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Chemical Research in Toxicology Aug 2022Molecular dynamics was used to optimize the droperidol-hERG complex obtained from docking. To accommodate the inhibitor, residues T623, S624, V625, G648, Y652, and F656...
Molecular dynamics was used to optimize the droperidol-hERG complex obtained from docking. To accommodate the inhibitor, residues T623, S624, V625, G648, Y652, and F656 did not move significantly during the simulation, while F627 moved significantly. Binding sites in cryo-EM structures and in structures obtained from molecular dynamics simulations were characterized using solvent mapping and Atlas ligands, which were negative images of the binding site, were generated. Atlas ligands were found to be useful for identifying human ether-á-go-go-related potassium channel (hERG) inhibitors by aligning compounds to them or by guiding the docking of compounds in the binding site. A molecular dynamics optimized structure of hERG led to improved predictions using either compound alignment to the Atlas ligand or docking. The structure was also found to be suitable to define a strategy for lowering inhibition based on the proposed binding mode of compounds in the channel.
Topics: Binding Sites; ERG1 Potassium Channel; Ether; Ether-A-Go-Go Potassium Channels; Humans; Ligands; Solvents
PubMed: 35895844
DOI: 10.1021/acs.chemrestox.2c00036 -
British Journal of Pharmacology Sep 2022HERG blocking drugs known for their propensity to trigger Torsades de Pointes (TdP) were reported to induce a sympatho-vagal coactivation and to enhance High Frequency...
BACKGROUND AND PURPOSE
HERG blocking drugs known for their propensity to trigger Torsades de Pointes (TdP) were reported to induce a sympatho-vagal coactivation and to enhance High Frequency heart rate (HFHR) and QT oscillations (HFQT) in telemetric data. The present work aimed to characterize the underlying mechanism(s) leading to these autonomic changes.
EXPERIMENTAL APPROACH
Effects of 15 torsadogenic hERG blocking drugs (astemizole, chlorpromazine, cisapride, droperidol, ibutilide, dofetilide, haloperidol, moxifloxacin, pimozide, quinidine, risperidone, sotalol, sertindole, terfenadine, and thioridazine) were assessed by telemetry in beagle dogs. Haemodynamic effects on diastolic and systolic arterial pressure were analysed from the first doses causing QTc prolongation and/or HFQT oscillations enhancement. Autonomic control changes were analysed using the high frequency autonomic modulation (HFAM) model.
KEY RESULTS
Except for moxifloxacin and quinidine, all torsadogenic hERG blockers induced parasympathetic activation or sympatho-vagal coactivation combined with enhancement of HFQT oscillations. These autonomic effects result from reflex compensatory mechanisms in response to mild haemodynamic side effects. These haemodynamic mechanisms were characterized by transient HR acceleration during HF oscillations. A phenomenon of concealed QT prolongation was unmasked for several torsadogenic hERG blockers under β-adrenoceptor blockade with atenolol. Resulting enhancement of HFQT oscillations was shown to contribute directly to triggering dofetilide-induced ventricular arrhythmias.
CONCLUSION AND IMPLICATIONS
This work supports for the first time a contribution of haemodynamic side properties to ventricular arrhythmias triggered by torsadogenic hERG blocking drugs. These haemodynamic side effects may constitute a second component of their arrhythmic profile, acting as a trigger alongside their intrinsic arrhythmogenic electrophysiological properties.
Topics: Animals; Arrhythmias, Cardiac; Dogs; Drug-Related Side Effects and Adverse Reactions; Electrocardiography; Ether-A-Go-Go Potassium Channels; Heart Rate; Long QT Syndrome; Moxifloxacin; Quinidine; Reflex; Torsades de Pointes
PubMed: 35751378
DOI: 10.1111/bph.15905 -
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 -
Clinical Toxicology (Philadelphia, Pa.) Sep 2022Duloxetine is a commonly used antidepressant that is a serotonin and norepinephrine reuptake inhibitor. We aimed to investigate the frequency and severity of clinical...
OBJECTIVE
Duloxetine is a commonly used antidepressant that is a serotonin and norepinephrine reuptake inhibitor. We aimed to investigate the frequency and severity of clinical effects following duloxetine overdose.
METHODS
We undertook a retrospective review of duloxetine overdoses (>120 mg) admitted to two tertiary toxicology units between March 2007 and May 2021. Demographic information, details of ingestion (dose, co-ingestants), clinical effects, investigations (ECG parameters including QT interval), complications (coma [GCS < 9], serotonin toxicity, seizures and cardiovascular effects), length of stay [LOS] and intensive care unit [ICU] admission were extracted from a clinical database.
RESULTS
There were 241 duloxetine overdoses (>120 mg), median age 37 years (interquartile range [IQR]: 25-48 years) and there were 156 females (65%). The median dose was 735 mg (IQR: 405-1200 mg). In 177 patients, other medications were co-ingested, most commonly alcohol, paracetamol, quetiapine, diazepam, ibuprofen, pregabalin and oxycodone. These patients were more likely to be admitted to ICU (12 [7%] vs. none; = 0.040), develop coma (16 [9%] vs. none; = 0.008) and hypotension [systolic BP < 90 mmHg] (15 [8%] vs. one; = 0.076). Sixty four patients ingested duloxetine alone with a median dose of 840 mg (180-4200 mg). The median LOS, in the duloxetine only group, was 13 h (IQR:8.3-18 h), which was significantly shorter than those taking coingestants, 19 h (IQR:12-31 h; = 0.004). None of these patients were intubated. Six patients developed moderate serotonin toxicity, without complications and one had a single seizure. Tachycardia occurred in 31 patients (48%) and mild hypertension (systolic BP > 140 mmHg) in 29 (45%). One patient had persistent sympathomimetic toxicity, and one had hypotension after droperidol. Two patients of 63 with an ECG recorded had an abnormal QT: one QT 500 ms, HR 46 bpm, which resolved over 3.5 h and a second with tachycardia (QT 360 ms, HR 119 bpm). None of the 64 patients had an arrhythmia.
CONCLUSION
Duloxetine overdose most commonly caused sympathomimetic effects and serotonin toxicity, consistent with its pharmacology, and did not result in coma, arrhythmias or intensive care admission, when taken alone in overdose.
Topics: Acetaminophen; Adult; Antidepressive Agents; Arrhythmias, Cardiac; Coma; Diazepam; Droperidol; Drug Overdose; Duloxetine Hydrochloride; Female; Humans; Hypotension; Ibuprofen; Middle Aged; Norepinephrine; Oxycodone; Pregabalin; Quetiapine Fumarate; Seizures; Serotonin; Sympathomimetics; Tachycardia
PubMed: 35658766
DOI: 10.1080/15563650.2022.2083631 -
The American Journal of Emergency... Aug 2022Pain is a common complaint precipitating emergency department (ED) visit, occurring in more than half of patient encounters. While opioids are effective for acute pain... (Review)
Review
Pain is a common complaint precipitating emergency department (ED) visit, occurring in more than half of patient encounters. While opioids are effective for acute pain management in the Emergency Department (ED), the associated adverse effects, including respiratory and central nervous system depression, nausea, vomiting, and constipation, and physical manifestations of use, including tolerance, dependence and misuse leading to overdose and death, accentuate the need for non-opioid alternatives and/or multi-modal pain control. This review will provide examples of non-opioid pain management strategies and multimodal regimens for treatment of acute pain in the ED.
Topics: Acute Pain; Analgesics, Non-Narcotic; Analgesics, Opioid; Anti-Inflammatory Agents, Non-Steroidal; Emergency Service, Hospital; Humans; Pain Management
PubMed: 35636044
DOI: 10.1016/j.ajem.2022.05.022 -
Emergency Medicine Australasia : EMA Oct 2022Headache is a common presenting complaint to the ED. Using time from the first provider to discharge as a surrogate for effectiveness, we aimed to determine if... (Observational Study)
Observational Study
OBJECTIVE
Headache is a common presenting complaint to the ED. Using time from the first provider to discharge as a surrogate for effectiveness, we aimed to determine if intranasal (IN) droperidol is as beneficial as usual treatment for acute headache in the ED.
METHODS
There were 1213 consecutive presentations of adults with acute headache over a 42-month period. Electronic records for each event were interrogated, 406 events met pre-determined exclusion criteria. Of the remaining 805 eligible patient events, 139 received IN droperidol, whereas 666 were given usual therapy.
RESULTS
There was a 20 min reduction of mean and median ED length of stay (LOS) for the group that got treated with IN droperidol.
CONCLUSIONS
IN droperidol reduced LOS in the ED. There are potential cost savings of this effective treatment via this novel route. A prospective multi-centre study of the use of IN droperidol for the treatment of acute headache in the ED is recommended.
Topics: Adult; Droperidol; Emergency Service, Hospital; Headache; Humans; Prospective Studies; Retrospective Studies
PubMed: 35568501
DOI: 10.1111/1742-6723.14006 -
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 -
The American Journal of Emergency... May 2022The objective of this study was to compare the combination of intramuscular (IM) droperidol/midazolam to haloperidol/lorazepam regarding time to sedation in patients... (Observational Study)
Observational Study
STUDY OBJECTIVES
The objective of this study was to compare the combination of intramuscular (IM) droperidol/midazolam to haloperidol/lorazepam regarding time to sedation in patients with acute undifferentiated agitation in the emergency department (ED).
METHODS
This was a prospective, unblinded observational study in the ED of a university teaching hospital. Subjects with acute undifferentiated agitation refractory to verbal de-escalation were assigned to receive a combination of either haloperidol 5 mg/lorazepam 2 mg or droperidol 5 mg/midazolam 5 mg IM. The primary outcome was the proportion of patients adequately sedated at 10 min defined as ED Sedation Assessment Tool (SAT) score of 0 or less. Secondary outcomes included change in ED SAT score at 5, 15, 30, and 60 min, the need for oxygen supplementation, and the need for airway intervention.
RESULTS
A total of 86 patients were enrolled in the study, with 43 patients receiving droperidol/midazolam and 43 patients receiving haloperidol/lorazepam. Ten minutes after receiving medication, 51.2% of patients in the droperidol/midazolam group were adequately sedated compared to 7% of patients in the haloperidol/lorazepam group (OR: 14; 95% CI: 3.7, 52.1). Median time to adequate sedation was 10 min for the droperidol/midazolam group and 30 min for the haloperidol/lorazepam group. Eleven patients (25.6%) in the droperidol/midazolam group received oxygen supplementation compared to four patients (9.3%) in the haloperidol/lorazepam group. No study patients experienced extrapyramidal symptoms or required endotracheal intubation.
CONCLUSION
Intramuscular droperidol/midazolam was superior to intramuscular haloperidol/lorazepam in achieving adequate sedation at 10 min. Patients in the droperidol/midazolam arm may be more likely to receive oxygen supplementation than those in the haloperidol/lorazepam arm.
Topics: Antipsychotic Agents; Droperidol; Emergency Service, Hospital; Haloperidol; Humans; Lorazepam; Midazolam; Prospective Studies; Psychomotor Agitation
PubMed: 35287091
DOI: 10.1016/j.ajem.2022.02.042 -
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