids than do patients without IBD. Considering patients with IBD potentially require high-dose opioids, identifying those requiring higher opioid doses will allow clinicians to optimize the perioperative opioid dose and avoid insufficient pain management or complications of opioid overdose. Therefore, we conducted this study to identify predictive factors that might influence postoperative opioid consumption in patients with IBD.
METHODS
This single-center, historical cohort study reviewed the medical records of all patients admitted to the IBD center of our institution for surgery and who used intravenous fentanyl patient-controlled analgesia (PCA) after open abdominal surgery between June 2013 and April 2017. Ultimately, 179 patients were enrolled in the analysis. Variables expected to influence and/or represent pain, analgesia, inflammation, disease condition, and extent of surgery were selected as potential explanatory variables for predicting postoperative opioid consumption. Multivariable linear regression analysis was used to examine the effect of independent variables on postoperative fentanyl consumption.
RESULTS
Of the nine predictive variables selected using the stepwise-selection method, eight were significant. Intraoperative fentanyl consumption, current smoking, ulcerative colitis, administration of biologics during the month before surgery, and the use of supplementary analgesics had a significant increasing effect on postoperative fentanyl consumption, whereas droperidol concentration in the PCA solution, age, and diabetes mellitus had a significant decreasing effect. Preoperative use of opioids was a non-significant variable. The adjusted coefficient of determination was 0.302.
CONCLUSIONS
Intraoperative fentanyl consumption, current smoking, ulcerative colitis, administration of biologics during the month before surgery, and the use of supplementary analgesics had a significant increasing effect, whereas droperidol concentration in the PCA solution, age, and diabetes mellitus had a significant decreasing effect on postoperative fentanyl consumption. These factors should be considered when adopting postoperative intravenous fentanyl PCA administration for patients with IBD.
TRIAL REGISTRATION
Registry: UMIN Clinical Trials Registry.
CLINICAL TRIAL NUMBER
UMIN000031198 . Date of registration: February 8, 2018.
Topics: Analgesia, Patient-Controlled; Analgesics; Analgesics, Opioid; Biological Products; Cohort Studies; Colitis, Ulcerative; Droperidol; Fentanyl; Humans; Inflammatory Bowel Diseases; Pain, Postoperative; Retrospective Studies
PubMed: 35277136
DOI: 10.1186/s12871-022-01606-8 -
The American Journal of Emergency... Feb 2022To assess the QTc interval variation after low-dose droperidol in a population of undifferentiated, stable, and non-agitated patients receiving droperidol in the... (Observational Study)
Observational Study
OBJECTIVE
To assess the QTc interval variation after low-dose droperidol in a population of undifferentiated, stable, and non-agitated patients receiving droperidol in the emergency department.
METHODS
Prospective cohort study of patients aged ≥12 years of age who received low-dose droperidol (≤ 2.5 mg) for indications other than acute behavioral disturbances. QTc intervals were monitored in real-time during pre-specified observation periods in the ED. Primary outcome was variation of QTc interval after droperidol administration, defined as the maximum delta (change) of QTc interval. Other outcomes included proportion of patients with a QTc ≥ 500 ms after droperidol, delta ≥ +60 ms, and incidence of clinical adverse events. Patients were monitored up to 30 min after IV bolus and up to 46 min after infusion.
RESULTS
A total of 68 patients were included (mean age 42.1 years, 66.2% females). The median dose of droperidol was 1.875 mg (range 0.625 mg, 2.5 mg) and 94.1% received droperidol for headache management. Most patients received droperidol as a 2-min bolus (n = 41, 60.3%). The mean maximum delta of QTc interval after droperidol across all 68 patients was +29.9 ms (SD 15). A total of 12 patients (17.6%) experienced a QTc interval ≥ 500 ms during the observation period after droperidol, and 3 patients (4.4%) had a delta QTc ≥ +60 ms. There were no serious arrhythmias, such as TdP, or deaths among the 68 participants in this study (0/68). However, 13.2% (n = 9) had at least one non-serious adverse event including restlessness and/or anxiety.
CONCLUSION
The QTc interval slightly increased after droperidol administration, but these prolongations were brief, mostly below 500 msec and did not lead to serious arrhythmias. The yield of continuous cardiac monitoring in patients receiving low doses of droperidol is likely low.
Topics: Adjuvants, Anesthesia; Adult; Antiemetics; Dose-Response Relationship, Drug; Droperidol; Emergency Service, Hospital; Female; Humans; Long QT Syndrome; Male; Prospective Studies; Young Adult
PubMed: 34959024
DOI: 10.1016/j.ajem.2021.12.039 -
RSC Medicinal Chemistry Nov 2021Tuberculosis (TB), caused by (), is a deadly bacterial disease. Drug-resistant strains of make eradication of TB a daunting task. Overexpression of the enhanced...
Tuberculosis (TB), caused by (), is a deadly bacterial disease. Drug-resistant strains of make eradication of TB a daunting task. Overexpression of the enhanced intracellular survival (Eis) protein by confers resistance to the second-line antibiotic kanamycin (KAN). Eis is an acetyltransferase that acetylates KAN, inactivating its antimicrobial function. Development of Eis inhibitors as KAN adjuvant therapeutics is an attractive path to forestall and overcome KAN resistance. We discovered that an antipsychotic drug, haloperidol (HPD, ), was a potent Eis inhibitor with IC = 0.39 ± 0.08 μM. We determined the crystal structure of the Eis-haloperidol () complex, which guided synthesis of 34 analogues. The structure-activity relationship study showed that in addition to haloperidol (), eight analogues, some of which were smaller than , potently inhibited Eis (IC ≤ 1 μM). Crystal structures of Eis in complexes with three potent analogues and droperidol (DPD), an antiemetic and antipsychotic, were determined. Three compounds partially restored KAN sensitivity of a KAN-resistant strain K204 overexpressing Eis. The Eis inhibitors generally did not exhibit cytotoxicity against mammalian cells. All tested compounds were modestly metabolically stable in human liver microsomes, exhibiting 30-60% metabolism over the course of the assay. While direct repurposing of haloperidol as an anti-TB agent is unlikely due to its neurotoxicity, this study reveals potential approaches to modifying this chemical scaffold to minimize toxicity and improve metabolic stability, while preserving potent Eis inhibition.
PubMed: 34825186
DOI: 10.1039/d1md00239b -
The American Journal of Emergency... Jan 2022Safe and effective tranquilization of the acutely agitated patient is challenging, and head-to-head comparisons of medications are limited. We aimed to identify the most... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Safe and effective tranquilization of the acutely agitated patient is challenging, and head-to-head comparisons of medications are limited. We aimed to identify the most optimal agent(s) for rapid tranquilization of the severely agitated patient in the emergency department (ED).
METHODS
The protocol for systematic review was registered (PROSPERO; CRD42020212534). We searched MEDLINE, Embase, PsycINFO, and Cochrane Database/CENTRAL from inception to June 2, 2021. We limited studies to randomized controlled trials that enrolled adult ED patients with severe agitation and compared drugs for rapid tranquilization. Predetermined outcomes were: 1) Adequate sedation within 30 min (effectiveness), 2) Immediate, serious adverse event - cardiac arrest, ventricular tachydysrhythmia, endotracheal intubation, laryngospasm, hypoxemia, hypotension (safety), and 3) Time to adequate sedation (effect onset). We extracted data according to PRISMA-NMA and appraised trials using Cochrane RoB 2 tool. We performed Bayesian network meta-analysis (NMA) using a Markov Chain Monte Carlo method with random-effects model and vague prior distribution to calculate odds ratios with 95% credible intervals for dichotomous outcomes and frequentist NMA to calculate mean differences with 95% confidence intervals for continuous outcomes. We assessed confidence in results using CINeMA. We used surface under the cumulative ranking (SUCRA) curves to rank agent(s) for each outcome.
RESULTS
Eleven studies provided data for effectiveness (1142 patients) and safety (1147 patients). Data was insufficient for effect onset. The NMA found that ketamine (SUCRA = 93.0%) is most likely to have superior effectiveness; droperidol-midazolam (SUCRA = 78.8%) is most likely to be safest. There are concerns with study quality and imprecision. Quality of the point estimates varied for effectiveness but mostly rated "very low" for safety.
CONCLUSIONS
Available evidence suggests that ketamine and droperidol have intermediate effectiveness for rapid tranquilization of the severely agitated patient in the ED. There is insufficient evidence to definitively determine which agent(s) may be safest or fastest-acting. Further, direct-comparison study of ketamine and droperidol is recommended.
Topics: Adult; Droperidol; Emergence Delirium; Emergency Service, Hospital; Humans; Ketamine; Network Meta-Analysis; Psychomotor Agitation; Randomized Controlled Trials as Topic; Severity of Illness Index; Treatment Outcome
PubMed: 34823192
DOI: 10.1016/j.ajem.2021.11.011 -
Medical Principles and Practice :... 2022Several forms of cannabinoids are currently being used to manage nausea and vomiting (N/V). Emerging cases of refractory N/V associated with chronic cannabis use among...
INTRODUCTION
Several forms of cannabinoids are currently being used to manage nausea and vomiting (N/V). Emerging cases of refractory N/V associated with chronic cannabis use among adults and older patients have been reported named cannabis hyperemesis syndrome (CHS). CHS is a condition that leads to repeated and severe N/V in long-term users of cannabinoids.
OBJECTIVE
The aim of this study was to outline current treatments for the management of CHS.
METHODS
A systematic review was conducted using PubMed, Ovid MEDLINE, Cochrane Central, EMBASE, and Google Scholar. Databases were used to search for articles on CHS published from January 2009 to June 2021, yielding 225 results of which 17 were deemed relevant and underwent review by 2 separate reviewers.
RESULTS
The duration of cannabis administration ranged between 6 months to 11 years may precipitate symptoms of CHS. The Rome IV diagnostic criteria of CHS require cannabinoid use and persistence of N/V symptoms for at least the past 6 months. Cannabis cessation is noted to be the most successful management, but other treatments also demonstrated symptom relief; these include hot water hydrotherapy, topical capsaicin cream, haloperidol, droperidol, benzodiazepines, propranolol, and aprepitant administration.
CONCLUSION
More research on CHS is needed to enhance knowledge translation, education, and create awareness in the medical community on the side effects of cannabinoids and to propose the best treatment options.
Topics: Adult; Analgesics; Cannabinoids; Cannabis; Humans; Marijuana Abuse; Syndrome; Vomiting
PubMed: 34724666
DOI: 10.1159/000520417 -
Microsystems & Nanoengineering 2021Cardiovascular disease (CVD) is the number one cause of death in humans. Arrhythmia induced by gene mutations, heart disease, or hERG K channel inhibitors is a serious...
Cardiovascular disease (CVD) is the number one cause of death in humans. Arrhythmia induced by gene mutations, heart disease, or hERG K channel inhibitors is a serious CVD that can lead to sudden death or heart failure. Conventional cardiomyocyte-based biosensors can record extracellular potentials and mechanical beating signals. However, parameter extraction and examination by the naked eye are the traditional methods for analyzing arrhythmic beats, and it is difficult to achieve automated and efficient arrhythmic recognition with these methods. In this work, we developed a unique automated template matching (ATM) cardiomyocyte beating model to achieve arrhythmic recognition at the single beat level with an interdigitated electrode impedance detection system. The ATM model was established based on a rhythmic template with a data length that was dynamically adjusted to match the data length of the target beat by spline interpolation. The performance of the ATM model under long-term astemizole, droperidol, and sertindole treatment at different doses was determined. The results indicated that the ATM model based on a random rhythmic template of a signal segment obtained after astemizole treatment presented a higher recognition accuracy (100% for astemizole treatment and 99.14% for droperidol and sertindole treatment) than the ATM model based on arrhythmic multitemplates. We believe this highly specific ATM method based on a cardiomyocyte beating model has the potential to be used for arrhythmia screening in the fields of cardiology and pharmacology.
PubMed: 34567738
DOI: 10.1038/s41378-021-00251-4 -
Journal of Paediatrics and Child Health Jan 2022Studies reporting factors associated with paediatric/adolescent acute behavioural disturbance (ABD) in the Emergency Department (ED) are lacking. The aim of this study...
AIM
Studies reporting factors associated with paediatric/adolescent acute behavioural disturbance (ABD) in the Emergency Department (ED) are lacking. The aim of this study is to describe paediatric/adolescent ED presentations involving ABD events.
METHODS
A retrospective chart review of presentations involving ABD events, identified via hospital security log, to a tertiary referral paediatric ED during the 2017 calendar year. Data reported included: cause of presentation, use of sedation/physical restraint, ED/inpatient length of stay (LOS) and time requiring security staff presence.
RESULTS
From 280 reported ABD episodes 26 were excluded leaving 254 events involving 150 patients across 233 presentations of whom 38 (25.3%) presented on multiple occasions. Median age was 14 years (interquartile range (IQR): 13-16), 132/233 (56.7%) were female, 167/233 (71.7%) primary mental health complaints, 30/233 (12.9%) deliberate self-harm, 18/233 (7.7%) deliberate self-poisoning, 11/233 (4.7%) acute intoxication and 7/233 (3.0%) other. Transport to hospital involved police and ambulance in 124/233 (53.2%), ambulance only 71/233 (30.5%), police only 16/233 (6.9%), relative or carer 20/233 (8.6%), with self-presentation in 2/233 (0.9%). Sedation or physical restraint was used in 81/233 (34.8%), both 38/233 (16.3%), restraint only 26/233 (11.2%) and sedation only 17/234 (7.3%). Intra-muscular droperidol accounted for 57/96 (59.4%) sedations, IM/IV benzodiazepines 15/96 (15.6%), IM/IV ketamine 5/96 (5.2%) and 19/96 (19.8%) other. Discharge from ED occurred in 171/233 (73.1%) with median ED LOS 5.1 h (IQR: 3.5-7.7) and median hospital LOS 92.4 h (IQR: 47.5-273.4) for those admitted. The Mental Health Act was utilised in 183/233 (78.5%) presentations. Median security staff time requirement per presentation was 2.4 h (IQR: 1.0-3.9).
CONCLUSIONS
Paediatric/adolescent ED presentations involving ABD are primarily due to mental health complaints. Less than half require the use of sedation/physical restraint. Time requiring security staff involvement is a significant resource consumption.
Topics: Adolescent; Child; Emergency Service, Hospital; Female; Humans; Length of Stay; Patient Discharge; Police; Retrospective Studies
PubMed: 34375471
DOI: 10.1111/jpc.15668