Sample records for droperidol metoclopramida tropisetron

  1. Droperidol/fentanyl, diazepam/pentazocine: a comparison.


    Bond, A C; Thompson, M A


    Anaesthesia with a combination of diazepam and pentazocine is compared with the well established technique of neuroleptanaesthesia using droperidol and fentanyl. The former compared favourably, producing similar cardiovascular stability, rapid recovery of conciousness and postoperative analgesia.

  2. Tropisetron attenuates cisplatin-induced nephrotoxicity in mice.


    Zirak, Mohammad Reza; Rahimian, Reza; Ghazi-Khansari, Mahmoud; Abbasi, Ata; Razmi, Ali; Mehr, Shahram Ejtemaei; Mousavizadeh, Kazem; Dehpour, Ahmad Reza


    Nephrotoxicity is one of the most important complications of cisplatin, a potent chemotherapeutic agent used in the treatment of various malignancies. 5-HT3 antagonists are widely used to counteract chemotherapy-induced emesis and new studies reveal that they poses notable anti-inflammatory properties. In current study, we investigated the effects of 5-HT3 antagonists on cisplatin induced nephrotoxicity in mice. To identify the underlying mechanism of renal protection by tropisetron, we investigated the probable involvement of alpha7 nicotinic acetylcholine receptor (α7nAChR). A single injection of cisplatin (20mg/kg; i.p) induced nephrotoxicity, 5-HT3 antagonists (tropisetron, granisetron and ondansetron,) were given twice daily for 3 day (3mg/kg; i.p). Finally animals were euthanized and blood sample was collected to measure urea and creatinin level. Also kidneys were removed for histopathological examination and biochemical measurements including glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD) activity, inducible nitric oxide synthase (iNOS) expression and inflammatory cytokines. Tropisetron decreased the expression of inflammatory molecules including tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β) and iNOS and improved histopathological damage and renal dysfunction. However other 5-HT3 antagonists, granisetron or ondansetron do not have any elicit effects on biochemical markers and histological damages. Since methyllycaconitine, antagonist of α7nAChR, was unable to reverse the beneficial effect of tropisetron, we concluded that this effect of tropisetron is not mediated by α7nAChR.Our results showed that tropisetron treatment markedly ameliorated the experimental cisplatin induced-nephrotoxicity and this effect might be 5-HT3 receptor and α7nAChR independent.

  3. The neuroprotective effect of tropisetron on vincristine-induced neurotoxicity.


    Barzegar-Fallah, Anita; Alimoradi, Houman; Mehrzadi, Saeed; Barzegar-Fallah, Niloofar; Zendedel, Adib; Abbasi, Ata; Dehpour, Ahmad Reza


    Vincristine (VCR) peripheral neuropathy is a dose-limiting side effect. Several studies have shown that tropisetron, a 5-HT3 receptor antagonist, exerts anti-inflammatory and immunomodulatory properties. Current study was designed to investigate a suppressive effect of tropisetron on VCR-induced neuropathy and whether this effect exerts through the 5-HT3 receptor or not. Neuropathy was induced in rats by administration of vincristine (0.5mg/kg, 3 intraperitoneal injections on alternate days) and in treatment group, tropisetron (3mg/kg); m-chlorophenylbiguanide (mCPBG), a selective 5-HT3 receptor agonist (15mg/kg); tropisetron (3mg/kg) plus mCPBG (15mg/kg); granisetron, another selective 5-HT3 receptor antagonist (3mg/kg) were administered intraperitoneally 1h prior to vincristine injection. Hot plate, open field tests (total distance moved, mean velocity and percentage of total duration of the movement) and motor nerve conduction velocity (MNCV) were performed to evaluate the sensory and motor neuropathy. Further, plasma levels of tumor necrosis factor-alpha (TNF-α) and interleukin-2 (IL-2) and the level of TNF-α in sciatic nerve were assessed as well as histological examination. In only VCR-treated rats hot plate latencies were significantly increased, total distance moved, mean velocity, total duration of the movement and sciatic MNCV significantly decreased compared with control. In tropisetron and tropisetron plus mCPBG groups, one injection of tropisetron prior to each VCR injection robustly diminished TNF-α and IL-2 levels, and also prevented mixed sensory-motor neuropathy, as indicated by less mortality rate, better general conditions, behavioral and electrophysiological studies. Moreover, pathological evidence confirmed the results obtained from other findings. But granisetron and mCPBG had no significant effect on the mentioned parameters. In conclusion, these studies demonstrate that tropisetron significantly suppressed VCR-induced neuropathy and could

  4. 21 CFR 522.800 - Droperidol and fentanyl citrate injection.

    Code of Federal Regulations, 2013 CFR


    ... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Droperidol and fentanyl citrate injection. 522.800 Section 522.800 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS IMPLANTATION OR INJECTABLE DOSAGE FORM NEW ANIMAL...

  5. 21 CFR 522.800 - Droperidol and fentanyl.

    Code of Federal Regulations, 2014 CFR



  6. 21 CFR 522.800 - Droperidol and fentanyl citrate injection.

    Code of Federal Regulations, 2012 CFR


    ... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Droperidol and fentanyl citrate injection. 522.800 Section 522.800 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS IMPLANTATION OR INJECTABLE DOSAGE FORM NEW ANIMAL...

  7. [Continuous epidural administration of droperidol to prevent postoperative nausea and vomiting].


    Hayashi, Kenji; Higuchi, Jun; Sakio, Hideaki; Tanaka, Yoshikazu; Onoda, Noboru


    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.

  8. What Can We Learn From Two Consecutive Cases? Droperidol May Abolish TcMEPs

    PubMed Central

    González, Ángel Saponaro; Lorensu, Pedro Javier Pérez; Gómez, Santiago Chaves; Medina, Josué Francisco Nodarse; Dios, Jose Ángel Torres


    Droperidol is a D2 receptor antagonist currently used in Europe for preventing postoperative nausea and vomiting. It was used to perform neurolept anaesthesia in combination with fentanyl until a Food and Drug Administration (FDA) ‘black box’ warning restricted its use due to cardiovascular side effects in 2001. There is no literature regarding the effects of droperidol on transcranial motor evoked potentials (TcMEPs) elicited by electrical stimulation. Our aim was to report two cases of spine surgery in which TcMEPs were lost due to droperidol administration. We report the cases of a 4-year-old male with scoliosis undergoing correction and a 58-year-old woman with metastasis on the D8 vertebrae undergoing kyphosis correction. Intraoperative neurophysiological monitoring was achieved through TcMEPs and somatosensory evoked potentials (SEPs). Intraoperative neurophysiological monitoring (IONM) showed a temporal loss of TcMEPs without SEPs changes coinciding with the administration of droperidol. TcMEP stimulation parameters were changed to double train of pulses, with the aim to elicit them, obtaining responses. Five minutes after droperidol administration, TcMEPs were equal to those at baseline. Droperidol used as prophylaxis for postoperative nausea abolishes TcMEPs. Changing stimulation parameters to double train of pulses, it allows to bypass droperidol central action, achieving monitorable TcMEPs. PMID:28377841

  9. High dose droperidol and QT prolongation: analysis of continuous 12-lead recordings

    PubMed Central

    Calver, Leonie; Isbister, Geoffrey K


    Aims To investigate the QT interval after high dose droperidol using continuous 12-lead Holter recordings. Methods This was a prospective study of patients given droperidol with a continuous Holter recording. Patients were recruited from the DORM II study which included patients with aggression presenting to the emergency department. Patients initially received 10 mg droperidol as part of a standardized sedation protocol. An additional 10 mg dose was given after 15 min if required and further doses at the clinical toxicologist's discretion. Continuous 12-lead Holter recordings were obtained for 2–24 h utilizing high resolution digital recordings with automated QT interval measurement. Electrocardiograms were extracted hourly from Holter recordings. The QT interval was plotted against heart rate (HR) on the QT nomogram to determine if it was abnormal. QTcF (Fridericia's HR correction) was calculated and >500 ms was defined as abnormal. Results Forty-six patients had Holter recordings after 10–40 mg droperidol and 316 QT–HR pairs were included. There were 32 abnormal QT measurements in four patients, three given 10 mg and one 20 mg. In three of the four patients QTcF >500 ms but only in one taking methadone was the timing of QTcF >500 ms consistent with droperidol dosing. Of the three other patients, one took amphetamines, one still had QT prolongation 24 h after droperidol and one took a lamotrigine overdose. No patient given >30 mg had a prolonged QT. There were no arrhythmias. Conclusion QT prolongation was observed with high dose droperidol. However, there was little evidence supporting droperidol being the cause and QT prolongation was more likely due to pre-existing conditions or other drugs. PMID:24168079

  10. Tropisetron ameliorates early diabetic nephropathy in streptozotocin-induced diabetic rats.


    Barzegar-Fallah, Anita; Alimoradi, Houman; Asadi, Firouzeh; Dehpour, Ahmad Reza; Asgari, Mojgan; Shafiei, Massoumeh


    It has been well established that oxidative stress and inflammation are involved in the pathogenesis of diabetic nephropathy. It has been shown that tropisetron exerts anti-inflammatory and immunomodulatory properties. The current study was designed to investigate protective effects of tropisetron on early diabetic nephropathy in streptozotocin-induced diabetic rats. Rats were divided into six groups: (i) untreated diabetic (streptozotocin group); (ii) untreated control; (iii) diabetic rats treated with tropisetron (3 mg/kg); (iv) normal rats treated with tropisetron (3 mg/kg); (v) diabetic rats treated with granisetron (3 mg/kg); and (vi) normal rats treated with granisetron (3 mg/kg); rats began receiving treatment at the time of diabetes induction for 2 weeks. At the termination of the experiments, bodyweight, kidney index, urinary albumin excretion, and glomerular filtration rate were measured. The levels of oxidative stress markers and tumour necrosis factor-α were also determined. Streptozotocin-treated animals showed significant loss of bodyweight and renal enlargement and dysfunction. Diabetic rats also exhibited an increase in malondialdehyde along with a significant decrease in glutathione, superoxide dismutase activity, and catalase activity. Furthermore, the diabetic animals demonstrated a significant rise in renal cortical, urinary tumour necrosis factor-α, and urinary albumin excretion. Both granisetron and tropisetron decreased blood glucose in diabetic animals, but this decrease was not significant for granisetron. Treatment with tropisetron, but not granisetron, prevented increases in oxidative stress and tumour necrosis factor-α, decreased urinary cytokine excretion and albuminuria, and improved renal morphological damage. In conclusion, the present study suggests that tropisetron may be a protective agent in early diabetic nephropathy, and its action is mediated, at least in part, by anti-oxidative and anti-inflammatory mechanisms that appear

  11. Tropisetron suppresses colitis-associated cancer in a mouse model in the remission stage.


    Amini-Khoei, Hossein; Momeny, Majid; Abdollahi, Alireza; Dehpour, Ahmad Reza; Amiri, Shayan; Haj-Mirzaian, Arya; Tavangar, Seyed Mohammad; Ghaffari, Seyed Hamid; Rahimian, Reza; Mehr, Shahram Ejtemaei


    Patients with inflammatory bowel disease (IBD) have a high risk for development of colitis-associated cancer (CAC). Serotonin is a neurotransmitter produced by enterochromaffin cells of the intestine. Serotonin and its receptors, mainly 5-HT3 receptor, are overexpressed in IBD and promote development of CAC through production of inflammatory cytokines. In the present study, we demonstrated the in vivo activity of tropisetron, a 5-HT3 receptor antagonist, against experimental CAC. CAC was induced by azoxymethane (AOM)/dextran sodium sulfate (DDS) in BALB/c mice. The histopathology of colon tissue was performed. Beta-catenin and Cox-2 expression was evaluated by immunohistochemistry as well as quantitative reverse transcription-PCR (qRT-PCR). Alterations in the expression of 5-HT3 receptor and inflammatory-associated genes such as Il-1β, Tnf-α, Tlr4 and Myd88 were determined by qRT-PCR. Our results showed that tumor development in tropisetron-treated CAC group was significantly lower than the controls. The qRT-PCR analysis demonstrated that the expression of 5-HT3 receptor was significantly increased following CAC induction. In addition, tropisetron reduced expression of β-catenin and Cox-2 in the CAC experimental group. The levels of Il-1β, Tnf-α, Tlr4 and Myd88 were significantly decreased upon tropisetron treatment in the AOM/DSS group. Taken together, our data show that tropisetron inhibits development of CAC probably by attenuation of inflammatory reactions in the colitis.

  12. The effect of paracetamol and tropisetron on pain: experimental studies and a review of published data.


    Tiippana, Elina; Hamunen, Katri; Kontinen, Vesa; Kalso, Eija


    Experimental studies suggest that paracetamol-induced analgesia is mediated via central serotonergic pathways and attenuated by 5-HT3-antagonists. However, clinical studies do not support this, and 5-HT3-antagonists are expected to reduce pain by blocking the descending pronociceptive pathway. The current project tested whether tropisetron attenuates analgesia by paracetamol. Two randomized, double-blind, crossover studies with 18 healthy male volunteers in each were performed. Pain stimuli were cold water immersion (cold pressor test), contact heat pain (study 1) and electrical stimulation (study 2). In both studies, tropisetron 5 mg i.v. or saline was administered, followed by paracetamol 2 g i.v. 30 min. later. Individual changes in heat and cold pain intensity, cold pain tolerance and unpleasantness were recorded. The same thresholds were also expressed as scores (% of the individual score at baseline). Additionally, previously published findings on the effects of paracetamol and its interaction with 5HT3-antagonists in human experimental pain models were reviewed. After calculation of the sensory and pain scores (%), tropisetron seemed to amplify the analgesic action of paracetamol. Paracetamol 2 g i.v. did not show any statistically significant analgesia in thermal tests (study 1), or differences in sensory, pain detection or moderate pain thresholds of the electrical stimulus (study 2). As paracetamol did not have a measurable analgesic effect in these tests, no conclusions can be drawn about the interaction between paracetamol and tropisetron. However, tropisetron may have an analgesic effect of its own. Clinicians should not avoid using these drugs together, unless larger clinical studies indicate otherwise.

  13. [Tropisetron for the prevention of nausea and vomiting during chemotherapy: multicenter clinical study].


    Gutiérrez, J; Bronfman, L; Cao, C; Vásquez, A; Derio, L; Rosas, J; del Castillo, C; Yáñez, M; Fodor, M; Gallardo, J; Cerda, B; Torres, R; Orlandi, L; Orlandi, F; Kleinman, S; Vogel, C


    The antiemetic effect of tropisetron was studied in 97 cancer patients (67 men, 30 women) receiving cisplatin in doses of 75 mg/m2 or higher. On 279 chemotherapy cycles studied (max 6 per patient) 5 mg of tropisetron was administered once a day i.v on day 1 and p.o. on days 2 to 6. Efficacy preventing vomiting and nausea was measured in 24 hour period as: complete control O episodes, major control 1 to 2 episodes, minor control 3 to 4 episodes and no control 5 or more episodes. Satisfactory vomiting control (complete and major) was 69%, 63%, 82%, 88%, 96% and 96% in days 1 to 6 of cycle 1. Satisfactory nausea control (complete and major) for the same days was 70%, 66%, 72%, 85%, 92% and 97%. Similar data was obtained for the subsequent cycles. Complete vomiting control was obtained in 47%, 35%, 56%, 72%, 81% and 84% and for nausea in 42%, 39%, 48%, 64%, 81% and 87%. 19 patients presented adverse effects (19.6%). Only 2 headache episodes had a definite relation with the antiemetic drug. 12 patients discontinued the medication; 6 due to drug inefficacy, 2 to illness unrelated to the drug, 1 to lack of collaboration, and 3 due to other reasons. We conclude that tropisetron allows satisfactory control of acute and delayed vomiting in a high percentage of patients treated with high doses of cisplatin. The drug does not have significant secondary effects. Tropisetron administration in only one daily dose implies an evident advantage and a treatment cost reduction.

  14. Middle latency auditory evoked potentials during total intravenous anesthesia with droperidol, ketamine and fentanyl.


    Kudoh, A; Matsuki, A


    We investigated whether total intravenous anesthesia with ketamine, fentanyl and droperidol would affect middle latency auditory evoked potentials and explicit memory, and whether dreams during the anesthesia are related to plasma concentrations of fentanyl and the infusion technique. A total number of 40 patients were the subjects for this study. Twenty patients (group A) were maintained with intravenous ketamine 2 mg kg-1 hr-1 and fentanyl 5 micrograms kg-1 hr-1 for the first 60 min and 3 micrograms kg-1 hr-1 for the next 90 min, and droperidol 0.1 mg kg-1. The remaining 20 patients (group B) were maintained with intravenous ketamine 2 mg kg-1 hr-1, droperidol 0.1 mg kg-1 and fentanyl 50-100 micrograms in a bolus intermittently as needed by vital signs such as increases in heart rate and arterial blood pressure. Middle latency auditory evoked potentials, plasma fentanyl and ketamine levels were measured; explicit memory and dreams were also estimated. There were no patients who recollected explicit memories of intraoperative events in both groups. The middle latency auditory evoked potentials were not significantly changed during the anesthesia in both groups. We could find no significant differences in latencies and amplitudes of the middle latency auditory evoked potentials between the both groups. Plasma fentanyl levels of group B patients were significantly lower than those of group A patients and the incidence of the dreams was significantly higher in group B patients. We conclude that the anesthesia with ketamine, fentanyl and droperidol is not associated with the explicit memories, though the middle latency auditory evoked potentials were not significantly changed as compared with those in the waking state. In addition, dreams during the anesthesia may correlate with plasma fentanyl concentrations or the infusion technique.

  15. Spinal 5-HT3 receptor mediates nociceptive effect on central neuropathic pain; possible therapeutic role for tropisetron

    PubMed Central

    Nasirinezhad, Farinaz; Hosseini, Marjan; Karami, Zohre; Yousefifard, Mahmoud; Janzadeh, Autosa


    Objectives To test the analgesic effect of 5-HT-3 receptor antagonist, tropisetron, in a clip compression injury model of spinal cord pain in rats. Methods Four weeks post compression of the spinal cord at lumbar level, tropisetron was administered intrathecally at 100 μg and 150 μg dosages. Behavioral tests were assessed before administration. Fifteen minutes after injection, behavioral tests were repeated. Randall-Sellitto and plantar test was used for mechanical and thermal hyperalgesia, respectively. Mechanical and cold allodynia were evaluated by Von Frey filament and acetone droplets, respectively. The analgesic effect of tropisetron was compared with intrathecal administration of salicylate. Locomotor score was evaluated by Basso, Beattie and Bresnahan (BBB) test every week after spinal cord injury. Results Intrathecal administration of tropisetron, decreased hyperalgesia and mechanical allodynia, but not cold allodynia were observed after compression of the spinal cord. Conclusion Blockade of 5-HT-3 receptors by tropisetron at the spinal level induces an antinociceptive effect on chronic central neuropathic pain and suggests that this compound may have potential clinical utility for the management of central neuropathic pain, particularly in patients with hyperalgesia and tactile allodynia. PMID:26338446

  16. Effect of intravenous tropisetron on modulation of pain and central hypersensitivity in chronic low back pain patients.


    Neziri, Alban Y; Dickenmann, Martina; Scaramozzino, Pasquale; Andersen, Ole K; Arendt-Nielsen, Lars; Dickenson, Anthony H; Curatolo, Michele


    The activation of 5-hydroxytryptamine-3 (5-HT-3) receptors in spinal cord can enhance intrinsic spinal mechanisms of central hypersensitivity, possibly leading to exaggerated pain responses. Clinical studies suggest that 5-HT-3 receptor antagonists may have an analgesic effect. This randomized, double-blind, placebo-controlled crossover study tested the hypothesis that the 5-HT-3 receptor antagonist tropisetron attenuates pain and central hypersensitivity in patients with chronic low back pain. Thirty patients with chronic low back pain, 15 of whom were women (aged 53 ± 14 years) and 15 men (aged 48 ± 14 years), were studied. A single intravenous injection of 0.9% saline solution, tropisetron 2mg, and tropisetron 5mg was administrated in 3 different sessions, in a double-blind crossover manner. The main outcome was the visual analogue scale (VAS) score of spontaneous low back pain before, and 15, 30, 60, and 90 minutes after drug administration. Secondary outcomes were nociceptive withdrawal reflexes to single and repeated electrical stimulation, area of reflex receptive fields, pressure pain detection and tolerance thresholds, conditioned pain modulation, and area of clinical pain. The data were analyzed by analysis of variance and panel multiple regressions. All 3 treatments reduced VAS scores. However, there was no statistically significant difference between tropisetron and placebo in VAS scores. Compared to placebo, tropisetron produced a statistically significant increase in pain threshold after single electrical stimulation, but no difference in all other secondary outcomes was found. A single-dose intravenous administration of tropisetron in patients with chronic low back pain had no significant specific effect on intensity of pain and most parameters of central hypersensitivity.

  17. Stability of butorphanol-tropisetron mixtures in 0.9% sodium chloride injection for patient-controlled analgesia use.


    Chen, Fu-Chao; Shi, Xiao-Ya; Li, Peng; Yang, Jin-Guo; Zhou, Ben-Hong


    Tropisetron is an adjuvant for butorphanol used in intravenous patient-controlled analgesia (PCA) and has been reported to provide superior pain control. It is efficacious in reducing the incidence of postoperative nausea and vomiting. However, this admixture is not available commercially and stability data applicable to hospital practice are limited. This study aimed to describe the drug compounding and evaluates the long-term (up to 14 days) stability of butorphanol and tropisetron in 0.9% sodium chloride injection for PCA use.In this study, commercial solutions of butorphanol tartrate and tropisetron hydrochloride were combined and further diluted with 0.9% sodium chloride injection to final concentrations of butorphanol tartrate 0.08 mg/mL and tropisetron hydrochloride 0.05 mg/mL. The polyolefin bags and glass bottles were stored at 4°C and 25°C for up to 14 days. The drug stabilities were determined by visual inspection, pH measurement, and high-pressure liquid chromatography assay of drug concentrations.The data obtained for admixtures prepared and stored at temperatures of 25°C and 4°C show the drugs have maintained at least 98% of the initial concentration. All solutions remained clear and colorless over the 14-day period, and the pH value did not change significantly.The results indicate that admixtures of butorphanol tartrate 0.08 mg/mL and tropisetron hydrochloride 0.05 mg/mL in 0.9% sodium chloride injection solution were stable for 14 days when stored in polyolefin bags or glass bottles at 4°C and 25°C and protected from light. The infusion is feasible for manufacturing in pharmacy aseptic units and can be stored for up to 14 days for routine use in PCA infusions.

  18. The effects of the 5-HT3 receptor antagonist tropisetron on cocaine-induced conditioned taste aversions.


    Briscione, Maria A; Serafine, Katherine M; Merluzzi, Andrew P; Rice, Kenner C; Riley, Anthony L


    Although cocaine readily induces taste aversions, little is known about the mechanisms underlying this effect. Recent work has shown that cocaine's actions on serotonin (5-HT) may be involved. To address this possibility, the present experiments examined a role of the specific 5-HT receptor, 5-HT3, in this effect given that it is implicated in a variety of behavioral effects of cocaine. This series of investigations first assessed the aversive effects of the 5-HT3 receptor antagonist tropisetron alone (Experiment 1). Specifically, in Experiment 1 male Sprague-Dawley rats were given repeated pairings of a novel saccharin solution and tropisetron (0, 0.056, 0.18 and 0.56mg/kg). Following this, a non-aversion-inducing dose of tropisetron (0.18mg/kg) was assessed for its ability to block aversions induced by a range of doses of cocaine (Experiment 2). Specifically, in Experiment 2 animals were given access to a novel saccharin solution and then injected with tropisetron (0 or 0.18mg/kg) followed by an injection of various doses of cocaine (0, 10, 18 and 32mg/kg). Cocaine induced dose-dependent taste aversions that were not blocked by tropisetron, suggesting that cocaine's aversive effects are not mediated by 5-HT, at least at this specific receptor subtype. At the intermediate dose of cocaine, aversions appeared to be potentiated, suggesting 5-HT3 may play a limiting role in cocaine's aversive effects. These data are discussed in the context of previous examinations of the roles of serotonin, dopamine, and norepinephrine in cocaine-induced aversions.

  19. Physicochemical stability of ternary admixtures of butorphanol, ketamine, and droperidol in polyolefin bags for patient-controlled analgesia use

    PubMed Central

    Fang, Baoxia; Wang, Linhai; Gu, Junfeng; Chen, Fuchao; Shi, Xiao-ya


    Background Delivery of drug admixtures by intravenous patient-controlled analgesia is a common practice for the management of postoperative pain; however, analytical confirmation of the compatibility and stability of butorphanol tartrate, ketamine hydrochloride, and droperidol combined in ternary admixtures is not available. Methods Butorphanol tartrate, ketamine hydrochloride, and droperidol have been examined for compatibility and stability when combined with 0.9% sodium chloride injection stored at 4°C and 25°C with light protection for a total of 14 days. Concentrations were 0.067 mg/mL, 1.33 mg/mL, and 0.033 mg/mL for butorphanol tartrate, ketamine hydrochloride, and droperidol, respectively. Drug concentrations were determined using high-performance liquid chromatographic analysis. Results All three drugs were very stable (>97%) at 4°C and 25°C for 14 days. The ternary admixtures were initially clear and colorless throughout the observation period, and the pH value did not change significantly. Conclusion The results confirm that the ternary admixture of butorphanol tartrate 0.067 mg/mL, ketamine hydrochloride 1.33 mg/mL, and droperidol 0.033 mg/mL in 0.9% sodium chloride injection were stable for 14 days when stored in polyolefin bags at 4°C and 25°C and protected from light. PMID:27920502

  20. Tropisetron Protects Against Acetaminophen-Induced Liver Injury via Suppressing Hepatic Oxidative Stress and Modulating the Activation of JNK/ERK MAPK Pathways

    PubMed Central

    Lee, Hung-Chen; Liao, Chia-Chih; Li, Allen H.


    Objectives. To investigate the protective effects of tropisetron on acetaminophen- (APAP-) induced liver injury in a mice model. Methods. C57BL/6 male mice were given tropisetron (0.3 to 10 mg/kg) 30 minutes before a hepatotoxic dose of acetaminophen (300 mg/kg) intraperitoneally. Twenty hours after APAP intoxication, sera alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, hepatic myeloperoxidase (MPO), malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) activities, and liver histopathological changes were examined. The MAP kinases were also detected by western blotting. Results. Our results showed that tropisetron pretreatment significantly attenuated the acute elevations of the liver enzyme ALT level, hepatic MPO activity, and hepatocytes necrosis in a dose-dependent manner (0.3–10 mg/kg) in APAP-induced hepatotoxicity mice. Tropisetron (1 and 3 mg/kg) suppressed APAP-induced hepatic lipid peroxidation expression and alleviated GSH and SOD depletion. Administration of tropisetron also attenuated the phosphorylation of c-Jun-NH2-terminal protein kinase (JNK) and extracellular signal-regulated kinase (ERK) caused by APAP. Conclusion. Our data demonstrated that tropisetron's hepatoprotective effect was in part correlated with the antioxidant, which were mediated via JNK and ERK pathways on acetaminophen-induced liver injury in mice. PMID:27891510

  1. Reduction of nausea and vomiting from epidural opioids by adding droperidol to the infusate in home-bound patients.


    Aldrete, J A


    In 184 adult patients with severe nonmalignant low back pain from postlaminectomy syndrome, temporary lumbar epidural catheters were infused with either 0.25% bupivacaine 92 mL, fentanyl 600 micrograms, and droperidol 5 mg (Group A), or 0.25% bupivacaine 92 mL, fentanyl 600 micrograms, and NaCl 0.9% 2 mL (Group B). Infusion rates ranged from 0.5 to 2 mL per hour, with an option for turning the infusion off when the patient had no pain and turning it on when the pain returned. Infusions were continued from 2 to 55 days, during which time the patient was at home. In Group A, only two patients had nausea without emesis, while in Group B, nausea occurred in 18 patients (P < 0.04) and four vomited (P < 0.05). The number of patients with headache, pruritus, somnolence, and/or numbness was minimal and without statistically significant group differences. During treatments, pain levels were 2 or less on a 10-cm visual analogue scale. Added to the epidural infusate, droperidol appears to significantly reduce nausea and vomiting in ambulatory patients receiving fentanyl and bupivacaine in extended epidural infusions. The possibility that droperidol potentiates analgesic effects could not be evaluated.

  2. Tropisetron sensitizes α7 containing nicotinic receptors to low levels of acetylcholine in vitro and improves memory-related task performance in young and aged animals.


    Callahan, Patrick M; Bertrand, Daniel; Bertrand, Sonia; Plagenhoef, Marc R; Terry, Alvin V


    Tropisetron, a 5-HT3 receptor antagonist commonly prescribed for chemotherapy-induced nausea and vomiting also exhibits high affinity, partial agonist activity at α7 nicotinic acetylcholine receptors (α7 nAChRs). α7 nAChRs are considered viable therapeutic targets for neuropsychiatric disorders such as Alzheimer's disease (AD). Here we further explored the nAChR pharmacology of tropisetron to include the homomeric α7 nAChR and recently characterized heteromeric α7β2 nAChR (1:10 ratio) and we evaluated its cognitive effects in young and aged animals. Electrophysiological studies on human nAChRs expressed in Xenopus oocytes confirmed the partial agonist activity of tropisetron at α7 nAChRs (EC50 ∼2.4 μM) with a similar effect at α7β2 nAChRs (EC50 ∼1.5 μM). Moreover, currents evoked by irregular pulses of acetylcholine (40 μM) at α7 and α7β2 nAChRs were enhanced during sustained exposure to low concentrations of tropisetron (10 and 30 nM) indicative of a "priming" or co-agonist effect. Tropisetron (0.1-10 mg/kg) improved novel object recognition performance in young Sprague-Dawley rats and in aged Fischer rats. In aged male and female rhesus monkeys, tropisetron (0.03-1 mg/kg) produced a 17% increase from baseline levels in delayed match to sample long delay accuracy while combination of non-effective doses of donepezil (0.1 mg/kg) and tropisetron (0.03 and 0.1 mg/kg) produced a 24% change in accuracy. Collectively, these animal experiments indicate that tropisetron enhances cognition and has the ability to improve the effective dose range of currently prescribed AD therapy (donepezil). Moreover, these effects may be explained by tropisetron's ability to sensitize α7 containing nAChRs to low levels of acetylcholine.

  3. Acute treatment with 5-HT3 receptor antagonist, tropisetron, reduces immobility in intact female rats exposed to the forced swim test.


    Bravo, Gabriela; Maswood, Sharmin


    The effects of tropisetron, a 5-HT3 receptor antagonist, were evaluated in adult Fischer female rats exposed to the Forced Swim Test (FST). Rats selected on the days of proestrus or estrus was immersed in a cylinder of water for 2 consecutive days. Rats were exposed to the FST for 15 min on day 1 (pretest), followed by a 5-min session (test), 24 h later. The proestrous-estrous group consisted of rats that were exposed to the FST on their proestrous stage (pretest); then 24 h later the same rats were exposed to the FST on their estrous stage (test). Rats in the estrous-diestrous group were exposed to the FST on their estrous stage (pretest) and 24 h later on their diestrous stage (test). Rats were injected intraperitoneally with saline or 1.0 or 2.0 mg/kg tropisetron 30 min prior to exposure to the cylinder on the test day. Immobility, swimming, and struggling behaviors were scored for 5 min. There was a significant decline in immobility after treatment with 2.0 mg/kg tropisetron in both groups. In addition, a significant decline in swimming was observed in the estrous rats (proestrous-estrous group) after treatment with 2.0 mg/kg tropisetron. There were no significant effects of tropisetron on struggling in any groups examined.

  4. Involvement of nitric oxide-cyclic guanosine monophosphate pathway in the antidepressant-like effect of tropisetron and ondansetron in mice forced swimming test and tail suspension test.


    Haj-Mirzaian, Arya; Kordjazy, Nastaran; Amiri, Shayan; Haj-Mirzaian, Arvin; Amini-Khoei, Hossien; Ostadhadi, Sattar; Dehpour, AhmadReza


    Antidepressant-like effects of 5-hydroxytryptamine subtype 3 (5-HT3) antagonists including tropisetron and ondansetron have been previously demonstrated in the literature. It was reported that stimulation of 5-HT3 receptors activate the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway, which is involved in regulation of behavioral and emotional functions. In our study, treating animals with tropisetron (5, 10, and 30mg/kg) and ondansetron (0.01 and 0.1µg/kg) significantly decreased the immobility time in forced swimming test (FST) and tail-suspension test (TST). Co-administration of subeffective doses of tropisetron (1mg/kg) and ondansetron (0.001µg/kg) with subeffective dose of l-NAME (10mg/kg, nonselective NO synthase (NOS) inhibitor) and 7-nitroindazole (25mg/kg, neural NOS inhibitor) exerted antidepressant-like effect in FST and TST, while aminoguanidine (50mg/kg, inducible NOS inhibitor) did not enhance the antidepressant-like effect of 5-HT3 antagonists. Besides, l-arginine (750mg/kg, NO precursor) and sildenafil (5mg/kg, phosphodiesterase inhibitor) suppressed the anti-immobility effect of 5-HT3 antagonists. None of the treatments altered the locomotor behavior of mice in open-field test. Also, hippocampal (but not cortical) nitrite level was significantly lower in tropisetron and ondansetron-treated mice compared with saline-injected mice. Also, co-administration of 7-nitroindazole with tropisetron or ondansetron caused a significant decrease in hippocampal nitrite levels. In conclusion, we suggest that antidepressant-like effect of tropisetron and ondansetron are partially mediated by modulation of NO-cGMP pathway.

  5. Effects of droperidol on depolarization-induced automaticity, maximum upstroke velocity (Vmax) and the kinetics of recovery of Vmax in guinea-pig ventricular myocardium.


    Grant, A O; Hondeghem, L M; Katzung, B G


    The neuroleptic drug droperidol has been shown to have clinically useful antiarrhythmic activity. Prior reports have resulted in conflicting conclusions regarding actions on ventricular myocardial fibers. The present study was carried out to determine whether droperidol did in fact affect the electrophysiological properties of guinea-pig papillary muscle fibers. By means of microelectrode recordings from preparations mounted in a single sucrose gap, the effects of concentrations from 10(-6) to 4 X 10(-5) M were studied on depolarization-induced automaticity, and on Vmax and its recovery time under several conditions of membrane potential, stimulation rate and external ion concentration. The results showed that at clinically relevant concentrations, droperidol significantly slows ventricular pacemaker activity, a depression reversible by epinephrine. Furthermore, Vmax was decreased and the time constant for Vmax recovery was significantly prolonged under several conditions which pertain to clinical arrhythmias, i.e., reduced membrane potential, elevated extracellular potassium concentrations and increased stimulation rate.

  6. Simultaneous Determination of Dexamethasone, Ondansetron, Granisetron, Tropisetron, and Azasetron in Infusion Samples by HPLC with DAD Detection

    PubMed Central

    Chen, Fu-chao; Wang, Lin-hai; Guo, Jun; Shi, Xiao-ya


    A simple and rapid high-performance liquid chromatography with diode array detector (HPLC-DAD) method has been developed and validated for simultaneous quantification of five antiemetic agents in infusion samples: dexamethasone, ondansetron, granisetron, tropisetron, and azasetron. The chromatographic separation was achieved on a Phenomenex C18 column (4.6 mm × 150 mm, 5 μm) using acetonitrile-50 mM KH2PO4 buffer-triethylamine (25 : 74 : 1; v/v; pH 4.0). Flow rate was 1.0 mL/min with a column temperature of 30°C. Validation of the method was made in terms of specificity, linearity, accuracy, and intra- and interday precision, as well as quantification and detection limits. The developed method can be used in the laboratory to routinely quantify dexamethasone, ondansetron, granisetron, tropisetron, and azasetron simultaneously and to evaluate the physicochemical stability of referred drugs in mixtures for endovenous use. PMID:28168082

  7. [Clinical study on total intravenous anesthesia with droperidol, fentanyl and ketamine--12. Effects on plasma complement and immunoglobulin concentrations].


    Hashimoto, H; Araki, I; Sato, T; Takagi, Y; Hashimoto, Y; Ishihara, H; Matsuki, A


    Complements and immunoglobulins in the plasma are the important humoral factors to maintain immunity. As there is no study on immune response to total intravenous anesthesia with droperidol, fentanyl and ketamine (DFK), twelve patients who underwent abdominal, neck dissection, or plastic surgery were studied to determine plasma concentrations of complements and immunoglobulins. In five patients of isoflurane group, anesthesia was induced with intravenous thiopental 5 and succinylcholine 0.8-1 and maintained with 1-2% isoflurane in nitrous oxide (50%) and oxygen (50%). The remaining seven patients of the DFK group received intravenous droperidol 0.25, fentanyl 1-2, ketamine 1-1.5 and succinylcholine 0.8-1 for the induction of anesthesia, and then they were given a total dose of fentanyl 5-15, ketamine 2 and oxygen (30%) for the maintenance of anesthesia. Vecuronium was given intravenously as needed. Lactated Ringer's solution was used for intraoperative fluid replacement. A total of 40 ml of arterial blood was drawn on four occasions, just before the induction of anesthesia, at the recovery from anesthesia, on the third and tenth post-operative days. Plasma concentrations of complements (C3.C4) and immunoglobulins (IgG.IgA.IgM.IgD) were measured by immuno-turbidimetry. C3 concentrations in the plasma decreased significantly when the patients recovered from anesthesia, but they increased significantly on the third and tenth post-operative days in the isoflurane group. In the DFK group, they increased significantly on the tenth post-operative day only. No significant difference in the C3 concentrations was detected between two groups at any time of measurement.(ABSTRACT TRUNCATED AT 250 WORDS)

  8. HPLC, TLC, and first-derivative spectrophotometry stability-indicating methods for the determination of tropisetron in the presence of its acid degradates.


    Abdel-Fattah, Laila S; El-Sherif, Zeinab A; Kilani, Khadiga M; El-Haddad, Dalia A


    Three stability-indicating assay methods were developed for the determination of tropisetron in a pharmaceutical dosage form in the presence of its degradation products. The proposed techniques are HPLC, TLC, and first-derivative spectrophotometry (1D). Acid degradation was carried out, and the degradation products were separated by TLC and identified by IR, NMR, and MS techniques. The HPLC method was based on determination of tropisetron in the presence of its acid-induced degradation product on an RP Nucleosil C18 column using methanol-water-acetonitrile-trimethylamine (65 + 20 + 15 + 0.2, v/v/v/v) mobile phase and UV detection at 285 nm. The TLC method was based on the separation of tropisetron and its acid-induced degradation products, followed by densitometric measurement of the intact spot at 285 nm. The separation was carried out on silica gel 60 F254 aluminum sheets using methanol-glacial acetic acid (22 + 3, v/v) mobile phase. The 1D method was based on the measurement of first-derivative amplitudes of tropisetron in H2O at the zero-crossing point of its acid-induced degradation product at 271.9 nm. Linearity, accuracy, and precision were found to be acceptable over concentration ranges of 40-240 microg/mL, 1-10 microg/spot, and 6-36 micro/mL for the HPLC, TLC, and 1D methods, respectively. The suggested methods were successfully applied for the determination of the drug in bulk powder, laboratory-prepared mixtures, and a commercial sample.

  9. Fentanyl-droperidol-nitrous oxide anaesthesia in patients with ischaemic heart disease and various degrees of left ventricular functional impairment.


    Milocco, I; Schlossman, D; William-Olsson, G; Appelgren, L K


    Haemodynamic stability and left ventricular function (LVF) during induction of anaesthesia and sternotomy were compared in three groups of patients with ischaemic heart disease, angiographically classified as having good, poor and depressed LVF. Anaesthesia was given with fentanyl-droperidol and nitrous oxide. The group with good LVF showed large variations in arterial pressure and heart rate between stimulated and unstimulated states with a reasonable preservation of LVF, expressed as stroke volume, through the whole observation period. The group with poor LVF showed monotonously falling arterial pressure, and no heart rate response to tracheal intubation. These patients maintained remarkably stable stroke volumes in connection with low afterloads. After nitrous oxide, additional volume loading was required because of profound hypotension. The majority of the patients in the intermediate group, labelled "depressed LVF", reacted to intubation and sternotomy with signs of left ventricular failure in connection with tachycardia and increased afterloads. The individual variations between patients with different degrees of left ventricular impairment were considerable, and these haemodynamic patterns need to be confirmed with a larger material.

  10. A low dose of droperidol decreases the desflurane concentration needed during breast cancer surgery: a randomized double-blinded study

    PubMed Central

    Adachi, Yushi U; Makita, Koshi


    Background Droperidol (DHB) reportedly reduces the dose of propofol needed to achieve hypnosis when anesthesia is induced and decreases the bispectral index (BIS) in propofol-sedated patients during spinal anesthesia. We reported previously that supplemental DHB decreased the BIS after the administration of sevoflurane and remifentanil. This study investigated the effect of DHB on desflurane (DES) consumption in a clinical setting. Methods We conducted a prospective, randomized double-blinded study of 35 women with American Society of Anesthesiologist physical status I or II who underwent a mastectomy. Either DHB (20 µg/kg) or a saline placebo was administered to patients 30 min after the induction of anesthesia. A blinded anesthesiologist maintained a BIS value of 50 during anesthesia by modulating inhaled DES concentrations that changed 0.5% at 2.5 min intervals and maintained analgesia via the constant administration of remifentanil by referring to vital signs. The primary endpoint was the effect of DHB on DES consumption. The secondary endpoints included blood circulatory parameters, the time from the end of surgery to extubation, and discharge time between the groups. Results The characteristics of the patients did not differ between the groups. The DHB group used a mean of 27.2 ± 6.0 ml of DES compared with 41.4 ± 9.5 ml by the placebo group (P < 0.05). Conclusions A small dose of DHB reduced the DES concentration needed to maintain a BIS of 50. Our results show that DHB reduced the consumption of DES without adverse effects. PMID:28184263

  11. Hypoxia switches episodic breathing to singlet breathing in red-eared slider turtles (Trachemys scripta) via a tropisetron-sensitive mechanism.


    Johnson, Stephen M; Krisp, Ashley R; Bartman, Michelle E


    Hypoxia-induced changes in the chelonian breathing pattern are poorly understood. Thus, breathing was measured in freely swimming adult red-eared slider turtles breathing air prior to breathing nitrogen for 4h. Ventilation increased 10-fold within 10min due to increased breath frequency and tidal volume. Breaths/episode decreased by ∼50% within after 1h of hypoxia while the number of singlet breaths increased from 3.1±1.6singlets/h to a maximum of 66.1±23.5singlets/h. Expiratory and inspiratory duration increased during hypoxia. For doublet and triplet breaths, expiratory duration increased during the first breath only, while inspiratory duration increased for all breaths. Tropisetron (5-HT3 receptor antagonist, 5mg/kg) administration prior to hypoxia attenuated the hypoxia-induced increase in singlet breath frequency. Along with results from previous in vitro studies, this study suggests that 5-HT3 receptor activation may be required for the hypoxia-induced increase in singlet breathing pattern in red-eared slider turtles.

  12. Simultaneous RP-HPLC-DAD quantification of bromocriptine, haloperidol and its diazepane structural analog in rat plasma with droperidol as internal standard for application to drug-interaction pharmacokinetics

    PubMed Central

    Billups, Johnique; Jones, Cynthia; Jackson, Tanise L.; Ablordeppey, Seth Y.; Spencer, Shawn D.


    A simple and rapid RP-HPLC-DAD method was developed and validated for simultaneous determination of the dopamine antagonists haloperidol, its diazepane analog, and the dopamine agonist bromocriptine in rat plasma, to perform pharmacokinetic drug-interaction studies. Samples were prepared for analysis by acetonitrile (22.0 μg/mL) plasma protein precipitation with droperidol as an internal standard, followed by a double-step liquid-liquid extraction with hexane:chloroform (70:30) prior to C-18 separation. Isocratic elution was achieved using a 0.1% (v/v) trifluoroacetic acid in deionized water, methanol and acetonitrile (45/27.5/27.5, v/v/v). Triple-wavelength diode-array detection at the λmax of 245 nm for haloperidol, 254 nm for the diazepane analog and droperidol, and 240 nm for bromocriptine was carried out. The LLOQ of DAL, HAL, and BCT were 45.0, 56.1, and 150 ng/mL, respectively. In rats, the estimated pharmacokinetic parameters (i.e., t1/2, CL, and Vss) of HAL when administered with DAL and BCT were t1/2 = 16.4 min, Vss = 0.541 L/kg for HAL, t1/2 = 28.0 min, Vss = 2.00 L/kg for DAL, and t1/2 = 24.0 min, Vss = 0.106 L/kg for BCT. The PK parameters for HAL differed significantly from those previously reported, which may be an indication of a drug-drug interaction. PMID:19908205

  13. 21 CFR 522.800 - Droperidol and fentanyl citrate injection.

    Code of Federal Regulations, 2011 CFR


    ... use. (1) It is used in dogs as an analgesic and tranquilizer and for general anesthesia. (2) It is... sulfate administered at the rate of 0.02 milligram per pound of body weight. (ii) For general...

  14. 21 CFR 522.800 - Droperidol and fentanyl citrate injection.

    Code of Federal Regulations, 2010 CFR


    ... use. (1) It is used in dogs as an analgesic and tranquilizer and for general anesthesia. (2) It is... sulfate administered at the rate of 0.02 milligram per pound of body weight. (ii) For general...

  15. Effect of naloxone on intravenous fentanyl patient-controlled analgesia after laparoscopic cholecystectomy

    PubMed Central

    Zheng, Jun; Han, Wen; Han, Xiao-Dong; Ma, Xiao-Yuan; Zhang, Pengbo


    Abstract This study aims to evaluate the effect of naloxone on intravenous fentanyl patient-controlled analgesia after laparoscopic cholecystectomy under total intravenous anesthesia. A total of 90 patients, who underwent intravenous fentanyl patient-controlled analgesia after laparoscopic cholecystectomy under total intravenous anesthesia, were included into this study. All patients were randomly divided into 3 groups (each group, n=30): naloxone group (naloxone+fentanyl), tropisetron group (tropisetron+fentanyl), and fentanyl group (fentanyl). Patients in each group were given a corresponding dose of naloxone. Postoperative analgesia effect and the incidence of side effects such as nausea and vomiting were observed. Small doses of naloxone or tropisetron combined with fentanyl used for intravenous patient-controlled analgesia can significantly reduce the incidence of nausea and vomiting. Six hours after surgery, visual analogue scale (VAS) scores were significantly lower in patients that underwent intravenous patient-controlled analgesia using low-dose naloxone combined with fentanyl compared with patients who received fentanyl alone; however, the postoperative analgesic effect of tropisetron was not observed. Compared with the combination of tropisetron and fentanyl, low-dose naloxone combined with fentanyl can obviously reduce the incidence of nausea and vomiting in patients who underwent intravenous patient-controlled analgesia after laparoscopic cholecystectomy, and enhance the analgesic effect of fentanyl 6 hours after surgery. Low-dose naloxone can reduce the incidence of nausea and vomiting in patients who underwent laparoscopic cholecystectomy under total intravenous anesthesia, and exhibits a certain synergic analgesic effect. PMID:27902584

  16. Effect of naloxone on intravenous fentanyl patient-controlled analgesia after laparoscopic cholecystectomy.


    Zheng, Jun; Han, Wen; Han, Xiao-Dong; Ma, Xiao-Yuan; Zhang, Pengbo


    This study aims to evaluate the effect of naloxone on intravenous fentanyl patient-controlled analgesia after laparoscopic cholecystectomy under total intravenous anesthesia.A total of 90 patients, who underwent intravenous fentanyl patient-controlled analgesia after laparoscopic cholecystectomy under total intravenous anesthesia, were included into this study. All patients were randomly divided into 3 groups (each group, n=30): naloxone group (naloxone+fentanyl), tropisetron group (tropisetron+fentanyl), and fentanyl group (fentanyl). Patients in each group were given a corresponding dose of naloxone. Postoperative analgesia effect and the incidence of side effects such as nausea and vomiting were observed.Small doses of naloxone or tropisetron combined with fentanyl used for intravenous patient-controlled analgesia can significantly reduce the incidence of nausea and vomiting. Six hours after surgery, visual analogue scale (VAS) scores were significantly lower in patients that underwent intravenous patient-controlled analgesia using low-dose naloxone combined with fentanyl compared with patients who received fentanyl alone; however, the postoperative analgesic effect of tropisetron was not observed. Compared with the combination of tropisetron and fentanyl, low-dose naloxone combined with fentanyl can obviously reduce the incidence of nausea and vomiting in patients who underwent intravenous patient-controlled analgesia after laparoscopic cholecystectomy, and enhance the analgesic effect of fentanyl 6 hours after surgery.Low-dose naloxone can reduce the incidence of nausea and vomiting in patients who underwent laparoscopic cholecystectomy under total intravenous anesthesia, and exhibits a certain synergic analgesic effect.

  17. A Randomized Prospective Trial Comparing Paravertebral Block and General Anesthesia for Operative Treatment of Breast Cancer

    DTIC Science & Technology


    Total Fluid Outputs Bolus Drug Totals 6 mg Vancomycin 450 ug Diphenhydramine 0.75 mg Ondansetron 30 mg Inhalation Drug Totals 1000 mg 25 mg 8mg...511.5L Fentanyl 450 ug Midazolam 6mg Propofol 30 mg Vancomycin 1000 mg Diphenhydramine 25 mg Droperidol 0.75 mg Ondansetron 8mg L/min [150...CASE NUMBER 2T7KHC0U.106 02 Umin Fentanyl M9 Midazolam mg Propofol mg Vancomycin mg Diphenhydramine mg Droperidol mg Ondansetron mg 07-20

  18. 5-HT3 receptors antagonists reduce serotonin-induced scratching in mice.


    Ostadhadi, Sattar; Kordjazy, Nastaran; Haj-Mirzaian, Arya; Mansouri, Parvin; Dehpour, Ahmad Reza


    Serotonin (5-hydroxytryptamine, 5-HT) acts as a pruritogen in humans and animals, but the mechanisms of action through that serotonin induces itch response have not been extensively discovered. In our study, we attempted to investigate the role of 5-HT3 receptors in scratching behavior due to intradermal serotonin injection. Intradermal injection of serotonin (14.1-235 nmol/site) into the nape of the neck of mice was performed to elicit itch. Scratching behavior was evaluated by measuring the number of bouts during 60 min after injection. We evaluated the effect of intraperitoneal pretreatment with ondansetron and tropisetron (0.1, 0.3, and 1 mg/kg) on itch induced by serotonin. Also, intradermal ondansetron and tropisetron at doses 50, 100, and 200 nmol/site were concurrently administrated with serotonin. Serotonin produced a significant enhancement in scratching at dose 141 nmol/site. Concurrent administration of ondansetron (50, 100, and 200 nmol/site) and tropisetron (100 and 200 nmol/site) with serotonin reduced scratching activity compared to the animals that only received serotonin. Also, pretreatment with intraperitoneal ondansetron and tropisetron (0.3 and 1 mg/kg) 30 min before serotonin attenuated the itch response. We showed that the scratching induced by intradermal serotonin is mediated by 5-HT3 receptors subtype. It can be concluded that 5-HT3 may play a role in mediating serotonin-associated itch responses, and we introduce 5-HT3 receptors as possible targets for antipruritic agents.

  19. Local-anesthetic like inhibition of the cardiac sodium channel Nav1.5 α-subunit by 5-HT3 receptor antagonists.


    Van't Klooster, Mariet P; Foadi, Nilufar; Hage, Axel; Stoetzer, Carsten; Wegner, Florian; Eberhardt, Mirjam; Leffler, Andreas


    5-hydroxytryptamine 3 receptor (5-HT3 receptor) antagonists are administered for prevention and therapy of nausea and vomiting. Although regarded as safe therapeutics, they can also provoke arrhythmias by prolonging the QRS interval. However, the mechanisms mediating this cardiotoxicity are poorly understood. Here we investigated effects of 5-HT3 receptor antagonists on the cardiac Na(+) channel Nav1.5. We explored the interaction of dolasetron, tropisetron, granisetron and ondansetron on the human α-subunit Nav1.5 heterologously expressed in HEK293 cells. Sodium currents were explored by means of whole-cell patch clamp recordings. All four substances inhibited the Nav1.5 in a concentration and state-dependent manner. Dolasetron displayed the lowest blocking efficacy, and tropisetron was the most potent blocker with a half maximum blocking concentration of 18µM for tonic block of inactivated channels. Tropisetron was also the most potent use-dependent inhibitor, and it also induced a strong open -channel block. Both tonic and use-dependent block by tropisetron were abbreviated on the local-anesthetic insensitive mutant Nav1.5-F1760A. Co-administration of tropisetron and the local anesthetic bupivacaine or the hypnotic propofol augmented inhibition of Nav1.5. Our data demonstrate that 5-HT3 receptor antagonists induce a local-anesthetic like inhibition of Nav1.5, and that they display different blocking efficacies. Reports on a relevant cardiotoxicity of dolasetron as opposed to other 5-HT3 receptor antagonists do not seem to correlate with a block of Nav1.5. As inhibition of Nav1.5 was enhanced by propofol and bupivacaine however, it is possible that a combined administration of Na(+) channel blockers and 5-HT3 receptor antagonists can provoke arrhythmias.

  20. The binding orientations of structurally-related ligands can differ; A cautionary note.


    Ruepp, Marc-David; Wei, Hao; Leuenberger, Michele; Lochner, Martin; Thompson, Andrew J


    Crystal structures can identify ligand-receptor interactions and assist the development of novel therapeutics, but experimental challenges sometimes necessitate the use of homologous proteins. Tropisetron is an orthosteric ligand at both 5-HT3 and α7 nACh receptors and its binding orientation has been determined in the structural homologue AChBP (pdbid: 2WNC). Co-crystallisation with a structurally-related ligand, granisetron, reveals an almost identical orientation (pdbid; 2YME). However, there is a >1000-fold difference in the affinity of tropisetron at 5-HT3 versus α7 nACh receptors, and α7 nACh receptors do not bind granisetron. These striking pharmacological differences prompt questions about which receptor the crystal structures most closely represent and whether the ligand orientations are correct. Here we probe the binding orientation of tropisetron and granisetron at 5-HT3 receptors by in silico modelling and docking, radioligand binding on cysteine-substituted 5-HT3 receptor mutants transiently expressed in HEK 293 cells, and synthetic modification of the ligands. For 15 of the 23 cysteine substitutions, the effects on tropisetron and granisetron were different. Structure-activity relationships on synthesised derivatives of both ligands were also consistent with different orientations, revealing that contrary to the crystallographic evidence from AChBP, the two ligands adopt different orientations in the 5-HT3 receptor binding site. Our results show that even quite structurally similar molecules can adopt different orientations in the same binding site, and that caution may be needed when using homologous proteins to predict ligand binding.

  1. Airborne testing of three antimotion sickness preparations

    NASA Technical Reports Server (NTRS)

    Johnson, W. H.; Money, K. E.; Graybiel, A.


    Thirteen human volunteers were exposed to weekly flights in which standardized, steep turns were used to produce motion sickness. A combination of promethazine hydrochloride (25 mg) plus ephedrine sulphate (25 mg) was found to be equally as effective as the combination of 1-scopolamine hydrobromide (0.35 mg) plus d-amphetamine sulphate (5 mg). Droperidol (2.5 mg) was indistinguishable from the placebo. It was concluded that the treatment of choice for motion sickness is promethazine plus ephedrine.

  2. A tribute to Dr. Paul A. J. Janssen: entrepreneur extraordinaire, innovative scientist, and significant contributor to anesthesiology.


    Stanley, Theodore H; Egan, Talmage D; Van Aken, Hugo


    Dr. Paul Janssen was the founder of Janssen Pharmaceutica and the developer of over 80 pharmaceutical compounds that proved useful in human, botanical, and veterinary medicine. He and his coworkers synthesized the fentanyl family of drugs, many other potent analgesics, droperidol, etomidate, and numerous other important medicines that were extremely useful in psychiatry, parasitology, gastroenterology, cardiology, virology, and immunology. Anesthesiology and medicine as a whole have benefited a great deal from his resourcefulness, creativity, and entrepreneurial spirit.

  3. Blockade of peripheral 5HT3 receptor attenuates the formalin-induced nocifensive behavior in persistent temporomandibular joint inflammation of rat.


    Okamoto, Keiichiro; Imbe, Hiroki; Tashiro, Akimasa; Kumabe, Shunji; Senba, Emiko


    The role of peripheral 5HT3 receptors in the orofacial nocifensive behavior induced by the injection of formalin into masseter muscle was evaluated. The behavioral activities evoked by the formalin injection exhibited a biphasic response in the rats with or without temporomandibular joint (TMJ) inflammation (CFA group or non-CFA group). The orofacial nocifensive behavioral activity was enhanced after TMJ inflammation. Systemic administration of tropisetron, 5HT3 receptor antagonist, reduced the nocifensive behavioral activities in the late phase of orofacial formalin test in CFA group, but not in non-CFA group. Local administration of tropisetron into the masseter muscle in CFA group, but not in non-CFA group also attenuated the behavioral activities in the late phase. Unexpectedly, low dose of local tropisetron reduced the nocifensive behavioral activities in the early phase of orofacial formalin test in CFA group. These data suggest that induction of TMJ inflammation causes the elevation of the orofacial nocifensive behavioral activities evoked by formalin injection into masseter muscle, and that peripheral 5HT3 receptors may play a critical role in nociception and the transmission of orofacial pain.

  4. From Chemotherapy-Induced Emesis to Neuroprotection: Therapeutic Opportunities for 5-HT3 Receptor Antagonists.


    Fakhfouri, Gohar; Mousavizadeh, Kazem; Mehr, Sharam Ejtemaei; Dehpour, Ahmad Reza; Zirak, Mohammad Reza; Ghia, Jean-Eric; Rahimian, Reza


    5-HT3 receptor antagonists are extensively used as efficacious agents in counteracting chemotherapy-induced emesis. Recent investigations have shed light on other potential effects (analgesic, anxiolytic, and anti-psychotic). Some studies have reported neuroprotective properties for the 5-HT3 receptor antagonists in vitro and in vivo. When administered to Aβ-challenged rat cortical neurons, 5-HT3 receptor antagonists substantially abated apoptosis, elevation of cytosolic Ca(2), glutamate release, reactive oxygen species (ROS) generation, and caspase-3 activity. In addition, in vivo studies show that 5-HT3 receptor antagonists possess, alongside their anti-emetic effects, notable immunomodulatory properties in CNS. We found that pretreatment with tropisetron significantly improved neurological deficits and diminished leukocyte transmigration into the brain, TNF-α level, and brain infarction in a murine model of embolic stroke. Our recent investigation revealed that tropisetron protects against Aβ-induced neurotoxicity in vivo through both 5-HT3 receptor-dependent and -independent pathways. Tropisetron, in vitro, was found to be an efficacious inhibitor of the signaling pathway leading to the activation of pro-inflammatory NF-κB, a transcription factor pivotal to the upregulation of several neuroinflammatory mediators in brain. This mini review summarizes novel evidence concerning effects of 5-HT3 antagonists and their possible mechanisms of action in ameliorating neurodegenerative diseases including Alzheimer, multiple sclerosis, and stroke. Further, we discuss some newly synthesized 5-HT3 receptor antagonists with dual properties of 5-HT3 receptor blockade/alpha-7 nicotinic receptor activator and their potential in management of memory impairment. Since 5-HT3 receptor antagonists possess a large therapeutic window, they can constitute a scaffold for design and synthesis of new neuroprotective medications.

  5. [acute dystonias in combined abuse of cocaine and neuroleptics].


    Horwitz, E H; van Harten, P N


    A 25-year-old mildly retarded black cocaine user was hospitalized 15 times in 10 years for recurrent maniform psychosis. During the last intake he developed severe dystonia following zuclopenthixol 50 mg and droperidol 10 mg i.m. In view of current knowledge regarding the pathophysiology of acute neuroleptic induced dystonias, this suggests that cocaine may be a risk factor for development of acute dystonia. However, only a few studies with small numbers of patients and/or poor design have been reported. Therefore the conclusion cannot be drawn that an anticholinergic should be added to neuroleptics in patients with cocaine abuse.

  6. Comparison of two intravenous sedation techniques for percutaneous radio frequency trigeminal rhizotomy. A pilot study.


    Speedie, L J; Tung, T J; Shane, S M; Chase, G A; Brake, N; Epstein, M H


    Conscious sedation, as used in dentistry and oral surgery, has been used satisfactorily to manage patients undergoing the intense pain encountered in radio frequency trigeminal rhizotomy for tic douloureux. The pain produced by this procedure cannot be blocked by local anesthesia. General anesthesia cannot be used because of the need for sensory testing in an awake, cooperative patient. Conscious sedation using alphaprodine, hydroxyzine, methohexital, and intensive behavioral modification was compared with a neuroleptic intravenous sedation technique using droperidol, fentanyl, and thiopental. Patients managed with conscious sedation were found to be more amnestic for the pain of surgery, a difference that persisted six months later.

  7. Induction of emesis in Suncus murinus by pyrogallol, a generator of free radicals.

    PubMed Central

    Torii, Y.; Saito, H.; Matsuki, N.


    1. We investigated whether or not pyrogallol, a generator of free radicals, is emetogenic in Suncus murinus, the house musk shrew. Pyrogallol (i.p.) caused dose-dependent emesis in suncus with an ED50 value of 77.3 mg kg-1. At a dose of 128 mg kg-1, all suncus vomited with mean latency of 18.8 +/- 5.2 min and the number of vomiting episodes was 8.6 +/- 2.9. 2. The prophylactic effects of N-(2-mercaptopropionyl)-glycine (MPG), an antioxidant, and tropisetron, a 5-hydroxytryptamine3 (5-HT3) receptor antagonist, were studied. Pyrogallol (128 mg kg-1, i.p.)-induced emesis was prevented by treatment with MPG (i.p.) or tropisetron (s.c.) with ID50 values of 149 mg kg-1 and 117 micrograms kg-1, respectively. 3. Pyrogallol-induced emesis was completely prevented by surgical abdominal vagotomy. 4. The present results indicate that pyrogallol-induced emesis is characteristically very similar to that caused by cisplatin and support the idea that generation of free radicals causes the release of peripheral 5-HT, which stimulates vagal afferent sensory nerves to cause emesis. PMID:8004387

  8. Downregulated hypothalamic 5-HT3 receptor expression and enhanced 5-HT3 receptor antagonist-mediated improvement in fatigue-like behaviour in cholestatic rats.


    Nguyen, H; Wang, H; le, T; Ho, W; Sharkey, K A; Swain, M G


    The serotonin neurotransmitter system, including the 5-HT(3) receptor, has been implicated in the genesis of fatigue in patients with liver disease. Therefore, we examined the possible role of 5-HT(3) receptors in cholestasis-associated fatigue. Rats were either bile duct resected (BDR) or sham resected and studied 10 days postsurgery. A significant decrease in hypothalamic 5-HT(3) receptor expression was detected by immunohistochemistry and Western blot in BDR vs sham rats, coupled with increased hypothalamic serotonin turnover identified by an elevated 5-hydroxyindoleacetic acid (5-HIAA) to 5-HT ratio in BDR vs sham rats. To examine fatigue-like behaviour, an activity meter was used. BDR rats exhibited significantly lower locomotor activity than did sham animals. Subcutaneous injection of the 5-HT(3) receptor antagonist tropisetron (0.1 mg kg(-1)) resulted in significantly increased locomotor activity in BDR rats compared to the activity in saline-treated controls, but was without effect in sham rats. However, a 10-fold higher dose of tropisetron significantly increased locomotor activity in both BDR and sham rats compared to saline-injected controls. These findings indicate that cholestasis in the rat is associated with increased hypothalamic serotonin turnover, decreased hypothalamic 5-HT(3) receptor expression, and enhanced sensitivity to locomotor activation induced by 5-HT(3) receptor antagonism, thereby implicating the 5-HT(3) receptor system in cholestasis associated fatigue.

  9. Systemic injection of p-chloroamphetamine eliminates the effect of the 5-HT3 compounds on learning.


    Hong, E; Meneses, A


    There is evidence that 5-HT3 antagonists enhance learning and memory; however, their mechanisms of action are unknown. The aim of the present work was to investigate further the role of 5-HT3 receptors involved in learning, using the specific 5-HT3 agonist 1-(m-chlorophenyl)-biguanide (mCPBG) and the 5-HT3 antagonists ondansetron and tropisetron. p-Chloroamphetamine (PCA) pretreatment was used to determine whether pre- or postsynaptic 5-HT3 receptors are involved in learning. The posttraining intraperitoneal (IP) injection of each drug was analyzed on a lever-press response on autoshaping, which is an associative learning task. The results showed that mCPBG impaired retention of the conditioned response (CR), whereas tropisetron and ondansetron improved it. In other animals, PCA alone did not affect CR but was able to block the effects of the 5-HT3 ligands. The present data suggest that the actions of 5-HT3 compounds could be due to their interaction with presynaptic 5-HT3 receptors.

  10. Influence of dopamine as noradrenaline precursor on the secretory function of the bovine corpus luteum in vitro.

    PubMed Central

    Kotwica, J.; Skarzynski, D.; Bogacki, M.; Miszkiel, G.


    1. Dopamine is assumed to affect the ovary function after its conversion into noradrenaline (NA). 2. To study this bovine luteal slices from 11-14 days of the oestrous cycle were preincubated for 24 h to recover beta-receptors and next they were incubated for 1, 2 or 4 h with (a) different doses of dopamine; (b) dopamine together with a beta-antagonist (propranolol) or with a dopamine receptor blocker (droperidol); (c) dopamine with a dopamine-beta-hydroxylase inhibitor. 3. Dopamine stimulated the luteal content of oxytocin (OT) and progesterone. This effect was inhibited by propanolol but not by droperidol. 4. Dopamine added to the medium was followed by an increase of noradrenaline there. This rise was dose and time-dependent. 5. The dopamine-beta-hydroxylase inhibitor, inhibited the stimulating effect of dopamine on luteal progesterone and OT content. 6. Bovine corpus luteum can synthesize de novo NA from dopamine as a precursor. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 PMID:8842430

  11. [The metoclopramide effect on enteral nutrition tolerance and mechanical ventilation associated pneumonia in neuro critically ill patients].


    Acosta-Escribano, Jose; Almanza López, Susana; Plumed Martín, Lidia; García Martinez, Miguel Angel; Tajadura Manjarín, Nuria


    Introducción: El uso de procinéticos en el paciente crítico con nutrición enteral, tienen como objetivo el reducir el aumento del residuo gástrico (RG). Analizamos su eficacia en la mejoría del aporte enteral y sobre la reducción en la incidencia complicaciones gastrointestinales (CGI) y neumonía, en pacientes críticos, con lesión neurológica Objetivos: Medir los efectos en la administración metoclopramida (MCG) durante los primeros cinco días con nutrición enteral, versus control (GC), sobre el volumen de dieta enteral administrada, el número de complicaciones gastrointestinales y la incidencia de neumonía asociada a ventilación mecánica (NAVM); en enfermos neurocríticos de etiología traumática y vascular. Métodos: De los 150 pacientes NC ingresados de forma consecutiva, 109 fueron aleatorizados en dos grupos: 58 MCG y 51 GC. Los objetivos primarios fueron: nutricionales: el volumen de dieta administrada (VDA), el volumen eficaz (VEM), el número de complicaciones gastrointestinales (CGI) y la tasa de suspensión temporal y definitiva de la dieta. Infecciosos: incidencia de neumonía asociada a ventilación mecánica (NAVM). Fueron objetivos secundarios: la duración de la ventilación mecánica, la estancia en UCI y hospitalaria, la secuela neurológica grave al alta y la mortalidad a los 30 días. Resultados: No se observaron diferencias en los parámetros de gravedad entre grupos al ingreso. Un incremento significativo fue observado en el análisis global y a los cinco días (p < 0,03) del VEM en el grupo de MCG. Los valores del VDA global y durante las dos fases de estudio, el número de CGI y el número de suspensiones parciales y definitivas de la dieta o el número de NAVM fueron similares en ambos grupos, no significativos. Tampoco se observaron diferencias en los diferentes objetivos secundarios Conclusión: El uso de metoclopramida en el enfermo neurocrítico, no es eficaz en la disminución de las CGI, en las dosis y tiempo de

  12. [Psychiatric drugs as risk factor in fatal heat stroke].


    Fijnheer, R; van de Ven, P J; Erkelens, D W


    Two men aged 33 and 31 years suffered a fatal heat stroke on a warm summer day. One of them used pimozide and clomipramine, the other zuclopenthixol, dexetimide, droperidol, promethazine and propranolol as psychiatric medication. Both of them had a body temperature > 42.3 degrees C, without perspiring. At first only a comatose situation with practically normal laboratory values existed; this was rapidly followed by massive liver damage, disseminated intravascular coagulation, anaemia, thrombopenia and acute renal failure. In spite of adequate and rapid treatment these complications were fatal. Both patients used medication with an antidopaminergic and anticholinergic (side) effect. The set point of the temperature regulation centre can be elevated by the antidopaminergic activity of antipsychotics. Use of anticholinergic medication can disturb the thermoregulation via inhibition of the parasympathicomimetically mediated sweat secretion. It is recommended to point out the danger of unusually high outdoor temperatures to patients using this medication.

  13. Neuroleptanesthesia for the guinea pig. An ideal anesthetic procedure for long-term physiological studies of the cochlea.


    Evans, E F


    The guinea pig is notoriously difficult to anesthetize with conventional agents. Cardiorespiratory depression by general depressant anesthetic agents can render the cochlea abnormal. I report a technique that uses the specific neuroleptic and analgesia properties of the agents droperidol and phenoperidine, respectively, in combination with small doses of pentobarbital sodium, which is required only to produce unconsciousness. These agents can be given intraperitoneally, intramuscularly, or intravenously. The regimen allows performance of substantial surgery (including intracranial) and long-term (minimum, six to ten hours) physiological studies, such as those on the cochlea, with excellent cardiorespiratory stability. The method has been in continuous use in this laboratory since 1974 for single-fiber recordings from the cochlear nerve of normal and kanamycin-treated guinea pigs. This method has proved to be substantially more effective than use of pentobarbital, thiopental sodium, urethan, chloralose, or ketamine alone.

  14. Randomized, placebo-controlled trial of K1 acupoint acustimulation to prevent cisplatin- or oxaliplatin-induced nausea

    PubMed Central

    Shen, Yehua; Liu, Luming; Chiang, Joseph S.; Meng, Zhiqiang; Garcia, M. Kay; Chen, Zhen; Peng, Huiting; Bei, Wenying; Zhao, Qi; Spelman, Amy R.; Cohen, Lorenzo


    Background More than 70% of cancer patients experience chemotherapy-induced nausea and vomiting (CINV). We examined the effects of electrostimulation of the K1 acupoint located on the sole of the foot, as it is thought to have potential to control CINV. Methods In this trial, 103 patients diagnosed with primary or metastatic liver cancer were recruited before trans-catheter arterial infusion (TAI) of cisplatin (CDDP) or oxaliplatin (OXA) and randomized to group A (N=51; treated with the antiemetic tropisetron and acustimulation at the K1 acupoint for 20 minutes, 1-2 hours before TAI on the first day and then daily for the subsequent 5 days) or group B (N=53; treated with tropisetron and electrostimulation at a placebo point on the heel). The rate, intensity, and duration of nausea and vomiting were collected at baseline and then daily for 5 days after TAI. Quality of life was assessed daily using the MD Anderson Symptom Inventory (MDASI) and the EuroQoL scale. Results No differences were found between groups A and B in the incidence and degree of nausea or vomiting on day 1 or the consecutive 5 days. Patients in group A had better EuroQoL scores than did patients in group B (A: 72.83 versus B: 65.94, P = 0.04) on day 4 but not on the other days. No group differences were noted at any time point for MDASI scores. Conclusions Electrostimulation of K1 combined with antiemetics did not result in initial prevention of CDDP- or OXA-induced nausea or vomiting. PMID:25204437

  15. Synergistic antiemetic interactions between serotonergic 5-HT3 and tachykininergic NK1-receptor antagonists in the least shrew (Cryptotis parva).


    Darmani, Nissar A; Chebolu, Seetha; Amos, Barry; Alkam, Tursun


    Significant electrophysiological and biochemical findings suggest that receptor cross-talk occurs between serotonergic 5-HT(3)- and tachykininergic NK(1)-receptors in which co-activation of either receptor by ineffective doses of their corresponding agonists (serotonin (5-HT) or substance P (SP), respectively) potentiates the activity of the other receptor to produce a response. In contrast, selective blockade of any one of these receptors attenuates the increase in abdominal vagal afferent activity caused by either 5-HT or SP. This interaction has important implications in chemotherapy-induced nausea and vomiting (CINV) since 5-HT(3)- and NK(1)-receptor antagonists are the major classes of antiemetics used in cancer patients receiving chemotherapy. The purpose of this study was to demonstrate whether the discussed interaction produces effects at the behavioral level in a vomit-competent species, the least shrew. Our results demonstrate that pretreatment with either a 5-HT(3) (tropisetron)- or an NK(1) (CP99,994)-receptor specific antagonist, attenuates vomiting caused by a selective agonist (2-methyl 5-HT or GR73632, respectively) of both emetic receptors. In addition, relative to each antagonist alone, their combined doses were 4-20 times more potent against vomiting caused by each emetogen. Moreover, combined sub-maximal doses of the agonists 2-methyl 5-HT and GR73632, produced 8-12 times greater number of vomits relative to each emetogen tested alone. However, due to large variability in vomiting caused by the combination doses, the differences failed to attain significance. The antiemetic dose-response curves of tropisetron against both emetogens were U-shaped probably because larger doses of this antagonist behave as a partial agonist. The data demonstrate that 5-HT(3)- and NK(1)-receptors cross-talk to produce vomiting, and that synergistic antiemetic effects occur when both corresponding antagonists are concurrently used against emesis caused by each

  16. [Postoperative nausea and vomiting and opioid-induced nausea and vomiting: guidelines for prevention and treatment].


    Gómez-Arnau, J I; Aguilar, J L; Bovaira, P; Bustos, F; De Andrés, J; de la Pinta, J C; García-Fernández, J; López-Alvarez, S; López-Olaondo, L; Neira, F; Planas, A; Pueyo, J; Vila, P; Torres, L M


    Postoperative nausea and vomiting (PONV) causes patient discomfort, lowers patient satisfaction, and increases care requirements. Opioid-induced nausea and vomiting (OINV) may also occur if opioids are used to treat postoperative pain. These guidelines aim to provide recommendations for the prevention and treatment of both problems. A working group was established in accordance with the charter of the Sociedad Española de Anestesiología y Reanimación. The group undertook the critical appraisal of articles relevant to the management of PONV and OINV in adults and children early and late in the perioperative period. Discussions led to recommendations, summarized as follows: 1) Risk for PONV should be assessed in all patients undergoing surgery; 2 easy-to-use scales are useful for risk assessment: the Apfel scale for adults and the Eberhart scale for children. 2) Measures to reduce baseline risk should be used for adults at moderate or high risk and all children. 3) Pharmacologic prophylaxis with 1 drug is useful for patients at low risk (Apfel or Eberhart 1) who are to receive general anesthesia; patients with higher levels of risk should receive prophylaxis with 2 or more drugs and baseline risk should be reduced (multimodal approach). 4) Dexamethasone, droperidol, and ondansetron (or other setrons) have similar levels of efficacy; drug choice should be made based on individual patient factors. 5) The drug prescribed for treating PONV should preferably be different from the one used for prophylaxis; ondansetron is the most effective drug for treating PONV. 6) Risk for PONV should be assessed before discharge after outpatient surgery or on the ward for hospitalized patients; there is no evidence that late preventive strategies are effective. 7) The drug of choice for preventing OINV is droperidol.

  17. A Factorial Trial of Six Interventions for the Prevention of Postoperative Nausea and Vomiting

    PubMed Central

    Apfel, Christian C.; Korttila, Kari; Abdalla, Mona; Kerger, Heinz; Turan, Alparslan; Vedder, Ina; Zernak, Carmen; Danner, Klaus; Jokela, Ritva; Pocock, Stuart J.; Trenkler, Stefan; Kredel, Markus; Biedler, Andreas; Sessler, Daniel I; Roewer, Norbert


    Background Untreated, one third of surgical patients suffer postoperative nausea and vomiting (PONV). The relative benefit of prophylactic interventions remains unknown, as does the efficacy of combining interventions. We therefore compared the efficacy of six antiemetic interventions and their combinations. Methods 5199 patients at high risk for PONV participated in a randomized, controlled trial of factorial design powered to evaluate interactions between up to three antiemetic interventions. 4123 patients were randomly assigned to one of 64 possible combinations of six prophylactic interventions: 1) 4 mg vs. no ondansetron; 2) 4 mg vs. no dexamethasone; 3) 1.25 mg vs. no droperidol; 4) propofol vs. a volatile anesthetic; 5) nitrogen vs. nitrous oxide; and 6) remifentanil vs. fentanyl. An additional 796 patients were randomized to 4 of all 6 interventions and an additional 280 patients were randomized to 80% oxygen in nitrogen as a third alternative to intervention 5. The blindly evaluated primary outcome was PONV within 24 hours. Results 5123 (99%) patients randomized to four interventions and 4086 of the 4123 patients (99%) randomized to all six interventions completed the study. Based on 4086 patients, ondansetron, dexamethasone, and droperidol each reduced PONV risk by about 26%. Propofol reduced risk by 19% and nitrogen by 12%; risk reduction with total intravenous anesthesia was thus similar to that resulting from antiemetics. All interventions acted independently, so that relative risk reduction for combined interventions could be estimated by the product of individual relative risk reductions. Similar results were obtained when all 5123 patients were analyzed. Conclusions Since each antiemetic drug and the total intravenous anesthesia similarly reduce relative risk, it seems sensible to use the least expensive or safest intervention first. Absolute risk is reduced less by additional interventions since the apparent baseline risk is already reduced. It is

  18. P2X3 receptors induced inflammatory nociception modulated by TRPA1, 5-HT3 and 5-HT1A receptors.


    Krimon, Suzy; Araldi, Dionéia; do Prado, Filipe César; Tambeli, Cláudia Herrera; Oliveira-Fusaro, Maria Cláudia G; Parada, Carlos Amílcar


    It has been described that endogenous ATP via activation of P2X3 and P2X2/3 receptors contributes to inflammatory nociception in different models, including the formalin injected in subcutaneous tissue of the rat's hind paw. In this study, we have evaluated whether TRPA1, 5-HT3 and 5-HT1A receptors, whose activation is essential to formalin-induced inflammatory nociception, are involved in the nociception induced by activation of P2X3 receptors on subcutaneous tissue of the rat's hind paw. We have also evaluated whether the activation of P2X3 receptors increases the susceptibility of primary afferent neurons to formalin action modulated by activation of TRPA1, 5-HT3 or 5-HT1A receptors. Nociceptive response intensity was measured by observing the rat's behavior and considering the number of times the animal reflexively raised its hind paw (flinches) in 60min. Local subcutaneous administration of the selective TRPA1, 5-HT3 or 5-HT1A receptor antagonists HC 030031, tropisetron and WAY 100,135, respectively, prevented the nociceptive responses induced by the administration in the same site of the non-selective P2X3 receptor agonist αβmeATP. Administration of the selective P2X3 and P2X2/3 receptor antagonist A-317491 or pretreatment with oligonucleotides antisense against P2X3 receptor prevented the formalin-induced behavioral nociceptive responses during the first and second phases. Also, the co-administration of a subthreshold dose of αβmeATP with a subthreshold dose of formalin induced nociceptive behavior, which was prevented by local administration of tropisetron, HC 030031 or WAY 100, 135. These findings have demonstrated that the activation of P2X3 receptors induces inflammatory nociception modulated by TRPA1, 5-HT3 and 5-HT1A receptors. Also, they suggest that inflammatory nociception is modulated by the release of endogenous ATP and P2X3 receptor activation, which in turn, increases primary afferent nociceptor susceptibility to the action of inflammatory

  19. 5-HT induces cAMP production in crypt colonocytes at a 5-HT4 receptor.


    Albuquerque, F C; Smith, E H; Kellum, J M


    Previous studies demonstrate that both 5-hydroxytryptamine (5-HT) and cyclic AMP (cAMP) induce chloride efflux from crypt colonocytes in the rat distal colon; antagonist studies suggest that the 5-HT response is mediated primarily by the 5-HT4 receptor. Since this receptor is known to be positively coupled to adenylate cyclase, we postulated that 5-HT should induce generation of cAMP, which should be inhibited by 5-HT4 antagonists. Method. Mucosal cells from rat distal colon were taken by a sequential calcium chelation technique for enrichment of crypt cells. Cytokeratin stains demonstrated that >99% of cells were colonocytes. [3H]Thymidine uptake studies demonstrate a fivefold increased incorporation in this cell preparation compared to earlier fractions. 3-Isobutyl-l-methylxanthine (IBMX, 100 microM) was added to all cell suspensions in order to prevent cAMP metabolism. Cell suspensions were incubated for 2 min at 37 degreesC with different concentrations of 5-HT (n = 7). cAMP was measured by enzyme immunoassay. In another series of experiments, 5-HT (0.3 microM) stimulation of cAMP was similarly measured in the presence and absence of 5-HT receptor antagonists: 10 microM 5-HTP-DP (5-HT1P; n = 4), 0.1 microM ketanserin (5-HT2A; n = 4), 0.3 microM ondansetron (5-HT3; n = 4), 3 microM tropisetron (5-HT3 and 5-HT4; n = 4), and 10 nM GR-113808 (5-HT4; n = 5). Results. 5-HT produced a dose-dependent increase in cAMP. The increase was significant at concentrations >/=0.3 microM when compared to cells incubated with IBMX alone. In the second series of experiment, 5-HT-induced generation of cAMP at a dose of 0.3 microM was significantly inhibited in the presence of GR-113808 and tropisetron. Conclusion. 5-HT acts at a 5-HT4 receptor to induce production of cAMP in rat distal crypt colonocytes.

  20. Effects of various serotonin agonists, antagonists, and uptake inhibitors on the discriminative stimulus effects of methamphetamine in rats.


    Munzar, P; Laufert, M D; Kutkat, S W; Nováková, J; Goldberg, S R


    Neurochemical studies indicate that methamphetamine increases central serotonin (5-HT) levels more markedly than other psychomotor stimulants such as amphetamine or cocaine. In the present study, we investigated 5-HT involvement in the discriminative stimulus effects of methamphetamine. In Sprague-Dawley rats trained to discriminate 1.0 mg/kg methamphetamine i.p. from saline under a fixed-ratio schedule of food presentation, the effects of selected 5-HT agonists, antagonists, and uptake inhibitors were tested. Fluoxetine (1.8-18.0 mg/kg) and clomipramine (3.0-18.0 mg/kg), selective serotonin uptake inhibitors, did not produce any methamphetamine-like discriminative stimulus effects when administered alone, but fluoxetine (5.6 mg/kg), unlike clomipramine (5.6 mg/kg), significantly shifted the methamphetamine dose-response curve to the left. Both 8-hydroxy-2-dipropylaminotetralin (0.03-0.56 mg/kg), a full agonist, and buspirone (1.0-10.0 mg/kg), a partial agonist at 5-HT(1A) receptors, partially generalized to the training dose of methamphetamine but only at high doses that decreased response rate. This generalization was antagonized by the coadministration of the 5-HT(1A) antagonist WAY-100635 (1.0 mg/kg). WAY-100635 (1.0 mg/kg) also partially reversed the leftward shift of the methamphetamine dose-response curve produced by fluoxetine. (+/-)-1-(2, 5-Dimethoxy-4-iodophenyl)-2-aminopropane (0.3 mg/kg), a 5-HT(2A/2C) agonist, shifted the methamphetamine dose-response curve to the left, and this leftward shift was antagonized by the coadministration of ketanserin (3.0 mg/kg), a 5-HT(2A/2C) antagonist. Ketanserin (3.0 mg/kg) also produced a shift to the right in the methamphetamine dose-response curve and completely reversed the leftward shift in the methamphetamine dose-response curve produced by fluoxetine. In contrast, tropisetron (1.0 mg/kg), a 5-HT(3) antagonist, produced a shift to the left of the methamphetamine dose-response curve, and this effect of tropisetron

  1. Effects of 5-HT receptor agonists on depolarization-induced [3H]-noradrenaline release in rabbit hippocampus and human neocortex.

    PubMed Central

    Allgaier, C.; Warnke, P.; Stangl, A. P.; Feuerstein, T. J.


    1. The present study attempted to determine whether noradrenaline (NA) release in rabbit hippocampus and human neocortex is modulated by presynaptic 5-hydroxytryptamine (5-HT) receptors. 2. Slices of rabbit hippocampus and human neocortex, loaded with [3H]-noradrenaline ([3H]-NA) were superfused and the effects of 5-hydroxytryptamine (5-HT) receptor ligands on electrically evoked [3H]-NA release were investigated. 3. In rabbit hippocampus, 5-HT, 5-carboxamidotryptamine (5-CT; 32 microM) and 2-CH3-5-HT (32 microM) increased [3H]-NA release elicited with 360 pulses/3 Hz. Facilitation of transmitter release was not influenced by the 5-HT3 receptor antagonist, tropisetron but was prevented by the alpha 2-adrenoceptor antagonist, rauwolscine. When autoinhibition was avoided by stimulating the tissue with 4 pulses/100 Hz (pseudo-one pulse-(POP) stimulation), 2-CH3-5-HT decreased evoked transmitter release, whereas 5-HT and 5-CT had no effect. Inhibition caused by 2-CH3-5-HT was not affected by tropisetron but counteracted by the alpha 2-adrenoceptor ligands, clonidine and rauwolscine. Inhibition caused by clonidine was diminished in the presence of 5-CT or 2-CH3-5-HT. 4. In human neocortex, [3H]-NA release elicited with 360 pulses/3 Hz was increased by 10 microM 5-HT and 32 microM 5-CT, whereas 2-CH3-5-HT was ineffective. [3H]-NA release evoked with a modified POP stimulation (2 bursts of 4 pulses/100 Hz, 3.5 min apart) was not affected by 2-CH3-5-HT or 5-CT. 5. The present results indicate that 5-HT, 2-CH3-5-HT and 5-CT can act on presynaptic alpha 2-autoreceptors as partial agonists (2-CH3-5-HT; in rabbit hippocampal tissue) or antagonists (5-HT and 5-CT; in tissue of rabbit hippocampus and human neocortex). Furthermore the existence of autoinhibition dictates whether these drugs cause facilitation of release, inhibition or have no effect. PMID:8528558

  2. Anesthesiologists' practice patterns for treatment of postoperative nausea and vomiting in the ambulatory Post Anesthesia Care Unit

    PubMed Central

    Macario, Alex; Claybon, Louis; Pergolizzi, Joseph V


    Background When patients are asked what they find most anxiety provoking about having surgery, the top concerns almost always include postoperative nausea and vomiting (PONV). Only until recently have there been any published recommendations, mostly derived from expert opinion, as to which regimens to use once a patient develops PONV. The goal of this study was to assess the responses to a written survey to address the following questions: 1) If no prophylaxis is administered to an ambulatory patient, what agent do anesthesiologists use for treatment of PONV in the ambulatory Post-Anesthesia Care Unit (PACU)?; 2) Do anesthesiologists use non-pharmacologic interventions for PONV treatment?; and 3) If a PONV prophylaxis agent is administered during the anesthetic, do anesthesiologists choose an antiemetic in a different class for treatment? Methods A questionnaire with five short hypothetical clinical vignettes was mailed to 300 randomly selected USA anesthesiologists. The types of pharmacological and nonpharmacological interventions for PONV treatment were analyzed. Results The questionnaire was completed by 106 anesthesiologists (38% response rate), who reported that on average 52% of their practice was ambulatory. If a patient develops PONV and received no prophylaxis, 67% (95% CI, 62% – 79%) of anesthesiologists reported they would administer a 5-HT3-antagonist as first choice for treatment, with metoclopramide and dexamethasone being the next two most common choices. 65% (95% CI, 55% – 74%) of anesthesiologists reported they would also use non-pharmacologic interventions to treat PONV in the PACU, with an IV fluid bolus or nasal cannula oxygen being the most common. When PONV prophylaxis was given during the anesthetic, the preferred PONV treatment choice changed. Whereas 3%–7% of anesthesiologists would repeat dose metoclopramide, dexamethasone, or droperidol, 26% (95% confidence intervals, 18% – 36%) of practitioners would re-dose the 5-HT3-antagonist

  3. 5-Hydroxytryptamine (5-HT)4 receptors in post mortem human brain tissue: distribution, pharmacology and effects of neurodegenerative diseases.

    PubMed Central

    Reynolds, G P; Mason, S L; Meldrum, A; De Keczer, S; Parnes, H; Eglen, R M; Wong, E H


    1. The distribution, pharmacology and effects of neurodegenerative diseases on 5-HT4 receptors in human brain have been characterized in vitro. 2. The 5-HT4 receptor in post mortem human brain tissue was specifically labelled with [3H]-GR 113808. In human putamen, this ligand labelled a homogeneous population of sites, with an apparent affinity (-log Kd) of 10.1 and a density (Bmax) of 5.73 fmol mg-1 tissue. The pharmacology of this site was characterized by use of a series of displacing ligands, and the following rank order of apparent affinities (with mean +/- s.d. -log Ki values in parentheses) was generated: GR113808 (10.05 +/- 0.04) > SDZ 205,557 (8.65 +/- 0.08) > DAU 6285 (7.95 +/- 0.04) > BIMU-1 (7.81 +/- 0.06) > DAU 6215 (7.42 +/- 0.23) > tropisetron (7.39 +/- 0.23) > 5-HT (7.32 +/- 1.00) > BIMU-8 (7.25 +/- 0.04) > (R)-zacopride (5.82 +/- 0.04). The Hill coefficients were not significantly different from unity, consistent with an interaction at a single site. A comparison of the affinities of these compounds with those obtained from guinea-pig striatum indicated no evidence of species differences. 3. The regional distribution of 5-HT4 receptors was assessed by determining the density of binding sites for [3H]-GR 113808.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7780656

  4. Re-examination for pharmacological properties of serotonin-induced tachycardia in isolated guinea-pig atrium.


    Nishio, H; Fujii, A; Nakata, Y


    In the presence of 10(-6) M atropine, 5-HT induced a positive chronotropic and inotropic effect in isolated guinea-pig atrium preparation. Both propranolol, a beta-adrenoceptor blocker, and imipramine, a 5-HT uptake inhibitor, did not affect the response induced by 5-HT, indicating that a tyramine-like mechanism is not involved. The positive chronotropic effect of 5-HT was mimicked by several 5-HT3 receptor agonists. N omega-Methyl-5-HT, reported to have a high affinity for 5-HT1B recognition sites, was found to act as a 5-HT3 receptor agonist with higher efficacy. The other 5-HT receptor agonists tested did not produced any responses. The positive chronotropic effect of 5-HT was inhibited by various 5-HT3 receptor antagonists, such as tropisetron, granisetron, ondansetron, cisapride and zacopride, but it was unaffected by various 5-HT receptor antagonists which are not selective for 5-HT3 receptor. Thus, the positive chronotropic response to 5-HT is a direct effect, and it was suggested to be mediated by 5-HT3 receptor subtype with rather an atypical profile.

  5. Anti-Hu antibodies activate enteric and sensory neurons

    PubMed Central

    Li, Qin; Michel, Klaus; Annahazi, Anita; Demir, Ihsan E.; Ceyhan, Güralp O.; Zeller, Florian; Komorowski, Lars; Stöcker, Winfried; Beyak, Michael J.; Grundy, David; Farrugia, Gianrico; De Giorgio, Roberto; Schemann, Michael


    IgG of type 1 anti-neuronal nuclear antibody (ANNA-1, anti-Hu) specificity is a serological marker of paraneoplastic neurological autoimmunity (including enteric/autonomic) usually related to small-cell lung carcinoma. We show here that IgG isolated from such sera and also affinity-purified anti-HuD label enteric neurons and cause an immediate spike discharge in enteric and visceral sensory neurons. Both labelling and activation of enteric neurons was prevented by preincubation with the HuD antigen. Activation of enteric neurons was inhibited by the nicotinic receptor antagonists hexamethonium and dihydro-β-erythroidine and reduced by the P2X antagonist pyridoxal phosphate-6-azo (benzene-2,4-disulfonic acid (PPADS) but not by the 5-HT3 antagonist tropisetron or the N-type Ca-channel blocker ω-Conotoxin GVIA. Ca++ imaging experiments confirmed activation of enteric neurons but not enteric glia. These findings demonstrate a direct excitatory action of ANNA-1, in particular anti-HuD, on visceral sensory and enteric neurons, which involves nicotinic and P2X receptors. The results provide evidence for a novel link between nerve activation and symptom generation in patients with antibody-mediated gut dysfunction. PMID:27905561

  6. Expression of 5-HT3 receptors by extrinsic duodenal afferents contribute to intestinal inhibition of gastric emptying.


    Raybould, Helen E; Glatzle, Jorg; Robin, Carla; Meyer, James H; Phan, Thomas; Wong, Helen; Sternini, Catia


    Intestinal perfusion with carbohydrates inhibits gastric emptying via vagal and spinal capsaicin-sensitive afferent pathways. The aim of the present study was to determine the role of 1) 5-hydroxytryptamine (5-HT)(3) receptors (5-HT(3)R) in mediating glucose-induced inhibition of gastric emptying and 2) 5-HT(3)R expression in vagal and spinal afferents in innervating the duodenum. In awake rats fitted with gastric and duodenal cannulas, perfusion of the duodenum with glucose (50 and 100 mg) inhibited gastric emptying. Intestinal perfusion of mannitol inhibited gastric emptying only at the highest concentration (990 mosm/kgH(2)O). Pretreatment with the 5-HT(3)R antagonist tropisetron abolished both glucose- and mannitol-induced inhibition of gastric emptying. Retrograde labeling of visceral afferents by injection of dextran-conjugated Texas Red into the duodenal wall was used to identify extrinsic primary afferents. Immunoreactivity for 5-HT(3)R, visualized with an antibody directed to the COOH terminus of the rat 5-HT(3)R, was found in >80% of duodenal vagal and spinal afferents. These results show that duodenal extrinsic afferents express 5-HT(3)R and that the receptor mediates specific glucose-induced inhibition of gastric emptying. These findings support the hypothesis that enterochromaffin cells in the intestinal mucosa release 5-HT in response to glucose, which activates 5-HT(3)R on afferent nerve terminals to evoke reflex changes in gastric motility. The primary glucose sensors of the intestine may be mucosal enterochromaffin cells.

  7. Palonosetron-5-HT3 Receptor Interactions As Shown by a Binding Protein Cocrystal Structure.


    Price, Kerry L; Lillestol, Reidun K; Ulens, Chris; Lummis, Sarah C R


    Palonosetron is a potent 5-HT3 receptor antagonist and an effective therapeutic agent against emesis. Here we identify the molecular determinants of compound recognition in the receptor binding site by obtaining a high resolution structure of palonosetron bound to an engineered acetylcholine binding protein that mimics the 5-HT3 receptor binding site, termed 5-HTBP, and by examining the potency of palonosetron in a range of 5-HT3 receptors with mutated binding site residues. The structural data indicate that palonosetron forms a tight and effective wedge in the binding pocket, made possible by its rigid tricyclic ring structure and its interactions with binding site residues; it adopts a binding pose that is distinct from the related antiemetics granisetron and tropisetron. The functional data show many residues previously shown to interact with agonists and antagonists in the binding site are important for palonosetron binding, and indicate those of particular importance are W183 (a cation-π interaction and a hydrogen bond) and Y153 (a hydrogen bond). This information, and the availability of the structure of palonosetron bound to 5-HTBP, should aid the development of novel and more efficacious drugs that act via 5-HT3 receptors.

  8. Changes in characteristics of the specific binding of [3H]LY-278584, a 5-HT3-receptor antagonist, on differentiated NG108-15 cells.


    Matsushima, Kayoko; Imanishi, Takashi; Asano, Hajime; Funakami, Yoshinori; Wada, Tetsuyuki; Ichida, Seiji


    We have reported previously that the concentration of intracellular Ca2+ evoked by serotonin (5-HT) was significantly augmented in differentiated NG108-15 (NG) cells treated with dibutyryl cAMP and the enhanced response occurred via 5-HT3 receptors. We investigated changes in the characteristics for specific binding of [(3)H]LY-278584 (a specific antagonist of the 5-HT3 receptor) on membranes from differentiated NG cells. The results indicated that the K(d) and B(max) values for the specific binding to differentiated NG cells were significantly smaller and larger, respectively, than those for undifferentiated NG cells. The binding was significantly inhibited by 10 nM tropisetron, a specific 5-HT3-receptor antagonist, but not by any other types of 5-HT-receptor antagonists. These results suggested that the enhanced response by 5-HT in differentiated NG cells was due to both qualitative and quantitative changes in the 5-HT3 receptor.

  9. [5-HT3 receptor antagonist als analgetics in rheumatic diseases].


    Müller, W; Fiebich, B L; Stratz, T


    Various rheumatic diseases like fibromyalgia, systemic inflammatory rheumatic disorders and localized diseases, such as arthritides and activated arthroses, tendinopathies and periarthropathies, as well as trigger points can be improved considerably by treatment with the 5-HT3 receptor antagonist tropisetron. Particularly in the latter group of diseases, local injections have done surprisingly rapid analgesic action. This effect matches that of local anesthetics, but lasts considerably longer and is comparable to local injections of local anesthetics combined with corticosteroids. The action of the 5-HT3 receptor antagonists can be attributed to an antinociceptive effect that occurs at the same time as an antiphlogistic and probably also an immunosuppressive effect. Whereas an inhibited release of substance P from the nociceptors, and possibly some other neurokins as well, seems to be the most likely explanation for the antinociceptive action, the antiphlogistic effect is primarily due to an inhibited formation of various different phlogistic substances; in some conditions, like systemic inflammatory rheumatic diseases, for example, the 5-HT3 receptor antagonists may exert an immunosuppressive effect in addition to this.

  10. Effects of iodoproxyfan, a potent and selective histamine H3 receptor antagonist, on alpha 2 and 5-HT3 receptors.


    Schlicker, E; Pertz, H; Bitschnau, H; Purand, K; Kathmann, M; Elz, S; Schunack, W


    We determined the affinity and/or potency of the novel H3 receptor antagonist iodoproxyfan at alpha 2 and 5-HT3 receptors. Iodoproxyfan and rauwolscine (a reference alpha 2 ligand) (i) monophasically displaced 3H-rauwolscine binding to rat brain cortex membranes (pKi 6.79 and 8.59); (ii) facilitated the electrically evoked tritium overflow from superfused mouse brain cortex slices preincubated with 3H-noradrenaline (pEC50 6.46 and 7.91) and (iii) produced rightward shifts of the concentration-response curve (CRC) of (unlabelled) noradrenaline for its inhibitory effect on the evoked overflow (pA2 6.65 and 7.88). In the guinea-pig ileum, iodoproxyfan 6.3 mumol/l failed to evoke a contraction by itself but depressed the maximum of the CRC of 5-hydroxytryptamine (pD'2 5.24). Tropisetron (a reference 5-HT3 antagonist) produced rightward shifts of the CRC of 5-hydroxytryptamine (pA2 7.84). In conclusion, the affinity/potency of iodoproxyfan at H3 receptors (range 8.3-9.7 [1]) exceeds that at alpha 2 receptors by at least 1.5 log units and that at 5-HT3 receptors by at least 3 log units.

  11. Targeting of α7 Nicotinic Acetylcholine Receptors in the Treatment of Schizophrenia and the Use of Auditory Sensory Gating as a Translational Biomarker

    PubMed Central

    Hashimoto, Kenji


    Accumulating evidence suggests that the α7 subtype of nicotinic acetylcholine receptors (nAChRs) plays a key role in inflammatory processes, thought to be involved in the pathophysiology of neuropsychiatric diseases, such as schizophrenia and Alzheimer’s disease. Preclinical and clinical studies showed that the diminished suppression of P50 auditory evoked potentials in patients with schizophrenia may be associated with a decreased density of α7 nAChRs in the brain. This points to a role for auditory sensory gating (P50) as a translational biomarker. A number of agonists and positive allosteric modulators (PAMs) for α7 nAChR promoted beneficial effects in animal models with sensory gating and cognitive deficits. Additionally, several clinical studies showed that α7 nAChR agonists could improve suppression in auditory P50 evoked potentials, as well as cognitive deficits, and negative symptoms in patients with schizophrenia. Taken together, α7 nAChR presents as an extremely attractive therapeutic target for schizophrenia. In this article, the author discusses recent findings on α7 nAChR agonists such as DMXB-A, RG3487, TC-5619, tropisetron, EVP-6124 (encenicline), ABT-126, AQW051 and α7 nAChR PAMs such as JNJ-39393406, PNU-120596 and AVL-3288 (also known as UCI-4083), and their potential as therapeutic drugs for neuropsychiatric diseases, such as schizophrenia. PMID:26044974

  12. [Anesthesiologic management of ankle joint osteosynthesis in the 35th week of pregnancy in a patient with Charcot-Marie-Tooth syndrome].


    Kirmayer, U J; Preisz, A


    We describe the case of an extremely overweight woman in her 35 th week of pregnancy with a manifest Charcot-Marie-Tooth syndrome (CMT), on whom a tibial fracture was operated under general anaesthesia. Anaesthesia was induced with thiopental, droperidol, fentanyl and maintained with nitrous oxide and isoflurane. Atracurium was administered as a muscle relaxant agent. Depolarizing muscle relaxants have not been used because of a significantly increased risk of hyperkalemia. The immediate intubation using the principle of a so-called "priming dose" was within normal limits. CMT syndrome is a very rare hereditary autosomal dominant degenerative disease of the peripheral nervous system. The main site of manifestation is the peroneus muscle. In case of affection of the respiratory muscular system, which acutely can occur postoperatively even without any suspicious findings in the preoperatively performed lung function tests, an insufficiency of the respiratory tract is predominant and may require a postoperative intensive care with a prolonged artificial respiration. With the application of non-depolarizing muscle relaxants significant prolongations of the half-life period have occasionally been observed. Therefore we recommend the monitoring of the neuromuscular blockade perioperatively using the train-of-four ratio. An extraordinary progression of the disease frequently occurs during pregnancy.

  13. Vascular dopamine receptors: Demonstration and characterization by in vitro studies.


    Brodde, O E


    Substantial evidence has accumulated that in certain vascular beds dopamine produces its relaxant effect through stimulation of specific dopamine receptors. The goal of this review is to describe several in vitro models (perfused mesenteric vessels of the dog; renal, mesenteric, splenic, coronary and cerebral arterial strips of rabbits, dogs and cats; perfused kidney of the rat) recently developed to demonstrate such specific relaxations induced by dopamine and dopaminomimetics. On these models studies on structure-activity relationship for activation of the dopamine receptor resulted in the following order of potency for agonists: SK&F 38393 (partial agonist) greater than epinine greater than A-6, 7-DTN greater than or equal to dopamine greater than N, N-di-n-propyl-dopamine (partial agonist) greater than apomorphine (partial agonist). The dopamine receptor antagonists (+)-butaclamol, cis-alpha-flupenthixol, metoclopramide, droperidol and bulbocapnine were found to competitively antagonize dopamine induced relaxation. In addition, in two isolated organ systems (rabbit mesenteric artery, rat perfused kidney) stereospecificity of the vascular dopamine receptor was demonstrated with the isomers of butaclamol. With the development of several in vitro models demonstrating a specific antagonism against dopamine induced relaxation an important requirement for definition of a specific dopamine receptor if fulfilled according to classical pharmacological criteria. Thus, there can be do doubt on the existence of post-synaptic dopamine receptors mediating vasodilation in certain vascular tissues.

  14. The effect of betahistine on vestibular habituation: comparison of rotatory and sway habituation training.


    Mierzwinski, J; Kazmierczak, H; Pawlak-Osinska, K; Piziewicz, A


    This study was designed to investigate the effect of histaminergic agonists and antagonists on the acquisition of vestibular habituation. The experimental animals, pigeons, were subjected to unilateral rotatory and sway habituation training sessions. The habituation of postural reflexes and post-rotatory head nystagmus was assessed. Vestibular habituation in the control group was achieved by adopting the kinetic reflex posture after approximately 9 training sessions, and after 10 and 14 training sessions, respectively for 50% reduction of the total number of beats (TNB) and the duration of post-rotatory head nystagmus. In the sway adaptation test control pigeons needed nearly 15 training sessions while pigeons receiving betahistine adapted after approximately 8 sessions. Administration of histamine and, most notably, betahistine accelerated the process, while both H1 and H2 antagonists (clemastine, cimetidine) tended to retard it, indicating a less significant contribution of H2 receptors. The cholinergic agent physostigmine strongly retarded habituation while the anticholinergic agent scopolamine markedly accelerated it. In addition the adrenomimetic agent ephedrine also accelerated habituation while the adrenolytic agent droperidol retarded reduction of nystagmus beats. The results indicate that histaminergic receptors play a significant role in the vestibular habituation mechanism but are intricately involved with other types of receptors. Betahistine is clearly the agent of choice for attenuating vestibular effects.

  15. Effect of structural analogs of butaclamol (a new antipsychotic drug) on striatal homovanillic acid and adenyl cyclase of olfactory tubercle in rats.


    Pugsley, T A; Merker, J; Lippman, W


    The 3-isopropyl (I), 3-cyclohexyl (II) and 3-phenyl (III) analogs of the new antipsychotic drug butaclamol, which contains a 3-tertiary butyl group, and their respective (+)-enantiomers, but not (-)-enantiomers, caused a dose related elevation of rat striatal homovanillic acid concentration, indicative of an increased dopamine (DA) turnover; droperidol also exhibited this activity. The order of activity of the (+)-enantiomers was (butaclamol) approximately II greater than I greater than III. A decrease in striatal DA was observed with (+)-I and (+)-III at the highest dose used, but not at one-half the dose. Each analog antagonized the DA-induced increase in adenyl cyclase (EC activity of olfactory tubercle homogenates, the order of activity of the racemates (except for II) AND (+)-ENANTIOMERS BEING (BUTACLAMOL) APPROXIMATELY I greater than III greater than II. The (+)-enantiomers of butaclamol and analogs were two to four times more potent than their respective racemates, with (+)-butaclamol and (+)-I displaying activity generally equivalent to fluphenazine. The respective (-)-enantiomers were ineffective indicating a stereochemical specificity for DA-receptor blockade. Such analogs presented should be of value in elucidating dopaminergic mechansims.

  16. Stereospecific antagonism by d-butaclamol of dopamine-induced relaxation of the isolated rabbit mesenteric artery.


    Brodde, O E; Freistühler, J; Meyer, F J


    We characterized the properties of vascular dopamine receptors on isolated rabbit mesenteric arteries preincubated with phenoxybenzamine (10(-5) M) and contracted with prostaglandin F2 alpha (PGF2 alpha). The dose-response curve for dopamine-induced relaxation was shifted to the right by the dopamine receptor antagonist d-butaclamol (10(-7)--3 X 10(-6) M) in a concentration-dependent manner. The pA2 value for d-butaclamol was calculated as 6.77. In contrast, even a very high concentration (3 X 10(-6) M) of l-butaclamol had no effect, indicating that vascular dopamine receptors require stereospecificity of antagonists. In the same preparation the mechanism of relaxation by 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (A-6,7-DTN; 3 X 10(-7)--10(-4) M) and bromocriptine (10(-6)--3 X 10(-4) M) was found to be dopaminomimetic, since only the dopamine receptor antagonists droperidol (10(-5) M) and metoclopramide (5 X 10(-5) M) could inhibit relaxations, whereas the beta-adrenoceptor antagonists pindolol (10(-7) M) and propranolol (10(-6) M) were without effect. It is concluded that receptors specific for dopamine exist on the rabbit mesenteric artery, which may tentatively be classified as belonging to the D1-type.

  17. Pharmacological profile of the receptors that mediate external carotid vasoconstriction by 5-HT in vagosympathectomized dogs.


    Villalón, C M; Ramírez-San Juan, E; Castillo, C; Castillo, E; López-Muñoz, F J; Terrón, J A


    1. 5-Hydroxytryptamine (5-HT) can produce vasodilatation or vasoconstriction of the canine external carotid bed depending upon the degree of carotid sympathetic tone. Hence, external carotid vasodilatation to 5-HT in dogs with intact sympathetic tone is primarily mediated by prejunctional 5-HT1-like receptors similar to the 5-HT1D subtype, which inhibit the carotid sympathetic outflow. The present investigation is devoted to the pharmacological analysis of the receptors mediating external carotid vasoconstriction by 5-HT in vagosympathectomized dogs. 2. Intracarotid (i.c.) infusions for 1 min of 5-HT (0.3, 1, 3, 10, 30 and 100 micrograms) resulted in dose-dependent decreases in both external carotid blood flow and the corresponding conductance; both mean arterial blood pressure and heart rate remained unchanged during the infusions of 5-HT. These responses to 5-HT were resistant to blockade by antagonists at 5-HT2 (ritanserin) and 5-HT3/5-HT4 (tropisetron) receptors, but were partly blocked by the 5-HT1-like and 5-HT2 receptor antagonist, methiothepin (0.3 mg kg-1); higher doses of methiothepin (1 and 3 mg kg-1) caused little, if any, further blockade. These methiothepin (3 mg kg-1)-resistant responses to 5-HT were not significantly antagonized by MDL 72222 (0.3 mg kg-1) or tropisetron (3 mg kg-1). 3. The external carotid vasoconstrictor effects of 5-HT were mimicked by the selective 5-HT1-like receptor agonist, sumatriptan (3, 10, 30 and 100 micrograms during 1 min, i.c.), which produced dose-dependent decreases in external carotid blood flow and the corresponding conductance; these effects of sumatriptan were dose-dependently antagonized by methiothepin (0.3, 1 and 3 mg kg-1), but not by 5-HT1D-like receptor blocking doses of metergoline (0.1 mg kg-1). 4. The above vasoconstrictor effects of 5-HT remained unaltered after administration of phentolamine, propranolol, atropine, hexamethonium, brompheniramine, cimetidine and haloperidol, thus excluding the

  18. Pharmacological profile of the receptors that mediate external carotid vasoconstriction by 5-HT in vagosympathectomized dogs.

    PubMed Central

    Villalón, C. M.; Ramírez-San Juan, E.; Castillo, C.; Castillo, E.; López-Muñoz, F. J.; Terrón, J. A.


    1. 5-Hydroxytryptamine (5-HT) can produce vasodilatation or vasoconstriction of the canine external carotid bed depending upon the degree of carotid sympathetic tone. Hence, external carotid vasodilatation to 5-HT in dogs with intact sympathetic tone is primarily mediated by prejunctional 5-HT1-like receptors similar to the 5-HT1D subtype, which inhibit the carotid sympathetic outflow. The present investigation is devoted to the pharmacological analysis of the receptors mediating external carotid vasoconstriction by 5-HT in vagosympathectomized dogs. 2. Intracarotid (i.c.) infusions for 1 min of 5-HT (0.3, 1, 3, 10, 30 and 100 micrograms) resulted in dose-dependent decreases in both external carotid blood flow and the corresponding conductance; both mean arterial blood pressure and heart rate remained unchanged during the infusions of 5-HT. These responses to 5-HT were resistant to blockade by antagonists at 5-HT2 (ritanserin) and 5-HT3/5-HT4 (tropisetron) receptors, but were partly blocked by the 5-HT1-like and 5-HT2 receptor antagonist, methiothepin (0.3 mg kg-1); higher doses of methiothepin (1 and 3 mg kg-1) caused little, if any, further blockade. These methiothepin (3 mg kg-1)-resistant responses to 5-HT were not significantly antagonized by MDL 72222 (0.3 mg kg-1) or tropisetron (3 mg kg-1). 3. The external carotid vasoconstrictor effects of 5-HT were mimicked by the selective 5-HT1-like receptor agonist, sumatriptan (3, 10, 30 and 100 micrograms during 1 min, i.c.), which produced dose-dependent decreases in external carotid blood flow and the corresponding conductance; these effects of sumatriptan were dose-dependently antagonized by methiothepin (0.3, 1 and 3 mg kg-1), but not by 5-HT1D-like receptor blocking doses of metergoline (0.1 mg kg-1). 4. The above vasoconstrictor effects of 5-HT remained unaltered after administration of phentolamine, propranolol, atropine, hexamethonium, brompheniramine, cimetidine and haloperidol, thus excluding the

  19. Study on the interactions of antiemetic drugs and 12-tungstophosphoric acid by absorption and resonance Rayleigh scattering spectra and their analytical applications.


    Wang, Yaqiong; Liu, Shaopu; Liu, Zhongfang; Yang, Jidong; Hu, Xiaoli


    In 0.1 mol L(-1) HCl medium, antiemetic drugs (ATM), such as granisetron hydrochloride (GS) and tropisetron hydrochloride (TS), reacted with H(3)PW(12)O(40)·nH(2)O and formed 3:1 ion-association complex of [(ATM)(3)PW(12)O(40)], then self-aggregated into nanoparticles-[(ATM)(3)PW(12)O(40)](n) with an average size of 100 nm. The reaction resulted in the enhancement of resonance Rayleigh scattering (RRS) and the absorption spectra. The increments of scattering intensity (ΔI(RRS)) and the change of absorbance (ΔA) were both directly proportional to the concentrations of ATM in certain ranges. Accordingly, two new RRS and spectrophotometric methods were proposed for ATM detection. The detection limits (3σ) of GS and TS were 3.2 ng mL(-1) and 4.0 ng mL(-1)(RRS method), 112.5 ng mL(-1) and 100.0 ng mL(-1)(spectrophotometric method). These two methods were applied to determine GS in orally disintegrating tablets and the results were in good agreement with the official method. The ground-state geometries and electronic structures of GS and TS were optimized by the hybrid density functional theory (DFT) method and the shape of [(ATM)(3)PW(12)O(40)](n) was characterized by atomic force microscopy (AFM). Take the RRS method with higher sensitivity as an example, the reaction mechanism and the reasons for enhancement of scattering were discussed.

  20. Treatment of established postoperative nausea and vomiting: a quantitative systematic review

    PubMed Central

    Kazemi-Kjellberg, Faranak; Henzi, Iris; Tramèr, Martin R


    Background The relative efficacy of antiemetics for the treatment of postoperative nausea and vomiting (PONV) is poorly understood. Methods Systematic search (MEDLINE, Embase, Cochrane Library, bibliographies, any language, to 8.2000) for randomised comparisons of antiemetics with any comparator for the treatment of established PONV. Dichotomous data on prevention of further nausea and vomiting, and on side effects were combined using a fixed effect model. Results In seven trials (1,267 patients), 11 different antiemetics were tested without placebos; these data were not further analysed. Eighteen trials (3,809) had placebo controls. Dolasetron 12.5–100 mg, granisetron 0.1–3 mg, tropisetron 0.5–5 mg, and ondansetron 1–8 mg prevented further vomiting with little evidence of dose-responsiveness; with all regimens, absolute risk reductions compared with placebo were 20%–30%. The anti-nausea effect was less pronounced. Headache was dose-dependent. Results on propofol were contradictory. The NK1 antagonist GR205171, isopropyl alcohol vapor, metoclopramide, domperidone, and midazolam were tested in one trial each with a limited number of patients. Conclusions Of 100 vomiting surgical patients receiving a 5-HT3 receptor antagonist, 20 to 30 will stop vomiting who would not have done so had they received a placebo; less will profit from the anti-nausea effect. There is a lack of evidence for a clinically relevant dose-response; minimal effective doses may be used. There is a discrepancy between the plethora of trials on prevention of PONV and the paucity of trials on treatment of established symptoms. Valid data on the therapeutic efficacy of classic antiemetics, which have been used for decades, are needed. PMID:11734064

  1. Peristalsis in the Guinea pig small intestine in vitro is impaired by acetaminophen but not aspirin and dipyrone.


    Herbert, Michael K; Weis, Rebecca; Holzer, Peter; Roewer, Norbert


    Inhibition of intestinal peristalsis is a major side effect of opioid analgesics. It is unknown whether non-opioid analgesics, such as acetaminophen, acetylsalicylic acid, and dipyrone, exert any effect on intestinal motility. In the current in vitro study we examined the effect of these analgesics on intestinal peristalsis and analyzed some of their mechanisms of action. In isolated segments of the guinea pig small intestine peristalsis was triggered by a perfusion-induced increase of the intraluminal pressure. The peristaltic pressure threshold (PPT) at which peristaltic waves were elicited was used to quantify drug effects on peristalsis. Vehicle (Tyrode's solution), acetaminophen (0.01-100 microM), acetylsalicylic acid (100-300 microM), and dipyrone (10-100 microM) were added extraserosally to the organ bath. Acetaminophen concentration-dependently increased PPT and abolished peristalsis in four of six segments at the concentration of 10 microM and in all segments tested at 100 microM (EC50=6.0 microM). The increase in PPT resulting from 3 microM acetaminophen was reduced by naloxone and apamin but not changed by L-nitro-arginine methylester (L-NAME), its inactive enantiomer D-NAME, acetylsalicylic acid, methysergide, or tropisetron. Acetylsalicylic acid and dipyrone did not affect peristalsis. The results reveal, for the first time, that acetaminophen concentration-dependently impairs intestinal peristalsis, whereas acetylsalicylic acid and dipyrone lacked such an effect. The inhibition caused by acetaminophen involves transmitters acting via small conductance Ca2+-activated potassium channels, endogenous opioidergic pathways, and presumably inhibition of cyclooxygenase-3.

  2. Role of 5-HT3 receptors in basal and K(+)-evoked dopamine release from rat olfactory tubercle and striatal slices.

    PubMed Central

    Zazpe, A; Artaiz, I; Del Río, J


    1. The present study was aimed at examining the role of 5-HT3 receptors in basal and depolarization-evoked dopamine release from rat olfactory tubercle and striatal slices. [3H]-dopamine ([3H]-DA) release was measured in both brain regions and endogenous dopamine release from striatal slices was also studied. 2. The selective 5-HT3 receptor agonist 2-methyl-5-HT (0.5-10 microM) produced a concentration-dependent increase in [3H]-DA efflux evoked by K+ (20 mM) from slices of rat olfactory tubercle. 1-Phenylbiguanide (PBG) and 5-HT also increased K(+)-evoked [3H]-DA efflux. 3. 5-HT (1-100 microM) increased in a concentration-dependent manner basal [3H]-DA release from olfactory tubercle and striatal slices as well as endogenous DA release from striatal slices. The selective 5-HT3 receptor agonists 2-methyl-5-HT and 1-phenylbiguanide were weaker releasing agents. In all cases, the release was Ca2+ independent and tetrodotoxin insensitive. 4. 5-HT3 receptor antagonists such as ondansetron, granisetron and tropisetron (0.2 microM) significantly blocked the enhanced K(+)-evoked [3H]-DA efflux from rat olfactory tubercle slices induced by 2-methyl-5HT. A ten fold higher concentration of the 5-HT2 receptor antagonist ketanserin was ineffective. 5. Much higher concentrations, up to 50 microM, of the same 5-HT3 receptor antagonists did not block the increase in basal [3H]-DA release from striatal or olfactory tubercle slices induced by 5-HT or the release of endogenous DA induced by 5-HT from striatal slices.2+ off PMID:7858893

  3. Role of catecholamines and serotonin receptor subtypes in nefopam-induced antinociception.


    Girard, Philippe; Coppé, Marie-Claude; Verniers, Danielle; Pansart, Yannick; Gillardin, Jean-Marie


    The non-opiate analgesic nefopam has been shown to inhibit monoamines uptake, but little is known about receptor subtypes effectively involved in its analgesic effect. In vitro binding assays yielded the following measures of affinity (IC(50)): serotonergic 5-HT(2C) (1.4 microM), 5-HT(2A) (5.1 microM), 5-HT(3) (22.3 microM), 5-HT(1B) (41.7 microM), 5-HT(1A) (64.9 microM), adrenergic alpha(1) (15.0 microM) and dopaminergic D(1) (100 microM). Subcutaneous nefopam administration dose-dependently inhibited pain in acetic acid-induced writhing (1-30 mg kg(-1)) and formalin (1-10 mg kg(-1)) tests in the mouse. Pretreatments with adrenergic alpha(1) (prazosin) and alpha(2) (yohimbine), and serotonergic 5-HT(1B) (GR127935) receptor antagonists significantly increased the nefopam ED(50) in the writhing test. The serotonergic 5-HT(2C) (RS102221) and the dopaminergic D(2) (sulpiride) receptor antagonists inhibited nefopam antinociception in the formalin test. However, in both tests, nefopam analgesic activity was not modified by the following receptor antagonists: dopaminergic D(1) (SCH23390), serotonergic 5-HT(1A) (NAN-190, WAY100635), 5-HT(2A) (R96544, ketanserin), 5-HT(3) (tropisetron), and 5-HT(4) (SDZ205557). In conclusion, nefopam analgesic activity could be modulated by the adrenergic alpha(1) and alpha(2) receptors, the dopaminergic D(2) receptors, and the serotonergic 5-HT(1B) and 5-HT(2C) receptor subtypes.

  4. Hepatocyte nuclear factor 1 regulates the expression of the organic cation transporter 1 via binding to an evolutionary conserved region in intron 1 of the OCT1 gene.


    O'Brien, Valerie P; Bokelmann, Kristin; Ramírez, Jacqueline; Jobst, Karoline; Ratain, Mark J; Brockmöller, Jürgen; Tzvetkov, Mladen V


    The organic cation transporter 1 (OCT1), also known as solute carrier family 22 member 1, is strongly and specifically expressed in the human liver. Here we show that the hepatocyte nuclear factor 1 (HNF1) regulates OCT1 transcription and contributes to the strong, liver-specific expression of OCT1. Bioinformatic analyses revealed strong conservation of HNF1 binding motifs in an evolutionary conserved region (ECR) in intron 1 of the OCT1 gene. Electrophoretic mobility shift and chromatin immunoprecipitation assays confirmed the specific binding of HNF1 to the intron 1 ECR. In reporter gene assays performed in HepG2 cells, the intron 1 ECR increased SV40 promoter activity by 22-fold and OCT1 promoter activity by 13-fold. The increase was reversed when the HNF1 binding sites in the intron 1 ECR were mutated or the endogenous HNF1α expression was downregulated with small interfering RNA. Following HNF1α overexpression in Huh7 cells, the intron 1 ECR increased SV40 promoter activity by 11-fold and OCT1 promoter activity by 6-fold. Without HNF1α overexpression, the increases were only 3- and 2-fold, respectively. Finally, in human liver samples, high HNF1 expression was significantly correlated with high OCT1 expression (r = 0.48, P = 0.002, n = 40). In conclusion, HNF1 is a strong regulator of OCT1 expression. It remains to be determined whether genetic variants, disease conditions, or drugs that affect HNF1 activity may affect the pharmacokinetics and efficacy of OCT1-transported drugs such as morphine, tropisetron, ondansetron, tramadol, and metformin. Beyond OCT1, this study demonstrates the validity and usefulness of interspecies comparisons in the discovery of functionally relevant genomic sequences.

  5. [Clinical characteristics research of shenmai injection treating tumor based on hospital information system in real world].


    Hu, Yuan-Chun; Xie, Yan-Ming; Yang, Wei; Wang, Yong-Yan; Wang, Lian-Xin; Tang, Hao; Zhuang, Yan


    The study was to research the clinical characteristics of Shenmai injection treating tumor based on hospital information system, including the characteristics of the age, the sex, the dosage, the course of the treatment and the combination drugs. The data of tumor patients injected with Shenmai injection was analyzed. The information was collected from the hospital information system (HIS) in twenty hospitals of grade III-A. The method of frequencies and association rules was used in this reaearch. The patients over 45 years old were up to 3 338, about 79.36% of the whole. The ratio of male and female was 1.73: 1. The hospitalization day between 15 and 28 was most. The complications of the hypertension and coronary heart disease happened most. The support was 5.939% and 5.099% respectively. Fifty-five patients had the traditional Chinese medicine (TCM) syndrome of Qi-Yin deficiency, about 14.78% of the whole. There were 8 491 patients treated with the single dose of 81 to 100 mL, about 48.70% of the whole. The main combination drugs were dexamethasone, tropisetron and maxolon. The confidence was 44.63%, 31.22% and 20.53% respectively. The information from HIS showed that tumor patients used Shenmai injection were most quinquagenarian with smooth condition. The dose of the Shenmai injection sometimes was higher than that of the drug use instructions in clinical. Shenmai injection was most often combined with glucocorticoid, antemetic and nutritional support medicine when treating tumor in clinical.

  6. Evidence based knee injections for the management of arthritis

    PubMed Central

    Cheng, Olivia T.; Souzdalnitski, Dmitri; Vrooman, Bruce; Cheng, Jianguo


    Objective Arthritis of the knee affects 46 million Americans. We aimed to determine the level of evidence of intraarticular knee injections in the management of arthritic knee pain. Methods We systematically searched PUBMED/MEDLINE and the Cochrane databases for articles published on knee injections and evaluated their level of evidence and recommendations according to established criteria. Results The evidence supports the use of intraarticular corticosteroid injections for rheumatoid arthritis (1A+ level), osteoarthritis (1A+ level), and juvenile idiopathic arthritis (2C+ level). Pain relief and functional improvement are significant for months up to one year after the injection. Triamcinolone hexacetonide offers an advantage over triamcinolone acetonide and should be the intraarticular steroid of choice (2B+ level). Intraarticular injection of hyaluronate may provide longer pain relief than steroid injection in osteoarthritis (2B+ level). It can also be effective for rheumatoid arthritis knee pain (1A+ level). However, it is only recommended for patients with significant surgical risk factors and for patients with mild radiographic disease in whom conservative treatment has failed (2B± level). Botulinum toxin Type A injection is effective in reducing arthritic knee pain (2B+ level) and so is tropisetron (2B+ level) and tanezumab (2B+ level). The new agents, such as rAAV2-TNFR:Fc, SB-210396/CE 9.1, and various radioisotopes have provided various degrees of success, but their long-term safety and efficacy remains to be determined. Conclusions We conclude that strong evidence supports the use of intraarticular knee injection as a valuable intervention in the continuum of management of arthritis between conservative treatment and knee surgeries. PMID:22621287

  7. Perioperative management of hereditary arrhythmogenic syndromes.


    Staikou, C; Chondrogiannis, K; Mani, A


    Patients with inherited cardiac channel disorders are at high risk of perioperative lethal arrhythmias. Preoperative control of symptoms and a multidisciplinary approach are required for a well-planned management. Good haemodynamic monitoring, adequate anaesthesia and analgesia, perioperative maintenance of normocarbia, normothermia, and normovolaemia are important. In congenital long QT syndrome, torsades de pointes should be prevented with magnesium sulphate infusion and avoidance of drugs such as droperidol, succinylcholine, ketamine, and ondansetron. Propofol and epidural anaesthesia represent safe choices, while caution is needed with volatile agents. In Brugada syndrome, β-blockers, α-agonists, and cholinergic drugs should be avoided, while isoproterenol reverses the ECG changes. Propofol, thiopental, and volatiles have been used uneventfully. In congenital sick sinus syndrome, severe bradycardia resistant to atropine may require isoproterenol or epinephrine. Anaesthetics with vagolytic properties are preferable, while propofol and vecuronium should be given with caution due to risk of inducing bradyarrhythmias. Neuraxial anaesthesia should produce the least autonomic imbalance. Arrhythmogenic right ventricular dysplasia/cardiomyopathy induces ventricular tachyarrhythmias, which should be treated with β-blockers. Generally, β-adrenergic stimulation and catecholamine release should be avoided. Halothane and pancuronium are contraindicated, while large doses of local anaesthetics and epinephrine should be avoided in neuraxial blocks. In catecholaminergic polymorphic ventricular tachycardia, β-blocker treatment should be continued perioperatively. Catecholamine release and β-agonists, such as isoproterenol, should be avoided. Propofol and remifentanil are probably safe, while halothane and pancuronium are contraindicated. Regional anaesthesia, without epinephrine, is relatively safe. In suspicious cardiac deaths, postmortem examination and familial

  8. Cardiovascular Side Effects of New Antidepressants and Antipsychotics: New Drugs, old Concerns?

    PubMed Central

    Pacher, Pal; Kecskemeti, Valeria


    The cardiovascular toxicity of older generation of tricyclic antidepressants (e.g. imipramine, desipramine, amitriptyline, clomipramine) and neuroleptics (e.g. haloperidol, droperidol, thioridazine, pimozide) is well established. These drugs inhibit cardiovascular Na+, Ca2+ and K+ channels often leading to life-threatening arrhythmia. To overcome the toxicity of old generation of antidepressants and antipsychotics, selective serotonin reuptake inhibitor antidepressants (SSRIs: fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, venlafaxin) and several new antipsychotics (e.g. clozapine, olanzapine, risperidone, sertindole, aripiprazole, ziprasidone, quetiapine) were introduced during the past decade. Although these new compounds are not more effective in treating psychiatric disorders than older medications, they gained incredible popularity since they have been reported to have fewer and more benign side effect profile (including cardiovascular) than predecessors. Surprisingly, an increasing number of case reports have demonstrated that the use of SSRIs and new antipsychotics (e.g. clozapine, olanzapine, risperidone, sertindole, aripiprazole, ziprasidone, quetiapine) is associated with cases of arrhythmias, prolonged QTc interval on electrocardiogram (ECG) and orthostatic hypotension in patients lacking cardiovascular disorders, raising new concerns about the putative cardiovascular safety of these compounds. In agreement with these clinical reports these new compounds indeed show marked cardiovascular depressant effects in different mammalian and human cardiovascular preparations by inhibiting cardiac and vascular Na+, Ca2+ and K+ channels. Taken together, these results suggest that the new generation of antidepressants and antipsychotics also have clinically important cardiac as well as vascular effects. Clinicians should be more vigilant about these potential adverse reactions and ECG control may be suggested during therapy, especially in patients with

  9. Plasma catecholamines during an ultrarapid heroin detoxification.


    Macedo, T R; Relvas, J; Fontes Ribeiro CA; Pacheco, F; Morgadinho, M T; Pinto, C M; Gomes, P C; Ventura, M; Henriques, V; Nunes, S V; Ruis, G R; Ramalheira, C; Boto, I; Vale, L L


    The adrenergic system has long been known to be activated in a situation of stress and thus during opiate withdrawal. A method for detoxification that decreases the stimulation of the sympathetic nervous system will prevent changes of catecholamine levels. Some of such methods have been developed. One of them uses direct transition from heroin to oral naltrexone after deep sedation with midazolam in conjunction with naloxone, droperidol, ondansetron, and clonidine treatment for 24 hours. Can such method prevent adrenergic changes? Moreover, 5-HT has been related to mood disorders. This study aims to determine plasma catecholamines and 5-HT before heroin withdrawal, during the day of the withdrawal, and at the ends of the first day, the first week, and the first 6 months. Forty-three patients with more than 6 years of drug abuse volunteered to seek help to detoxify. After clinical evaluation, blood samples were taken. Plasma catecholamines were isolated by standard alumina procedures and measured by high-performance liquid chromatography with electrochemical detection. Only for NE was there a significant decrease in the day of heroin withdrawal with deep sedation, followed the next day by an increase. During the following days, NE plasma concentrations returned slowly to basal levels. Epinephrine and dopamine plasma levels did not significantly change. Platelet 5-HT levels progressively decreased from the day before detoxification until the last period of observation. We also found that there were no abrupt changes in cardiovascular functions. In conclusion, our results suggest that this type of ultrarapid opiate detoxification prevents the dramatic activation of the autonomic nervous system.

  10. [Malignant hyperthermia in Austria. III. Anesthesia in susceptible patients].


    Mauritz, W; Hackl, W; Sporn, P; Steinbereithner, K


    Anesthesia in patients susceptible to malignant hyperthermia (MH) is generally considered to be very risky, although - with one notable exception - there are no prospective studies about anesthetic management in a large number of such patients. The prophylactic use of dantrolene has been recommended in MH patients, although there is no strong evidence supporting this - despite the fact that dantrolene may have serious side effects. We therefore decided to report the results of our own anesthetic technique for MH patients, as our technique does not include the prophylactic use of dantrolene. From 1981 to 1988, 19 operations on 16 MH-susceptible patients were performed. Patients 1-4 were pediatric survivors of an MH episode, where MH susceptibility was confirmed by muscle biopsy and in vitro contracture tests in at least one parent; patients 5-7 were survivors of an MH crisis, and they later underwent diagnostic muscle biopsies themselves; all other patients (nos. 8-16) were relatives of MH survivors with positive in vitro contracture tests. Diazepam, pentobarbital, pethidine, and chlorprothixene were used for premedication; no prophylactic dantrolene was given. Anesthesia was induced by thiopentone and was continued by nitrous oxide/oxygen, fentanyl, and droperidol; alcuronium, atracurium, and vecuronium were administered as necessary. Pyridostigmine, atropine, and naloxone were used if appropriate. New or disposable tubings were used for ventilation, and the vaporizers were removed from the anesthesia machines. ECG and body temperature were recorded in all patients; blood pressure was monitored invasively if indicated; end tidal CO2 was monitored whenever possible.(ABSTRACT TRUNCATED AT 250 WORDS)

  11. Characterization of prejunctional 5-HT receptors mediating inhibition of sympathetic vasopressor responses in the pithed rat.


    Villalón, C M; Contreras, J; Ramírez-San Juan, E; Castillo, C; Perusquía, M; Terrón, J A


    1. It has recently been shown that continuous infusions of 5-hydroxytryptamine (5-HT) are able to inhibit, in a dose-dependent manner, the pressor responses induced by preganglionic (T7-T9) sympathetic stimulation in pithed rats pretreated with desipramine (50 micrograms kg-1, i.v.). This inhibitory effect, besides being significantly more pronounced at lower frequencies of stimulation (0.03-I Hz) and devoid of tachyphylaxis, is reversible after interrupting the infusions of 5-HT (up to 5.6 micrograms kg-1 min-1). In the present study we have characterized the pharmacological profile of the receptors mediating the above inhibitory effect of 5-HT. 2. The inhibition induced by 5.6 micrograms kg-1 min-1 of 5-HT on sympathetically-induced pressor responses was not blocked after i.v. treatment with physiological saline (1 ml kg-1), ritanserin (0.1 mg kg-1), MDL 72222 (0.15 mg kg-1) or tropisetron (3 mg kg-1), which did not modify the sympathetically-induced pressor responses per se, but was significantly antagonized by the 5-HT1-like and 5-HT2 receptor antagonist, methysergide (0.3 mg kg-1), which also produced a slight attenuation of the pressor responses to 0.03 and 0.1 Hz per se. 3. Unexpectedly and contrasting with methysergide, the 5-HT1-like and 5-HT2 receptor antagonists, methiothepin (0.01, 0.03 and 0.1 mg kg-1) and metergoline (1 and 3 mg kg-1), apparently failed to block the above 5-HT-induced inhibition. Nevertheless, it is noteworthy that these antagonists also blocked the electrically-induced pressor responses per se, presumably by blockade of vascular alpha 1-adrenoceptors and, indeed, this property might have masked their potential antagonism at the inhibitory 5-HT1-like receptors. 4. Consistent with the above findings, 5-carboxamidotryptamine (5-CT, a potent 5-HT1-like receptor agonist), metergoline and methysergide mimicked the inhibitory action of 5-HT with the following rank order of agonist potency: 5CT > > 5-HT > metergoline > or = methysergide. 5

  12. Multiple 5-HT receptors in the guinea-pig superior cervical ganglion.

    PubMed Central

    Watkins, C. J.; Newberry, N. R.


    1. We have studied the pharmacology of the depolarization by 5-hydroxytryptamine (5-HT) of the guinea-pig isolated superior cervical ganglion (SCG) using the grease-gap technique. We studied the effects of selective and non-selective antagonists on the responses to 5-HT and other 5-HT receptor agonists. 2. We have extended the pharmacology of the 5-HT3 receptor in this preparation by studying the effects of granisetron, BRL 46470 and mianserin on the concentration-response curve (CRC) to 2-methyl-5-HT. As with other 5-HT3 receptor antagonists, these compounds exhibited a lower affinity for guinea-pig 5-HT3 receptors than for rat 5-HT3 receptors. 3. We have confirmed that low concentrations of 5-HT (< or = 1 microM) mediate ketanserin-sensitive responses and higher concentrations of 5-HT also recruit 5-HT3 receptors. The responses to low concentrations of 5-HT were antagonized by low concentrations of ketanserin, spiperone, mianserin, DOI and LSD indicating probably mediation by 5-HT2A receptors. At high concentrations, the hallucinogen, DOI, but not LSD, evoked a ketanserin-sensitive depolarization. 4. Although mianserin could bind to the 5-HT2A receptors in this preparation, we could not demonstrate a down-regulation of depolarizations evoked by these receptors after a 10 day oral treatment with mianserin (10 mg kg-1, daily). 5. 5-Carboxamidotryptamine (5-CT) evoked a prolonged depolarization. Although high concentrations of 5-CT (> or = microM) appeared to activate 5-HT2A receptors, lower concentrations of 5-CT evoked a response with a distinct pharmacology. After studying the action of 20 selective and non-selective 5-HT receptor ligands we believe that this response may be mediated by a novel receptor; but its pharmacology is closest to that of receptors in the 5-HT2 receptor family. Like 5-CT, 5-HT (3-300 microM) could evoke an LSD-sensitive response in the presence of the 5-HT2 receptor antagonist, ketanserin and the 5-HT3 receptor antagonist, tropisetron

  13. 5-Chloroindole: a potent allosteric modulator of the 5-HT3 receptor

    PubMed Central

    Newman, Amy S; Batis, Nikolaos; Grafton, Gillian; Caputo, Francesca; Brady, Catherine A; Lambert, Jeremy J; Peters, John A; Gordon, John; Brain, Keith L; Powell, Andrew D; Barnes, Nicholas M


    Background and Purpose The 5-HT3 receptor is a ligand-gated ion channel that is modulated allosterically by various compounds including colchicine, alcohols and volatile anaesthetics. However the positive allosteric modulators (PAMs) identified to date have low affinity, which hinders investigation because of non-selective effects at pharmacologically active concentrations. The present study identifies 5-chloroindole (Cl-indole) as a potent PAM of the 5-HT3 receptor. Experimental Approach 5-HT3 receptor function was assessed by the increase in intracellular calcium and single-cell electrophysiological recordings in HEK293 cells stably expressing the h5-HT3A receptor and also the mouse native 5-HT3 receptor that increases neuronal contraction of bladder smooth muscle. Key Results Cl-indole (1–100 μM) potentiated agonist (5-HT) and particularly partial agonist [(S)-zacopride, DDP733, RR210, quipazine, dopamine, 2-methyl-5-HT, SR57227A, meta chlorophenyl biguanide] induced h5-HT3A receptor-mediated responses. This effect of Cl-indole was also apparent at the mouse native 5-HT3 receptor. Radioligand-binding studies identified that Cl-indole induced a small (∼twofold) increase in the apparent affinity of 5-HT for the h5-HT3A receptor, whereas there was no effect upon the affinity of the antagonist, tropisetron. Cl-indole was able to reactivate desensitized 5-HT3 receptors. In contrast to its effect on the 5-HT3 receptor, Cl-indole did not alter human nicotinic α7 receptor responses. Conclusions and Implications The present study identifies Cl-indole as a relatively potent and selective PAM of the 5-HT3 receptor; such compounds will aid investigation of the molecular basis for allosteric modulation of the 5-HT3 receptor and may assist the discovery of novel therapeutic drugs targeting this receptor. Linked Articles Recent reviews on allosteric modulation can be found at: Kenakin, T (2013). New concepts in pharmacological efficacy at 7TM receptors: IUPHAR Review 2

  14. Pharmacological profile of the 5-HT-induced inhibition of cardioaccelerator sympathetic outflow in pithed rats: correlation with 5-HT1 and putative 5-ht5A/5B receptors

    PubMed Central

    Sánchez-López, Araceli; Centurión, David; Vázquez, Erika; Arulmani, Udayasankar; Saxena, Pramod R; Villalón, Carlos M


    Continuous infusions of 5-hydroxytryptamine (5-HT) inhibit the tachycardiac responses to preganglionic (C7-T1) sympathetic stimulation in pithed rats pretreated with desipramine. The present study identified the pharmacological profile of this inhibitory action of 5-HT. The inhibition induced by intravenous (i.v.) continuous infusions of 5-HT (5.6 μg kg−1 min−1) on sympathetically induced tachycardiac responses remained unaltered after i.v. treatment with saline or the antagonists GR 127935 (5-HT1B/1D), the combination of WAY 100635 (5-HT1A) plus GR 127935, ritanserin (5-HT2), tropisetron (5-HT3/4), LY215840 (5-HT7) or a cocktail of antagonists/inhibitors consisting of yohimbine (α2), prazosin (α1), ritanserin, GR 127935, WAY 100635 and indomethacin (cyclooxygenase), but was abolished by methiothepin (5-HT1/2/6/7 and recombinant 5-ht5A/5B). These drugs, used in doses high enough to block their respective receptors/mechanisms, did not modify the sympathetically induced tachycardiac responses per se. I.v. continuous infusions of the agonists 5-carboxamidotryptamine (5-CT; 5-HT1/7 and recombinant 5-ht5A/5B), CP 93,129 (r5-HT1B), sumatriptan (5-HT1B/1D), PNU-142633 (5-HT1D) and ergotamine (5-HT1B/1D and recombinant 5-ht5A/5B) mimicked the above sympatho-inhibition to 5-HT. In contrast, the agonists indorenate (5-HT1A) and LY344864 (5-ht1F) were inactive. Interestingly, 5-CT-induced cardiac sympatho-inhibition was abolished by methiothepin, the cocktail of antagonists/inhibitors, GR 127935 or the combination of SB224289 (5-HT1B) plus BRL15572 (5-HT1D), but remained unchanged when SB224289 or BRL15572 were given separately. Therefore, 5-HT-induced cardiac sympatho-inhibition, being unrelated to 5-HT2, 5-HT3, 5-HT4, 5-ht6, 5-HT7 receptors, α1/2-adrenoceptor or prostaglandin synthesis, seems to be primarily mediated by (i) 5-HT1 (probably 5-HT1B/1D) receptors and (ii) a novel mechanism antagonized by methiothepin that, most likely, involves putative 5-ht5A/5B

  15. Characterization of prejunctional 5-HT receptors mediating inhibition of sympathetic vasopressor responses in the pithed rat.

    PubMed Central

    Villalón, C. M.; Contreras, J.; Ramírez-San Juan, E.; Castillo, C.; Perusquía, M.; Terrón, J. A.


    1. It has recently been shown that continuous infusions of 5-hydroxytryptamine (5-HT) are able to inhibit, in a dose-dependent manner, the pressor responses induced by preganglionic (T7-T9) sympathetic stimulation in pithed rats pretreated with desipramine (50 micrograms kg-1, i.v.). This inhibitory effect, besides being significantly more pronounced at lower frequencies of stimulation (0.03-I Hz) and devoid of tachyphylaxis, is reversible after interrupting the infusions of 5-HT (up to 5.6 micrograms kg-1 min-1). In the present study we have characterized the pharmacological profile of the receptors mediating the above inhibitory effect of 5-HT. 2. The inhibition induced by 5.6 micrograms kg-1 min-1 of 5-HT on sympathetically-induced pressor responses was not blocked after i.v. treatment with physiological saline (1 ml kg-1), ritanserin (0.1 mg kg-1), MDL 72222 (0.15 mg kg-1) or tropisetron (3 mg kg-1), which did not modify the sympathetically-induced pressor responses per se, but was significantly antagonized by the 5-HT1-like and 5-HT2 receptor antagonist, methysergide (0.3 mg kg-1), which also produced a slight attenuation of the pressor responses to 0.03 and 0.1 Hz per se. 3. Unexpectedly and contrasting with methysergide, the 5-HT1-like and 5-HT2 receptor antagonists, methiothepin (0.01, 0.03 and 0.1 mg kg-1) and metergoline (1 and 3 mg kg-1), apparently failed to block the above 5-HT-induced inhibition. Nevertheless, it is noteworthy that these antagonists also blocked the electrically-induced pressor responses per se, presumably by blockade of vascular alpha 1-adrenoceptors and, indeed, this property might have masked their potential antagonism at the inhibitory 5-HT1-like receptors. 4. Consistent with the above findings, 5-carboxamidotryptamine (5-CT, a potent 5-HT1-like receptor agonist), metergoline and methysergide mimicked the inhibitory action of 5-HT with the following rank order of agonist potency: 5CT > > 5-HT > metergoline > or = methysergide. 5

  16. Evidence for 5-HT1B/1D and 5-HT2A receptors mediating constriction of the canine internal carotid circulation

    PubMed Central

    Centurión, David; Ortiz, Mario I; Sánchez-López, Araceli; De Vries, Peter; Saxena, Pramod R; Villalón, Carlos M


    The present study has investigated the preliminary pharmacological profile of the receptors mediating vasoconstriction to 5-hydroxytryptamine (5-HT) in the internal carotid bed of vagosympathectomised dogs. One minute intracarotid infusions of the agonists 5-HT (0.1–10 μg min−1), sumatriptan (0.3–10 μg min−1; 5-HT1B/1D), 5-methoxytryptamine (1–100 μg min−1; 5-HT1, 5-HT2, 5-HT4, 5-ht6 and 5-HT7) or DOI (0.31–10 μg min−1; 5-HT2), but not 5-carboxamidotryptamine (0.01–0.3 μg min−1; 5-HT1, 5-ht5A and 5-HT7), 1-(m-chlorophenyl)-biguanide (mCPBG; 1–1000 μg min−1; 5-HT3) or cisapride (1–1000 μg min−1; 5-HT4), resulted in dose-dependent decreases in internal carotid blood flow, without changing blood pressure or heart rate. The vasoconstrictor responses to 5-HT, which remained unaffected after saline, were resistant to blockade by i.v. administration of the antagonists ritanserin (100 μg kg−1; 5-HT2A/2B/2C) in combination with tropisetron (3000 μg kg−1; 5-HT3/4) or the cyclo-oxygenase inhibitor, indomethacin (5000 μg kg−1), but were abolished by the 5-HT1B/1D receptor antagonist, GR127935 (30 μg kg−1). Interestingly, after administration of GR127935, the subsequent administration of ritanserin unmasked a dose-dependent vasodilator component. GR127935 or saline did not practically modify the vasoconstrictor effects of 5-MeO-T. In animals receiving GR127935, the subsequent administration of ritanserin abolished the vasoconstrictor responses to 5-MeO-T unmasking a dose-dependent vasodilator component. The vasoconstriction induced by sumatriptan was antagonized by GR127935, but not by ritanserin. Furthermore, ritanserin (100 μg kg−1) or ketanserin (100 μg kg−1; 5-HT2A), but not GR127935, abolished DOI-induced vasoconstrictor responses. The above results suggest that 5-HT-induced internal carotid vasoconstriction is predominantly mediated by 5-HT1B/1D and 5-HT2A receptors

  17. Myocyte cellular hypertrophy and hyperplasia contribute to ventricular wall remodeling in anemia-induced cardiac hypertrophy in rats.

    PubMed Central

    Olivetti, G.; Quaini, F.; Lagrasta, C.; Ricci, R.; Tiberti, G.; Capasso, J. M.; Anversa, P.


    To determine the effects of chronic anemia on the functional and structural characteristics of the heart, 1-month-old male rats were fed a diet deficient in iron and copper, which led to a hemoglobin concentration of 4.63 g/dl, for 8 weeks. At sacrifice, under fentanyl citrate and droperidol anesthesia, systolic, diastolic, and mean arterial blood pressures were decreased, whereas differential pressure was increased. Left ventricular systolic pressure and the ventricular rate of pressure rise (mmHg/s) were reduced by 9% and 14%, respectively. Moreover, developed peak systolic ventricular pressure and maximal dP/dt diminished 14% and 12%. After perfusion fixation of the coronary vasculature and the myocardium, at a left ventricular intracavitary pressure equal to the in vivo measured end diastolic pressure, a 10% thickening of the left ventricular wall was measured in association with a 13% increase in the equatorial cavitary diameter and a 44% augmentation in ventricular mass. The 52% hypertrophy of the right ventricle was characterized by an 11% thicker wall and a 37% larger ventricular area. The 33% expansion in the aggregate myocyte volume of the left ventricle was found to be due to a 14% myocyte cellular hypertrophy and a 17% myocyte cellular hyperplasia. These cellular parameters were calculated from the estimation of the number of myocyte nuclei per unit volume of myocardium in situ and the evaluation of the distribution of nuclei per cell in enzymatically dissociated myocytes. Myocyte cellular hyperplasia provoked a 9% increase in the absolute number of cells across the left ventricular wall. In contrast, myocyte cellular hypertrophy (42%) was responsible for the increase in myocyte volume of the right ventricle. The proliferative response of left ventricular myocytes was not capable of restoring diastolic cell stress, which was enhanced by the changes in ventricular anatomy with anemia. In conclusion, chronic anemia induced an unbalanced load on the left

  18. Multimodal Protocol Reduces Post-operative Nausea and Vomiting in Patients Undergoing LeFort I Osteotomy

    PubMed Central

    Brookes, Carolyn Dicus; Berry, John; Rich, Josiah; Golden, Brent A; Turvey, Timothy A; Blakey, George; Kopp, Vincent; Phillips, Ceib; Anderson, Jay


    Purpose To assess the impact of a multimodal antiemetic protocol on postoperative nausea and vomiting (PONV) after LeFort I osteotomy. Methods Consecutive subjects undergoing LeFort I osteotomy with or without additional procedures at a single academic institution were recruited as the intervention cohort for an IRB-approved prospective clinical trial with a retrospective comparison group. The intervention cohort was managed with a multimodal antiemetic protocol including total intravenous anesthesia; prophylactic ondansetron, steroids, scopolamine, and droperidol; gastric decompression at surgery end; opioid-sparing analgesia; avoidance of morphine and codeine; prokinetic erythromycin; and minimum 25 mL/kg fluids. The comparison group consisted of consecutive subjects from a larger study who underwent similar surgical procedures prior to protocol implementation. Data including occurrence of PONV were extracted from medical records. Data were analyzed bivariately with Fisher’s Exact and Wilcoxon Rank Sum Tests. Logistic regression was used to compare the likelihood of nausea and vomiting in the two cohorts controlling for demographic and surgery characteristics. P<0.05 was considered significant. Results The intervention (n=93) and comparison (n=137) groups were similar in terms of gender (58% and 65% female, P=0.29), race (72% and 71% Caucasian, P=0.85), age (median 19 and 20 years old, P=0.75), proportion of subjects with known risk factors for PONV (P=0.34), percentage undergoing bimaxillary surgery (60% for both groups), and percentage for whom surgery time was over 180 minutes (63% versus 59%, P=0.51). Prevalence of PON was significantly lower in the intervention group than the comparison group (24% versus 70%, P<0.0001). Prevalence of POV was likewise significantly lower in the intervention group (11% versus 28%, P=0.0013). The likelihood that subjects in the comparison group would experience nausea was 8.9 and vomiting 3.7 times higher than in the

  19. Drug interactions with cisapride: clinical implications.


    Michalets, E L; Williams, C R


    avoiding coadministration of cisapride with amiodarone, cimetidine (alternatives are famotidine, nizatidine, ranitidine or one of the proton pump inhibitors), diltiazem and verapamil (the dihydropyridine calcium antagonists are alternatives), grapefruit juice, isoniazid, metronidazole, quinine, quinupristin/dalfopristin and zileuton (montelukast is an alternative). Pharmacodynamic interactions with cisapride involve drugs that have the potential to have additive effects on the QT interval. We do not recommend use of cisapride with class Ia and III antiarrhythmic drugs or with adenosine, bepridil, cyclobenzaprine, droperidol, haloperidol, nifedipine (immediate release), phenothiazine antipsychotics, tricyclic and tetracyclic antidepressants or vasopressin. Vigilance is advised if anthracyclines, cotrimoxazole (trimethoprim-sulfamethoxazole), enflurane, halothane, isoflurane, pentamidine or probucol are used with cisapride. In addition, uncorrected electrolyte disturbances induced by diuretics may increase the risk of torsade de pointes. Patients receiving cisapride should be promptly treated for electrolyte disturbances.

  20. A critical review of controlled clinical trials for peripheral neuropathic pain and complex regional pain syndromes.


    Kingery, W S


    data indicating that guanethidine and reserpine IVRBs were ineffective, and limited trial data indicating that droperidol and atropine IVRBs were ineffective. No placebo controlled data were available to evaluated sympathetic ganglion blocks (SGBs) with local anesthetics, surgical sympathectomy, or physical therapy. Only the capsaicin trials presented data which allowed for meta-analysis. This meta-analysis demonstrated a significant capsaicin effect with a pooled odds ratio of 2.35 (95% confidence intervals 1.48, 3.22). The methods scores were higher (P < 0.01) for the PNP trials (66.2 +/- 1.5, n = 66) than the CRPS trials (57.6 +/- 2.9, n = 26). The CRPS trials tended to use less subjects and were less likely to use placebo controls, double-blinding, or perform statistical tests for differences in outcome measures between groups. There was almost no overlap in the controlled trial literature between treatments for PNP and CRPS, and treatments used in both conditions (intravenous phentolamine and epidural clonidine) had similar results.

  1. The interaction of trichloroethanol with murine recombinant 5-HT3 receptors.

    PubMed Central

    Downie, D L; Hope, A G; Belelli, D; Lambert, J J; Peters, J A; Bentley, K R; Steward, L J; Chen, C Y; Barnes, N M


    108-15 cells or HEK 293 cells. Similarly, competition for [3H]-granisetron binding by the 5-HT3 receptor antagonists ondansetron and tropisetron was unaffected. However, competition for [3H]-granisetron binding by the 5-HT3 receptor agonists, 5-HT, 2-methyl-5-HT and phenylbiguanide was enhanced by trichloroethanol (2.5 mM).(ABSTRACT TRUNCATED AT 400 WORDS) PMID:7541281

  2. Characterization of putative 5-HT7 receptors mediating tachycardia in the cat

    PubMed Central

    Villalón, Carlos M; Heiligers, Jan P C; Centurión, David; De Vries, Peter; Saxena, Pramod R


    It has been suggested that the tachycardic response to 5-hydroxytryptamine (5-HT) in the spinal-transected cat is mediated by ‘5-HT1-like' receptors since this effect, being mimicked by 5-carboxamidotryptamine (5-CT), is not modified by ketanserin or MDL 72222, but it is blocked by methiothepin, methysergide or mesulergine. The present study was set out to reanalyse this suggestion in terms of the IUPHAR 5-HT receptor classification schemes proposed in 1994 and 1996. Intravenous (i.v.) bolus injections of the tryptamine derivatives, 5-CT (0.01, 0.03, 0.1, 0.3, 1, 3, 10 and 30 μg kg−1), 5-HT (3, 10 and 30 μg kg−1) and 5-methoxytryptamine (3, 10 and 30 μg kg−1) as well as the atypical antipsychotic drug, clozapine (1000 and 3000 μg kg−1) resulted in dose-dependent increases in heart rate, with a rank order of agonist potency of 5-CT >> 5-HT > 5-methoxytryptamine >> clozapine. The tachycardic effects of 5-HT and 5-methoxytryptamine were dose-dependently antagonized by i.v. administration of lisuride (30 and 100 μg kg−1), ergotamine (100 and 300 μg kg−1) or mesulergine (100, 300 and 1000 μg kg−1); the highest doses of these antagonists used also blocked the tachycardic effects of 5-CT. Clozapine (1000 and 3000 μg kg−1) did not affect the 5-HT-induced tachycardia, but attenuated, with its highest dose, the responses to 5-methoxytryptamine and 5-CT. However, these doses of clozapine as well as the high doses of ergotamine (300 μg kg−1) and mesulergine (300 and 1000 μg kg−1) also attenuated the tachycardic effects of isoprenaline. In contrast, 5-HT-, 5-methoxytryptamine- and 5-CT-induced tachycardia were not significantly modified after i.v. administration of physiological saline (0.1 and 0.3 ml kg−1), the 5-HT1B/1D receptor antagonist, GR127935 (500 μg kg−1) or the 5-HT3/4 receptor antagonist, tropisetron (3000 μg kg−1). Intravenous injections of the 5-HT1 receptor agonists

  3. Stimulation of the wrist acupuncture point PC6 for preventing postoperative nausea and vomiting

    PubMed Central

    Lee, Anna; Chan, Simon KC; Fan, Lawrence TY


    -analyses of the primary outcomes, based on a 30% risk ratio reduction in PONV. Main results We included 59 trials involving 7667 participants. We rated two trials at low risk of bias in all domains (selection, attrition, reporting, blinding and other). We rated 25 trials at high risk in one or more risk-of-bias domains. Compared with sham treatment, PC6 acupoint stimulation significantly reduced the incidence of nausea (RR 0.68, 95% CI 0.60 to 0.77; 40 trials, 4742 participants), vomiting (RR 0.60, 95% CI 0.51 to 0.71; 45 trials, 5147 participants) and the need for rescue antiemetics (RR 0.64, 95% CI 0.55 to 0.73; 39 trials, 4622 participants). As heterogeneity among trials was substantial and there were study limitations, we rated the quality of evidence as low. Using trial sequential analysis, the required information size and boundary for benefit were reached for both primary outcomes. PC6 acupoint stimulation was compared with six different types of antiemetic drugs (metoclopramide, cyclizine, prochlorperazine, droperidol. ondansetron and dexamethasone). There was no difference between PC6 acupoint stimulation and antiemetic drugs in the incidence of nausea (RR 0.91, 95% CI 0.75 to 1.10; 14 trials, 1332 participants), vomiting (RR 0.93, 95% CI 0.74 to 1.17; 19 trials, 1708 participants), or the need for rescue antiemetics (RR 0.87, 95% CI 0.65 to 1.16; 9 trials, 895 participants). We rated the quality of evidence as moderate, due to the study limitations. Using trial sequential analyses, the futility boundary was crossed before the required information size was surpassed for both primary outcomes. Compared to antiemetic drugs, the combination of PC6 acupoint stimulation and antiemetic therapy reduced the incidence of vomiting (RR 0.56, 95% CI 0.35 to 0.91; 9 trials, 687 participants) but not nausea (RR 0.79, 95% CI 0.55 to 1.13; 8 trials, 642 participants). We rated the quality of evidence as very low, due to substantial heterogeneity among trials, study limitations and

  4. Interventions for preventing nausea and vomiting in women undergoing regional anaesthesia for caesarean section

    PubMed Central

    Griffiths, James D; Gyte, Gillian ML; Paranjothy, Shantini; Brown, Heather C; Broughton, Hannah K; Thomas, Jane


    , 720 women). There were also reductions in postoperative nausea (average RR 0.40, 95% CI 0.25 to 0.64, four studies, 405 women) and vomiting (average RR 0.50, 95% CI 0.32 to 0.77, five studies, 565 women). We did not detect a significant reduction in intraoperative vomiting (average RR 0.56, 95% CI 0.31 to 1.00, seven studies, 668 women). Dopamine antagonists demonstrated a reduction in intraoperative nausea (average RR 0.38, 95% CI 0.25 to 0.57, nine studies, 636 women) and intraoperative vomiting (average 0.39, 95% CI 0.24 to 0.64, eight studies, 536 women), with similar reductions in postoperative nausea (average RR 0.60, 95% CI 0.40 to 0.91, five studies, 412 women) and vomiting (average RR 0.57, 95% CI 0.36 to 0.91, six studies, 472 women). These differences were observed with both metoclopramide and droperidol. Sedatives (most commonly propofol) demonstrated a reduction in intraoperative nausea (average RR 0.71, 95% CI 0.52 to 0.96, four studies, 285 women) and intraoperative vomiting (average RR 0.42, 95% CI 0.26 to 0.68, four studies, 285 women), also with a reduction in postoperative nausea (average RR 0.25, 95% CI 0.09 to 0.71, two studies 145 women) and vomiting (average RR 0.09, 95% CI 0.03 to 0.28, two studies, 145 women). Acupressure was found to be effective for intraoperative nausea (average RR 0.59, 95% CI 0.38 to 0.90, six studies, 649 women) but not postoperative nausea (average RR 0.83, 95% CI 0.68 to 1.00, three studies, 429 women). Acupressure was not effective at reducing vomiting either intraoperatively (average RR 0.74, 95% CI 0.46 to 1.18, six studies, 649 women) or postoperatively (average RR 0.69, 95% CI 0.45 to 1.06, three studies, 429 women). Other effective intervention classes included corticosteroids, antihistamines, and anticholinergics. There were insufficient data to demonstrate any class of intervention was superior to another. There were no significant differences observed in the comparison of combined versus single interventions