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The cannabinoid receptor 1 (CB ) is the principal target of the psychoactive constituent of marijuana, the partial agonist Δ -tetrahydrocannabinol (Δ -THC). Here we report two agonist-bound crystal structures of human CB in complex with a tetrahydrocannabinol (AM11542) and a hexahydrocannabinol (AM841) at 2.80 Å and 2.95 Å resolution, respectively. The two CB -agonist complexes reveal important conformational changes in the overall structure, relative to the antagonist-bound state, including a 53% reduction in the volume of the ligand-binding pocket and an increase in the surface area of the G-protein-binding region. In addition, a 'twin toggle switch' of Phe200 and Trp356 (superscripts denote Ballesteros-Weinstein numbering) is experimentally observed and appears to be essential for receptor activation. The structures reveal important insights into the activation mechanism of CB and provide a molecular basis for predicting the binding modes of Δ -THC, and endogenous and synthetic cannabinoids. The plasticity of the binding pocket of CB seems to be a common feature among certain class A G-protein-coupled receptors. These findings should inspire the design of chemically diverse ligands with distinct pharmacological properties.

The primary objective of this study was to examine the common usage patterns of droperidol in the relatively unrestricted environment of an urban, academic medical center. We focused specifically on the most common use of droperidol in our department: patients with a chief complaint of abdominal pain, nausea, and/or vomiting. For this retrospective, observational, single-center study, we extracted records of all administrations of droperidol from August 2019 to August 2020. Patients with a chief complaint of abdominal pain, nausea, or vomiting, or any combination thereof, were included in data analysis. Between April 2019 to August 2020, 830 discrete patient visits involving droperidol administration were identified, comprising 706 patients. The average age was 39 years old with a range of 15 to 80. Seven patients (0.08%) were younger than 18, and 35 (4%) were older than 65. Five hundred sixty-five patients (68%) were female. Droperidol doses ranged from 0.625 mg to 5 mg intravenous (IV), with a median dose of 0.625 mg (interquartile range 0.625–1.25 mg), with 590 patients (71%) receiving a dose of 0.625 mg. Only 19 patients (2.3%) had a documented adverse event. Seven had akathisia or restlessness, 7 had anxiety or agitation, 3 had dystonia or stiffness, 1 had fatigue, and 1 had dizziness. For the entire cohort, there were no cardiac dysrhythmias, syncope, seizures, other major adverse events, or fatalities recorded. At one institution, droperidol is being used commonly for the chief complaints of abdominal pain, nausea, and/or vomiting. The preferred dosing is nearly universally below the 2.5 mg IV dose for which the FDA warning applies. Similar to previous studies, identification of adverse events was rare, and no major adverse outcomes such as dysrhythmia or death were identified. •The indications for which droperidol is commonly used are abdominal pain, nausea, and vomiting.•Droperidol is commonly being used at doses well below the dose for which the FDA black box warning applies.•Side effects of IV droperidol at commonly used doses are both rare and minor.•No major side effects, including no deaths, associated with droperidol were noted in this study.

This study sought to assess the cardiorespiratory safety of parenteral olanzapine and benzodiazepine combination treatment compared to parenteral droperidol or haloperidol and benzodiazepine combination treatment. This was a retrospective chart review conducted in adult emergency department patients who received intramuscular (IM) or intravenous (IV) droperidol, haloperidol, or olanzapine within one hour of IM or IV benzodiazepine. Patients were stratified into groups based on whether they received either olanzapine in combination with a benzodiazepine (n = 48) or droperidol or haloperidol in combination with a benzodiazepine (n = 48). Patients in each group had a decrease in their systolic blood pressure (SBP) after IM/IV olanzapine and IM/IV droperidol or haloperidol when used in combination with an IM/IV benzodiazepine ((Olanzapine + benzodiazepine (mmHg), median (IQR): Pre-SBP: 132 (117–151) vs. Post-SBP: 117 (99–131), p < 0.01) (Droperidol or haloperidol + benzodiazepine (mmHg), median (IQR): Pre-SBP: 138 (122–149) vs. Post-SBP: 106 (98–127), p < 0.01)). Both groups had similar percent SBP decreases post-combination treatment (Olanzapine + benzodiazepine (15.6 %) vs. Droperidol or haloperidol + benzodiazepine (15.2 %); p = 0.55). We did not observe any statistically significant between group differences for hypotension (Olanzapine + benzodiazepine: 1/48, 2.1 % vs. Droperidol or haloperidol + benzodiazepine: 3/48, 6.3 %; p = 0.62)), escalation in oxygen requirements (Olanzapine + benzodiazepine: 7/48, 14.6 %) vs. Droperidol or haloperidol + benzodiazepine: 5/48, 10.4 %; p = 0.76)), or intubation due to cardiorespiratory depression (Olanzapine + benzodiazepine: 0/0, 0 % vs. Droperidol or haloperidol + benzodiazepine: 0/0, 0 %; p = 1.00)). This study found decreases in SBP after administering parenteral olanzapine and parenteral droperidol or haloperidol in combination with a parenteral benzodiazepine. The percent change in SBP and the frequency of hypotensive episodes post-combination treatment were not different between groups. There were also no differences between groups in need of increased oxygen requirements post-combination treatment or need for intubation due to cardiorespiratory depression. This study suggests parenteral olanzapine in combination with a parenteral benzodiazepine may have comparable cardiorespiratory safety versus parenteral droperidol or haloperidol in combination with a parenteral benzodiazepine when treating agitation in the adult ED.

Background Droperidol is a first-generation antipsychotic medication that has been used for various indications in the emergency department (ED); however, its use has been controversial due to reports of QT prolongation and the risk of torsades de pointes (TdP). The aim of the study is to evaluate the safety of droperidol administration in the ED. Methods This was a retrospective study, conducted at an academic level I trauma center. System-generated reports were used to identify all droperidol administrations in the ED from the time that droperidol was reintroduced to the institutional formulary on July 1, 2019 through January 31, 2023. The major safety endpoint was a composite of the incidence of QTc interval prolongation, incidence of TdP, ventricular arrhythmia, or hypotension. Results A total of 327 administrations of droperidol were identified in 245 patients in the ED. The composite safety endpoint occurred in 30 (9.1%) administrations. None of these events were classified as “probable” or “definite” on the Naranjo adverse drug reaction probability scale. No episodes of TdP or serious ventricular arrhythmia were reported. Higher cumulative droperidol dose and creatinine clearance < 60 mL/min were associated with an increased odds of developing QTc prolongation (OR 1.27 [CI 1.04–1.56]) and (OR 1.01 [CI 1.0-1.02]), respectively. Conclusions The study supports the use of low dose droperidol for various indications in the ED. There were no serious adverse events reported that could be directly attributed to droperidol use; however, it is crucial to consider the potential dose dependent impact on QTc prolongation.

Droperidol is a dopamine-2 receptor antagonist in the class of butyrophenone antipsychotics with antiemetic, sedative, analgesic, and anxiolytic properties. In the postoperative setting, droperidol provides an opioid sparing effect and decreases nausea/vomiting. Another butyrophenone antipsychotic, haloperidol, has been shown to reduce morphine milliequivalents (MME) administered when used for abdominal pain in the emergency department (ED). The purpose of this study is to evaluate if the use of droperidol for undifferentiated abdominal pain reduces the amount of MME administered in the ED. This retrospective, single-center study included patients ≥18 years old who presented to the ED for undifferentiated abdominal pain. Patients must have had two separate encounters for abdominal pain, one encounter where they received droperidol and one encounter where they did not receive droperidol but did receive an opioid. The primary outcome was the difference in MME administered between the two separate patient encounters. Secondary outcomes included utilization rates of rescue antiemetics, rescue analgesics, admission to the hospital, hospital length of stay, and adverse effects (including arrhythmias and extrapyramidal symptoms). Fifty patients with self-matched encounters were evaluated. A majority of the patients were female (33/50, 66 %) with a median age of 38 years old. All doses of droperidol were intravenous and the majority of patients received a dose of 2.5 mg (34/50, 68 %; range 1.25–5 mg). Non-droperidol encounters received significantly more MME compared to droperidol encounters (19.4 MME [IQR 12–30] vs 10 MME [IQR 0–20], p-value 0.0002). There were no statistically significant differences between the secondary outcomes. Among patients presenting to the ED for abdominal pain, droperidol administration resulted in a significant reduction in MME administration. Future research should include prospective studies, comparison of droperidol to haloperidol, and investigate droperidol use beyond the ED for these encounters.

Abstract Pheochromocytomas/paragangliomas are characterized by a unique molecular landscape that allows their assignment to clusters based on underlying genetic alterations. With around 30% to 35% of Caucasian patients (a lower percentage in the Chinese population) showing germline mutations in susceptibility genes, pheochromocytomas/paragangliomas have the highest rate of heritability among all tumors. A further 35% to 40% of Caucasian patients (a higher percentage in the Chinese population) are affected by somatic driver mutations. Thus, around 70% of all patients with pheochromocytoma/paraganglioma can be assigned to 1 of 3 main molecular clusters with different phenotypes and clinical behavior. Krebs cycle/VHL/EPAS1-related cluster 1 tumors tend to a noradrenergic biochemical phenotype and require very close follow-up due to the risk of metastasis and recurrence. In contrast, kinase signaling–related cluster 2 tumors are characterized by an adrenergic phenotype and episodic symptoms, with generally a less aggressive course. The clinical correlates of patients with Wnt signaling–related cluster 3 tumors are currently poorly described, but aggressive behavior seems likely. In this review, we explore and explain why cluster-specific (personalized) management of pheochromocytoma/paraganglioma is essential to ascertain clinical behavior and prognosis, guide individual diagnostic procedures (biochemical interpretation, choice of the most sensitive imaging modalities), and provide personalized management and follow-up. Although cluster-specific therapy of inoperable/metastatic disease has not yet entered routine clinical practice, we suggest that informed personalized genetic-driven treatment should be implemented as a logical next step. This review amalgamates published guidelines and expert views within each cluster for a coherent individualized patient management plan. Graphical Abstract Graphical Abstract

Haloperidol and droperidol are antipsychotic medications with multimodal pharmacodynamic effects making them useful in the emergency department (ED). Data suggests that droperidol and haloperidol may reduce morphine milliequivalents (MME) administered when used for undifferentiated abdominal pain (UAP) in the ED. However, there is a paucity of data comparing the two agents in this cohort. The purpose of this study was to assess the efficacy of haloperidol versus droperidol in reducing MME requirements for UAP in the ED. This retrospective, single-center study included patients ≥18 years old who presented to the ED for UAP. Patients were excluded if they required urgent surgery or received haloperidol or droperidol for agitation. The primary outcome was the difference in MME administered in the ED between patients who received haloperidol versus droperidol. Secondary outcomes included rates of rescue antiemetics, rescue analgesics, admission to the hospital, hospital length of stay, and adverse effects. A total of 100 patients were evaluated, with 50 patients receiving haloperidol and 50 patients receiving droperidol. Patients in the haloperidol group received a lower median MME compared to those in the droperidol group (0 MME [IQR 0–10] vs 10 MME [IQR 0–20], p-value 0.033). There was no statistical difference between secondary outcomes evaluated, including safety events. Haloperidol was associated with a significant reduction in MME administration compared to droperidol for UAP in the ED. Large high-quality data sets are needed to confirm haloperidol's role in multimodal pain management of UAP compared to droperidol.

Gastroparesis is a syndrome of delayed gastric emptying without obstruction. There are high rates of Emergency Department (ED) visits due to gastroparesis, and this chronic disease is difficult to treat which often leads to hospital admissions. This study aimed to evaluate the impact droperidol administration has on opioid therapy, symptom relief, co-administration of antiemetic and prokinetic medications, disposition, cost, and length of stay (LOS) of patients presenting to the ED. A total of 431 patients were identified and 233 met the inclusion criteria. Droperidol administration reduced the number of patients requiring opioid therapy (108/233 [46%] vs 139/233 [60%], P-value 0.0040), reduced patient-reported pain scales by 4 points, and reduced antiemetic therapy requirement (140/233 [60%] vs 169/233 [73%], P-value 0.0045). No differences were found in terms of ED LOS (Median 6 h [IQR 4–8] vs 5 h [IQR 4–9], P-value 0.3638), hospital LOS (Median 6 h [IQR 4–30 vs 7 h [IQR 4–40], P-value 0.8888), hospital admission rates (67/233 [29%] vs 71/233 [31%], P-value 0.6101), ED cost to the facility (Median $1462 [IQR $1114 - $1986] vs $1481 [IQR $1034 - $2235], P-value 0.0943), or hospital cost (Median $4412 [IQR $2359 - $9826] vs $4672 [IQR $2075 - $9911], P-value 0.3136). In patients with gastroparesis presenting to the ED, droperidol reduced opioid use, improved pain control, and decreased antiemetic use without any differences in MME per dose, length of stay, hospital admission rate, or cost.

Background: The dopamine D2/D3 antagonist amisulpride has demonstrated its superiority and efficacy in prophylaxis of postoperative nausea and vomiting (PONV). Given the branded intravenous amisulpride (Barhemsys[R]) has not been approved in China, there is unmet clinical need for amisulpride. Our primary objective was to ascertain the efficacy and safety of the generic intravenous amisulpride (QLG2069) in the prophylaxis of PONV. Methods: In this phase III, multicenter, randomized, double-blind, placebo-controlled study, 551 adult Chinese patients (with [greater than or equal to]2 Apfel risk factors for PONV) undergoing elective laparoscopic gynecological or abdominal surgery were randomly allocated in a 1:1 ratio to receive either generic intravenous amisulpride or placebo. The primary endpoint was the complete response (CR) rate, defined as the proportion of patients demonstrating neither emetic episodes (vomiting/retching) nor requiring rescue antiemetics throughout the 24-hour postoperative window. Results: Totally, 542 patients (amisulpride group: n=275; placebo group: n=267) were included in the full analysis set. Amisulpride demonstrated significantly higher CR rate compared to placebo (53.82% vs 40.07%; P=0.0011) within 24-h postoperative period. Patients treated with intravenous amisulpride exhibited significantly lower incidence of moderate-to-severe nausea (28.36% vs 37.08%; P=0.0266) and emesis (44.73% vs 57.30%; P=0.0030) compared to the incidence in the placebo group. The proportion of patients without nausea was numerically higher (45.09%) in the amisulpride group compared to that in the placebo group (37.45%), although the difference did not reach statistical significance (P=0.0685). No significant difference in the proportions of patients receiving rescue medication was noticed between the two groups (21.09% vs 28.09%; P=0.0569). The incidence of adverse events were comparable in two groups. Conclusion: The generic intravenous amisulpride was safe and effective in prophylaxis of PONV in Chinese patients with moderateto-high risk of PONV to were undergoing laparoscopic gynecological or abdominal surgery. Keywords: generic intravenous amisulpride, postoperative nausea and vomiting, complete response

Agitation and aggression are significant problems in acute psychiatric units. There is little consensus on which drug is most effective and safest for sedation of these patients. To compare the effectiveness and safety of haloperidol v. droperidol for patients with agitation and aggression. In a masked, randomised controlled trial (ACTRN12611000565943) intramuscular droperidol (10 mg) was compared with intramuscular haloperidol (10 mg) for adult patients with acute behavioural disturbance in a psychiatric intensive care unit. The primary outcome was time to sedation within 120 min. Secondary outcomes were use of additional sedation, adverse events and staff injuries. From 584 patients, 110 were randomised to haloperidol and 118 to droperidol. Effective sedation occurred in 210 (92%) patients within 120 min. There was no significant difference in median time to sedation: 20 min (interquartile range 15-30, range 10-75) for haloperidol v. 25 min (IQR 15-30, range 10-115) for droperidol (P = 0.89). Additional sedation was used more often with haloperidol (13% v. 5%, P = 0.06), but adverse effects were less common with haloperidol (1% v. 5%, P = 0.12). There were 8 staff injuries. Both haloperidol and droperidol were effective for sedation of patients with acute behavioural disturbance.