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Purpose: Perioperative shivering is common and can occur as a result of hypothermia or changes in the threshold of thermoregulation. Droperidol usage for anesthesia is currently limited to its sedative and antiemetic effects. We investigated the effects of high and low doses of droperidol on the shivering threshold in rabbits., Methods: Forty-two male Japanese white rabbits were anesthetized with isoflurane and randomly assigned to the control, high-dose, or low-dose group. Rabbits in the high-dose group received a 5 mg/kg droperidol bolus followed by continuous infusion at 5 mg/kg/h, those in the low-dose group received a 0.5 mg/kg droperidol bolus, and those in the control group received the same volume of saline as the high-dose group. Body temperature was reduced at a rate of 2-3 °C/h, and the shivering threshold was defined as the subject's core temperature (°C) at the onset of shivering., Results: The shivering thresholds in the control, high-dose, and low-dose groups were 38.1 °C ± 1.1 °C, 36.7 °C ± 1.2 °C, and 36.9 °C ± 1.0 °C, respectively. The shivering thresholds were significantly lower in the high-dose and low-dose groups than in the control group (P < 0.01). The thresholds were comparable between the high-dose and low-dose groups., Conclusions: Droperidol in high and low doses effectively reduced the shivering threshold in rabbits. Droperidol has been used in low doses as an antiemetic. Low doses of droperidol can reduce the incidence of shivering perioperatively and during the induction of therapeutic hypothermia., (© 2023. The Author(s) under exclusive licence to Japanese Society of Anesthesiologists.)

Lung fibrosis is characterized by abnormal accumulation of Thy-deficient fibroblasts in the interstitium of the alveolar space. We have previously shown in bleomycin-treated chimeric Thy1-deficient mice with wild-type lymphocytes that Thy1-deficient fibroblasts accumulate and promote fibrosis and an "inflammation-free" environment. Here, we aimed to identify the critical effects of Thy1, or the absence of Thy1, in lung myofibroblast profibrotic functions, particularly proliferation and collagen deposition. Using specific Thy1 siRNA in Thy1-positive cells, Thy1 knockout cells, Thy1 cDNA expression vector in Thy1-deficient cells, and Thy1 cross-linking, we evaluated cell proliferation (assessed by cell mass and BrdU uptake), differentiation (using immunofluorescence), and collagen deposition (using Sircol assay). We found that myofibroblast Thy1 cross-linking and genetic manipulation modulate cell proliferation and expression of Fgf (fibroblast growth factor) and Angtl (angiotensin) receptors (using qPCR) that are involved in myofibroblast proliferation, differentiation, and collagen deposition. In conclusion, lung myofibroblast downregulation of Thy1 expression is critical to increase proliferation, differentiation, and collagen deposition.

The cannabinoid receptor 1 (CB 1 ) is the principal target of the psychoactive constituent of marijuana, the partial agonist Δ 9 -tetrahydrocannabinol (Δ 9 -THC). Here we report two agonist-bound crystal structures of human CB 1 in complex with a tetrahydrocannabinol (AM11542) and a hexahydrocannabinol (AM841) at 2.80 Å and 2.95 Å resolution, respectively. The two CB 1 -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 3.36 and Trp356 6.48 (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 1 and provide a molecular basis for predicting the binding modes of Δ 9 -THC, and endogenous and synthetic cannabinoids. The plasticity of the binding pocket of CB 1 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.

Background and Objective: Droperidol and ondansetron prolong QT interval, a circumstance that has raised some concerns regarding the possibility of inducing torsades de pointes (TdP). However drug-induced spatial dispersion of ventricular repolarization has been shown to be the principal arrhythmogenic substrate for TdP. The aim of this study is to explore the effects of droperidol and ondansetron on the dispersion of repolarization, measured using the T peak-to-end interval (Tp-e) and Tp-e/QT and Tp-e/RR(1/2) ratios in surgical anesthetized patients., Methods: A randomized, double-blind study carried out on sixty-three adult patients without cardiac disease or factors favoring QT prolongation and undergoing non-cardiac surgery were randomly assigned to the droperidol or ondansetron group. Under propofol anesthesia, a 12-lead EKG was obtained, and 1.25mg droperidol or 4mg ondansetron was injected. Five minutes later, a new 12-lead EKG was recorded. EKG analyses were independently performed by two cardiologists blinded to the state of the traces or group allocation. QT, RR and Tp-e intervals were measured by averaging five successive beats in leadII (QT) or V5 (Tp-e). The mean value for each measurement was calculated for statistical analysis., Results: Thirty-two patients (19 women) received droperidol, and 31 (22 women) ondansetron. Droperidol and ondansetron prolonged the QTcF interval (Fridericia formula) by 6.8 and 7.2ms (mean values) respectively, but neither droperidol nor ondansetron increased the Tp-e interval or Tp-e/QT and Tp-e/RR(1/2) ratios., Conclusion: At antiemetic doses, neither ondansetron (4mg) nor droperidol (1.25mg) increases the dispersion of ventricular repolarization in healthy adult patients anesthetized with propofol., (Copyright © 2014 Sociedad Española de Anestesiología, Reanimación y Terapéutica del Dolor. Publicado por Elsevier España, S.L.U. All rights reserved.)

A patient developed acute dystonia following intravenous administration of metocroplamide 20 mg. A 34-year-old woman underwent right hepatectomy, under general anesthesia managed with desflurane, remifentanil, and rocuronium. At the start of surgery, droperidol 1.5 mg was given intravenously for anti-emetic prophylaxis. Operation was completed uneventfully. Intravenous patient-controlled analgesia (i.v.-PCA) with fentanyl, containing droperidol, was selected for postoperative pain management The patient showed a reasonable postoperative course; however, around 15 hours post-operatively, she complained of nausea, although droperidol 2.625 mg had been administrated (maximum dose). Nausea subsequently disappeared following intravenous metocroplamide 20 mg, and i.v.-PCA was terminated. The patient gradually complained of excessive sleepiness. Finally, she showed akinesis and bilateral oculomotor disturbance 140 minutes after metocroplamide administration. However, her vital signs remained stable. Examinations including magnetic resonance imaging, electroencephalogram, and blood test did not show abnormalities. She was diagnosed with acute dystonia. She recovered without medications 300 minutes after the onset of akinesis. She could communicate with her eyes, opening/closing, throughout this episode. The effects of antiemetics acting on different receptors are additive. However, we should remember that coadministration of metocroplamide and butyrophenone induces extrapyramidal signs like acute dystonia. Intraoperative management extending beyond postoperative antiemetic therapy is necessary.

We have studied the effects of chlorpromazine, acepromazine, droperidol, and transcranial electroanesthesia upon evacuation function of the stomach in piglets and the effects of leu-enkephalin and glycyl-proline upon secretory activity of the stomach in dogs and rats during surgical stress to optimize anesthetic dosage. All pharmaceutical and nonpharmaceutical methods of anesthesia used in the experiments were implemented by actiovating stress-limiting systems in post-operational period. Leu-enkephalin, apart from stimulating the stress-limiting factors of neurohumoral systems of the organism, shifted the vector ratio of aggressive and protective factors of gastric mucosa toward strengthening of the latter. The opposite trends of changes in the secretory activity of the stomach of rats in response to surgical stress can be leveled using glycyl-proline as a component of anesthesia.

The study aimed at validating an increasing-temperature water bath suitable for determining the noxious heat threshold for use in mice. The noxious heat threshold was determined by immersing the tail of the gently held awake mouse into a water container whose temperature was near-linearly increased at a rate of 24°C/min. until the animal withdrew its tail, that is, heating attained the noxious threshold. The effects of standard analgesic, neuroleptic and anxiolytic drugs were investigated in a parallel way on both the noxious heat threshold and the psychomotor activity assessed by the open field test. Morphine, diclofenac and metamizol (dipyrone) elevated the heat threshold of mice with minimum effective doses of 6, 30 and 1000 mg/kg i.p., respectively. These doses of morphine and diclofenac failed to induce any remarkable effect on psychomotor activity in the open field test while that of metamizol exerted a profound inhibition. The anxiolytic diazepam and the neuroleptic droperidol at doses evoking a mild and moderate, respectively, psychomotor inhibition failed to alter the heat threshold. Combination of a subliminal dose of morphine (regarding both antinociceptive and psychomotor inhibitory action) with diclofenac, metamizol, diazepam or droperidol at doses also subliminal regarding the thermal antinociceptive effect elevated the noxious heat threshold without major additional effects in the open field test. It is concluded that the increasing-temperature water bath is suitable for studying the thermal antinociceptive effects of morphine and diclofenac as well as the morphine-sparing action of diclofenac, metamizol, droperidol and diazepam. Behavioural testing is recommended when testing analgesics., (© 2013 Nordic Pharmacological Society. Published by John Wiley & Sons Ltd.)

N-methyl-d-aspartate (NMDA) receptors can be inhibited by inhalational anesthetics in vitro at clinically relevant concentrations. Here, to clarify the role of NMDA receptors in anesthetic-induced unconsciousness, we examined the hypnotic properties of isoflurane, sevoflurane and nitrous oxide in NMDA receptor GluN2A subunit knockout mice. The hypnotic properties of inhalational anesthetics were evaluated in mice in the loss of righting reflex (LORR) assay by measuring the 50% concentration for LORR (LORR ED(50)). Knockout mice displayed isoflurane and sevoflurane LORR ED(50) values similar to wild-type controls, indicating no significant contribution of these receptors to the hypnotic action of halogenated anesthetics. However, compared with wild-type controls, mutant mice displayed larger isoflurane LORR ED(50) values in the presence of nitrous oxide, indicating a resistance to this gaseous anesthetic. Knockout mice have enhanced brain monoaminergic activity which occurs secondary to NMDA receptor dysfunction, and the observed resistance to the isoflurane LORR ED(50)-sparing effect of nitrous oxide could be abolished by pretreatment with the dopamine D(2) receptor antagonist droperidol or with the serotonin 5-HT(2A) receptor antagonist ketanserin. Thus, resistance to nitrous oxide in knockout mice appears to be a secondary phenomenon of monoaminergic origin and not a direct result of impaired NMDA receptor function. Our results indicate that NMDA receptors are not critically involved in the hypnotic action of conventionally-used inhalational anesthetics. Also, they suggest that increased brain monoaminergic tone can diminish the effects of general anesthesia. Finally, they provide further evidence that changes secondary to genetic manipulation can explain the results obtained in global knockouts., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Although accumulating evidence suggests that arousal pathways in the brain play important roles in emergence from general anesthesia, the roles of monoaminergic arousal circuits are unclear. In this study, the authors tested the hypothesis that methylphenidate (an inhibitor of dopamine and norepinephrine transporters) induces emergence from isoflurane general anesthesia., Methods: Using adult rats, the authors tested the effect of intravenous methylphenidate on time to emergence from isoflurane general anesthesia. They then performed experiments to test separately for methylphenidate-induced changes in arousal and changes in minute ventilation. A dose-response study was performed to test for methylphenidate-induced restoration of righting during continuous isoflurane general anesthesia. Surface electroencephalogram recordings were performed to observe neurophysiological changes. Plethysmography recordings and arterial blood gas analysis were performed to assess methylphenidate-induced changes in respiratory function. Intravenous droperidol was administered to test for inhibition of methylphenidate's actions., Results: Methylphenidate decreased median time to emergence from 280 to 91 s. The median difference in time to emergence without methylphenidate compared with administration of methylphenidate was 200 [155-331] s (median, [95% CI]). During continuous inhalation of isoflurane, methylphenidate induced return of righting in a dose-dependent manner, induced a shift in electroencephalogram power from delta (less than 4 Hz) to theta (4-8 Hz), and induced an increase in minute ventilation. Administration of intravenous droperidol (0.5 mg/kg) before intravenous methylphenidate (5 mg/kg) largely inhibited methylphenidate-induced emergence behavior, electroencephalogram changes, and changes in minute ventilation., Conclusions: Methylphenidate actively induces emergence from isoflurane general anesthesia by increasing arousal and respiratory drive, possibly through activation of dopaminergic and adrenergic arousal circuits. The authors' findings suggest that methylphenidate may be useful clinically as an agent to reverse general anesthetic-induced unconsciousness and respiratory depression at the end of surgery.

Background: Droperidol is a highly potent butyrophenone used for the therapy of postoperative nausea and vomiting. Its cardiac safety in cardiovascular-healthy patients and those with long QT (LQT) syndrome is a matter of debate. In this study, we investigated whether droperidol has subtype-specific effects in cellular and computational models of LQT syndrome., Methods: Left ventricular cardiac myocytes were isolated from adult guinea pig hearts. LQT1-like behavior was pharmacologically induced by chromanol 293B (10 micromol/L) and LQT2-like states by E4031 (10 micromol/L). Computational analysis was performed using the Luo-Rudy dynamic model. Data are given as mean + or - SEM., Results: In control myocytes, droperidol lengthened action potentials in a concentration-dependent manner with a maximal prolongation of 37% + or - 13% (n = 4) at a concentration of 0.6 micromol/L. In LQT1-like myocytes, droperidol (0.6 micromol/L) further prolonged action potentials by 31% + or - 6% (n = 6) but shortened action potentials of LQT2-like myocytes by 11% + or - 2% (n = 8). Computational modeling supported the concept that droperidol, in addition to the rapid component of the delayed K(+) current, blocks depolarizing targets, such as the L-type Ca(2+) current, the Na(+)-Ca(2+) exchanger, and the Na(+)-K(+) adenosine triphosphatase., Conclusions: Droperidol has more detrimental effects on cardiac repolarization of LQT1-like than of LQT2-like myocytes suggesting subtype-specific cardiotoxic effects in patients with LQT syndrome. The subtype specificity of droperidol seems to be caused by a complex interaction of droperidol with several different molecular targets. This interaction deserves further investigation to establish the feasibility of a subtype-directed approach in the perioperative management of patients with LQT syndrome.

Background: Acute behavioural disturbance (ABD) is an increasing problem in emergency departments. This study aimed to determine the impact of a structured intramuscular (IM) sedation protocol on the duration of ABD in the emergency department., Methods: A historical control study was undertaken comparing 58 patients who required physical restraint and parenteral sedation with the structured IM sedation protocol, to 73 historical controls treated predominantly by intravenous sedation, according to individual clinician preference. The primary outcome was the duration of the ABD defined as the time security staff were required. Secondary outcomes were the requirement for additional sedation, drug related-adverse effects and patient and staff injuries., Results: The median duration of the ABD in patients with the new sedation protocol was 21 minutes (IQR: 15 to 35 minutes; Range: 5 to 78 minutes) compared to a median duration of 30 minutes (IQR: 15 to 50 minutes; Range: 5 to 135 minutes) in the historical controls which was significantly different (p = 0.03). With IM sedation only 27 of 58 patients (47%; 95% CI: 34% to 60%) required further sedation compared to 64 of 73 historical controls (88%; 95%CI: 77% to 94%). There were six (10%) drug-related adverse events with the new IM protocol [oxygen desaturation (5), oxygen desaturation/airway obstruction (1)] compared to 10 (14%) in the historical controls [oxygen desaturation (5), hypoventilation (4) and aspiration (1)]. Injuries to staff occurred with three patients using the new sedation protocol and in seven of the historical controls. Two patients were injured during the new protocol and two of the historical controls., Conclusion: The use of a standardised IM sedation protocol was simple, more effective and as safe for management of ABD compared to predominantly intravenous sedation.

Dopamine (DA) regulates pain perception in the central nervous system (CNS). However, the mechanism of the action of DA in pain-related neurons of the parafascicular nucleus (Pf) is not clear. The present study aimed to determine the effect of DA and its receptor antagonist, droperidol on the pain-evoked responses of the pain-excited neurons (PEN) and pain-inhibited neurons (PIN) in the Pf of rats and to analyze the mechanisms underlying this effect. The trains of electric impulses applied to the sciatic nerve were used as noxious stimulation. The discharges of PEN and PIN in the Pf were recorded by using a glass microelectrode. The results showed that, in the Pf, intra-Pf microinjection of DA (5 microg/0.5 microl) increased the frequency of noxious stimulation-induced discharges of the PEN and decreased the frequency of those of the PIN, while the intra-Pf administration of droperidol (0.15 microg/0.5 microl) produced an opposite effect. On the basis of the above-mentioned findings, we could conclude that DA and its receptors in the Pf are involved in the modulation of the nociceptive response by regulating the discharges of PEN and PIN.

Background: Until recently, the N-methyl-D-aspartate (NMDA) receptor was considered to possibly mediate the immobility produced by inhaled anesthetics such as isoflurane and nitrous oxide. However, new evidence suggests that the role of this receptor in abolition of the movement response may be less important than previously thought. To provide further evidence supporting or challenging this view, we examined the anesthetic potencies of isoflurane and nitrous oxide in genetically modified animals with established NMDA receptor dysfunction caused by GluRepsilon1 subunit knockout., Methods: The immobilizing properties of inhaled anesthetics in mice quantitated by the minimum alveolar anesthetic concentration (MAC) were evaluated using the classic tail clamp method., Results: Compared with wild-type controls, NMDA receptor GluRepsilon1 subunit knockout mice displayed larger isoflurane MAC values indicating a resistance to the immobilizing action of isoflurane. Knockout mice were previously shown to have enhanced monoaminergic tone as a result of genetic manipulation, and this increase in MAC could be abolished in our experiments by pretreatment with the serotonin 5-hydroxytryptamine type 2A receptor antagonist ketanserin or with the dopamine D2 receptor antagonist droperidol at doses that did not affect MAC values in wild-type animals. Mutant mice also displayed resistance to the isoflurane MAC-sparing effect of nitrous oxide, but this resistance was similarly abolished by ketanserin and droperidol. Thus, resistance to the immobilizing action of inhaled anesthetics in knockout mice seems to be secondary to increased monoaminergic activation after knockout rather than a direct result of impaired NMDA receptor function., Conclusions: Our results confirm recent findings indicating no critical contribution of NMDA receptors to the immobility induced by isoflurane and nitrous oxide. In addition, they demonstrate the ability of changes secondary to genetic manipulation to affect the results obtained in global knockout studies.

Sedation for gastrointestinal endoscopies is obtained by opioids, benzodiazepines, propofol, ketamine and/or droperidol. The pharmacokinetic profile of some sedatives/anesthetics renders them advantageous over others. Opioids, mainly pethidine and fentanyl, are the most popular. Though newer opioids provide a faster recovery, fentanyl is safe and advantageous due to its lower cost. Remifentanil, due to its pharmacokinetic profile (elimination half-life: 9 min), is advantageous for ambulatory patients, though it is not known whether the high cost compensates the benefits. Midazolam is the benzodiazepine of choice as it has a shorter duration of action and a better pharmacokinetic profile than diazepam. Propofol, an intravenous anesthetic, has become very popular for gastrointestinal endoscopies in sedative doses. The opioid and benzodiazepine antagonists, naloxone and flumazenil, are indicated only in particular circumstances, like deep sedation with threatening respiratory depression. Ketamine and droperidol are not popular agents for sedation in the modern endoscopic practice., (Copyright 2010 S. Karger AG, Basel.)

Droperidol and ondansetron are potent anti-emetic agents which are often administered together. Although both drugs prolong QT interval in man by inhibition of Human Ether-a-go-go Related Gene-coded potassium channels, only droperidol was tested using more integrated experimental models. Therefore, we studied the effects of both compounds and their combination on action potentials (AP) of rabbit Purkinje fibers using conventional intracellular glass microelectrode. Purkinje fibers, driven at 1 Hz, were exposed to increasing concentrations (from 0.001 to 10 microm) of droperidol (n = 7) or ondansetron (n = 8) at 30 min intervals at 36.5 degrees C. Other fibers were exposed to a constant droperidol concentration (0.1 microm) alone (n = 7) or together with the same increasing concentrations of ondansetron (n = 6). Droperidol increased AP duration measured at 90% repolarization (APD90) in a concentration-dependent manner from 4.4 +/- 0.8% (mean +/- SEM) after 1 nm to a maximum of 158 +/- 72% after 1 microm. Ondansetron significantly increased APD90 by 5.3 +/- 2.1% at 100 nm up to 76 +/- 14% after 10 microm. Early after-depolarization occurred in 6/7 fibers exposed to droperidol and 1/8 fibers exposed to ondansetron. When given together, pure additive effects were observed. The concentrations that increased APD90 by 50% were 0.25 +/- 0.25 microm droperidol, 3.8 +/- 2.4 microm ondansetron and 1.5 +/- 0.8 microm ondansetron when given together with droperidol. Both ondansetron and droperidol prolong AP duration in Purkinje fibers, droperidol being 10 times more potent than ondansetron. Combination of ondansetron and droperidol exhibits an additive effect on AP duration. However, within clinically relevant concentrations, ondansetron does not further increase the AP prolongation caused by droperidol alone.

Background: Droperidol and ondansetron have previously been found to prolong the QT interval in the treatment of postoperative nausea and vomiting. However, this adverse effect has never been confirmed and compared with both drugs under controlled conditions. The objective was to study the effects of droperidol and ondansetron alone or in combination on QT interval duration in healthy subjects., Methods: Sixteen healthy volunteers, eight males and eight females, were enrolled in this prospective, double-blind, randomized, placebo-controlled study. Subjects received 1 mg droperidol, 4 mg ondansetron, 1 mg droperidol plus 4 mg ondansetron, or a placebo, intravenously in a crossover design. Fridericia-corrected QT interval (QTcF) and plasma concentrations were measured repeatedly during 10 h at each study period. The primary endpoint was the maximal placebo time-matched and baseline-subtracted QTcF prolongation (DeltaDeltaQTcF)., Results: Compared with placebo, both droperidol and ondansetron significantly prolonged the QTcF interval. DeltaDeltaQTcF prolongation was 25 +/- 8 ms after droperidol, significantly greater than the 17 +/- 10-ms prolongation with ondansetron (P = 0.014). The combination of droperidol and ondansetron significantly increased the mean maximal DeltaDeltaQTcF by 28 +/- 10 ms. The combination induced greater QTcF prolongation compared with ondansetron alone (P = 0.001), but not with droperidol alone (P = 0.33). There was no significant pharmacokinetic interaction between droperidol and ondansetron., Conclusions: Under controlled conditions, both droperidol and ondansetron either alone or in combination induced significant marked QTc interval prolongation. However, the combination of both drugs did not significantly increase QTc prolongation compared with that induced by droperidol alone.

Droperidol causes the blockage of the dopamine receptors in the central nervous system that are involved in pain transmission. However, the mechanism of action of droperidol in pain-related neurons is not clear, and it is still unknown whether opioids are involved in the modulation of this processing. The present study examines the effect of droperidol on the pain-evoked response of pain-excitation neurons (PENs) and pain-inhibition neurons (PINs) in the caudate nucleus (Cd) of rats. The trains of electric impulses applied to the sciatic nerve were used as noxious stimulation. Our results revealed that droperidol decreased the frequency of PEN discharge, and increased the frequency PIN discharge evoked by the noxious stimulation in the Cd of normal rats, while administration of droperidol to morphine-dependent rats produced the opposite response. Those demonstrated that droperidol is involved in the modulation of nociceptive information transmission in Cd, and there were completely opposite responses to painful stimulation between normal and morphine-dependent rats after administration of droperidol.

Background: Droperidol has a central antiemetic action and is widely used in the fields of psychiatry, anesthesia, and emergency medicine. It has been associated with prolongation of the QT interval of the electrocardiogram, and it may also be associated with torsades de pointes and sudden death. Although QT prolongation is consistent with droperidol-induced increases in cardiac ventricular action potential duration, the cellular mechanism for these observations has not been clearly studied. The rapidly activating delayed rectifier potassium channel, IKr, is a primary site of action of drugs causing QT prolongation and is encoded by the human-ether-a-go-go-related gene (HERG). To determine the mechanism underlying these clinical findings, we investigated the effect of droperidol on human HERG potassium channels., Methods: Wild type and mutant HERG channels were heterologously expressed in human embryonic kidney 293 cells, and the current was recorded by using whole cell patch clamp technique (22-24 degrees C)., Results: HERG tail currents following test pulses to 50 mV were inhibited by droperidol with an IC(50) of 77.3 +/- 9.6 nM (n = 8). The onset of block was fast and inhibition was completely reversible upon washout. Droperidol affected HERG channels mainly in their open and inactivated states. The effects were use-dependent with a stronger steady-state level of block at higher frequencies. The activation curve was slightly shifted towards more negative potentials (P < 0.05, n = 8) and the time course of inactivation was significantly decreased (P < 0.05, n = 8) by 100 nM droperidol. But there was no relevant effect on HERG channel deactivation. The potency for block of HERG channels by droperidol was significantly decreased with mutation of Phe-656 to Thr or mutation of Ser-631 to Ala, respectively. However, mutation of Phe-656 to Met or the double mutation F656M/S631A had no effect on channel sensitivity to block by droperidol., Conclusions: Droperidol potently inhibits transfected HERG channels and this is the probable mechanism for QT prolongation. Channel blockade shows greatest affinity for the open and inactivated state. Aromatic residue at position 656 may participate in droperidol binding, and inactivation gating can induce a conformational state that optimizes droperidol binding to the channel.

Introduction: Regulatory guidelines require investigation of the liability for delayed ventricular repolarization by new chemical entities within a broad concentration range in-vitro. However, investigation can be limited by poor drug aqueous solubility, and by solvent physicochemical attributes that disrupt cell membrane integrity. Although excipients or solubilizing agents may aid to achieve the necessary high concentrations, no comprehensive overview on the suitability of solvents for in-vitro electrophysiological safety studies exists., Methods: Excipients were tested for potential interference with the hERG (human ether-a-go-go-related gene) K(+) current (whole-cell voltage-clamp, 23+/-2 degrees C), and the shape of rabbit Purkinje fiber action potentials (conventional glass microelectrode technique, 37+/-1 degrees C)., Results and Discussion: Water-soluble complexation builders/carriers had little effect on hERG K(+) current at up to 50 mg/ml (BSA, bovine serum albumin) and 11 mg/ml (HP-beta-CD, hydroxypropyl-beta-cyclodextrin; IC(20), concentration of 20% inhibition). Water-soluble organic (co)solvents inhibited hERG K(+) currents (IC(20), %/mM): 0.7/152, ethanol; 0.9/67, Transcutol; 1.2/154, DMSO (dimethylsulfoxide); 1.6/389, acetonitrile; 1.9/48, polyethylene glycol 400; 2.1/660, methanol. Part of their inhibitory effect is attributed to the osmolality of extracellular solutions, because hERG IC(20) and extrapolated osmolality at the hERG IC(20) strongly correlate. Water-soluble non-ionic solubilizers/surfactants are potent inhibitors of hERG K(+) current with IC(20) concentrations of 0.07% (Cremophor EL) or lower (Tween 20, Tween 80: approximately 0.001%). Part of this inhibitory effect is attributed to their interaction with lipid membranes, because hERG inhibition occurs close to critical micelle concentrations (Cremophor, approximately 0.009%; Tween 20, approximately 0.007%). Purkinje fiber action potentials are little affected by HP-beta-CD at up to 2 mg/ml, while DMSO tends to shorten the action potential duration at 1%., Conclusion: When conducting electrophysiological in-vitro assessments of drug effects, solubilizers/surfactants (Cremophor EL, Tween 20, Tween 80) should be avoided. Instead, water-soluble organic (co)solvents (methanol, acetonitrile, DMSO) or complexation builders/carriers (HP-beta-CD, BSA) appear to be more favorable.

Objective: To investigate the influence of dopamine (DA) and DA receptor's antagonist on the transmission of noxious information in the central nervous system of normal rats or morphinistic rats., Methods: The influence of DA on the electric activity of the pain-excited neuron (PEN) in the caudate nucleus (Cd) of normal rats or morphinistic rats was recorded after the sciatic nerve was noxiously stimulated., Results: DA shortened the average latency of the evoked discharge of PEN in the Cd of normal rats, indicating that DA could increase the activity of PEN and pain sensitivity in normal rats. This effect could be inhibited by Droperidol. DA increased the average latency of the evoked discharge of PEN in the Cd of morphinistic rats, indicating that DA could inhibit the activity of PEN and pain sensitivity in morphinistic rats., Conclusion: The responses to painful stimulation were completely opposite between normal rats and morphinistic rats after the intracerebroventricular injection of DA.

Background: The cardiac safety of droperidol given at antiemetic doses is a matter of debate. Although droperidol potently inhibits human ether-a-go-go-related gene (HERG) channels, the molecular mode of this interaction is unknown. The role of amino acid residues typically mediating high-affinity block of HERG channels is unclear. It is furthermore unresolved whether droperidol at antiemetic concentrations induces action potential prolongation and arrhythmogenic early afterdepolarizations in cardiac myocytes., Methods: Molecular mechanisms of HERG current inhibition by droperidol were established using two-electrode voltage clamp recordings of Xenopus laevis oocytes expressing wild-type and mutant channels. The mutants T623A, S624A, V625A, Y652A, and F656A were generated by site-directed mutagenesis. The effect of droperidol on action potentials was investigated in cardiac myocytes isolated from guinea pig hearts using the patch clamp technique., Results: Droperidol inhibited currents through HERG wild-type channels with a concentration of half-maximal inhibition of 0.6-0.9 microM. Droperidol shifted the channel activation and the steady state inactivation toward negative potentials while channel deactivation was not affected. Current inhibition increased with membrane potential and with increasing duration of current activation. Inhibition of HERG channels was similarly reduced by all mutations. Droperidol at concentrations between 5 and 100 nM prolonged whereas concentrations greater than 300 nm shortened action potentials. Early afterdepolarizations were not observed., Conclusions: Droperidol is a high-affinity blocker of HERG channels. Amino acid residues typically involved in high-affinity block mediate droperidol effects. Patch clamp results and computational modeling allow the hypothesis that interaction with calcium currents may explain why droperidol at antiemetic concentrations prolongs the action potential without inducing early afterdepolarizations.

Background: Clinical studies suggest that tramadol-induced analgesia is partially antagonized by ondansetron., Aims: To investigate the type of interaction between tramadol and two anti-emetics on antinociception and gastrointestinal transit in mice., Methods: We assessed the antinociceptive (acetic acid writhing test, plantar test) and antitransit (charcoal meal) effects of tramadol individually, and combined with ondansetron or droperidol in female Swiss CD-1 mice. Isobolograms and analysis of variance were used to determine the type of interaction., Results: In the writhing test, tramadol, ondansetron and droperidol, each induced dose-related inhibition of nociception. The ED(50)'s were: tramadol 4.2+/-0.33 mg kg(-1); ondansetron 1.03+/-0.05 mg kg(-1), and droperidol 1.00+/-0.14 mg kg(-1). Dose-response curves were also obtained with tramadol combined with ondansetron or droperidol at 1:1 fixed ratios. The isobolographic analysis demonstrated antagonism for both combinations. In the plantar test, the ED(50) for tramadol was 51.4+/-2.3 mg kg(-1), but no dose-response curves could be obtained with ondansetron or droperidol individually. The interaction was assessed from dose-response curves to tramadol in the presence of a fixed dose of ondansetron (0.1 mg kg(-1)) or droperidol (0.05 mg kg(-1)). The results show antagonism between tramadol-ondansetron (p<0.05) and no interaction for the tramadol-droperidol combination. Both anti-emetics antagonized the antitransit effects of tramadol., Conclusions: The interaction of tramadol with ondansetron or droperidol on antinociception can be antagonistic or additive, depending on the type of stimuli. Both anti-emetics antagonize the anti-transit effects of tramadol. The results demonstrate antagonism between tramadol and the two anti-emetics for analgesia and inhibition of gastrointestinal transit, supporting previous clinical studies.

Background: The sigma-1 receptor is functionally linked with psychotomimetic effects of various drugs. A sigma-1 receptor agonist enhances bradykinin-induced intracellular Ca(2+) concentration ([Ca(2+)]i) increase and induces c-Fos expression in a part of the brain. The aim of this study was to investigate the effects of several intravenous anaesthetics on the sigma-1 receptor., Methods: First, using Wistar rat brains, (+)[(3)H]SKF-10,047, a selective sigma-1 receptor agonist was displaced by propofol, dexmedetomidine, droperidol, and thiopental. Second, Fura-2 loaded NG-108 cells were incubated with (+)pentazocine, a selective sigma-1 receptor agonist, and propofol and then its fluorescence was observed after stimulation with bradykinin. Third, male ICR mice received Intrafat or propofol intraperitoneally (i.p.), followed by pentazocine i.p. Brain slices were prepared and Fos-like immunoreactivity was detected using an immunohistochemical method. results: Propofol, droperidol, and dexmedetomidine displaced (+)[(3)H]SKF-10,047 binding in a concentration-dependent manner with Ki50s of 10.2 +/- 0.6, 0.17 +/- 0.03, 5.73 +/- 1.2 microM, respectively. Thiopental sodium was practically ineffective. Propofol produced a statistically significant reduction in the maximal binding capacity (Bmax) but did not affect the dissociation constant (K(d)). (+)Pentazocine significantly enhanced bradykinin-induced [Ca(2+)]i increases, but propofol did not affect it. Pentazocine induced marked Fos-LI positive cells in the posterior cingulate and retrosplenial cortices (PC/RS), which was significantly reduced by propofol., Conclusions: These results suggest that propofol may be a sigma-1 receptor antagonist, and that various effects of propofol on the brain may be mediated, at least partly, by the sigma-1 receptor.

Background: Droperidol is a known effective adjunctive agent for sedation/analgesia during endoscopic procedures, particularly in patients who are difficult to sedate with narcotics and benzodiazepines alone. However, the Food and Drug Administration (FDA) warning about potential droperidol-related fatal cardiac arrhythmias, issued in December 2001, led to concern about its safety in current clinical practice., Objective: In this study, we evaluated the effects of droperidol on the Bazett's corrected QT interval (QTcB) administered to patients undergoing ERCP and frequency of cardiac arrhythmias., Design: We retrospectively reviewed the medical records of patients who, at our institute, underwent ERCP while under sedation/analgesia and who received droperidol. Our protocol for patients who are considered to be candidates for droperidol use includes obtaining an ECG before and 1 to 3 hours after the procedure., Results: From April 2002 to October 2004, 6292 ERCPs were performed, of which 3113 patients with normal baseline QTcB (2001 women, 1112 men) received droperidol. Mean dosages were 4.3 mg (range, 1.25-10 mg) in women and 4.5 mg (range, 1.25-13.75 mg) in men. A total of 233 patients (7.48%; 133 women, 100 men) developed QTcB prolongation. Mean increases of the QTcB above the upper limit of normal were 16 milliseconds in women (range, 1-194 milliseconds) and 22 milliseconds in men (range, 1-310 milliseconds). Of these, 15 patients (0.48%; 8 women, 7 men) had marked prolongation of the QTcB (defined QTcB, >500 milliseconds). No serious dysrhythmias occurred., Conclusions: Droperidol at usual doses during sedation/analgesia may precipitate QTcB prolongation above the normal range. However, no QT-related arrhythmias were noted in this study. Clinically significant cardiac events are probably rare with droperidol, despite documented QTcB effects. Baseline electrocardiogram for excluding patients with prolonged baseline QTcB and 1 to 3 hours afterward monitoring appears adequate when using droperidol. The study is still too small to detect very infrequent arrhythmia events.

Droperidol produces the inhibition of K+ channels in cardiac myocytes. However, the effects of droperidol on K+ channels have not been studied in blood vessels. Therefore, we designed the present study to determine whether droperidol modulates the activity of adenosine triphosphate (ATP)-sensitive K+ channels in vascular smooth muscle cells. Rat aortic rings without endothelium were suspended or used for isometric force and membrane potential recordings, respectively. Vasorelaxation and hyperpolarization induced by levcromakalim (10(-8) to 10(-5) M or 10(-5) M, respectively) were completely abolished by the ATP-sensitive K+ channel antagonist glibenclamide (10(-5) M). Droperidol (10(-7) M) and an alpha-adrenergic receptor antagonist phentolamine (3 x 10(-9) M) caused a similar vasodilator effect (approximately 20% of vasorelaxation compared with maximal vasorelaxation induced by papaverine [3 x 10(-4) M]), whereas glibenclamide did not alter vasorelaxation induced by droperidol. Droperidol (3 x 10(-8) M to 10(-7) M) augmented vasorelaxation and hyperpolarization produced by levcromakalim, whereas phentolamine (3 x 10(-9) M) did not alter this vasorelaxation. Glibenclamide (10(-5) M) abolished the vasodilating and hyperpolarizing effects of levcromakalim in the aorta treated with droperidol (10(-7) M). These results suggest that droperidol augments vasodilator activity via ATP-sensitive K+ channels. However, it is unlikely that this augmentation is mediated by the inhibition of alpha-adrenergic receptors in vascular smooth muscles.

We studied the interaction between the sympathetic and parasympathetic parts of the autonomic nervous system in the regulation of smooth muscles in the femoral artery and trachea. It was shown that this regulation involves ganglionic serotoninergic neurons transmitting excitation to 5-HT, receptors in the effector tissues.

Droperidol (Dehydrobenzperidol, Dehidrobenzoperidol, Dridol, Droleptan, Inapsine) is a dopamine D(2) receptor antagonist that has been widely used in adults and children for the prevention and treatment of postoperative nausea and vomiting (PONV) over several decades and, more recently, for the prevention of opioid-induced PONV during patient-controlled analgesia (PCA) in adults. In well controlled clinical trials of patients undergoing surgery, the efficacy of single-dose intravenous (IV) droperidol in preventing PONV was similar to that of ondansetron and dexamethasone. Droperidol significantly reduced opioid-induced PONV in adults during PCA and had a morphine-sparing effect. Droperidol is generally well tolerated and the incidence of adverse effects is similar to that observed with placebo and the serotonin 5-HT(3) receptor antagonists (setrons). Guidelines recommend that, in adults, droperidol monotherapy be considered for those at moderate risk of PONV, and droperidol in combination with a setron and/or dexamethasone be considered for patients at moderate or high risk of PONV. In children with moderate or high risk of PONV, droperidol is recommended for first-line use in some countries, and second-line use in others.

Background: At dosages above 0.1 mg/kg, droperidol induces a dose-dependent QTc interval prolongation. Although subject to controversy, low-dose droperidol has recently been suspected to induce cardiac arrhythmias. Hence, 5-hydroxytryptamine type 3 antagonists have become the first-line drug for management of postoperative nausea and vomiting. These drugs are also known to prolong the QTc interval at high dosages. This study describes QTc interval changes associated with postoperative nausea and vomiting treatment by droperidol or ondansetron at low doses., Methods: Eighty-five patients with postoperative nausea and vomiting were included in this prospective, single-blind study. Patients received either 0.75 mg intravenous droperidol (n = 43) or 4 mg intravenous ondansetron (n = 42). Electrocardiographic recordings were obtained before administration of antiemetic drug and then 1, 2, 3, 5, 10, and 15 min after. Electrocardiographic monitoring was maintained for 3 h in eight patients in each group., Results: The QTc interval was prolonged (> 450 ms in men, > 470 ms in women) in 21% of the patients before antiemetic drug administration. This was significantly correlated with lower body temperature and longer duration of anesthesia. Compared with predrug QTc measurement, both antiemetics were associated with a significant QTc interval prolongation (P < 0.0001). The mean maximal QTc interval prolongation was 17 +/- 9 ms after droperidol occurring at the second minute and 20 +/- 13 ms after ondansetron at the third minute (both P < 0.0001). Compared with predrug measurement, the QTc interval was significantly lower after the 90th minute in both groups., Conclusions: Droperidol and ondansetron induced similar clinically relevant QTc interval prolongations. When used in treatment of postoperative nausea and vomiting, a situation where prolongation of the QTc interval seems to occur, the safety of 5-hydroxytryptamine type 3 antagonists may not be superior to that of low-dose droperidol.

Background: Droperidol has recently been associated with cardiac arrhythmias and sudden cardiac death. Changes in action potential duration seem to be the cause of the arrhythmic behavior, which can lead to alterations in intracellular free Ca concentration ([Ca]i). Because [Ca]i and myofilament Ca sensitivity are key regulators of myocardial contractility, the authors' objective was to identify whether droperidol alters [Ca]i or myofilament Ca sensitivity in rat ventricular myocytes and to identify the cellular mechanisms responsible for these effects., Methods: Freshly isolated rat ventricular myocytes were obtained from adult rat hearts. Myocyte shortening, [Ca]i, nitric oxide production, intracellular pH, and action potentials were monitored in cardiomyocytes exposed to droperidol. Langendorff perfused hearts were used to assess overall cardiac function., Results: Droperidol (0.03-1 mum) caused concentration-dependent decreases in peak [Ca]i and shortening. Droperidol inhibited 35 mm KCl-induced increase in [Ca]i, with little direct effect on sarcoplasmic reticulum Ca stores. Droperidol had no effect on action potential duration but caused a rightward shift in the concentration-response curve to extracellular Ca for shortening, with no concomitant effect on peak [Ca]i. Droperidol decreased pHi and increased nitric oxide production. Droperidol exerted a negative inotropic effect in Langendorff perfused hearts., Conclusion: These data demonstrate that droperidol decreases cardiomyocyte function, which is mediated by a decrease in [Ca]i and a decrease in myofilament Ca sensitivity. The decrease in [Ca]i is mediated by decreased sarcolemmal Ca influx. The decrease in myofilament Ca sensitivity is likely mediated by a decrease in pHi and an increase in nitric oxide production.

Introduction: Postoperative nausea and vomiting (PONV) is a common problem with no simple solution. This review highlights factors that are known to increase the risk of PONV. It examines the various data on pharmacological and non-pharmacological methods that have been used to prevent PONV., Methods: Peer-reviewed journals on the subject were covered., Conclusion: Patient, surgical and anaesthetic factors increase the risk of PONV. While patient and surgical factors are understandably difficult to control, a multimodal approach involving both pharmacological and non-pharmacological interventions has been successfully adopted to reduce the incidence of PONV. Various factors have been identified to categorise patients into different profiles to determine their risk of PONV. Perioperative strategies can then be targeted at these patient groups.

BOLD-contrast functional magnetic resonance imaging (MRI) was used to assess the evolution of tumor oxygenation and blood flow after administration of four different anesthetics: pentobarbital (60 mg/kg), ketamine/xylazine (80/8 mg/kg), fentanyl/droperidol (0.078/3.9 mg/kg), and isoflurane (1.5%). Gradient echo sequences were carried out at 4.7 Tesla in a TLT tumor model implanted in the muscle of NMRI mice. In parallel experiments, tumor blood flow and tumor pO2 were measured using the OxyLite/OxyFlo probe system. A comparison was made with the changes occurring in the skeletal muscle (host tissue). The signal intensity was dramatically decreased in tumors after administration of anesthetics, except isoflurane. These results correlated well with measurements of oxygenation and blood perfusion. Isoflurane produced constant muscle pO2 and blood perfusion although large transient fluctuations in pO2 and blood flow were reported in some tumors. Our results emphasize the need for careful monitoring of the effects of anesthesia when trying to identify new therapeutic approaches that are aimed at modulating tumor hemodynamics.

Generalized epileptic seizures produce widespread physiological changes in the brain. Recent studies suggest that "generalized" seizures may not involve the whole brain homogeneously. For example, electrophysiological recordings in WAG/Rij rats, an established model of human absence seizures, have shown that spike-and-wave discharges are most intense in the perioral somatosensory cortex and thalamus, but spare the occipital cortex. Is this heterogeneous increased neuronal activity matched by changes in local cerebral blood flow sufficient to meet or exceed cerebral oxygen consumption? To investigate this, we performed blood oxygen level-dependent functional magnetic resonance imaging (fMRI) measurements at 7T with simultaneous electroencephalogram recordings. During spontaneous spike-wave seizures in WAG/Rij rats under fentanylhaloperidol anesthesia, we found increased fMRI signals in focal regions including the perioral somatosensory cortex, known to be intensely involved during seizures, whereas the occipital cortex was spared. For comparison, we also studied bicuculline-induced generalized tonic-clonic seizures under the same conditions, and found fMRI increases to be larger and more widespread than during spike-and-wave seizures. These findings suggest that even in regions with intense neuronal activity during epileptic seizures, oxygen delivery exceeds metabolic needs, enabling fMRI to be used for investigation of dynamic cortical and subcortical network involvement in this disorder.

Unlabelled: Controversy surrounds the use of the antiemetic droperidol, because of the Food and Drug Administration-imposed "black box" warning alleging that even small doses of the drug can lead to serious (even fatal) arrhythmias when it is used for antiemetic prophylaxis during the perioperative period. We used mathematical modeling of electrocardiographic QT interval data published in a peer-reviewed manuscript to evaluate the relationship between the dose of droperidol (0.1-0.25 mg/kg i.v.) and QT(c) prolongation. In comparing the calculated QT(c) values based on the logarithm model (27-63 ms), the linear model (27-67 ms) and the square-root model (36-57 ms) to the actual measured QT(c) values (37-59 ms), the square-root model provided the best simulation of the experimental findings. Other models that we evaluated included the polynomial model and various exponent models (e.g., quartic-root model, cubic-root model, square model, and cubic model). The estimated median prolongation of the median QT(c) interval produced by droperidol 0.625-1.25 mg i.v. would vary from 9 +/- 3 to 18 +/- 3 ms. Therefore, this regression analysis suggests that small "antiemetic" doses of droperidol (< or =1.25 mg) would be unlikely to produce proarrhythmogenic effects in the perioperative period., Implications: Using a square-root curve fit model to evaluate the relationship between the dose of droperidol and QT(c) prolongation, small-dose droperidol (0.625-1.25 mg i.v.) would be expected to produce <30-ms prolongation of the QT(c) interval. Therefore, small "antiemetic" doses of droperidol would not be expected to produce proarrhythmogenic effects when used for prophylaxis in surgical patients.

Study Objective: To evaluate the potential of compounds commonly used in anesthesia practice to affect the intracellular oxidant-antioxidant homeostasis of peripheral blood lymphocytes at clinically relevant concentrations; and to study the changes in reactive oxygen species production and measure the mitochondrial glutathione content., Design: Prospective, in vitro study., Setting: Experimental medical research laboratory at a University Hospital., Measurements: Lymphocytes were isolated from the peripheral blood of 15 healthy donors and incubated for 12 hours at 37 degrees C with the following drug concentrations: thiopental sodium 20 mmoL/mL, droperidol 130 micromol/mL, propofol 60 mmoL/mL, and succinylcholine 17 mmoL/mL. Reactive oxygen species (ROS) generation was determined by hydroethidine and 2',7'-dichlorofluorescein diacetate methods. Mitochondrial glutathione level was assessed using monobromobimane staining., Measurements and Main Results: Thiopental-treated lymphocytes exhibited an overgeneration of ROS, but no change was detected in mitochondrial glutathione quantity. Propofol and droperidol could not induce any perturbative effect on the oxidative state of T cells, whereas succinylcholine was found to markedly affect lymphocyte oxidative state both by impairing glutathione content and promoting exaggerated production of ROS., Conclusion: Drugs commonly used in anesthesia practice may significantly alter the oxidative state of peripheral T cells. This mechanism could contribute to the immune suppression that occurs transiently in the early postoperative period.

The artificially ventilated guinea pig was frequently used for neurophysiological and respiratory studies. This species is also preferable for an evaluation of hemoglobin based artificial oxygen carriers, because its oxygen hemoglobin binding is very similar to that of man. But the narcosis of this animal-species is very difficult, because of cardiorespiratory depression induced by conventional procedures. The following intraperitoneal administered neuroleptanesthesia was proved in guinea pigs: 0.2 mg Fentanyl (Janssen/D), 10 mg Droperidol (Janssen/D) and 400 mg Urethan in 10 ml isotonic sodium chloride solution per kg body weight. Our new animal model with a special valve system enables to assess the gas exchange under spontaneous breathing, cardiovascular and the acid-base parameters. The vital parameters of animals were stable over 6 hours and very close to those of awake animals, especially the arterial average blood pressure. For that reason, this established neuroleptanesthesia of guinea pigs is preferable for research purpose. The fasted animals show significantly decreased values of arterial blood pH (7,345 vs. 7401), of heart frequency (244 vs. 277 min(-1)), and of ventilation value (167 vs. 205 ml/min) compared to non-fasted animals.

We studied the possibility of co-directed stimulatory effects of the sympathetic and parasympathetic systems on the motility of gallbladder, Oddi sphincter, and adjacent ascending portion of the duodenum. It is established that serotoninergic intramural neurons transmitting excitatory influences to(5)HT(1,2)-serotonin receptors of the effector tissues participate in this stimulatory effect.

Unlabelled: The effect of dopamine D2 receptor antagonists, such as chlorpromazine and haloperidol, on pupil size in awake subjects suggests that these drugs might also alter pupillary reflex dilation and pupil size during general anesthesia. Forty-seven patients undergoing lower abdominal surgery under combined epidural/general anesthesia were randomized to receive one of the 5 following open labeled drugs: 10 mL saline, 0.13 mg/kg ondansetron, 0.25 mg/kg metoclopramide, 0.5 mg/kg metoclopramide, or 0.02 mg/kg droperidol. Three measurements of reflex dilation were taken at 5-min intervals and after the last measurement (time 0) the drug was administered. Measurements were then taken 5, 10, 20, and 40 min after I.V. drug administration. Reflex dilation was induced by intermittent noxious stimulation of the C5 dermatome with a tetanic electric current (60-70 mamp, 100 Hz, 3-s duration) after a stable level of epidural analgesia had been established with 3/8% bupivacaine and maintained with a continuous infusion. Metoclopramide produced a small decrease in pupil diameter and transiently depressed reflex dilation, whereas droperidol decreased pupil size at 10 min and depressed reflex dilation throughout the 40-min study period. Maximal change in reflex dilation was -6.6 +/- 3.3 mm-sec after droperidol. Ondansetron had no effect on pupil diameter or reflex dilation. When pupillary diameter measurements are used to gauge opioid levels during experimental conditions or during surgical anesthesia, antiemetic medication acting on the dopamine D2 receptor should be avoided., Implications: Miosis is often considered an effect of opioid administration during general anesthesia, but other drugs, such as antiemetics, might produce a similar effect on the pupil. This study demonstrates that 2 antiemetics, droperidol and metoclopramide, constrict the pupil and block the pupillary dilation brought about by nociceptive stimuli.

Background: Droperidol increasingly is used as an effective adjunct for conscious sedation during endoscopic procedures. Given the concern for the effects of narcotics and benzodiazepines on sphincter of Oddi motility, and the potential difficulty in sedating patients undergoing sphincter of Oddi manometry, droperidol could be an ideal agent in this setting., Methods: Over a 43-month period, consecutive patients undergoing sphincter of Oddi manometry were studied prospectively. Sphincter of Oddi manometry was performed under general anesthesia in all but 10 patients. Standard retrograde pull-through techniques were used to examine the biliary and/or pancreatic sphincter, depending on the indication for sphincter of Oddi manometry. After the initial two pull-throughs, 5 mg of droperidol were given intravenously and measurements were repeated 5 minutes later., Results: A total of 55 patients were studied (42 women [76%], 13 men; mean age 43 years). The basal biliary sphincter pressures measured in 35 patients before and after droperidol were, respectively, 56 mm Hg and 48 mm Hg (p = 0.02); the basal pancreatic sphincter pressures measured in 22 patients before and after droperidol were, respectively, 92 mm Hg and 67 mm Hg (p = 0.29). By using a definition for sphincter of Oddi dysfunction of a basal pressure greater than 40 mm Hg, droperidol would have resulted in a change in diagnosis in 5 patients undergoing biliary manometry (one misclassified as sphincter of Oddi dysfunction, 4 misclassified as normal), and 6 patients undergoing pancreatic sphincter manometry (5 misclassified as sphincter of Oddi dysfunction, one misclassified as normal) (total 19% of procedures). No complication was associated with droperidol use., Conclusions: Droperidol alters basal sphincter pressures, which in some patients was clinically significant and would have resulted in misclassification. Although safe and well tolerated, droperidol appears to have subtle but clinically significant effects on the sphincter of Oddi.

Background: Performance of sphincter of Oddi manometry at ERCP is technically demanding and requires that the patient be well sedated. Droperidol is frequently administered when adequate sedation cannot be achieved with a benzodiazepine and meperidine. This study examined the effects of droperidol on the biliary and pancreatic sphincters., Methods: A total of 31 patients were prospectively evaluated by sphincter of Oddi manometry in the conventional retrograde fashion. Manometry was initially performed with intravenous administration of diazepam alone, diazepam plus meperidine or midazolam plus meperidine. Manometry was then repeated 5 minutes after droperidol was administered., Results: The basal pressure of the biliary sphincter and of the pancreatic sphincter were not significantly altered by droperidol. Concordance (normal vs. abnormal) between the basal sphincter pressure before and after droperidol was seen in 30 patients (97%). Droperidol also did not lead to a difference in phasic wave amplitude, duration, or frequency. Thirteen manometry tracings (42%) were judged as being qualitatively better after droperidol, whereas two (6.5%;

Droperidol attenuates airway smooth muscle contraction. However, the intracellular mechanisms involved in the droperidol-induced attenuation of airway smooth muscle contraction are not fully understood. We examined the effects of droperidol on contractile and phosphatidylinositol responses of the rat trachea. Droperidol dose dependently attenuated carbachol (CCh) induced tracheal ring contractions. The IC(50) of droperidol on CCh-induced tracheal ring contraction was 13 +/- 2 micromol/l. Droperidol attenuated CCh and aluminum fluoride stimulated inositol monophosphate accumulation. These results suggest that droperidol inhibits G protein coupled phospholipase C, resulting in attenuation of CCh-induced phosphatidylinositol response and subsequent attenuation of contractions of the rat trachea., (Copyright 2003 S. Karger AG, Basel)

In order to assess the response of plasma biochemical parameters to anaesthesia, 40 New Zealand White (NZW) rabbits were assigned to four treatment groups (n = 10): control (1 ml i.v. saline solution), fentanyl-droperidol (FD) (0.4 ml/kg s.c. of 'thalamonal' solution; 2.5 mg/ml droperidol, 0.05 mg/ml fentanyl), ketamine (K) (10 mg/kg i.v.) with either xylazine (X) (3 mg/kg i.v.) or diazepam (D) (2 mg/kg i.v.). Blood samples were obtained from the central ear artery at six time points: before injection, and at 10, 30, 60, 120 min and 24 h after injection of the anaesthetics/saline. Plasma ALT, AST, ALP, GGT, BUN, creatinine, phosphate and potassium levels were measured by the Hitachi 747 autoanalyser. The administration of K-X increased (P < 0.05) plasma ALT (from 11.4 +/- 0.9 to 20.2 +/- 1.7 IU/l, at 10 min), AST (from 10.5 +/- 3.3 to 34 +/- 2.1 IU/l, at 120 min), BUN (from 17.2 +/- 0.9 to 25.8 +/- 1.8 mg/dl, at 60 min) and creatinine concentrations (from 1 +/- 0.1 to 1.6 +/- 0.2 mg/dl, at 10 min). After K-D administration, we observed an increase (P < 0.05) in plasma ALT (from 11.4 +/- 0.9 to 20.2 +/- 1.1 IU/l, at 10 min), AST (from 11.4 +/- 1.6 to 28 +/- 3.7 IU/l, at 10 min), BUN (from 15.8 +/- 0.8 to 30 +/- 1.5 mg/dl, at 10 min) and creatinine levels (from 1 +/- 0.08 to 2.2 +/- 0.2 mg/dl, at 120 min). No significant changes were seen in the FD group. We conclude that K-X and K-D may affect plasma concentration of select serum enzymes and biochemical parameters. These results should be taken into account when blood samples are evaluated in treated rabbits.

In experiments on rats using an "illuminated area" avoidance test and a "threatening situation" avoidance test, preliminary i.p. administration and subsequent microinjection into the ventromedial hypothalamus of various combinations of monoamines, transmitter amino acids, and their agonists and antagonists demonstrated differences in the functional importance of the neurochemical profile of this limbic formation in mediating anxiety states of different origins. The neurochemical analysis with local intrahypothalamic administration of anxiosedative and anxioselective substances showed that the antiaversive actions of Campirone are obtained only in conditions in which the dominant motivation is fear, while chlordiazepoxide, Phenibut, and Indoter are also active in anxiety induced by negatively stressful zoosocial influences; these actions are mediated respectively by serotoninergic and GABAergic types of synaptic switching in the ventromedial hypothalamus.

Unlabelled: We investigated the effect of IV droperidol on the bispectral index (BIS) in conscious and propofol-sedated patients during spinal anesthesia. Thirty minutes after the induction of spinal anesthesia, 20 patients were given 2 mg of droperidol IV without administration of other sedatives (conscious group). Another group of patients were sedated with a propofol infusion to maintain BIS at 60 +/- 5 and were administered IV saline (placebo group; n = 20), droperidol 1 mg (dro-1 group; n = 20), or droperidol 2 mg (dro-2 group; n = 20) in a randomized order and in a double-blinded fashion. Although BIS remained the same in the conscious and placebo groups, it significantly decreased after administration of droperidol in the dro-1 and dro-2 groups. The decrease in BIS was significantly larger in the dro-2 group than in the dro-1 group. These results suggest that an antiemetic dose of droperidol enhances the hypnotic effect of propofol in a dose-dependent manner during spinal anesthesia., Implications: An antiemetic dose of IV droperidol causes a decrease in the bispectral index in patients sedated with propofol during spinal anesthesia. We conclude that droperidol may enhance the hypnotic effect of propofol.

Myocardial stunning, a transient contractile dysfunction that appears following a brief period of ischemia, is at least partly due to the production of oxygen-derived free radicals. The objective of the present study was to determine whether the Ginkgo biloba extract EGb761, which has antioxidant properties in vitro, can attenuate myocardial stunning in vivo. Forty-seven anesthetized open-chest farm pigs underwent 10 min of occlusion of the left anterior descending coronary artery (LAD), followed by 3 hours of reperfusion. They were pretreated with either physiological saline, 100 mg or 300 mg of EGb 761 (Protocol I) or 3 mg or 9 mg of ginkgolide B (GkB) (Protocol II). Contractile function was assessed by sonomicrometry. Both doses of EGb 761 significantly improved recovery of contractile function in the reperfused myocardium with segment shortening averaging 23 +/- 5 % of baseline values at 3 hours post-reflow in controls versus 81 +/- 10 % and 57 +/- 12 % in the EGb100 and EGb300 groups, respectively (p < 0.05 vs control in both cases). In contrast, neither dose of GkB improved functional recovery during reperfusion. ESR experiments revealed that EGb761 resulted in a 59 % decrease in myocardial spin-adduct release during reperfusion (p < 0.05 versus control and GkB groups). A significant 28 % decrease (p < 0.05 vs control group) was also obtained in GkB-treated animals. These results indicate that EGb 761 can attenuate myocardial stunning following a brief ischemic insult in the in situ pig heart by an effect that involves a decrease in the formation of free radicals. As the effect of EGb 761 on functional recovery cannot be explained by the presence of GkB, the beneficial action of the extract on myocardial stunning likely involves complementary effects of both its non-ginkgolide and ginkgolide constituents.

Background: Droperidol is used in neuroleptanesthesia and as an antiemetic. Although its antiemetic effect is thought to be caused by dopaminergic inhibition, the mechanism of droperidol's anesthetic action is unknown. Because gamma-aminobutyric acid type A (GABAA) and neuronal nicotinic acetylcholine receptors (nAChRs) have been implicated as putative targets of other general anesthetic drugs, the authors tested the ability of droperidol to modulate these receptors., Methods: gamma-Aminobutyric acid type A alpha1beta1gamma2 receptor, alpha7 and alpha4beta2 nAChRs were expressed in Xenopus oocytes and studied with two-electrode voltage clamp recording. The authors tested the ability of droperidol at concentrations from 1 nm to 100 microm to modulate activation of these receptors by their native agonists., Results: Droperidol inhibited the GABA response by a maximum of 24.7 +/- 3.0%. The IC50 for inhibition was 12.6 +/- 0.47 nm droperidol. At high concentrations, droperidol (100 microm) activates the GABAA receptor in the absence of GABA. Inhibition of the GABA response is significantly greater at hyperpolarized membrane potentials. The activation of the alpha7 nAChR is also inhibited by droperidol, with an IC50 of 5.8 +/- 0.53 microm. The Hill coefficient is 0.95 +/- 0.1. Inhibition is noncompetitive, and membrane voltage dependence is insignificant., Conclusions: Droperidol inhibits activation of both the GABAA alpha1beta1gamma2 and alpha7 nAChR. The submaximal GABA inhibition occurs within a concentration range such that it might be responsible for the anxiety, dysphoria, and restlessness that limit the clinical utility of high-dose droperidol anesthesia. Inhibition of the alpha7 nAChR might be responsible for the anesthetic action of droperidol.

This randomized double-blind trial was designed to evaluate the antiemetic effect of continuous epidural analgesia with droperidol mixed with bupivacaine and buprenorphine. We studied 78 patients for abdominal gynecological surgery under general-epidural anesthesia. After recovery from anesthesia, they received epidural administration of 0.25% bupivacaine 40 ml and buprenorphine 0.4 mg with or without droperidol 2.5-5.0 mg at a rate of 2 ml.h-1 for 24 hours. The addition of droperidol 5.0 mg led to serious undesirable effects. Droperidol 2.5 mg, however, showed not only significant antiemetic effect without any adverse action, but also the reduction of rescue analgesics. We conclude that the addition of a small dose of droperidol to epidural analgesics reduces the incidence of postoperative emesis and the requirement of rescue analgesics.