... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Droperidol and fentanyl citrate injection. 522.800... § 522.800 Droperidol and fentanyl citrate injection. (a) Specifications. Droperidol and fentanyl citrate injection is a sterile solution containing 20 milligrams of droperidol and 0.4 milligram of fentanyl...
... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Droperidol and fentanyl citrate injection. 522.800... § 522.800 Droperidol and fentanyl citrate injection. (a) Specifications. Droperidol and fentanyl citrate injection is a sterile solution containing 20 milligrams of droperidol and 0.4 milligram of fentanyl...
... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Droperidol and fentanyl. 522.800 Section 522.800... Droperidol and fentanyl. (a) Specifications. Each milliliter of solution contains 20 milligrams (mg) of droperidol and 0.4 mg of fentanyl citrate. (b) Sponsor. See No. 000061 in § 510.600(c) of this chapter....
Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder. Despite this, there are no drugs for preventing the onset of AD. Preclinical studies suggest that the interaction between amyloid-β peptides (Aβ) and the α7 nicotinic acetylcholine receptor (α7 nAChR) plays a key role in AD pathology, and that α7 nAChR agonists could act as potential therapeutic drugs for AD. A recent study demonstrated that tropisetron, a potent α7 nAChR agonist and serotonin 5-hydroxytryptamine3 receptor antagonist, also bound to the ectodomain of amyloid precursor protein. Furthermore, tropisetron promoted greater improvements in memory than current AD therapeutic drugs, such as memantine and donepezil. Positron emission tomography studies detected Aβ deposition and inflammation in the brains of subjects with amnestic mild cognitive impairment (MCI) before the onset of AD. Given the role of α7 nAChR in Aβ deposition and inflammation, tropisetron represents an attractive potential therapeutic drug to delay or prevent MCI and AD. Additionally as this drug is used internationally to treat chemotherapy-induced emesis, its safety record is already known.
Zhao, Feng; Cui, Suyang; Huang, Libing
Aim. This study investigated the effect of P6 EA on droperidol-induced QTc interval prolongation and Cx43 expression in ventricular muscle of rats. Methods. Twenty-four rats were randomly divided into control group (C), droperidol group (D), or EA group (E). C group rats were injected with normal saline. D group rats were injected with droperidol 0.13 mg/kg. E group rats were pretreated with EA at left P6 acupoint for 30 min and then injected with droperidol (0.13 mg/kg). QTc intervals were recorded at lead II in ECG within 120 min. Cx43 expression was measured by RT-PCR and western blotting. Result. Droperidol significantly prolonged QTc intervals compared with controls at 5 min, 10 min, 15 min, and 30 min (P < 0.05). P6 EA could significantly abbreviate the prolongation of QTc interval compared with droperidol group at 5 min, 10 min, 15 min, and 30 min (P < 0.05). Cx43 mRNA and proteins were significantly increased by P6 EA compared with droperidol group at 120 min (P < 0.05). There were no significant differences in Cx43 mRNA and protein expression between droperidol and control group at 120 min (P > 0.05). Conclusion. P6 EA could improve QTc interval prolongation induced by droperidol, which may relate to upregulation of Cx43 mRNA and protein. Antiemetic dose of droperidol had minor effects on Cx43 mRNA and protein expression at 120 min. PMID:25371698
Candelario-Jalil, Eduardo; Muñoz, Eduardo; Fiebich, Bernd L
Background Recent in vitro evidence indicates that blockade of 5-hydroxytryptamine (5-HT) receptor 3 (5-HT3) is able to confer protection in different models of neuronal injury. The purpose of the present study was to investigate the effect of tropisetron, a 5-HT3 receptor antagonist, on infarct size and neurological score in a model of ischemic stroke induced by permanent middle cerebral artery occlusion (pMCAO) in the rat. Methods Two different doses of tropisetron (5 and 10 mg/kg) or vehicle were administered intraperitoneally 30 min before pMCAO. Neurological deficit scores, mortality rate and infarct volume were determined 24 h after permanent focal cerebral ischemia. Results Tropisetron failed to reduce cerebral infarction. Animals receiving tropisetron showed a significant increase (p < 0.05) in neurological deficits and mortality rate. Conclusion Data from this study indicate that blockade of 5-HT3 receptors with tropisetron worsens ischemic brain injury induced by pMCAO. These findings could have important clinical implications. Patients taking tropisetron, and possibly other 5-HT3 antagonists, could potentially have a worse outcome following a brain infarct. PMID:18254974
Hung, Y C; Ho, Y Y; Shen, C L
Epidural administration of droperidol has been used to prevent postoperative nausea and vomiting (PONV) caused by opioids, but the adverse reactions were relatively neglected. We present a patient who received patient-controlled epidural analgesia (PCEA) with bupivacaine-morphine-droperidol mixture for one and half days following hemorrhoidectomy, developed paroxysmal adverse reactions of akathisia, dysphoria, and suicidal attempts 3 days after the initiation of the treatment. The use of droperidol in PCEA for prevention of nausea and vomiting therefore needs to be re-evaluated according to the serious side effects occurring in our case.
Kohnomi, Shuntaro; Suemaru, Katsuya; Goda, Mitsunori; Choshi, Tominari; Hibino, Satoshi; Kawasaki, Hiromu; Araki, Hiroaki
Nicotine has ameliorating effects on sensorimotor gating deficits in schizophrenia. We have shown that nicotine ameliorated disruption of prepulse inhibition (PPI) via the alpha(7) nicotinic acetylcholine receptor (nAChR) in Wistar rats. The 5-HT(3) receptor antagonist tropisetron was recently found to be an alpha(7) nAChR partial agonist. We initially investigated the effects of tropisetron on disruption of PPI induced by phencyclidine (PCP) (2mg/kg) or apomorphine (1mg/kg). Tropisetron had no effect on the disruption of PPI induced by PCP, but ameliorated the disruption by apomorphine. The ameliorating effect of tropisetron was antagonized by methyllycaconitine (2 or 5mg/kg), a partially selective alpha(7) nAChR antagonist. Next, to find the action site of tropisetron, we examined c-Fos protein expression in the nucleus accumbens (NAc), dorsolateral striatum (DLst) and ventral tegmental area (VTA). Tropisetron alone did not change the number of c-Fos-positive cells, whereas apomorphine increased the number of positive cells in the NAc and DLst. Tropisetron administration followed by apomorphine administration decreased the number of positive cells in the VTA compared with the apomorphine-alone group. These results suggest that tropisetron has an ameliorating effect on the sensorimotor gating deficits via the alpha(7) nAChR, and that one possible site of its action is the VTA.
Golemanov, D; Aminkov, B; Maneta, M
Studied were 7 clinically normal sheep chosen randomly (merino, Tsigai, and crosses of these as well as Stara Zagora breed and merino crosses), aged 2-3 years, at an average weight of 52.71 kg. I/v neuroleptanalgesia was carried out (with no surgery to follow) at preliminary premedication with atropini sulfas at 350 Y/kg M., in s/c application, and a mixture of Droperidol at 0.25 mg/kg M. and Fentanyl at 0.005 mg/kg M. in i/m application. Fifteen min later the basic portion of the Droperidol (0.25 mg/kg) and Fentanyl (0.010 mg/kg) mixture was introduced (i/v). The changes in the blood were followed up prior to and after anaesthesia at the 1st, 3rd, and 24th hour and on the 4th and 7th day with regard to hemoglobin, erythrocytes, erythrocyte sedimentation rate, hematocrit, leukocytes and leukocyte formula, total protein and protein fractions, Ca, P, Mg, Na, K, total and direct bilirubin, and fibrinogen. It was found that hemoglobin and erythrocyte values were close to the normal ones. The higher leukocyte count at the 3rd and 24th hour following neuroleptanalgesia was accompanied by transient moderate neutrophilia, lymphopenia, and very slight eosinopenia. The total protein, protein fractions, fibrinogen, total and direct bilirubin, Ca, Na, and K did not show essential changes. Phosphorus and Mg dropped at the 3rd and 24th hour, and on the 7th day did not come back to normal.
Kohnen, R; Färber, L; Späth, M
Vegetative and functional symptoms are, besides pain and tenderness of tender points, considered as additional information for the diagnosis of fibromyalgia (FM). In clinical trials, vegetative and functional symptoms have been included for selection of patients (e.g. sleep disturbances) and as secondary outcome parameters. Despite the relevance of these symptoms, no validated method is currently available but symptom lists are ad hoc developed by investigators. In this manuscript, data from a published double blind, randomised study are reanalysed which compared oral therapy over 10 days with 5 mg, 10 mg, and 15 mg to placebo in FM patients. This study applied a list of 17 vegetative and functional symptoms, which had to be scored by the patients by use of a 4-point severity scale (0 = none to 3 = severe). Factor analysis of the baseline data from 195 patients suggested to separate 6 sub-scales: Cardiovascular, gastrointestinal, psychiatric (sleep disturbance), nervous, autonomic system, and general disorders. Sleep disturbances, general symptoms (morning stiffness, fatigue) and autonomic symptoms (cold extremities, hyperhidrosis) were most severe in intensity. Analysis of sensitivity for treatment effects made use of differences between placebo and 5 mg tropisetron in changes between baseline and final assessment of the tropisetron trial. While, on the item level, differences in favour of tropisetron could only be demonstrated for sleep disorders, on the sub-scale level, also favourable effects of tropisetron could be shown for cardiovascular and nervous system complaints and, as a tendency, for general symptoms. On the other side, the sub-scale score of gastrointestinal symptoms worsened under tropisetron whilst it improved under placebo which effect was due to side effects of the active treatment. It is concluded that symptom clusters like sub-scales of a list of vegetative and functional symptoms will be more suitable for diagnostic purposes and evaluation of
Inta, Dragos; Vogt, Miriam A; Lima-Ojeda, Juan M; Pfeiffer, Natascha; Schneider, Miriam; Gass, Peter
The early postnatal period represents a critical time window for brain development. Transient Cajal-Retzius cells in layer I of the cortex play an important role in cortical lamination by modulating neuronal migration and maturation. Recent data have demonstrated that the 5-HT(3) receptor antagonist and alpha7 nicotinic receptor partial agonist tropisetron, acting via 5-HT(3) receptors expressed on Cajal-Retzius cells, can disturb the formation of cortical columns at perinatal stages. This process is thought to be involved in several neuropsychiatric disorders. Here we investigated the possible long-term behavioral effects of exposure to tropisetron at early postnatal stages in mice. We found that the administration of 1mg/kg, intraperitoneal (i.p.) tropisetron from postnatal days 2-12 (P2-P12) did not induce significant cognitive, schizophrenia-like or emotional alterations in tropisetron-treated animals as compared to controls, when tested in multiple behavioral assays. These results may be of relevance regarding the possible protracted deleterious neuropsychiatric effects of tropisetron during early life.
Tracz, Krzysztof; Owczuk, Radosław
AIM Drugs used for postoperative nausea and vomiting prophylaxis are believed to provoke torsadogenic changes in cardiac repolarization. The aim of this study was to assess the effect of small doses of droperidol on the parameters of cardiac repolarization, including the QTc interval and transmural dispersion of repolarization. METHODS A total of 75 patients were randomly allocated to receive 0.625 or 1.25 mg droperidol or 8 mg ondansetron. The QTc interval was calculated using Bazett's formula and the Framingham correction. The transmural dispersion of repolarization was determined as Tpeak–Tend time. RESULTS Transient QT prolongation, corrected with both formulae, followed 1.25 mg of droperidol 10 min after administration. No change in the QTc value was observed in the other groups. When corrected with Bazett's formula, QTc was prolonged above 480 ms in two patients receiving 1.25 mg droperidol (at the 10th and 20th minute of the study) and in one receiving ondansetron. No patients developed a QTcB prolongation over 500 ms. No increase above 480 ms was observed relative to the Framingham correction method. There were no significant differences in the Tpeak–Tend time either between or within the groups. CONCLUSION In men without cardiovascular disorders small doses (1.25 mg) of droperidol prophylaxis induced transient QTc prolongation without changes in transmural dispersion of repolarization. The apparently low risk of the drug applies only in low risk male patients with a low pro-QTc score. PMID:25293524
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. PMID:25674732
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. PMID:25674732
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. PMID:23415734
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.
Haj-Mirzaian, Arya; Amiri, Shayan; Amini-Khoei, Hossein; Rahimi-Balaei, Maryam; Kordjazy, Nastaran; Olson, Carl O; Rastegar, Mojgan; Naserzadeh, Parvaneh; Marzban, Hassan; Dehpour, Ahmad Reza; Hosseini, Mir-Jamal; Samiei, Elika; Mehr, Shahram Ejtemaei
Tropisetron, a 5-HT3 receptor antagonist widely used as an antiemetic, has been reported to have positive effects on mood disorders. Adolescence is a critical period during the development of brain, where exposure to chronic stress during this time is highly associated with the development of depression. In this study, we showed that 4 weeks of juvenile social isolation stress (SIS) provoked depressive-like behaviors in male mice, which was associated with disruption of mitochondrial function and nitric oxide overproduction in the cortical areas. In this study, tropisetron (5mg/kg) reversed the negative behavioral effects of SIS in male mice. We found that the effects of tropisetron were mediated through mitigating the negative activity of inducible nitric oxide synthase (iNOS) on mitochondrial activity. Administration of aminoguanidine (specific iNOS inhibitor, 20mg/kg) augmented the protective effects of tropisetron (1mg/kg) on SIS. Furthermore, l-arginine (nitric oxide precursor, 100mg/kg) abolished the positive effects of tropisetron. These results have increased our knowledge on the pivotal role of mitochondrial function in the pathophysiology of depression, and highlighted the role of 5-HT3 receptors in psychosocial stress response during adolescence. Finally, we observed that tropisetron alleviated the mitochondrial dysfunction through decreased nitrergic system activity in the cerebral cortex.
Madenoglu, Halit; Yildiz, Karamehmet; Dogru, Kudret; Kurtsoy, Ali; Güler, Gülen; Boyaci, Adem
This prospective, randomized, placebo-controlled, double-blinded study was designed to evaluate the efficacy of tropisetron in preventing postoperative nausea and vomiting after elective supratentorial craniotomy in adult patients. We studied 65 ASA physical status I-III patients aged 18 to 76 years who were undergoing elective craniotomy for resection of various supratentorial tumors. Patients were divided into two groups and received either 2 mg of tropisetron (group T) or saline placebo (group P) intravenously at the time of dural closure. A standard general anesthetic technique was used. Episodes of nausea and vomiting and the need for rescue antiemetic medication were recorded during 24 hours postoperatively. Demographic data, duration of surgery and anesthesia, and sedation scores were comparable in both groups. Nausea occurred in 30% of group T patients and in 46.7% of group P patients (P >.05). The incidence of emetic episodes was 26.7% and 56.7% in the two groups (P <.05). Rescue antiemetic medication was needed in 26.7% and 60% of the patients (P <.05). Administration of a single dose of tropisetron (2 mg intravenously) given at the time of dural closure was effective in reducing postoperative nausea and vomiting after elective craniotomy for supratentorial tumor resection in adult patients. PMID:12657991
Tasaka, Yuichi; Yasunaga, Daiki; Kiyoi, Takeshi; Tanaka, Mamoru; Tanaka, Akihiro; Suemaru, Katsuya; Araki, Hiroaki
Ulcerative colitis (UC) involves chronic inflammation of the large intestine. Several agents are used to treat UC, but adverse side effects are remaining problems. We examined the effect of tropisetron as a new type of drug for UC using a dextran sulfate sodium (DSS)-induced model of colitis in mice. We developed a DSS-induced model of colitis and calculated the Disease Activity Index and colon length. We measured myeloperoxidase activity and determined the protein level and mRNA level of cytokines in the colon. DSS-induced colitis was ameliorated by administration of tropisetron and PNU282987. Pre-administration of methyllycaconitine diminished the suppressive effect of tropisetron upon DSS-induced colitis. These findings suggested that α7 nicotinic acetylcholine receptors (α7 nAChRs) were related to the suppressive effect of tropisetron on DSS-induced colitis. Additionally, stimulation of α7 nAChRs decreased the colon level of interleukin-6 and interferon-γ upon DSS administration. Furthermore, stimulation of α7 nAChRs decreased macrophage infiltration, with expression of α7 nAChR increased by DSS administration. These results suggest that the underlying mechanism of this suppressive effect on DSS-induced colitis is via stimulation of α7 nAChRs and involves suppression of expression of pro-inflammatory cytokines. Tropisetron could be a new type of therapeutic agent for UC.
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.
Färber, L; Stratz, T H; Brückle, W; Späth, M; Pongratz, D; Lautenschläger, J; Kötter, I; Zöller, B; Peter, H H; Neeck, G; Welzel, D; Müller, W
We investigated the efficacy and tolerability of short-term treatment with tropisetron, a selective, competitive 5-HT3-receptor antagonist in fibromyalgia. The trial was designed as a prospective, multicenter, double-blind, parallel-group, dose-finding study. We randomly assigned 418 patients suffering from primary fibromyalgia to receive either placebo, 5 mg, 10 mg or 15 mg tropisetron once daily for 10 days. Clinical response was measured by changes in pain score, visual analog scale, tender point count and ancillary symptoms. Responders were prospectively defined as patients showing a 35% or higher reduction in pain score. Treatment with 5 mg tropisetron resulted in a significantly higher response rate (39.2%) than placebo (26.2%) (p < 0.05). In the visual analog scale, the group administered 5 mg tropisetron showed a significant improvement (p < 0.05) and the group administered 10 mg tropisetron showed a nonsignificant clinical benefit. The number of painful tender points was significantly reduced (p = 0.002) in the 5 mg tropisetron group. Regarding ancillary symptoms, the 5 mg tropisetron group showed a significant improvement (p < 0.05) in sleep and dizziness. The patients' overall assessment of efficacy was significantly higher for 5 mg (p = 0.016) and 10 mg (p = 0.002) tropisetron than for placebo. The safety and tolerability of tropisetron was good; gastrointestinal tract symptoms were the most frequently reported adverse events. Short-term treatment of fibromyalgia patients with 5 mg tropisetron for 10 days proved to be efficacious and well tolerated. In this study a bell-shaped dose-response curve was seen.
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. PMID:27001377
Bērziņš, Agris; Hodgkinson, Paul
(13)C, (15)N and (2)H solid-state NMR spectroscopy have been used to rationalize arrangement and dynamics of solvent molecules in a set of isostructural solvates of droperidol. The solvent molecules are determined to be dynamically disordered in the methanol and ethanol solvates, while they are ordered in the acetonitrile and nitromethane solvates. (2)H NMR spectra of deuterium-labelled samples allowed the characterization of the solvent molecule dynamics in the alcohol solvates and the non-stoichiometric hydrate. The likely motion of the alcohol molecules is rapid libration within a site, plus occasional exchange into an equivalent site related by the inversion symmetry, while the water molecules are more strongly disordered. DFT calculations strongly suggest that the differences in dynamics between the solvates are related to differences in the energetic penalty for reversing the orientation of a solvent molecule. PMID:25282618
Ohkawa, H; Iwakawa, T; Ohtomo, N; Kitayama, M; Miyahara, A; Matsuki, A
Effect of total intravenous anesthesia with droperidol, fentanyl and ketamine (DFK) on peripheral circulation was studied by examining core-peripheral temperature gradient in twenty five patients who underwent abdominal surgery. A core temperature probe was attached on the forehead and peripheral probe on the palm of the hand of the side on which the blood pressure cuff was not applied. The temperature gradient was less than three degrees centigrade in 60% of the patients and the gradient was significantly less as compared with that of isoflurane anesthesia even at 300 minutes after the start of surgical operation. This advantage would have been caused by such factors as circulatory stimulating effect of ketamine, sympathetic blocking effect by droperidol and adequate postoperative analgesia by fentanyl and norketamine, a metabolite of ketamine. The results suggest that DFK would exert a beneficial effect on peripheral circulation, particularly during prolonged surgical procedures.
Marty, M; Kleisbauer, J P; Fournel, P; Vergnenegre, A; Carles, P; Loria-Kanza, Y; Simonetta, C; de Bruijn, K M
The purpose of this study was to evaluate and compare the antiemetic effectiveness and tolerability of Navoban (tropisetron) and Zofran (ondansetron) following high-dose (> or = 50 mg/m2) cisplatin chemotherapy. In a randomised, multi-centre, double-blind, double-dummy, parallel group study, 117 evaluable chemotherapy-naive patients who received Navoban were compared with 114 who received Zofran. Patient diary cards were used to assess both acute (Day 1) and delayed (Days 2-6) nausea and vomiting. Total control of acute vomiting was achieved in 54% of Navoban and 65% of Zofran patients (p = 0.052), and total control of acute nausea in 66% and 62% respectively (p = 0.655). Total control of delayed vomiting was achieved in 44% of Navoban patients and 46% of Zofran patients (p = 0.765), and of delayed nausea in 56% and 47% respectively (p = 0.207). Both reactions combined were totally prevented during the entire 6-day trial period in 22% of Navoban and 24% of Zofran patients (NS), while a further 42% of patients in both groups remained largely free from both nausea and emesis. The few adverse reactions (e.g. headache, constipation, diarrhoea) were mainly mild and typical of the 5-HT3-receptor antagonists. In conclusion, there were no significant differences in efficacy and tolerability between Navoban 5 mg once daily and the highest recommended dose of Zofran (32 mg on Day 1, followed by 8 mg three times a day). PMID:7749165
Golemanov, D; Aminkov, B; Ianeva, V
Intravenous potentiated anesthesia was made with six clinically normal boars of the White Bulgarian breed, weighing 50 kg, premedication of Atropini sulfas (50 gamma/kg M., s/c) and of a mixture of Droperidol (0.25 mg/kg M.) and Fentanyl (0.05 mg/kg M.) introduced via Sinus venosus ophthalmicus being administered 15 min. prior to 13 mg/kg M. of 5% water solution of thiopental-sodium injected in the same sinus. Prior to and following anesthesia at the 1st, 3rd, and 24th hour and on the 4th and 7th day the blood was checked with regard to hemoglobin, erythrocytes, erythrocyte sedimentation rate, hematocrit, leukocytes and leukocyte formula, total protein and protein fractions, calcium, phosphorus, magnesium, sodium, potassium, chlorides, total and direct bilirubin, and fibrinogen. Hemoglobin, erythrocytes, and hematocrit were found to drop insignificantly mathematically. The rate of increase of the sedimentation did not fully correspond to the drop of the erythrocyte count. The increase in leukocytes was accompanied by transient neutrophilia, eosinopenia, and lymphopenia in the early hours following anesthesia. The changes in the total protein and protein fractions, fibrinogen, total and direct bilirubin, and the other element indices referred to were shown to be close to the physiologic levels.
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 4 h. Ventilation increased 10-fold within 10 min due to increased breath frequency and tidal volume. Breaths/episode decreased by ~50% within after 1 h of hypoxia while the number of singlet breaths increased from 3.1 ± 1.6 singlets/h to a maximum of 66.1 ± 23.5 singlets/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, 5 mg/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. PMID:25543027
Fang, Bao-xia; Li, Peng; Shi, Xiao-ya; Chen, Fu-chao; Wang, Lin-hai
Abstract The administration of drugs by patient-controlled analgesia (PCA) is routinely practiced for the management of postoperative pain. It is common for 2 or more drugs to be combined in PCA solutions. The combination of analgesics and antiemetic agents is frequently required. Unfortunately, the compatibility and stability of lornoxicam and antiemetic agents, such as droperidol, ondansetrone, granisetron, and tropisetron, has not been determined. The aim of this study was to evaluate the compatibility and stability of solutions containing lornoxicam with the 4 antiemetic agents in combination for PCA administration. In our study, test samples were prepared in triplicate by adding 40 mg lornoxicam and 5 mg droperidol, 8 mg ondansetron, 6 mg granisetron, or 5 mg tropisetron to 100-mL polyolefin bags of sodium chloride 0.9% and stored at 25 °C. The analgesic mixture samples were visually inspected for precipitation, cloudiness, and discoloration at each sampling interval. Drug concentrations were determined using high-performance liquid chromatographic (HPLC) analysis. No loss of lornoxicam occurred with any of the 4 antiemetic agents tested for up to 48 hours. However, the contents of droperidol, ondansetron, granisetron, and tropisetron were significant loss >48 hours. After storage of 4.0 to 48.0 hours, the presence of a slight precipitate was observed in all the injection combinations. The results indicate that combinations of lornoxicam with droperidol, ondansetrone, granisetron, or tropisetron in infusion solution during simulated intravenous PCA administration were incompatibility when stored protected from light at 25 °C. PMID:27336868
... 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...
... 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...
Joris, Jean L.; Poth, Norbert J.; Djamadar, Ahmed M.; Sessler, Daniel I.; Hamoir, Etienne E.; Defêchereux, Thierry R.; Meurisse, Michel R.; Lamy, Maurice L.
Summary Supplemental intra-operative oxygen (80%) halves the incidence of nausea and vomiting after open and laparoscopic abdominal surgery, perhaps by ameliorating the subtle intestinal ischemia associated with abdominal surgery. It is unlikely that thyroid surgery compromises intestinal perfusion. We therefore tested the hypothesis that supplemental perioperative oxygen does not reduce the risk of postoperative nausea and vomiting (PONV) after thyroidectomy. As a positive control, we simultaneously evaluated the anti-nausea efficacy of droperidol. One hundred and fifty patients undergoing thyroidectomy were given sevoflurane anaesthesia. After induction, patients were randomly assigned to the following treatments: 1) 30% oxygen, balance nitrogen; 2) 80% oxygen, balance nitrogen; or 3) 30% oxygen with droperidol 0.625 mg. The overall incidence of nausea during the first 24 postoperative hours was 48% in the patients given 30% oxygen, 46% in those given 80% oxygen, and 22% in those given droperidol (P = 0.004). There were no significant differences between the 30% and 80% oxygen groups in incidence or severity of PONV, the need for rescue anti-emetics, or patient satisfaction. Droperidol significantly shortened the time to first meal. Supplemental oxygen was ineffective in preventing nausea and vomiting after thyroidectomy, but droperidol halved the incidence. PMID:14633758
Voigt, Matthias; Fröhlich, Christian W.; Hüttel, Christiane; Kranke, Peter; Mennen, Jan; Boessneck, Oliver; Lenz, Christian; Erbes, Thalia; Ernst, Jürgen; Kerger, Heinz
Background This paper describes a randomized prospective study conducted in 308 patients undergoing caesarean section in spinal anaesthesia at a single hospital between 2010 and 2012 to find a suitable anti-emetic strategy for these patients. Material/Methods Spinal anesthesia was performed in left prone position, at L3/L4 with hyperbaric 0.5% Bupivacaine according to a cc/cm body height ratio. There were no opioids given peri-operatively. The patients received either no prophylaxis (Group I) or tropisetron and metoclopramide (Group II) or dimenhydrinate and dexamethasone (Group III), or tropisetron as a single medication (Group IV). The primary outcome was nausea and/or vomiting (NV) in the intraoperative, early (0–2 h) or late (2–24 h) postoperative period. Multivariate statistical analysis was conducted with a regression analysis and a backward elimination of factors without significant correlation. Results All prophylactic agents significantly reduced NV incidence intraoperatively. Relative risk reduction for NV by prophylaxis was most effective (59.5%) in Group II (tropisetron and metoclopramide). In Group III (dimenhydrinate and dexamethasone), NV risk was reduced by 29.9% and by 28.7% in Group IV (tropisetron mono-therapy). The incidence of NV in the early (0–2 h) and the late (2–24 h) postoperative period was low all over (7.8%), but the relative risk reduction of NV in the early postoperative period was 54.1% (Group IV), 45.1% (Group III), and 34.8% (Group II), respectively. In the late postoperative period, there was no significant difference between the 4 groups. Conclusions We recommend a prophylactic medication with tropisetron 2 mg and metoclopramide 20 mg for patients during caesarean section. These agents are safe, reasonably priced, and highly efficient in preventing nausea and vomiting. PMID:24226381
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.
Parada, C A; Tambeli, C H; Cunha, F Q; Ferreira, S H
Formalin injected subcutaneously into the paw is a widely used model of pain. This procedure evokes a short-lasting period of flinching (phase 1) and a long-lasting period of intense flinching (phase 2) following a very short period of quiescence. Phase 2 has been extensively used to support the involvement of central (spinal cord) sensitization in inflammatory hyperalgesia. The present study evaluated the contribution of stimulation of peripheral nociceptors by the release of endogenous mediators at the site of lesion. The participation of histamine and 5-hydroxytryptamine was demonstrated by the treatment of the rat hindpaws with selective histamine H1 (pyrilamine and meclizine) and histamine H2 (cimetidine) receptor antagonists or selective 5-hydroxytryptamine(1A) (WAY100,135) and 5-hydroxytryptamine(4/3) (tropisetron) receptor antagonists. The co-administration of pyrilamine or meclizine with formalin (1%) significantly reduced phases 1 and 2, while cimetidine had no effect. Pyrilamine administration during the period of quiescence (10min after formalin administration) caused strong dose-related inhibition of phase 2. The co-administration of tropisetron with formalin caused a blockade of both phases, while with WAY100,135 caused only inhibition of the phase 2. In contrast, tropisetron administrated during the period of quiescence did not cause antinociception. Histamine and 5-hydroxytryptamine receptors could be strongly activated in naïve animals by administration of a mixture of both agonists or compound 48/80 (2microg/paw) which is known to release both mediators from mast cells. Pretreatment of the paws with a mast cell stabilizer, sodium cromoglycate, significantly reduced the second phase of the formalin injection model. From these results we suggest that phases 1 and 2 of the formalin test are dependent upon the ongoing afferent input. Furthermore, while histamine H1 participates in both phases, 5-hydroxytryptamine(4/3) participates in phase 1 and 5
Benharkate, M; Zanini, V; Blanc, R; Boucheix, O; Coyez, F; Genevois, J P; Pairet, M
We studied the evolution in time of the main hemodynamic parameters in farm piglets and Göttingen and Yucatan miniature swine anesthetized with droperidol, flunitrazepam, and alpha-chloralose. Measurements included arterial pressure, heart rate, intraventricular pressure, and maximum rate of increase during contraction (dp/dt max). For each parameter and each strain of swine, we determined the mean stability period defined as the longest period of time during which the observed values ranged between their mean value +/- 15% and the mean absolute values during the stability period. In our experimental conditions, the parameters remained constant for 2 to 3.5 hours. Only minor interstrain variations were noticed. PMID:8459680
Toki, Keiko; Yokose, Masashi; Miyashita, Tetsuya; Sato, Hitoshi; Fujimoto, Hiroko; Yamamoto, Sayoko; Goto, Takahisa
Regional anesthesia, especially epidural anesthesia, rarely causes involuntary movement Here we present a case of a patient who demonstrated myoclonus-like involuntary movement of the lower limbs during continuous infusion of ropivacaine, fentanyl, and droperidol through the thoracic epidural catheter. This movement disappeared when the epidural infusion was stopped, but reappeared when the epidural infusion was restarted. Naloxone did not eliminate the movement The patient was thereafter discharged uneventfully. This case and other reports in the literature suggest that involuntary movement associated with regional anesthesia is rare and self-limiting. However, careful consideration should be given to exclude other, potentially dangerous complications. PMID:27483662
Stumpf, C; Gogolák, G; Huck, S; Andics, A
The synergistic action of seven central depressants three benzodiazepines, two neuroleptics on barbiturate and morphine on the anesthetic activity of nitrous oxide was studied in mice. The benzodiazipines and among them nitrazepam and flunitrazepam were found to be the most potent drugs in this respect; morphine on the other hand was innefective even in toxic doses. There was a significant difference in the slope of log dose-response curves; these curves were much steeper for pentobarbitone, droperidol and chlorpromazine than for nitrazepam, flunitrazepam, and diazepam. The theoretical and practical implications of this difference are discussed. PMID:1155749
Marshall, S D; Myles, P S
Many drugs used in anaesthesia may prolong the QT interval of the electrocardiogram (ECG), and recent U.S. Food and Drug Administration guidelines mandate monitoring of the ECG before, during and after droperidol administration. We surveyed 41 trainee and consultant anaesthetists in our Department to determine current practice and knowledge of the QT interval to investigate if this is a practical proposition. A response rate of 98% (40/41) was obtained. The majority of respondents expressed moderate to high levels of confidence in interpreting the ECG, and this was related to years of training (rho 0.36, P=0.024). A total of 27 respondents (65%) were able to correctly identify the QT interval on a schematic representation of the ECG, trainees 70% vs consultants 60%, P=0.51. When asked to name drugs that altered the QT interval, droperidol was included by 11 of the 40 respondents (28%); trainees 10% vs consultants 45%, OR 7.4 (95% CI: 1.3-41), P=0.013. Torsades de Pointes was correctly identified as a possible consequence of a prolonged QT interval by 65% of trainees and 70% of consultants, P=0.83. The results suggest that QT interval measurement is not widely practised by anaesthetists, although its clinical significance is well known, and interpretation would be unreliable without further education.
Shelley, A M; Catts, S V; Ward, P B; Andrews, S; Mitchell, P; Michie, P; McConaghy, N
This study examines the effect of decreased catecholamine transmission on event-related potential (ERP) indices of selective attention. Intravenous clonidine (1.5 micrograms/kg Catapres), droperidol (15 micrograms/kg Droleptan), or placebo were administered to healthy adult males prior to performance of a multidimensional auditory selective attention task (SAT) in which dichotically presented sequences of tone pips varied on dimensions of location (left or right ear), pitch (high or low), and duration (short or long). Subjects were required to make a button press response to infrequent "target" stimuli that matched a prespecified stimulus on the three dimensions. ERPs were recorded during the task. Clonidine led to a significant increase of processing negativity (PN) over 200-400 ms at the irrelevant location. Droperidol led to a significant increase in reaction time (RT), a significant decrease in hit rate, and an attenuation of PN over the 200- to 400-ms and 400- to 700-ms epochs. Neither substance led to a significant change in P3 amplitude. The role of catecholamines in the selective attention subprocesses of "tuning" and "switching" is discussed.
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
Modern management of fibromyalgia (FM) requires a holistic approach, which includes nonpharmacologic strategies (both exercise and behavioral strategies) and pharmacologic treatment. Despite only partial effects in some patients, tricyclic antidepressants, selective serotonin reuptake inhibitors, nonsteroidal antiinflammatory drugs, analgesics and opioids are in use. The use of antiepileptic drugs and antispasticity agents is mainly supported by anecdotal data. Three other classes of agents are currently thought to have useful potentials. N-methyl-D-aspartate-(NMDA-)mediated neurotransmission may play an important role in mediating wind-up and related phenomena in pain pathways. Recent studies have demonstrated that NMDA receptor antagonists improve pain symptoms in FM. But a poor side effect profile represents a significant problem. Cerebrospinal fluid substance P concentrations are significantly elevated in FM patients, but the analgesic potential of neurokinin-1 (NK1) receptor antagonists did not meet early expectations. Tropisetron, a 5-HT3 receptor antagonist, was tested in a multicenter, double-blind, randomized, placebo-controlled trial including 403 patients. In those receiving 5 mg tropisetron, 39.2% fulfilled the response criterion (pain reduction 35%) as compared to 26.2% in the placebo group (p=0.033). On 10 and 15 mg, the responder rates were smaller and statistically not significant. A total of 78 responders to therapy were followed up for 12 months. After the end of treatment, pain intensity rose within one month in all 4 groups. Patients having received 5 or 10 mg showed a less pronounced increase in pain. In addition, even 12 months after stopping treatment, pain was still markedly below baseline levels in the 5 and 10 mg groups. PMID:14648317
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
Chen, Fu-chao; Zhu, Jun; Li, Bin; Yuan, Fang-jun; Wang, Lin-hai
Background Mixing 5-hydroxytryptamine-3 (5-HT3) receptor antagonists with patient-controlled analgesia (PCA) solutions of tramadol has been shown to decrease the incidence of nausea and vomiting associated with the use of tramadol PCA for postoperative pain. However, such mixtures are not commercially available, and the stability of the drug combinations has not been duly studied. The study aimed to evaluate the stability of tramadol with three 5-HT3 receptor antagonists in 0.9% sodium chloride injection for PCA administration. Materials and methods Test samples were prepared by adding 1,000 mg tramadol hydrochloride, 8 mg ondansetron hydrochloride, and 6 mg granisetron hydrochloride or 5 mg tropisetron hydrochloride to 100 mL of 0.9% sodium chloride injection in polyolefin bags. The samples were prepared in triplicates, stored at either 25°C or 4°C for 14 days, and assessed using the following compatibility parameters: precipitation, cloudiness, discoloration, and pH. Chemical stability was also determined using a validated high-pressure liquid chromatography method. Results All of the mixtures were clear and colorless throughout the initial observation period. No change in the concentration of tramadol hydrochloride occurred with any of the 5-HT3 receptor antagonists during the 14 days. Similarly, little or no loss of the 5-HT3 receptor antagonists occurred over the 14-day period. Conclusion Our results suggest that mixtures of tramadol hydrochloride, ondansetron hydrochloride, granisetron hydrochloride, or tropisetron hydrochloride in 0.9% sodium chloride injection were physically and chemically stable for 14 days when stored in polyolefin bags at both 4°C and 25°C. PMID:27350741
Eglen, R. M.; Alvarez, R.; Johnson, L. G.; Leung, E.; Wong, E. H.
1. The interaction of the novel antagonist, SDZ 205,557 (2-methoxy-4-amino-5-chloro benzoic acid 2-(diethylamino) ethyl ester), at 5-HT3 and 5-HT4 receptors has been assessed in vitro and in vivo. 2. In guinea-pig hippocampus and in the presence of 0.4 microM 5-carboxamidotryptamine, 5-HT4-mediated stimulation of adenylyl cyclase was competitively antagonized by SDZ 205,557, with a pA2 value of 7.5, and a Schild slope of 0.81. In rat carbachol-contracted oesophagus, 5-HT4-receptor mediated relaxations were surmountably antagonized by SDZ 205,557 with a similar pA2 value (7.3). This value was agonist-independent with the exception of (R)-zacopride, against which a significantly lower value (6.4) was observed. 3. In functional studies of 5-HT3 receptors, SDZ 205,557 exhibited an affinity of 6.2 in guinea-pig ileum compared with 6.9 at binding sites labelled by [3H]-quipazine in NG108-15 cells. In the anaesthetized, vagotomized micropig, SDZ 205,557 produced only a transient blockade of 5-HT4-mediated tachycardia. This contrasted with tropisetron, which was active for over 60 min after administration. The half-lives for the inhibitory responses of SDZ 205,557 and tropisetron were 23 and 116 min, respectively. 4. In conclusion, SDZ 205,557 has similar affinity for 5-HT3 and 5-HT4 receptors. The apparent selectivity observed in guinea-pig is due to the atypical nature of the 5-HT3 receptor in this species. The short duration of action of this novel antagonist may complicate its use in vivo. SDZ 205,557 should, therefore, be used with appropriate caution in studies defining the 5-HT4 receptor. PMID:8448587
Hu, Ning; Wang, Tianxing; Wang, Qin; Zhou, Jie; Zou, Ling; Su, Kaiqi; Wu, Jieying; Wang, Ping
High-throughput and high clinical relevance methods are demanded to predict the drug-induced cardiotoxicity in pharmaceutical and biotechnology industries to effectively decrease late-stage drug attrition. In this study, human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were integrated into an interdigital impedance sensor array to fabricate a high performance iPSC-CM-based biosensor array with high-throughput and high-consistency beating pattern. Typical withdrawal approved drugs (astemizole, sertindole, cisapride, and droperidol) with hERG inhibition and positive control E-4031 were employed to determine the beating pattern function. From the results, it can be concluded that this iPSC-CM-based biosensor array can specifically differentiate the hERG inhibitors from the non-hERG inhibition compounds through beating pattern function. PMID:25153933
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. PMID:7617062
Binhas, M; Marty, J
Severe postsurgical pain contributes to prolonged hospital stay and is also believed to be a risk factor for the development of chronic pain. Locoregional anesthesia, which results in faster patient recovery with fewer side effects, is favored wherever feasible, but is not applicable to every patient. Systemic analgesics are the most widely used method for providing pain relief in the postoperative period. Improvements in postoperative systemic analgesia for pain management should be applied and predictive factors for severe postoperative pain should be anticipated in order to control pain while minimizing opioid side effects. Predictive factors for severe postoperative pain include severity of preoperative pain, prior use of opiates, female gender, non-laparoscopic surgery, and surgeries involving the knee and shoulder. Pre- and intraoperative use of small doses of ketamine has a preventive effect on postoperative pain. Multimodal or balanced analgesia (the combined use of various analgesic agents) such as NSAID/morphine, NSAID/nefopam, morphine/ketamine improves analgesia with morphine-sparing effects. Nausea and vomiting, the principle side effects of morphine, can be predicted using Apfel's simplified score; patients with a high Apfel score risk should receive preemptive antiemetic agents aimed at different receptor sites, such as preoperative dexamethasone and intraoperative droperidol. Droperidol can be combined with morphine for postoperative patient-controlled anesthesia (PCA). When PCA is used, dosage parameters should be adjusted every day based on pain evaluation. Patients with presurgical opioid requirements will require preoperative administration of their daily opioid maintenance dose before induction of anesthesia: PCA offers useful options for effective postsurgical analgesia using a basal rate equivalent to the patient's hourly oral usage plus bolus doses as required.
Tramèr, M. R.; Moore, R. A.; Reynolds, D. J.; McQuay, H. J.
OBJECTIVES: To test the evidence for a dose-response with ondansetron for treatment of postoperative nausea and vomiting and to establish whether differences in efficacy between doses are of clinical relevance. DESIGN: Quantitative systematic review of published randomised controlled trials. DATA SOURCES: Seven trials from 1991 to January 1996 retrieved from a systematic literature search (Medline, reference lists, hand searching of anaesthetic journals, manufacturer's database); no restriction on language. MAIN OUTCOME MEASURES: Estimation of efficacy (incidence of complete control of further nausea and vomiting) by using odds ratios and the "number needed to treat" method for early (within 6 hours of administration) and late (within 24 hours) periods. RESULTS: Four placebo controlled trials with 1043 patients studied intravenous ondansetron 1 mg, 4 mg, or 8 mg. All doses were more efficacious than placebo in preventing further episodes of nausea or vomiting. For combined data, the point estimates for the number needed to treat were between 3.1 (8 mg) and 3.8 (1 mg) for early efficacy and between 4.1 (8 mg) and 4.8 (1 mg) for late efficacy, without significant differences between doses. No difference was found between ondansetron and droperidol in two trials with 129 patients or between ondansetron and metoclopramide in one trial with 80 patients. CONCLUSIONS: Further nausea and vomiting could be prevented with ondansetron compared with placebo in 25% of patients who had nausea or vomiting (number needed to treat, about 4). There was no evidence of a clinically relevant dose-response between 1 mg and 8 mg or a difference between ondansetron and either droperidol or metoclopramide in a limited dataset. A false impression of ondansetron's efficacy may arise because a quarter of all relevant published reports are duplicates, and reporting of study results is uncritical. PMID:9133892
Neufeld, Susan M; Newburn-Cook, Christine V
The purpose of this meta-analysis was to assess the efficacy of prophylactic administration of 5-HT3 receptor antagonists for postoperative nausea and vomiting in neurosurgical patients at 24 and 48+ hours. After a systematic search, 7 published randomized placebo controlled trials involving 448 craniotomy patients (222 treatment, 226 control) were included in the meta-analysis. Study drugs included ondansetron, granisetron, and tropisetron. The cumulative incidence of emesis was significantly reduced in the treatment group at 24 hours [relative risk (RR)=0.50, 95% confidence interval (CI): 0.38-0.66] and 48+ hours (RR=0.52, 95% CI: 0.36-0.75). There were no differences between the treatment and control groups in the cumulative incidence of nausea at 24 hours (RR=0.76, 95% CI: 0.54-1.06) and 48+ hours (RR=0.81, 95% CI: 0.62-1.06). The cumulative incidence of both nausea and vomiting continued to increase after 24 hours in both groups. Despite the ability of 5-HT3 receptor antagonists to reduce emetic episodes, future investigations should seek to address the control of postoperative nausea and to reduce further postoperative emesis in this population. PMID:17198095
Li, Y F; Fu, S; Hu, W; Liu, J H; Finkel, K W; Gershenson, D M; Kavanagh, J J
Chronic kidney disease is a common occurrence in patients with gynecological cancer. Systemic anticancer treatment in such patients is a challenge for clinicians because of altered drug pharmacokinetics. For those drugs that are excreted mainly by the kidneys, decreased renal function may lead to increased systemic exposure and increased toxicity. Dose adjustment based on pharmacokinetic changes is required in this situation to avoid life-threatening toxicity. In this review, we summarize the nephrotoxicity and pharmacokinetic data of agents commonly used in systemic anticancer treatment of gynecological cancers and dose adjustment guidelines in the presence of impaired renal function. We review 17 medications that need dose adjustment (cisplatin, carboplatin, doxorubicin, epirubicin, cyclophosphamide, ifosfamide, topotecan, irinotecan, etoposide, capecitabine, bleomycin, methotrexate, actinomycin D, granulocyte-macrophage colony-stimulating factor, metoclopramide, cimetidine, and diphenhydramine) as well as 27 drugs that do not (paclitaxel, docetaxel, pegylated liposomal doxorubicin, gemcitabine, oxaliplatin, fluorouracil, vincristine, letrozole, anastrozole, tamoxifen, leuprorelin, megestrol, gefitinib, erlotinib, trastuzumab, leucovorin, granulocyte colony-stimulating factor, erythropoietin, ondansetron, granisetron, palonosetron, tropisetron, dolasetron, aprepitant, dexamethasone, lorazepam, and diazepam). We also review the formulae commonly used to estimate creatinine clearance, including Cockcroft-Gault, Chatelut, Jelliffe, Wright, and the Modification of Diet in Renal Disease study formulae.
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
Bourin, M; Hascoet, M; Deguiral, P
Serotonin (5-HT) is present in the gastrointestinal tract and is probably one of the compounds responsible for diarrhea in patients presenting with carcinoid syndrome. Intraperitoneal administration of L-5-hydroxytryptophan (L-5-HTP) at doses of 25 to 100 mg/kg dramatically increase defecation in mice. In this new paradigm, counting fecal boli deposited is simple and the appraised or inhibition of diarrhea induced by ip 25 mg/kg of L-5-HIP is very clear, with a good reproducibility of scores. L-5-HTP needs to be metabolized into 5-HT to be active; benserazide, an inhibitor of decarboxylase, antagonized the diarrhea induced by 5-HT. Among the 5-HT antagonists used in interaction with 5-HT, only these of the 5-HT3 type (ondansetron, granisetron, tropisetron) and, to a lesser extent 5-HT2 type (ritanserin), decreased the diarrhea induced by 5-HTP. The 5-HT4 receptor agonists from the benzamide family (metoclopramide and zacopride) increased defecation in mice but the effect failed to reach statistical significance.
Haga, K; Asano, K; Inaba, K; Morimoto, Y; Setoguchi, M
The effect of Y-25130 on gastric emptying of nutrient test meals (solid chow) was examined in mice. In a dose range of 0.01-1 mg/kg, p.o., Y-25130 significantly accelerated gastric emptying of solid meals in a dose-dependent manner, at an ED30 of 0.021 mg/kg. Other 5-hydroxytryptamine3 receptor antagonists and prokinetic agents having 5-hydroxytryptamine3 receptor antagonistic properties accelerated the emptying of solid meals in the following rank order of potency: Y-25130 = granisetron > or = tropisetron > ondansetron > cisapride > metoclopramide. The acceleration of the gastric emptying showed a good correlation with the antagonistic potencies of these compounds on 5-hydroxytryptamine3 receptors, determined by the inhibition test of the von Bezold-Jarisch reflex in anesthetized rats (r2 = 0.99). Domperidone (1 and 10 mg/kg, p.o.) and trimebutine (10 and 100 mg/kg, p.o.) failed to increase the rate of emptying from the stomach. Cisplatin (30 mg/kg, i.p.), a chemotherapeutic agent, significantly delayed the gastric emptying of solid meals, and Y-25130 (0.1-1 mg/kg, p.o.) prevented such a delay in emptying in a dose-dependent manner. These results suggest that Y-25130 accelerates the gastric emptying in mice by antagonism of the 5-hydroxytryptamine3 receptor. PMID:7625886
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.
Faigel, D O; Metz, D C; Kochman, M L
Torsade de pointes is an unusual life-threatening ventricular arrhythmia that has been associated with vasopressin, neuroleptic drugs, and electrolyte imbalances, including hypokalemia and hypomagnesemia. Over a 9-month period, we observed torsade de pointes in three patients with cirrhosis and bleeding esophageal varices who did not have prior cardiac disease. All had received endoscopic sclerotherapy and continuous infusions of vasopressin and nitroglycerin. For sedation, two patients received haloperidol and one droperidol. In addition, two patients had either hypokalemia or hypomagnesemia. In all three patients, there was prolongation of the electrocardiographic QT interval and a "long-short" initiating sequence followed by ventricular tachycardia with torsade de pointes morphology. All were successfully cardioverted; there was one late death due to aspiration and septicemia. We conclude that cirrhotics with variceal hemorrhage may be at increased risk of developing this arrhythmia in the setting of treatment with vasopressin, sedation with neuroleptic drugs, and electrolyte abnormalities. We urge close monitoring of these patients for cardiac arrhythmia and recommend that neuroleptics be used cautiously, if at all.
Neuroleptic malignant syndrome (NMS) is a potentially fatal condition composed of hyperthermia, extrapyramidal symptoms, autonomic nervous system disturbances, and altered levels of consciousness. Although uncertainty exists about its cause, most studies suggest it is the result of dopaminergic deficiency in the central nervous system, most commonly caused by neuroleptic medications. Excessive dopaminergic blockade occurs most commonly in psychiatric patients receiving neuroleptic medications, but many antiemetic medications used in anesthesia also have been implicated. Promethazine (Phenergan), prochlorperazine (Compazine), droperidol (Inapsine), and metoclopramide (Reglan) are most problematic. Reversal of dopaminergic blockade in the central nervous system is believed to be the treatment of choice for an acute episode of NMS. Once identified, withdrawal of causative medications, administration of dantrolene or dopamine agonists (bromocriptine and amantadine), and supportive measures will result in a 90% to 94% survival rate from the acute episode. Anesthetists must be aware of the pathophysiology, diagnosis, and treatment of this syndrome. Avoidance of neuroleptic medications, prompt diagnosis, and appropriate treatment will make the difference between success and failure when treating a patient during the acute phase of NMS.
Tanaka, Kazutaka; Takenami, Tamie; Hari, Junko; Kaneko, Haruka; Fujita, Tomoe; Okamoto, Hirotsugu
A 41-year-old woman with concomitant severe obesity, obstructive sleep apnea syndrome, and asthma was scheduled for endoscopic cholecystectomy. She was 165.8 cm tall and weighed 141.2 kg, with BMI of 51.4. We were concerned with difficulty in ventilation and intubation at the time of anesthesia induction and intra- and post-operative ventilatory failure. After sedation with fentanyl and droperidol together with intraoral local anesthesia with lidocaine (Xylocaine Viscous), the intubating laryngeal mask (ILMA) was inserted while awake, and after the confirmation of adequate ventilation, the bronchoscope was inserted into the guide. Although she received no nerve block, she did not choke at the time of intubation. Because of airway pressure elevation during surgery, volume-controlled ventilation was changed to pressure-controlled ventilation, and, because of a worsening P/F ratio, the recruitment procedure was performed during surgery, with a consequent improvement in the ratio. Although the use of the reservoir and NPPV equipment after extubation was considered, her respiratory status was stable, and she returned to her room with oxygen mask. PMID:26419104
Saluja, Hardeep; Mehanna, Ahmed; Panicucci, Riccardo; Atef, Eman
The purpose of this study is to confirm the impact of polar functional groups on inter and intra-molecular hydrogen bonding in haloperidol (HP) and droperidol (DP) and, hence, their effects on dissolution using a new approach. To confirm our theory, a new molecule: deshydroxy-haloperidol (DHP) was designed and its synthesis was requested from a contract laboratory. The molecule was then studied and compared to DP and HP. Unlike DHP, both the HP and DP molecules have hydrogen donor groups, therefore, DHP was used to confirm the relative effects of the hydrogen donor group on solubility and crystal packing. The solid dispersions of the three structurally related molecules: HP, DP, and DHP were prepared using PVPK30, and characterized using XRPD and IR. A comparative dissolution study was carried out in aqueous medium. The absence of a hydrogen bonding donor group in DHP resulted in an unexpected increase in its aqueous solubility and dissolution rate from solid dispersion, which is attributed to weaker crystal pack. The increased dissolution rate of HP and DP from solid dispersions is attributed to drug-polymer hydrogen bonding that interferes with the drug-drug intermolecular hydrogen bonding and provides thermodynamic stability of the dispersed drug molecules. The drug-drug intermolecular hydrogen bond is the driving force for precipitation and crystal packing. PMID:27258248
Hishigaki, Haretsugu; Kuhara, Satoru
Drug-induced QT interval prolongation is one of the most common reasons for the withdrawal of drugs from the market. In the past decade, at least nine drugs, i.e. terfenadine, astemizole, grepafloxacin, terodiline, droperidol, lidoflazine, sertindole, levomethadyl and cisapride, have been removed from the market or their use has been severely restricted because of drug-induced QT interval prolongation. Therefore, this irregularity is a major safety concern in the case of drugs submitted for regulatory approval. The most common mechanism of drug-induced QT interval prolongation may be drug-related inhibition of the human ether-á-go-go-related gene (hERG) channel, which subsequently results in prolongation of the cardiac action potential duration (APD). hERGAPDbase is a database of electrophysiological experimental data documenting potential hERG channel inhibitory actions and the APD-prolongation activities of chemical compounds. All data entries are manually collected from scientific papers and curated by a person. With hERGAPDbase, we aim to provide useful information for chemical and pharmacological scientists and enable easy access to electrophysiological experimental data on chemical compounds. Database URL: http://www.grt.kyushu-u.ac.jp/hergapdbase/.
Hishigaki, Haretsugu; Kuhara, Satoru
Drug-induced QT interval prolongation is one of the most common reasons for the withdrawal of drugs from the market. In the past decade, at least nine drugs, i.e. terfenadine, astemizole, grepafloxacin, terodiline, droperidol, lidoflazine, sertindole, levomethadyl and cisapride, have been removed from the market or their use has been severely restricted because of drug-induced QT interval prolongation. Therefore, this irregularity is a major safety concern in the case of drugs submitted for regulatory approval. The most common mechanism of drug-induced QT interval prolongation may be drug-related inhibition of the human ether-á-go-go-related gene (hERG) channel, which subsequently results in prolongation of the cardiac action potential duration (APD). hERGAPDbase is a database of electrophysiological experimental data documenting potential hERG channel inhibitory actions and the APD-prolongation activities of chemical compounds. All data entries are manually collected from scientific papers and curated by a person. With hERGAPDbase, we aim to provide useful information for chemical and pharmacological scientists and enable easy access to electrophysiological experimental data on chemical compounds. Database URL: http://www.grt.kyushu-u.ac.jp/hergapdbase/. PMID:21586548
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
Wardle, K. A.; Sanger, G. J.
1. Experiments were designed to characterize pharmacologically the contractile responses to 5-hydroxytryptamine (5-HT) in the guinea-pig isolated distal colon longitudinal muscle-myenteric plexus preparation (LMMP). 2. In the presence of methiothepin (100 nM) and granisetron (1 microM), 5-HT (10 pM-10 nM) produced concentration-dependent contractile responses of the guinea-pig distal colon LMMP, with a pEC50 of 9.2 +/- 0.08. 3. Responses to 5-HT were mimicked by a series of tryptamine analogues, with the following rank order of potency; 5-HT > 5-MeOT >> 5-CT > tryptamine > 2-Me-5-HT. All were found to be full agonists. 4. Responses to 5-HT were also mimicked by a series of substituted benzamide analogues. Their rank order of potency was 5-HT > renzapride > cisapride > (S)-zacopride > (R)-zacopride > metoclopramide. All were full agonists relative to 5-HT. 5. The benzimidazolone derivatives, BIMU 1 and BIMU 8 were approximately equipotent partial agonists (intrinsic activities of 0.8 +/- 0.07 and 0.5 +/- 0.08 respectively) in the guinea-pig distal colon. 6. Tropisetron produced a rightward displacement of the 5-HT concentration-effect curve, yielding an apparent pA2 of 6.4 +/- 0.1. The slope of the Schild plot (1.3 +/- 0.1) was significantly greater than unity. 7. SDZ 205,557 produced a concentration-dependent shift to the right of the 5-HT concentration-response curve, yielding an estimated pA2 of 7.8 +/- 0.1 and a slope which did not significantly deviate from unity.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8306106
Salzer, Isabella; Gantumur, Enkhbileg; Yousuf, Arsalan; Boehm, Stefan
Serotonin (5HT) is a constituent of the so-called "inflammatory soup" that sensitizes nociceptors during inflammation. Nevertheless, receptors and signaling mechanisms that mediate an excitation of dorsal root ganglion (DRG) neurons by 5HT remained controversial. Therefore, capsaicin-sensitive nociceptive neurons dissociated from rat DRGs were used to investigate effects of 5HT on membrane excitability and currents through ligand- as well as voltage-gated ion channels. In 58% of the neurons tested, 5HT increased action potential firing, an effect that was abolished by the 5HT2 receptor antagonist ritanserin, but not by the 5HT3 antagonist tropisetron. Unlike other algogenic mediators, such as PGE2 and bradykinin, 5HT did not affect currents through TTX-resistant Na(+) channels or Kv7 K(+) channels. In all neurons investigated, 5HT potentiated capsaicin-evoked currents through TRPV1 channels, an effect that was attenuated by antagonists at 5HT2A (4 F 4 PP), 5HT2B (SB 204741), as well as 5HT2C (RS 102221) receptors. 5HT triggered slowly arising inward Cl(-) currents in 53% of the neurons. This effect was antagonized by the 5HT2C receptor blocker only, and the current was prevented by an inhibitor of Ca(2+)-activated chloride channels (CaCC). The 5HT-induced increase in action potential firing was also abolished by this CaCC blocker and by the TRPV1 inhibitor capsazepine. Amongst the subtype selective 5HT2 antagonists, only RS 102221 (5HT2C-selectively) counteracted the rise in action potential firing elicited by 5HT. These results show that 5HT excites DRG neurons mainly via 5HT2C receptors which concomitantly mediate a sensitization of TRPV1 channels and an opening of CaCCs.
Arreola-Ramírez, José Luis; Vargas, Mario H; Manjarrez-Gutiérrez, Gabriel; Alquicira, Jesús; Gutiérrez, Julio; Córdoba, Guadalupe; Campos-Bedolla, Patricia; Segura-Medina, Patricia
Several contractile mediators involved in the antigen-induced airway obstruction have been identified, but the role of 5-HT (5-hydroxytryptamine or serotonin) has been scantily investigated. In this work, the potential role of 5-HT in the allergic bronchoconstriction was evaluated through a pharmacological approach and plasma 5-HT measurement in blood samples from the right and left ventricles of anesthetized guinea-pigs. Intravenous 5-HT caused a dose-dependent increase of the lung resistance in anesthetized, nonsensitized guinea pigs. Likewise, in sensitized animals the antigenic challenge with ovalbumin also caused a transient bronchoconstriction (356 ± 60% the basal value), which was largely inhibited by the blockade of serotonergic receptors with methiothepin plus tropisetron (134 ± 10%, P = .007). Sensitized animals tended to have plasma 5-HT concentrations higher than nonsensitized controls, and shortly after the peak of the allergic bronchoconstriction the 5-HT levels in the left ventricle (blood flowing out from lungs) tended to be higher than in the right ventricle (blood entering the lungs), although data dispersion precluded the obtaining of statistical significance. Interestingly, the degree of bronchoconstriction highly correlated with the concentrations of 5-HT found in the left ventricle and measured either in platelet-rich plasma (r = 0.97 P = .007) or platelet-poor plasma (r = 0.97, P = .006). After the obstructive response subsided these correlations were lost, but now the degree of bronchoconstriction turned to be correlated with 5-HT concentration in platelet concentrate (r = 0.76, P = .03). In conclusion, our results suggested that 5-HT is actively released from lungs during the antigenic challenge and that this autacoid is involved in the generation of the airway obstruction.
Lin, Yu-Jung; Lin, You Shuei; Lai, Ching Jung; Yuan, Zung Fan; Ruan, Ting; Kou, Yu Ru
The terminals of vagal lung C fibers (VLCFs) express various types of pharmacological receptors that are important to the elicitation of airway reflexes and the development of airway hypersensitivity. We investigated the blockade of the reflex and afferent responses of VLCFs to intravenous injections of agonists using perivagal treatment with antagonists (PAT) targeting the transient receptor potential vanilloid 1, P2X, and 5-HT(3) receptors in anesthetized rats. Blockading these responses via perivagal capsaicin treatment (PCT), which blocks the neural conduction of C fibers, was also studied. We used capsaicin, α,β-methylene-ATP, and phenylbiguanide as the agonists, and capsazepine, iso-pyridoxalphosphate-6-azophenyl-2',5'-disulfonate, and tropisetron as the antagonists of transient receptor potential vanilloid 1, P2X, and 5-HT(3) receptors, respectively. We found that each of the PATs abolished the VLCF-mediated reflex apnea evoked by the corresponding agonist, while having no effect on the response to other agonists. Perivagal vehicle treatment failed to produce any such blockade. These blockades had partially recovered at 3 h after removal of the PATs. In contrast, PCT abolished the reflex apneic response to all three agonists. Both PATs and PCT did not affect the myelinated afferent-mediated apneic response to lung inflation. Consistently, our electrophysiological studies revealed that each of the PATs prevented the VLCF responses to the corresponding agonist, but not to any other agonist. PCT inevitably prevented the VLCF responses to all three agonists. Thus these PATs selectively blocked the stimulatory action of corresponding agonists on the VLCF terminals via mechanisms that are distinct from those of PCT. PAT may become a novel intervention for studying the pharmacological modulation of VLCFs.
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 H3PW12O40·nH2O and formed 3:1 ion-association complex of [(ATM)3PW12O40], then self-aggregated into nanoparticles-[(ATM)3PW12O40]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 (ΔIRRS) 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)3PW12O40]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.
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
O’Brien, Valerie P.; Bokelmann, Kristin; Ramírez, Jacqueline; Jobst, Karoline; Ratain, Mark J.; Brockmöller, Jürgen
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. PMID:23922447
Gurrin, Lyle C; Sly, Peter D; Burton, Paul R
Randomized controlled clinical trials play an important role in the development of new medical therapies. There is, however, an ethical issue surrounding the use of randomized treatment allocation when the patient is suffering from a life threatening condition and requires immediate treatment. Such patients can only benefit from the treatment they actually receive and not from the alternative therapy, even if it ultimately proves to be superior. We discuss a novel new way to analyse data from such clinical trials based on the use of the recently developed theory of imprecise probabilities. This work draws an explicit distinction between the related but nevertheless distinct questions of inference and decision in clinical trials. The traditional question of scientific interest asks 'Which treatment offers the greater chance of success?' and is the primary reason for conducting the clinical trial. The question of decision concerns the welfare of the patients in the clinical trial, asking whether the accumulated evidence favours one treatment over the other to such an extent that the next patient should decline randomization and instead express a preference for one treatment. Consideration of the decision question within the framework of imprecise probabilities leads to a mathematical definition of equipoise and a method for governing the randomization protocol of a clinical trial. This paper describes in detail the protocol for the conduct of clinical trials based on this new method of analysis, which is illustrated in a retrospective analysis of data from a clinical trial comparing the anti-emetic drugs ondansetron and droperidol in the treatment of postoperative nausea and vomiting. The proposed methodology is compared quantitatively using computer simulation studies with conventional clinical trial designs and is shown to maintain high statistical power with reduced sample sizes, at the expense of a high type I error rate that we argue is irrelevant in some
Saumet, J L; Leftheriotis, G; Dittmar, A; Delhomme, G; Degoute, C S
The effect of general anaesthesia on skin blood flow in the left hand, measured by a new non-invasive probe using the thermal clearance method was examined. A mercury silastic gauge was placed around the third left finger and the plethysmographic wave amplitude was recorded to measure changes in finger pulse amplitude. Heart rate (HR), mean arterial blood pressure (MABP) and skin temperature were also recorded. General anaesthesia was induced by droperidol and phenoperidine injection and propanidid infusion in eight female patients. Skin thermal clearance, plethysmographic wave amplitude, HR, MABP and skin temperature were 0.40 +/- 0.02 w X m-1 degree C-1, 9 +/- 1 mm, 98 +/- 5 beats X min-1, 12.50 +/- 0.93 kPa and 33.3 +/- 3.4 degrees C respectively. The minimal value of MABP was 9.58 +/- 1.06 kPa, whereas skin thermal clearance, plethysmographic wave amplitude, HR and skin temperature increased to 0.45 +/- 0.02 w X m-1 degree C-1, 29 +/- 3 mm, 110 +/- 4 beats X min-1 and 34.4 +/- 0.4 degrees C. Changes in skin thermal clearance correlated well with plethysmographic wave amplitude. Statistically significant changes in these two parameters occurred before significant change in HR, MABP or skin temperature. The results show that the new non-invasive probe using the thermal clearance method appears to be a useful device for measuring cutaneous microcirculation in anaesthetized humans, and responds more quickly than change in skin temperature, which is a delayed effect of skin blood flow change. Our results also show that the intensity of cutaneous vasodilatation induced by general anaesthesia did not relate to the vascular tone before anaesthesia.
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
Peng, W L; Wu, G J; Sun, W Z; Fan, S Z; Chen, T L; Huang, F Y
The analgesic efficacy, side effects, and satisfaction of patient-controlled analgesia (PCA) with intravenous and epidural morphine for postoperative pain were evaluated in this study. Twenty patients undergoing major joint replacement surgery were randomly allocated to intravenous PCA (IPCA) group or epidural PCA (EPCA) group. All patients had a standardized balanced anesthesia, and an epidural catheter was introduced after the operation in EPCA group. Postoperative pain relief was evaluated with verbal pain scale. The result showed that pain intensity and pain relief were similar in either group without significant difference (p greater than 0.05). Morphine consumption in IPCA group was 1.72 +/- 0.30 mg/h in the postoperative 0 - 12 h and 1.14 +/- 0.44 mg/h in 12 - 24 h. In EPCA group, relatively low doses of morphine were used, i.e., 0.20 +/- 0.07 mg/h in the postoperative 0 - 12 h and 0.17 +/- 0.07 mg/h in 12 - 24 h. Both groups showed an "incomplete" but satisfactory analgesia with relatively low doses of morphine. The "equianalgesic dose ratio" of IPCA to EPCA with morphine was approximately 8.5:1. Sedation was minimal in both groups. No respiratory depression developed in all patients. Nausea and vomiting were the most prominent side effects which might limit the usefulness of PCA. The incidence was 5 out of 10 patients in IPCA group and 4 out of 10 patients in EPCA group, despite under the treatment of droperidol (15 micrograms/kg, iv, prn) for most of the patients.(ABSTRACT TRUNCATED AT 250 WORDS)
Sprigge, J S; Wynands, J E; Whalley, D G; Bevan, D R; Townsend, G E; Nathan, H; Patel, Y C; Srikant, C B
Plasma fentanyl concentrations were measured by radioimmunoassay in patients during aortocoronary bypass surgery and correlated with hemodynamic responses to surgical stimulation. Thirty patients scheduled for aortocoronary bypass surgery were divided into three groups of 10. Patients in group 1 received fentanyl, 30 micrograms/kg, as a loading dose followed by an infusion of 0.3 microgram/kg/min; those in group 2 received 40 micrograms/kg as a loading dose followed by an infusion of 0.4 microgram/kg/min; and those in group 3 received 50 micrograms/kg as the loading dose followed by an infusion of 0.5 microgram/kg/min. The total dose of fentanyl administered to each group up to the time of rewarming on cardiopulmonary bypass was 60 micrograms/kg, 90 micrograms/kg, respectively. Each of the dose regimens produced stable plasma concentrations starting approximately 20 minutes after induction and continuing until the infusion was discontinued. Patients in group 1 had a mean plasma concentration of 10 to 12 ng/ml in the stable period compared with 12 to 14 ng/ml in group 2 and 15 to 18 ng/ml in group 3. Fewer patients in group 3 responded to intubation and surgical stimulation than in the other groups, although the differences between groups were not statistically significant. Response to stimulation was treated by the administration of droperidol or volatile anesthetic agents. At a plasma concentration of 15 ng/ml, 50% of patients had an increase in systolic blood pressure which required treatment. This minimal intra-arterial concentration, analogous to MAC, can be achieved by the administration of fentanyl as a loading dose of 50 micrograms/kg followed by an infusion of 0.5 microgram/kg/min.
Titier, Karine; Girodet, Pierre-Olivier; Verdoux, Hélène; Molimard, Mathieu; Bégaud, Bernard; Haverkamp, Wilhelm; Lader, Malcolm; Moore, Nicholas
Syncope and sudden death are features of schizophrenia that can be attributed to ischaemic heart disease, the use of antipsychotics (because of proarrhythmia or other reasons such as pharyngeal dyskinesia) or the psychiatric disease itself. Cases have been described with most antipsychotics and have led to the withdrawal, temporary suspension from the market or restricted use of antipsychotics, such as sultopride, droperidol, sertindole or thioridazine. Reviewing the available data shows that all antipsychotics tested affect the cardiac potassium channel, with the concentration that produces 50% inhibition (IC50) ranging from 1 nmol/L (haloperidol) to 6 micromol/L (olanzapine). Experimental in vitro or in vivo electrophysiological studies have shown a dose-dependent increase in the duration of the action potential with various degrees of indicators of serious arrhythmogenicity. However, this does not always translate clinically into an increased duration of the QT interval or increased risk of torsade de pointes or sudden death in clinical trials or pharmacoepidemiological studies. In turn, QT prolongation in clinical trials does not always translate to an increased risk of torsade de pointes or sudden death. The reasons for these apparent discrepancies are unclear and could be related to insufficiently powered field studies, low plasma and tissue drug concentrations with reference to in vitro data or drug effects on other receptors or ion channels that have a protective effect. Alternatively, risks that were not apparent from preclinical or clinical data could be related to the use of the drug in high-risk patients, metabolic interactions or other factors that would only be encountered in large postmarketing populations. The assessment of cardiovascular safety, both preclinical and during premarketing clinical trials, needs to be supported by appropriately powered pharmacoepidemiology studies.
Petrenko, Andrey B; Yamakura, Tomohiro; Kohno, Tatsuro; Sakimura, Kenji; Baba, Hiroshi
N-methyl-d-aspartate (NMDA) receptors can be inhibited by inhalational anesthetics in vitro at clinically relevant concentrations. Here, to clarify the role of NMDA receptors in anesthetic-induced unconsciousness, we examined the hypnotic properties of isoflurane, sevoflurane and nitrous oxide in NMDA receptor GluN2A subunit knockout mice. The hypnotic properties of inhalational anesthetics were evaluated in mice in the loss of righting reflex (LORR) assay by measuring the 50% concentration for LORR (LORR ED(50)). Knockout mice displayed isoflurane and sevoflurane LORR ED(50) values similar to wild-type controls, indicating no significant contribution of these receptors to the hypnotic action of halogenated anesthetics. However, compared with wild-type controls, mutant mice displayed larger isoflurane LORR ED(50) values in the presence of nitrous oxide, indicating a resistance to this gaseous anesthetic. Knockout mice have enhanced brain monoaminergic activity which occurs secondary to NMDA receptor dysfunction, and the observed resistance to the isoflurane LORR ED(50)-sparing effect of nitrous oxide could be abolished by pretreatment with the dopamine D(2) receptor antagonist droperidol or with the serotonin 5-HT(2A) receptor antagonist ketanserin. Thus, resistance to nitrous oxide in knockout mice appears to be a secondary phenomenon of monoaminergic origin and not a direct result of impaired NMDA receptor function. Our results indicate that NMDA receptors are not critically involved in the hypnotic action of conventionally-used inhalational anesthetics. Also, they suggest that increased brain monoaminergic tone can diminish the effects of general anesthesia. Finally, they provide further evidence that changes secondary to genetic manipulation can explain the results obtained in global knockouts. PMID:23123346
Lychkova, Alla Edward; De Pasquale, Valeria; Avallone, Luigi; Puzikov, Alexander Michael; Pavone, Luigi Michele
Serotonin (5-HT) can stimulate the cholinergic system of the uterus by indirect actions on the modulation of reflexes and a direct action on smooth muscles. We investigated the role of 5-HT in the regulation of the cholinergic activity in the uterine parts of non-pregnant rabbits. The right vagus or pelvic nerve and the left sympathetic trunk were stimulated by an electrical field, and the uterine contractile activity was evaluated by measuring the amplitude and frequency of slow wave electromyogram (EMG), with the surface of microelectrodes applied to the uterus bottom, body, and cervix, respectively. Double stimulation of the vagus or pelvic nerve and the sympathetic trunk increased the frequency and the amplitude of the slow wave EMG in all the uterine parts. Furthermore, the administration of exogenous 5-HT increased the vagus or pelvic induced EMG activity in all parts of the uterus. Overall our results demonstrate that 5-HT enhances the vagus contractile activity with a magnitude of the effect decreasing from the bottom to the cervix, whereas 5-HT enhances the pelvic nerve contractile functions with a magnitude of the response increasing from the bottom to the cervix. The administration of droperidol, a 5-HT3 and 4 receptor inhibitor, and spiperone, a 5-HT2 receptor antagonist, inhibited the effect of the serotoninergic fibers of the sympathetic trunk to increase the vagus and pelvic nerve EMG activity. These data suggest that 5-HT stimulation of the parasympathetic nerves results in the induction of uterine contraction via the activation of 5-HT2, 3, and 4 receptor subfamilies. PMID:24892885
Cubeddu, Luigi X
Severe and occasionally fatal arrhythmias, commonly presenting as Torsade de Pointes [TdP] have been reported with Class III-antiarrhythmics, but also with non-antiarrhythmic drugs. Most cases result from an action on K+ channels encoded by the HERG gene responsible for the IKr repolarizing current, leading to a long QT and repolarization abnormalities. The hydrophobic central cavity of the HERG-K+ channels, allows a large number of structurally unrelated drugs to bind and cause direct channel inhibition. Some examples are dofetilide, quinidine, sotalol, erythromycin, grepafloxacin, cisapride, dolasetron, thioridazine, haloperidol, droperidol and pimozide. Other drugs achieve channel inhibition indirectly by impairing channel traffic from the endoplasmic reticulum to the cell membrane, decreasing channel membrane density (pentamidine, geldalamicin, arsenic trioxide, digoxin, and probucol). Whereas, ketoconazole, fluoxetine and norfluoxetine induce both direct channel inhibition and impaired channel trafficking. Congenital long QT syndrome, subclinical ion-channel mutations, subjects and relatives of subjects with previous history of drug-induced long QT or TdP, dual drug effects on cardiac repolarization [long QT plus increased QT dispersion], increased transmural dispersion of repolarization and T wave abnormalities, use of high doses, metabolism inhibitors and/or combinations of QT prolonging drugs, hypokalemia, structural cardiac disease, sympathomimetics, bradycardia, women and older age, have been shown to increase the risk for developing drug-induced TdP. Because most of these reactions are preventable, careful evaluation of risk factors and increased knowledge of drugs use associated with repolarization abnormalities is strongly recommended. Future genetic testing and development of practical and simple provocation tests are in route to prevent iatrogenic TdP. PMID:20676275
Peters, J. A.; Malone, H. M.; Lambert, J. J.
1. The biophysical and pharmacological properties of 5-hydroxytryptamine (5-HT)-evoked currents in rabbit nodose ganglion neurones in culture have been determined by use of the whole-cell and outside-out membrane patch recording modes of the patch-clamp technique. 2. In 49% of cells investigated the bath application of 10(-5) M 5-HT at negative holding potentials elicited an inward current. The whole-cell response to 5-HT reversed in sign (E5-HT) at approximately -2 mV and exhibited inward rectification. 3. The influence of various ion substitutions upon E5-HT established that the 5-HT-evoked current is mainly mediated by a mixed Na+, K+ cation conductance with little or no contribution from Cl- ions. The omission of Ca2+ and Mg2+ from the extracellular solution enhanced the amplitude of the 5-HT-induced current. 4. On isolated outside-out membrane patches, the bath application of 10(-6) M 5-HT induced single channel currents with a chord conductance of approximately 17 pS at -70 mV and an average slope conductance of 19 pS over the range -100 to -40 mV. The 5-HT-induced single channels exhibited modest inward rectification and were reduced in frequency, but not amplitude, by the 5-HT3 receptor antagonist metoclopramide (10(-6) M). 5. The bath application of 5-HT (3 x 10(-7)-3 x 10(-5) M) to whole cells voltage clamped at -60 mV produced dose-dependent inward currents which were mimicked by 2-methyl-5-HT and 1-phenylbiguanide with equipotent molar ratios, relative to 5-HT, of 2.5 and 32 respectively. 6. Whole-cell inward currents produced by the local pressure application of 5-HT (10(-5) M) were unaffected by 10(-6) M methysergide, 10(-6) M ketanserin or 10(-6) M citalopram, but were concentration-dependently antagonized by the selective 5-HT3 receptor antagonists tropisetron (IC50 = 4.6 x 10(-11) M) ondansetron (IC50 = 5.7 x 10(-11) M), and bemesetron (IC50 = 3.3 x 10(-10) M). The response to 5-HT was also blocked by the non-selective antagonists metoclopramide
Oster, Scott M.; Hauser, Sheketha R.; Toalston, Jamie E.; Bell, Richard L.; McBride, William J.; Rodd, Zachary A.
Ethanol (EtOH) and cocaine are both self-administered into the posterior ventral tegmental area (VTA). Self-administration of either drug is prevented by coadministration of a serotonin (5-HT3) receptor antagonist. Electrophysiological studies indicated that cocaine and EtOH can act synergistically to stimulate VTA dopamine neurons. The current experiment assessed whether cocaine and EtOH would synergistically interact to produce a reinforcing action within the posterior VTA. Adult female Wistar rats were randomly assigned to one of 13 groups. There were three control groups: artificial cerebrospinal fluid (aCSF), a subthreshold EtOH (100 mg%) group, and a subthreshold cocaine (25 pmol/100 nl) group. The other groups self-administered 50 or 75 mg% EtOH containing 6.25, 12.5, or 25 pmol/100 nl cocaine or 100 mg% EtOH containing 3.12, 6.25, 12.5, or 25 pmol/100 nl cocaine. All rats received the assigned infusate for sessions 1 through 4, aCSF alone in sessions 5 and 6, and the original infusate during session 7. The effects of adding a 5-HT3 receptor antagonist [tropisetron, C17H20N2O2 (ICS 205,930) and C17H22N4O.C4H4O4 (LY278-584)] on coadministration of EtOH and cocaine (75 mg% + 12.5 pmol/100 nl) were determined. Rats failed to self-administer aCSF or the subthreshold concentration of EtOH or cocaine. All three concentrations of EtOH (50, 75, and 100 mg%) combined with cocaine (12.5 and 25 pmol/100 nl) supported self-administration. Adding a 5HT3 receptor antagonist attenuated coadministration of EtOH + cocaine. Overall, the data indicate that the reinforcing properties of EtOH and cocaine interacted synergistically within the posterior VTA, and these synergistic effects were mediated, at least in part, by activation of local 5-HT3 receptors. PMID:22011435
Tjen-A-Looi, Stephanie C; Fu, Liang-Wu; Longhurst, John C
Activation of cardiac sympathetic afferents during myocardial ischaemia causes angina and induces important cardiovascular reflex responses. Reactive oxygen species (ROS) are important chemical stimuli of cardiac afferents during and after ischaemia. Iron-catalysed Fenton chemistry constitutes one mechanism of production of hydroxyl radicals. Another potential source of these species is xanthine oxidase-catalysed oxidation of purines. Polymorphonuclear leukocytes (PMNs) also contribute to the production of ROS in some conditions. The present study tested the hypothesis that both xanthine oxidase-catalysed oxidation of purines and neutrophils provide a source of ROS sufficient to activate cardiac afferents during ischaemia. We recorded single-unit activity of cardiac afferents innervating the ventricles recorded from the left thoracic sympathetic chain (T1-5) of anaesthetized cats to identify the afferents' responses to ischaemia. The role of xanthine oxidase in activation of these afferents was determined by infusion of oxypurinol (10 mg kg−1, i.v.), an inhibitor of xanthine oxidase. The importance of neutrophils as a potential source of ROS in the activation of cardiac afferents during ischaemia was assessed by the infusion of a polyclonal antibody (3 mg ml−1 kg−1, i.v.) raised in rabbits immunized with cat PMNs. This antibody decreased the number of circulating PMNs and, to a smaller extent, platelets. Since previous data suggest that platelets release serotonin (5-HT), which activates cardiac afferents through a serotonin receptor (subtype 3,5-HT3 receptor) mechanism, before treatment with the antibody in another group, we blocked 5-HT3 receptors on sensory nerve endings with tropisetron (300 μg kg−1, i.v.). We observed that oxypurinol significantly decreased the activity of cardiac afferents during myocardial ischaemia from 1.5 ± 0.4 to 0.8 ± 0.4 impulses s−1. Similarly, the polyclonal antibody significantly reduced the discharge frequency of
Marmura, Michael J; Silberstein, Stephen D; Schwedt, Todd J
, droperidol, chlorpromazine, and metoclopramide are probably effective (Level B). There is inadequate evidence for butalbital and butalbital combinations, phenazone, intravenous tramadol, methadone, butorphanol or meperidine injections, intranasal lidocaine, and corticosteroids, including dexamethasone (Level C). Octreotide is probably not effective (Level B). There is inadequate evidence to refute the efficacy of ketorolac nasal spray, intravenous acetaminophen, chlorpromazine injection, and intravenous granisetron (Level C). There are many acute migraine treatments for which evidence supports efficacy. Clinicians must consider medication efficacy, potential side effects, and potential medication-related adverse events when prescribing acute medications for migraine. Although opioids, such as butorphanol, codeine/acetaminophen, and tramadol/acetaminophen, are probably effective, they are not recommended for regular use. PMID:25600718
Kitazawa, Takio; Kubo, Osamu; Satoh, Masami; Taneike, Tetsuro
5-Hydroxytryptamine (5-HT; 1 nM–100 μM) concentration-dependently inhibited the amplitude and frequency of spontaneous contractions in longitudinal and circular muscles of the porcine myometrium. The circular muscle (EC50; 68–84 nM) was more sensitive than the longitudinal muscle (EC50; 1.3–1.44 μM) to 5-HT. To characterize the 5-HT receptor subtype responsible for inhibition of myometrial contractility, the effects of 5-HT receptor agonists on spontaneous contractions and of 5-HT receptor antagonists on inhibition by 5-HT were examined in circular muscle preparations.Pretreatment with tetrodotoxin (1 μM), propranolol (1 μM), atropine (1 μM), guanethidine (10 μM) or L-NAME (100 μM) failed to change the inhibition by 5-HT, indicating that the inhibition was due to a direct action of 5-HT on the smooth muscle cells.5-CT, 5-MeOT and 8-OH-DPAT mimicked the inhibitory response of 5-HT, and the rank order of the potency was 5-CT>5-HT>5-MeOT>8-OH-DPAT. On the other hand, oxymethazoline, α-methyl-5-HT, 2-methyl-5-HT, cisapride, BIMU-1, BIMU-8, ergotamine and dihydroergotamine had almost no effect on spontaneous contractions, even at 10–100 μM.Inhibition by 5-HT was not decreased by either pindolol (1 μM), ketanserin (1 μM), tropisetron (10 μM), MDL72222 (1 μM) or GR113808 (10 μM), but was antagonized by the following compounds in a competitive manner (with pA2 values in parentheses): methiothepin (8.05), methysergide (7.92), metergoline (7.4), mianserin (7.08), clozapine (7.06) and spiperone (6.86).Ro 20-1724 (20 μM) and rolipram (10 μM) significantly enhanced the inhibitory response of 5-HT, but neither zaprinast (10 μM) nor dipyridamole (10 μM) altered the response of 5-HT.5-HT (1 nM–1 μM) caused a concentration-dependent accumulation of intracellular cyclic AMP in the circular muscle.From the present results, the 5-HT receptor, which is functionally correlated with the 5-HT7 receptor, mediates the
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
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