Stability of tramadol with three 5-HT3 receptor antagonists in polyolefin bags for patient-controlled delivery systems.

PubMed

Chen, Fu-Chao; Zhu, Jun; Li, Bin; Yuan, Fang-Jun; Wang, Lin-Hai

2016-01-01

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. 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. 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. 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.

A review of granisetron, 5-hydroxytryptamine3 receptor antagonists, and other antiemetics.

PubMed

Hsu, Eric S

2010-01-01

Nausea and vomiting are 2 of the most upsetting adverse reactions of chemotherapy. Current guidelines propose 5-hydroxytryptamine3 (5-HT3) receptor antagonists as a pharmacologic intervention for acute and delayed nausea and vomiting [chemotherapy-induced nausea and vomiting (CINV)] associated with moderately and highly emetogenic chemotherapy. Meanwhile, both postoperative nausea and vomiting (PONV) and postdischarge nausea and vomiting are challenging situations after surgeries and procedures. Prophylactic and therapeutic combinations of antiemetics are recommended in patients at high risk of suffering from PONV and postdischarge nausea and vomiting. Granisetron (Kytril) is a selective 5-HT3 receptor antagonist that does not induce or inhibit the hepatic cytochrome P-450 system in vitro. There are also 4 other antagonists of 5-HT3 receptor (dolasetron, ondansetron, palonosetron, and tropisetron) being metabolized via the CYP2D6 and are subject to potential genetic polymorphism. The launch of a new class of antiemetics, the substance P/neurokinin1 receptor antagonists, was attributed to the scientific update on the central generator responsible for emesis and role of substance P. There has been mounting interest in exploring integrative medicine, either acupuncture or acustimulation of P6 (Nei-Kuwan), to complement the western medicine for prevention and management of nausea and vomiting. The potential application of cannabinoids, either alone or in combination with other agents of different mechanism, could contribute further to improve outcome in CINV. Implementation of future treatment guidelines for more effective management of CINV and PONV could certainly improve the efficacy and outcome of cancer and postoperative care.

Stability of tramadol with three 5-HT3 receptor antagonists in polyolefin bags for patient-controlled delivery systems

PubMed Central

Chen, Fu-chao; Zhu, Jun; Li, Bin; Yuan, Fang-jun; Wang, Lin-hai

2016-01-01

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

APF530 (granisetron injection extended-release) in a three-drug regimen for delayed CINV in highly emetogenic chemotherapy.

PubMed

Schnadig, Ian D; Agajanian, Richy; Dakhil, Christopher; Gabrail, Nashat Y; Smith, Robert E; Taylor, Charles; Wilks, Sharon T; Schwartzberg, Lee S; Cooper, William; Mosier, Michael C; Payne, J Yvette; Klepper, Michael J; Vacirca, Jeffrey L

2016-06-01

APF530, extended-release granisetron, provides sustained release for ≥5 days for acute- and delayed-phase chemotherapy-induced nausea and vomiting (CINV). We compared efficacy and safety of APF530 versus ondansetron for delayed CINV after highly emetogenic chemotherapy (HEC), following a guideline-recommended three-drug regimen. HEC patients received APF530 500 mg subcutaneously or ondansetron 0.15 mg/kg intravenously, with dexamethasone and fosaprepitant. Primary end point was delayed-phase complete response (no emesis or rescue medication). A higher percentage of APF530 versus ondansetron patients had delayed-phase complete response (p = 0.014). APF530 was generally well tolerated; treatment-emergent adverse event incidence was similar across arms, mostly mild-to-moderate injection-site reactions. APF530 versus the standard three-drug regimen provided superior control of delayed-phase CINV following HEC. ClinicalTrials.gov : NCT02106494.

Anti-Emetic Drug Effects on Performance Phase 1: Laboratory Study.

DTIC Science & Technology

1995-12-01

The objectives of this study were to evaluate the effects of two anti-emetic drugs, granisetron ( 2 mg p.o.) and ondansetron ( 8 mg p.o.) on basic...drugs of interest, granisetron and ondansetron, were extremely well tolerated and with no obvious side effects when compared to the placebo condition...evidence of any cognitive, psychomotor or subjective state changes caused by either granisetron or ondansetron.

APF530 versus ondansetron, each in a guideline-recommended three-drug regimen, for the prevention of chemotherapy-induced nausea and vomiting due to anthracycline plus cyclophosphamide–based highly emetogenic chemotherapy regimens: a post hoc subgroup analysis of the Phase III randomized MAGIC trial

PubMed Central

Schnadig, Ian D; Agajanian, Richy; Dakhil, Christopher; Gabrail, Nashat; Vacirca, Jeffrey; Taylor, Charles; Wilks, Sharon; Braun, Eduardo; Mosier, Michael C; Geller, Robert B; Schwartzberg, Lee; Vogelzang, Nicholas

2017-01-01

Background APF530, a novel extended-release granisetron injection, was superior to ondansetron in a guideline-recommended three-drug regimen in preventing delayed-phase chemotherapy-induced nausea and vomiting (CINV) among patients receiving highly emetogenic chemotherapy (HEC) in the double-blind Phase III Modified Absorption of Granisetron In the prevention of CINV (MAGIC) trial. Patients and methods This MAGIC post hoc analysis evaluated CINV prevention efficacy and safety of APF530 versus ondansetron, each with fosaprepitant and dexamethasone, in patient subgroup receiving an anthracycline plus cyclophosphamide (AC) regimen. Patients were randomized 1:1 to APF530 500 mg subcutaneously (granisetron 10 mg) or ondansetron 0.15 mg/kg intravenously (IV) (≤16 mg); stratification was by planned cisplatin ≥50 mg/m2 (yes/no). Patients were to receive fosaprepitant 150 mg IV and dexamethasone 12 mg IV on day 1, then dexamethasone 8 mg orally once daily on day 2 and twice daily on days 3 and 4. Patients were mostly younger females (APF530 arm, mean age 54.1 years, female, 99.3%; ondansetron arm, 53.8 years, female 98.3%). The primary end point was delayed-phase (>24–120 hours) complete response (CR). Results APF530 versus ondansetron regimens achieved numerically better CINV control in delayed and overall (0–120 hours) phases for CR, complete control, total response, rescue medication use, and proportion with no nausea. APF530 trends are consistent with the overall population, although not statistically superior given the underpowered AC subgroup analysis. The APF530 regimen in this population was generally well tolerated, with safety comparable to that of the overall population. Conclusion APF530 plus fosaprepitant and dexamethasone effectively prevented CINV among patients receiving AC-based HEC, a large subgroup in whom CINV control has traditionally been challenging. PMID:28579832

Transdermal granisetron.

PubMed

Duggan, Sean T; Curran, Monique P

2009-01-01

Granisetron is a highly selective serotonin 5-HT(3) receptor antagonist for the prevention of chemotherapy-induced nausea and vomiting. The transdermal granisetron system delivers continuous granisetron (3.1 mg/day) into the systemic circulation (via passive diffusion) for up to 7 days. In a large phase III trial in cancer patients receiving multi-day (3-5 days) moderately or highly emetogenic chemotherapy, transdermal granisetron applied 24-48 hours prior to chemotherapy and remaining in place for 7 days was noninferior to oral granisetron 2 mg once daily administered for 3-5 days 1 hour prior to chemotherapy. Efficacy was assessed according to the proportion of patients achieving complete response (no vomiting and/or retching, no more than mild nausea, no rescue medication) from the first day, until 24 hours after the start of the last day, of administration of the chemotherapy regimen. In a phase II trial in patients with cancer receiving single-day, moderately-emetogenic chemotherapy, transdermal granisetron applied at least 24 hours prior to chemotherapy and removed after 5 days was as effective as a single oral dose of granisetron 2 mg in achieving total control (no nausea, no vomiting/retching, no use of rescue medication and no study withdrawal) during the delayed (24-120 hours; primary endpoint) period after chemotherapy. Transdermal granisetron was generally well tolerated in clinical trials, with few adverse events being treatment related.

Protective effects of tropisetron on cerulein-induced acute pancreatitis in mice.

PubMed

Rahimian, Reza; Zirak, Mohammad Reza; Seyedabadi, Mohammad; Keshavarz, Mojtaba; Rashidian, Amir; Kazmi, Sareh; Jafarian, Amir Hossein; Karimi, Gholamreza; Mousavizadeh, Kazem

2017-09-01

Acute pancreatitis (AP) causes morbidity and mortality. The aim of the present study was to investigate the protective effect of tropisetron against AP induced by cerulein. Cerulein (50μg/kg, 5 doses) was used to induce AP in mice. Six hours after final cerulein injection, animals were decapitated. Hepatic/pancreatic enzymes in the serum, pancreatic content of malondialdehyde (MDA), pro-inflammatory cytokines and myeloperoxidase (MPO) activity were measured. Tropisetron significantly attenuated pancreatic injury markers and decreased the amount of elevated serum amylase, lipase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), MPO activities and pro-inflammatory cytokines levels caused by AP in mice. Tropisetron didn't affect the pancreatic levels of MDA. Our results suggest that tropisetron could attenuate cerulein-induced AP by combating inflammatory signaling. Further clinical studies are needed to confirm its efficacy in patients with AP. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Granisetron Injection

MedlinePlus

... and vomiting that may occur after surgery. Granisetron extended-release (long-acting) injection is used with other ... be injected intravenously (into a vein) and granisetron extended-release injection comes as a liquid to be ...

Granisetron as an add-on to risperidone for treatment of negative symptoms in patients with stable schizophrenia: randomized double-blind placebo-controlled study.

PubMed

Khodaie-Ardakani, Mohammad-Reza; Seddighi, Sahar; Modabbernia, Amirhossein; Rezaei, Farzin; Salehi, Bahman; Ashrafi, Mandana; Shams-Alizadeh, Narges; Mohammad-Karimi, Maryam; Esfandiari, Gholam-Reza; Hajiaghaee, Reza; Akhondzadeh, Shahin

2013-04-01

Some 5-HT3 antagonists such as ondansetron have shown beneficial effects on negative symptoms of patients with schizophrenia. We aimed to evaluate the efficacy of granisetron (another 5-HT3 antagonist) add-on therapy in the treatment of negative symptoms of patients with stable schizophrenia. In a randomized, double-blind, and placebo-controlled study, forty stable patients with schizophrenia (DSM-IV-TR), were randomized to either granisetron (1 mg twice daily) or placebo (twice daily) in addition to risperidone up to 6 mg/day for eight weeks. The patients were assessed using positive and negative syndrome scale (PANSS) and extrapyramidal symptom rating scale (ESRS) at baseline, week 4 and 8. Hamilton depression rating scale (HDRS) was used to assess depression at baseline and week 8. Thirty-eight patients completed the trial. Granisetron group showed a significantly greater improvement on negative subscale than the placebo group at endpoint [t(38) = 6.046, mean difference (±95% CI) = 3.2(1.8-3.7), P < 0.001]. The same effect was observed for total score [t(38) = 4.168, mean difference (95% CI) = 3.2(1.6-4.7), P < 0.001]. However the placebo and granisetron groups did not differ in their reduction of positive and general psychopathology symptoms scores. HDRS scores and its changes did not differ between the two groups. The ESRS score at week 4 was significantly lower in the granisetron than the placebo group while the two groups showed similar ESRS score at week 8. Frequency of other side effects was similar between the two groups. In summary, granisetron add-on can safely and effectively reduce the primary negative symptoms of patients with schizophrenia. Copyright © 2013 Elsevier Ltd. All rights reserved.

Anti-Emetic Drug Effects on Pilot Performance, Phase 2: Simulation Test.

DTIC Science & Technology

1996-04-01

The objectives of this study were to evaluate the effects of two anti-emetic drugs, granisetron (2 mg oral dose) and ondansetron (8 mg oral dose), on...and preduce no cognitive, psychomotor or subjective state changes. In this study, there was no evidence of performance degradation caused by either granisetron or ondansetron when tested in a complex military task environment.

Involvement of PPARγ in the protective action of tropisetron in an experimental model of ulcerative colitis.

PubMed

Rahimian, Reza; Zirak, Mohammad Reza; Keshavarz, Mojtaba; Fakhraei, Nahid; Mohammadi-Farani, Ahmad; Hamdi, Hanan; Mousavizadeh, Kazem

2016-09-20

Inflammatory bowel disease (IBD) is a chronic inflammation of the gastrointestinal (GI) tract. Tropisetron, a selective 5-HT 3 receptor antagonist, is highly used to counteract chemotherapy-induced emesis. Previous studies revealed the anti-inflammatory properties of this drug. The aim of this study was to evaluate the role of peroxisome proliferator-activated receptor gamma (PPARγ) receptor in the protective effect of tropisetron in an animal model of ulcerative colitis. Experimental colitis was induced by a single intra-colonic instillation of 4% (V/V) acetic acid in male rats. Tropisetron (3 mg/kg) and GW9662 (PPARγ antagonist) (5 mg/kg) were given twice daily for 2 days after colitis induction. Forty-eight hours after induction of colitis, colon was removed and macroscopic and microscopic features were given. Moreover, colonic concentrations of malondialdehyde (MDA), nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) levels, myeloperoxidase (MPO), and PPARγ activity were assessed. Both macroscopic and histopathological features of colonic injury were markedly ameliorated by tropisetron. Likewise, levels of NO, MDA, TNF-α, and IL-1β diminished significantly (p < .05). GW9662 reversed the effect of tropisetron on these markers partially or completely. In addition, tropisetron increased the PPARγ and decreased the MPO activity (p < .05). Tropisetron exerts notable anti-inflammatory effects in acetic acid-induced colitis in rats, which is probably mediated through PPARγ receptors.

Comparison of granisetron alone and granisetron plus dexamethasone in the prophylaxis of cytotoxic-induced emesis.

PubMed Central

Carmichael, J.; Bessell, E. M.; Harris, A. L.; Hutcheon, A. W.; Dawes, P. J.; Daniels, S.; Bessel, E. M.

1994-01-01

Two hundred and seventy-eight adult chemonaive patients, receiving moderately emetogenic chemotherapy were randomly allocated to receive either intravenous (i.v.) granisetron 3 mg plus i.v. dexamethasone 8 mg or i.v. granisetron 3 mg plus i.v. placebo dexamethasone prior to chemotherapy. Eight-two per cent of all patients recruited were female, and 91% of all patients consumed less than 10 units of alcohol per week, suggesting a study population with an increased risk of nausea and vomiting. In the first 24 h 85% of patients who received granisetron plus dexamethasone were complete responders compared with 75.9% of the patients receiving granisetron alone (P = 0.053). There were statistically significant improvements in complete response over 7 days (P = 0.029) and in the numbers of patients receiving rescue antiemetic (P = 0.0004). Toxicity was minimal with no significant differences between treatment groups. These results confirm the antiemetic activity of granisetron and show that it has an additive effect in combination with dexamethasone. PMID:7981069

Local treatment of tendinopathies and myofascial pain syndromes with the 5-HT3 receptor antagonist tropisetron.

PubMed

Müller, W; Stratz, T

2004-01-01

The use of local tropisetron injections improved the treatment of tendinopathies considerably, with the effect being comparable to the topical application of local anaesthetics combined with depot corticosteroids. On the other hand, local injection of prilocaine alone exerted a shorter and weaker effect on the condition. After it had been proven that systemic application of the 5-HT3 receptor antagonist tropisetron exerts an analgesic effect on musculoskeletal pain in fibromyalgia, we investigated the efficacy of the substance in tendinopathies and myofascial pain syndromes. Local injections of tropisetron as a treatment for trigger points in myofascial pain syndrome also brought about rapid and prolonged relief in the majority of cases. The analgesic effect was far superior to the action of local anaesthetics. The present findings indicate that the analgesic action of the 5-HT3 receptor antagonist tropisetron sets in rapidly and lasts for a long time. Various mechanisms are under discussion to explain the long duration of the effect. Tropisetron not only has an analgesic but probably also an antiphlogistic effect which can be attributed to the inhibited release of substance P and other neuropeptides from the nociceptors and the blocked release of phlogistic substances from macrophages, monocytes etc.

Protective Effect of Tropisetron on Rodent Hepatic Injury after Trauma-Hemorrhagic Shock through P38 MAPK-Dependent Hemeoxygenase-1 Expression

PubMed Central

Hwang, Tsong-Long; Tsai, Yung-Fong

2012-01-01

Tropisetron can decrease inflammatory cell responses and alleviate organ damage caused by trauma-hemorrhage, but the mechanism of these effects remains unknown. The p38 mitogen-activated protein kinase/hemeoxygenase-1 (p38 MAPK/HO-1) pathway exerts anti-inflammatory effects on different tissues. The aim of this study was to investigate whether p38 MAPK/HO-1 plays any role in the tropisetron-mediated attenuation of hepatic injury after trauma-hemorrhage. Male Sprague-Dawley rats underwent trauma-hemorrhage (mean blood pressure maintained at approximately 35–40 mmHg for 90 min), followed by fluid resuscitation. During resuscitation, several treatment regimens were administered: four doses of tropisetron alone (0.1, 0.3, 1, 3 mg/kg body weight), or a single dose of tropisetron (1 mg/kg body weight) with and without a p38 MAPK inhibitor (SB-203580, 2 mg/kg body weight) or HO antagonist (chromium-mesoporphyrin, 2.5 mg/kg body weight). Various parameters were measured, and the animals were sacrificed at 24 h post-resuscitation. The results showed that trauma-hemorrhage increased the following parameters: plasma concentrations of aspartate (AST) and alanine aminotransferases (ALT), hepatic myeloperoxidase (MPO) activity, and levels of cytokine-induced neutrophil chemoattractant-1 and -3 (CINC-1 and CINC-3), intercellular adhesion molecule-1 (ICAM-1), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and macrophage inflammatory protein-1α (MIP-1α). These parameters were significantly improved in the tropisetron-treated rats subjected to trauma-hemorrhage. Tropisetron treatment also increased hepatic p38 MAPK and HO-1 expression compared with vehicle-treated trauma-hemorrhaged rats. Co-administration of SB-203580 or chromium-mesoporphyrin with tropisetron abolished the tropisetron-induced beneficial effects on the above parameters and hepatic injury. These results suggest that the protective effect of tropisetron administration on alleviation of hepatic injury

Protective effect of tropisetron on rodent hepatic injury after trauma-hemorrhagic shock through P38 MAPK-dependent hemeoxygenase-1 expression.

PubMed

Liu, Fu-Chao; Yu, Huang-Ping; Hwang, Tsong-Long; Tsai, Yung-Fong

2012-01-01

Tropisetron can decrease inflammatory cell responses and alleviate organ damage caused by trauma-hemorrhage, but the mechanism of these effects remains unknown. The p38 mitogen-activated protein kinase/hemeoxygenase-1 (p38 MAPK/HO-1) pathway exerts anti-inflammatory effects on different tissues. The aim of this study was to investigate whether p38 MAPK/HO-1 plays any role in the tropisetron-mediated attenuation of hepatic injury after trauma-hemorrhage. Male Sprague-Dawley rats underwent trauma-hemorrhage (mean blood pressure maintained at approximately 35-40 mmHg for 90 min), followed by fluid resuscitation. During resuscitation, several treatment regimens were administered: four doses of tropisetron alone (0.1, 0.3, 1, 3 mg/kg body weight), or a single dose of tropisetron (1 mg/kg body weight) with and without a p38 MAPK inhibitor (SB-203580, 2 mg/kg body weight) or HO antagonist (chromium-mesoporphyrin, 2.5 mg/kg body weight). Various parameters were measured, and the animals were sacrificed at 24 h post-resuscitation. The results showed that trauma-hemorrhage increased the following parameters: plasma concentrations of aspartate (AST) and alanine aminotransferases (ALT), hepatic myeloperoxidase (MPO) activity, and levels of cytokine-induced neutrophil chemoattractant-1 and -3 (CINC-1 and CINC-3), intercellular adhesion molecule-1 (ICAM-1), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and macrophage inflammatory protein-1α (MIP-1α). These parameters were significantly improved in the tropisetron-treated rats subjected to trauma-hemorrhage. Tropisetron treatment also increased hepatic p38 MAPK and HO-1 expression compared with vehicle-treated trauma-hemorrhaged rats. Co-administration of SB-203580 or chromium-mesoporphyrin with tropisetron abolished the tropisetron-induced beneficial effects on the above parameters and hepatic injury. These results suggest that the protective effect of tropisetron administration on alleviation of hepatic injury

Randomised double-blind study comparing tropisetron alone and in combination with dexamethasone in the prevention of acute and delayed cisplatin-induced emesis.

PubMed

Garcia-del-Muro, X; Vadell, C; Pérez Manga, G; Bover, I; Rifá, J; Beltrán, M; Barros, M M; Germá, J R; Fabregat, X; Moreno, V; Salvador, A; Viladiu, P

1998-01-01

In a randomised, double-blind and parallel-design multicentre study, 282 chemotherapy-naive cancer patients received tropisetron 5 mg intravenously (i.v.) before high-dose cisplatin on day 1, and oral tropisetron 5 mg daily on days 2-6, in combination with either placebo (n = 143) or dexamethasone (n = 135), given i.v. on day 1 and orally on days 2-6. Complete protection from acute vomiting/nausea was achieved in 76.3%/79.3% of patients receiving the combination and in 55.2%/61.5% of those receiving tropisetron alone. Complete protection on days 2-6 from delayed vomiting/nausea was obtained in 60%/60% and 39.2%/40.6%, respectively. Tropisetron in combination with dexamethasone is safe and more effective than tropisetron alone in the prevention of both acute and delayed cisplatin-induced emesis.

Pharmacological characterization of the 5-HT receptor-mediated contraction in the mouse isolated ileum

PubMed Central

Tuladhar, B R; Womack, M D; Naylor, R J

2000-01-01

The pharmacological characterization of a 5-HT receptor-mediated contractile response in the mouse isolated ileum is described. In the presence of methysergide (1 μM), 5-hydroxytryptamine (5-HT, 0.3–100 μM) produced phasic concentration-dependent contractions of segments of the mouse isolated ileum with a pEC50 value of 5.47±0.09. The 5-HT3 receptor selective agonists m-chlorophenylbiguanide (0.3–100 μM, pEC50 5.81±0.04), 1-phenylbiguanide (3–100 μM, pEC50 5.05±0.06) and 2-methyl-5-HT (3–100 μM, pEC50 5.00±0.07) acted as full agonists to induce contractile responses. 5-methoxytryptamine (0.1–100 μM), RS 67506 (0.1–100 μM) and α-methyl-5-HT (0.1–100 μM) failed to mimic the 5-HT responses. The contractile response to 5-HT was not antagonized by either 5-HT2 receptor antagonists ritanserin (0.1 μM) or ketanserin (1 μM) nor the 5-HT4 receptor antagonist SB 204070 (0.1 μM). The 5-HT3 receptor selective antagonists granisetron (0.3–1 nM), tropisetron (1–10 nM), ondansetron (10 nM–1 μM) and MDL 72222 (10 nM–1 μM) caused rightward displacement of the concentration-response curves to 5-HT. The lower concentrations of the antagonists caused approximate parallel rightward shifts of the concentration-response curves to 5-HT with apparent pKB values for granisetron (9.70±0.39), tropisetron (9.18±0.20), ondansetron (8.84±0.24) and MDL 72222 (8.65±0.35). But higher concentrations of antagonists resulted in a progressive reduction in the maximum responses. The contractile response to 5-HT was abolished by tetrodotoxin (0.3 μM); atropine (0.1 and 1 μM) decreased the maximum response of the 5-HT concentration-response curve by approximately 65%. It is concluded that a neuronally located 5-HT3 receptor mediates a contractile response to 5-HT in the mouse ileum. The 5-HT3 receptor in the mouse ileum has a different pharmacological profile to that reported for the guinea-pig ileum. PMID:11139451

Granisetron adjunct to fluvoxamine for moderate to severe obsessive-compulsive disorder: a randomized, double-blind, placebo-controlled trial.

PubMed

Askari, Neda; Moin, Mahdieh; Sanati, Mohammad; Tajdini, Masih; Hosseini, Seyed-Mohammad-Reza; Modabbernia, Amirhossein; Najand, Babak; Salimi, Samrand; Tabrizi, Mina; Ashrafi, Mandana; Hajiaghaee, Reza; Akhondzadeh, Shahin

2012-10-01

Several small studies have shown beneficial effects of ondansetron, a serotonin 5-HT(3) receptor antagonist, in the treatment of obsessive-compulsive disorder (OCD). The efficacy of other 5-HT(3) receptor antagonists in patients with OCD is still unclear. Granisetron does not alter cytochrome P450 activity and might have a lower risk of drug interactions, a longer duration of action and a better tolerability profile than other 5-HT(3) receptor antagonists. The objective of this study was to assess the efficacy and tolerability of granisetron augmentation of fluvoxamine in patients with OCD. This was a two-centre, randomized, double-blind, placebo-controlled, parallel-group study conducted from November 2011 to March 2012. The study setting was outpatient clinics of two large referral centres. Study participants were men and women, aged 18-60 years, who met the diagnostic criteria of OCD based on the DSM-IV-TR and who had a Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score of at least 21. Participants were randomly assigned to granisetron (Kytril(®); SmithKline Beecham, Philadelphia, PA, USA) 1 mg every 12 hours or placebo every 12 hours in addition to fluvoxamine for 8 weeks. Patients were assessed using the Y-BOCS at baseline, second, fourth, sixth and eighth weeks. The primary outcome measure was the difference in the score change of Y-BOCS total score from baseline to week 8 between the two groups. We also compared changes in the obsession and compulsion subscales of the Y-BOCS, and frequencies of partial response (≥25% reduction in Y-BOCS score), complete response (≥35% reduction in Y-BOCS score) and remission (Y-BOCS score ≤16) between the two groups. Of the 42 included patients, 39 (20 in the placebo group, 19 in the granisetron group) completed the study. Significant time X treatment interaction was observed for total Y-BOCS (F [2.097, 79.678] = 4.941, p = 0.009), obsession (F [2.337, 88.799] = 4.938, p = 0.006) and compulsion (F [2.050, 77

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

PubMed

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

2015-02-01

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.

Stability of ondansetron hydrochloride injection in various beverages.

PubMed

Yamreudeewong, W; Danthi, S N; Hill, R A; Fox, J L

1995-09-15

The stability of ondansetron hydrochloride injection in beverages likely to be acceptable to patients was studied. Ondansetron hydrochloride injection (containing ondansetron 2 mg/mL) was added to apple juice, fruit punch, cherry-flavored drink, carbonated soft drinks, and hot tea to provide a nominal ondansetron concentration of 32.8, 64.5, or 95.2 micrograms/mL. Samples were stored at -3 to 28 degrees C (noncarbonated-beverage mixtures except tea), 2 to 28 degrees C (carbonated-beverage mixtures), and 25 degrees C (tea) and assayed for ondansetron concentration by high-performance liquid chromatography at 6, 24, 48, and 72 hours (noncarbonated-beverage mixtures except tea); 6, 24, and 48 hours (carbonated-beverage mixtures); and 1 hour (tea). More than 95% of the initial ondansetron concentration was retained in apple juice, fruit punch, cherry-flavored drink, Sprite, and Diet Coke throughout the periods studied. A precipitate formed immediately after ondansetron was added to hot tea, but the drug was chemically stable for at least one hour in this preparation. Ondansetron hydrochloride injection 32.7, 64.5, and 95.2 micrograms/mL (expressed as free base) was stable in various beverages when stored at -3 to 28 degrees C for up to 72 hours. Ondansetron at these same concentrations precipitated in hot tea preparations but was chemically stable for at least one hour.

Attenuation of oxidative and nitrosative stress in cortical area associates with antidepressant-like effects of tropisetron in male mice following social isolation stress.

PubMed

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

2016-06-01

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. Copyright © 2016 Elsevier Inc. All rights reserved.

Cardiac effects of granisetron in a prospective crossover randomized dose comparison trial.

PubMed

Cakir, F B; Yapar, O; Canpolat, C; Akalin, F; Berrak, S G

2012-10-01

Cardiac side effects of granisetron have been studied mostly in adult patients that are using cardiotoxic chemotherapeutics. There is limited evidence in pediatric age group and no information in pediatric oncology patients with non-cardiotoxic chemotherapeutics. In this prospective, crossover randomized study, the cardiac side effects of granisetron are compared in pediatric oncology patients who had carboplatin based chemotherapy. They were randomized to receive either 10 or 40 μg kg(-1) dose(-1) of granisetron before each cycle of chemotherapy. We drew blood for creatine phosphokinase (CPK), CPK-muscle band (MB) and Troponin-T before and 24 h after administering granisetron. Electrocardiography (ECG) tracings were taken at 0, 1, 2, 3, 6 and 24 h of granisetron. Twenty-four hours Holter ECG monitorisation was performed after each granisetron infusion. A total of 16 patients (median 8.7 years of age) were treated with weekly consecutive courses of carboplatin. There was bradycardia (p = 0.000) in patients that had granisetron at 40 μg/kg and PR interval was shortened in patients that had granisetron at 10 μg/kg dose (p = 0.021). At both doses of granisetron, QTc interval and dispersion were found to be similar. CPK, CK-MB and Troponin-T values were found to be normal before and 24 h after granisetron infusion. As the first study that has studied cardiac side effects of granisetron in patients that are not using cardiotoxic chemotherapeutics, we conclude that granisetron at 40 μg kg(-1) dose(-1) causes bradycardia only. We have also demonstrated that granisetron does not cause any clinically cardiac side effects either at 10 or 40 μg kg(-1) dose(-1). However, our results should be supported by prospective randomized studies with larger samples of patient groups.

Granisetron ameliorates acetic acid-induced colitis in rats.

PubMed

Fakhfouri, Gohar; Rahimian, Reza; Daneshmand, Ali; Bahremand, Arash; Rasouli, Mohammad Reza; Dehpour, Ahmad Reza; Mehr, Shahram Ejtemaei; Mousavizadeh, Kazem

2010-04-01

Inflammatory bowel disease (IBD) is a chronically relapsing inflammation of the gastrointestinal tract, of which the definite etiology remains ambiguous. Considering the adverse effects and incomplete efficacy of currently administered drugs, it is indispensable to explore new candidates with more desirable therapeutic profiles. 5-HT( 3) receptor antagonists have shown analgesic and anti-inflammatory properties in vitro and in vivo. This study aims to investigate granisetron, a 5-HT( 3) receptor antagonist, in acetic acid-induced rat colitis and probable involvement of 5-HT(3) receptors. Colitis was rendered by instillation of 1 mL of 4% acetic acid (vol/vol) and after 1 hour, granisetron (2 mg/kg), dexamethasone (1 mg/kg), meta-chlorophenylbiguanide (mCPBG, 5 mg/kg), a 5-HT( 3) receptor agonist, or granisetron + mCPBG was given intraperitoneally. Twenty-four hours following colitis induction, animals were sacrificed and distal colons were assessed macroscopically, histologically and biochemically (malondialdehyde, myeloperoxidase, tumor necrosis factor-alpha, interleukin-1 beta and interleukin-6). Granisetron or dexamethasone significantly (p < .05) improved macroscopic and histologic scores, curtailed myeloperoxidase activity and diminished colonic levels of inflammatory cytokines and malondialdehyde. The protective effects of granisetron were reversed by concurrent administration of mCPBG. Our data suggests that the salutary effects of granisetron in acetic acid colitis could be mediated by 5-HT(3) receptors.

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

PubMed

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

2017-05-01

Tropisetron, a 5-HT 3 receptor antagonist commonly prescribed for chemotherapy-induced nausea and vomiting also exhibits high affinity, partial agonist activity at α7 nicotinic acetylcholine receptors (α7 nAChRs). α7 nAChRs are considered viable therapeutic targets for neuropsychiatric disorders such as Alzheimer's disease (AD). Here we further explored the nAChR pharmacology of tropisetron to include the homomeric α7 nAChR and recently characterized heteromeric α7β2 nAChR (1:10 ratio) and we evaluated its cognitive effects in young and aged animals. Electrophysiological studies on human nAChRs expressed in Xenopus oocytes confirmed the partial agonist activity of tropisetron at α7 nAChRs (EC 50 ∼2.4 μM) with a similar effect at α7β2 nAChRs (EC 50 ∼1.5 μM). Moreover, currents evoked by irregular pulses of acetylcholine (40 μM) at α7 and α7β2 nAChRs were enhanced during sustained exposure to low concentrations of tropisetron (10 and 30 nM) indicative of a "priming" or co-agonist effect. Tropisetron (0.1-10 mg/kg) improved novel object recognition performance in young Sprague-Dawley rats and in aged Fischer rats. In aged male and female rhesus monkeys, tropisetron (0.03-1 mg/kg) produced a 17% increase from baseline levels in delayed match to sample long delay accuracy while combination of non-effective doses of donepezil (0.1 mg/kg) and tropisetron (0.03 and 0.1 mg/kg) produced a 24% change in accuracy. Collectively, these animal experiments indicate that tropisetron enhances cognition and has the ability to improve the effective dose range of currently prescribed AD therapy (donepezil). Moreover, these effects may be explained by tropisetron's ability to sensitize α7 containing nAChRs to low levels of acetylcholine. Copyright © 2017 Elsevier Ltd. All rights reserved.

A CASE OF GRANISETRON ASSOCIATED INTRAOPERATIVE CARDIAC ARREST.

PubMed

Al Harbi, Mohammed; Al Rifai, Derar; Al Habeeb, Hassan; Wambi, Freddie; Geldhof, Georges; Dimitriou, Vassilios

2016-02-01

We report a case of intraoperative severe bradycardia that resulted in asystole and cardiac arrest shortly after (<2 min) intravenous granisetron 1mg for postoperative nausea and vomiting prophylaxis, that occurred in a female patient who underwent an elective total thyroidectomy. After two cycles of cardiopulmonary resuscitation and defibrillation, spontaneous circulation and sinus rhythm returned successfully. Postoperatively, the patient was diagnosed with a drug-induced long QT syndrome. At the time of the event, granisetron was the only medication administered. Furthermore, there was no reason to suspect electrolyte abnormalities. We explore the association of the onset of severe sinus bradycardia with the intravenous administration of granisetron.

Ondansetron-induced dystonia, hypoglycemia, and seizures in a child.

PubMed

Patel, Aneet; Mittal, Shweta; Manchanda, Samiksha; Puliyel, Jacob Mammen

2011-01-01

To document ondansetron-induced dystonia, hypoglycemia, and seizures in a child. A 4-year-old boy was admitted with dystonia following an intravenous dose of ondansetron 2 mg (0.13 mg/kg) that he had received for vomiting that day. In the emergency department, he developed generalized tonicclonic seizures lasting for a few minutes. He was administered lorazepam 1.5 mg (0.1 mg/kg) to control the seizures. His blood glucose level was 10 mg/dL; the hypoglycemia responded promptly to intravenous dextrose 10% (7 mL/kg). Serum electrolytes, renal profile, capillary blood gas, and results of a computed tomography scan of the brain were normal. Subsequent blood glucose values were within normal range. On follow-up after 7 days, the child was healthy with no recurrences of the symptoms. A provisional diagnosis of ondansetron-induced acute dystonia with seizures and hypoglycemia was made. Ondansetron is an antiemetic known for its safety profile. There have been a few case reports of extrapyramidal adverse effects and seizures from this drug but none of ondansetron-associated hypoglycemia. 5-Hydroxytryptamine (5-HT(3)) receptors are involved in arginine vasopressin-mediated release of adrenocorticotropin hormone and cortisol in response to stress. Blunting of this stress response by ondansetron, a 5-HT(3) receptor antagonist, could have caused the hypoglycemia in this patient. According to the Naranjo scale, ondansetron was probably the cause of the dystonia and seizures, and possibly the cause of the hypoglycemia. Other potential explanations for hypoglycemia were considered but were thought to be less likely. Dystonia and seizures have been associated with ondansetron in a few case reports. In addition, clinicians need to consider hypoglycemia as a possible adverse effect of ondansetron.

Preoperative use of granisetron plus dexamethasone and granisetron alone in prevention of post operative nausea and vomiting in tonsillectomy.

PubMed

Islam, M R; Haq, M F; Islam, M A; Meftahuzzaman, S M; Sarkar, S C; Rashid, H; Rashid, H U

2011-07-01

This prospective study was done for to see the efficacy of preoperative use of granisetron plus dexamethasone (Group A) & granisetron (Group B) alone for the postoperative prevention of nausea & vomiting after tonsillectomy operation. One hundred patients undergoing tonsillectomy & adenoidectomy operation under general anaesthesia who were admitted in the Mymensingh Medical College Hospital during the period from July 2008 to June 2009 with American Society of Anaesthesiologists (ASA) grade I & II with age 3-40 years, body weight 10-60 kgs, were studied. Observation of this study was analyzed in the light of comparison between the two groups. All results were expressed as mean±SEM. Age in Group A 15.98±1.028 & Group B 17.18±0.961 years; Weight in Group A 38.40±1.492 & Group B 39.76±1.561 kgs and operational duration in Group A 52.60±0.786 & Group B 52.70±0.823 minutes. The studied groups were statistically matched for age, weight, duration of surgery. We observed that the effects of combination of granisetron & dexamthasone are more than granisetron alone in prevention of nausea & vomiting after tonsillectomy operation. The frequency of vomiting was 4% in combination & 16% in single therapy which is statically significant (p<0.05).

Prophylactic isopropyl alcohol inhalation and intravenous ondansetron versus ondansetron alone in the prevention of postoperative nausea and vomiting in high-risk patients.

PubMed

Radford, Kennett D; Fuller, Thomas N; Bushey, Brent; Daniel, Carole; Pellegrini, Joseph E

2011-08-01

Patients identified as high risk for postoperative nausea and vomiting (PONV) are often treated prophylactically with intravenous (IV) ondansetron and an additional agent. Limited options exist for a second agent with no adverse effects. The purpose of this investigation was to determine if combining the prophylactic inhalation of isopropyl alcohol (IPA) vapors, an agent with no adverse effects, with IV ondansetron would be more effective than IV ondansetron alone in the prevention of PONV in high-risk patients. A total of 76 patients at high risk for PONV were randomized into control (n = 38) and experimental (n = 38) groups. All patients received IV ondansetron before emergence from general anesthesia. In addition, the experimental group inhaled IPA vapors before induction. Severity of PONV was measured using a 0 to 10 verbal numeric rating scale. Other measured variables included time to onset and incidence of PONV, 24-hour composite nausea score, and satisfaction with nausea control. No significant differences in demographics, surgical or anesthesia time, number of risk factors, severity or incidence of PONV, or satisfaction scores were noted. Prophylactic inhalation of IPA vapors in combination with IV ondansetron was no more efficacious than IV ondansetron alone in the prevention of PONV in a high-risk population.

Evaluation of anticonvulsant and nootropic effect of ondansetron in mice.

PubMed

Jain, S; Agarwal, N B; Mediratta, P K; Sharma, K K

2012-09-01

The role of serotonin receptors have been implicated in various types of experimentally induced seizures. Ondansetron is a highly selective 5-hydroxytryptamine 3 (5-HT(3)) receptor antagonist used as antiemetic agent for chemotherapy-, and radiotherapy-induced nausea and vomiting. The present study was carried out to examine the effect of ondansetron on electroshock, pentylenetetrazole (PTZ)-induced seizures and cognitive functions in mice. Ondansetron was administered intraperitoneally (i.p.) at doses of 0.5, 1.0 and 2.0 mg/kg (single dose) to observe its effect on the increasing current electroshock seizure (ICES) test and PTZ-induced seizure test. In addition, a chronic study (21 days) was also performed to assess the effects of ondansetron on electroshock-induced convulsions and cognitive functions. The effect on cognition was assessed by elevated plus maze and passive avoidance paradigms. Phenytoin (25 mg/kg, i.p.) was used as a standard anticonvulsant drug and piracetam (200 mg/kg) was administered as a standard nootropic drug. The results were compared with an acute study, wherein it was found that the administration of ondansetron (1.0 and 2.0 mg/kg) significantly raised the seizure-threshold current as compared to control group in the ICES test. Similar results were observed after chronic administration of ondansetron. In PTZ test, ondansetron in all the three tested doses failed to show protective effect against PTZ-induced seizure test. Administration of ondansetron for 21 days significantly decreased the transfer latency (TL) and prolonged the step-down latency (SDL). The results of present study suggest the anticonvulsant and memory-enhancing effect of ondansetron in mice.

Involvement of N-methyl-d-aspartate receptors in the antidepressant-like effect of 5-hydroxytryptamine 3 antagonists in mouse forced swimming test and tail suspension test.

PubMed

Kordjazy, Nastaran; Haj-Mirzaian, Arya; Amiri, Shayan; Ostadhadi, Sattar; Amini-Khoei, Hossein; Dehpour, Ahmad Reza

2016-02-01

Recent evidence indicates that 5-hydroxytryptamine 3 (5-HT3) antagonists such as ondansetron and tropisetron exert positive behavioral effects in animal models of depression. Due to the ionotropic nature of 5-HT3 and N-methyl-d-aspartate (NMDA) receptors, plus their contribution to the pathophysiology of depression, we investigated the possible role of NMDA receptors in the antidepressant-like effect of 5-HT3 receptor antagonists in male mice. In order to evaluate the animals' behavior in response to different treatments, we performed open-field test (OFT), forced swimming test (FST), and tail-suspension test (TST), which are considered as valid tasks for measuring locomotor activity and depressive-like behaviors in mice. Our data revealed that intraperitoneal (i.p.) administration of tropisetron (5, 10, and 30mg/kg) and ondansetron (0.01, and 0.1μg/kg) significantly decreased the immobility time in FST and TST. Also, co-administration of subeffective doses of tropisetron (1mg/kg, i.p.) or ondansetron (0.001μg/kg, i.p.) with subeffective doses of NMDA receptor antagonists, ketamine (1mg/kg, i.p.), MK-801 (0.05mg/kg, i.p.) and magnesium sulfate (10mg/kg, i.p.) resulted in a reduced immobility time both in FST and TST. The subeffective dose of NMDA (NMDA receptor agonist, 75mg/kg, i.p.) abolished the effects of 5-HT3 antagonists in FST and TST, further supporting the presumed interaction between 5-HT3 and NMDA receptors. These treatments did not affect the locomotor behavior of animals in OFT. Finally, the results of our study suggest that the positive effects of 5-HT3 antagonists on the coping behavior of mice in FST and TST are at least partly mediated through NMDA receptors participation. Copyright © 2015 Elsevier Inc. All rights reserved.

Development and validation of a sensitive liquid chromatographic-tandem mass spectrometric method for the simultaneous analysis of granisetron and 7-hydroxy granisetron in human plasma and urine samples: application in a clinical pharmacokinetic study in pregnant subject.

PubMed

Zhao, Yang; Chen, Hui-Jun; Caritis, Steve; Venkataramanan, Raman

2016-02-01

A liquid chromatography-tandem mass spectrometric method for the quantification of granisetron and its major metabolite, 7-hydroxy granisetron in human plasma and urine samples was developed and validated. Respective stable isotopically labeled granisetron and 7-hydroxy granisetron were used as internal standards (IS). Chromatography was performed using an Xselect HSS T3 analytical column with a mobile phase of 20% acetonitrile in water (containing 0.2 mM ammonium formate and 0.14% formic acid, pH 4) delivered in an isocratic mode. Tandem mass spectrometry operating in positive electrospray ionization mode with multiple reaction monitoring was used for quantification. The standard curves were linear in the concentration ranges of 0.5-100 ng/mL for granisetron and 0.1-100 ng/mL for 7-hydroxy granisetron in human plasma samples, and 2-2000 ng/mL for granisetron and 2-1000 ng/mL for 7-hydroxy granisetron in human urine samples, respectively. The accuracies were >85% and the precision as determined by the coefficient of variations was <10%. No significant matrix effects were observed for granisetron or 7-hydroxy granisetron in either plasma or urine samples. Granisetron was stable under various storage and experimental conditions. This validated method was successfully applied to a pharmacokinetic study after intravenous administration of 1 mg granisetron to a pregnant subject. Copyright © 2015 John Wiley & Sons, Ltd.

Efficacy of granisetron in preventing postanesthetic shivering.

PubMed

Sajedi, Parvin; Yaraghi, Ahmad; Moseli, Heidar Ali

2008-12-01

Recently, 5-hydroxytryptamine 3 (5-HT3) receptor antagonists have been reported to prevent postanesthetic shivering. This placebo-controlled study was performed to evaluate the efficacy of granisetron, a 5-HT3 antagonist, in comparison with meperidine and tramadol in preventing postanesthetic shivering. In this prospective, randomized, double-blind study, 132 ASA I and II patients undergoing elective orthopedic surgery under standardized general anesthesia were included. At the end of surgery, patients were randomly assigned to one of four groups (each group n = 33) using a double-blinded protocol. Group T received 1 mg/kg tramadol, group G received 40 microg/kg granisetron (an antiemetic dose), group M received 0.4 mg/kg meperidine, and group P received saline 0.9% as placebo. Shivering was graded according to the following: 0 = no shivering; 1 = piloerection, peripheral vasoconstriction or peripheral cyanosis without other cause; 2 = visible muscular activity confined to one muscle group; 3 = visible muscular activity in more than one muscle group; and 4 = gross muscular activity involving the entire body. The emergence time from anesthesia, defined as the time between withdrawal of isoflurane and tracheal extubation, was documented. The number of patients with observable shivering was 19 in group P, nine in group G, seven in group T and six in group M. Granisetron significantly reduced the incidence of shivering in comparison with placebo (p = 0.013). Although the frequency of shivering was higher with granisetron in comparison to tramadol and meperidine, it was not statistically significant (p > 0.05). The number of patients with a shivering score of 2, 3 and 4 was significantly higher in group P compared with the other groups (p = 0.001). Both meperidine and tramadol caused a significantly prolonged emergence time (20.58 +/- 3.56 and 16.45 +/- 4.13 minutes, respectively) as opposed to granisetron (13.58 +/- 3.41 minutes) and placebo (12.61 +/- 3.31 minutes

Administration of ondansetron is associated with lethal outcome.

PubMed

Gener, Blanca; Burns, Jarrett M; Griffin, Susanne; Boyer, Edward W

2010-06-01

We report here the case of a child with a known muscular abnormality and susceptibility to malignant hyperthermia who abruptly died after receiving a therapeutic dose of ondansetron. Also, we discuss the pharmacodynamic relationship of ondansetron to malignant hyperthermia in a susceptible host.

Characterisation of the cytochrome P450 enzymes involved in the in vitro metabolism of granisetron.

PubMed Central

Bloomer, J C; Baldwin, S J; Smith, G J; Ayrton, A D; Clarke, S E; Chenery, R J

1994-01-01

1. The metabolism of granisetron was investigated in human liver microsomes to identify the specific forms of cytochrome P450 responsible. 2. 7-hydroxy and 9'-desmethyl granisetron were identified as the major products of metabolism following incubation of granisetron with human liver microsomes. At low, clinically relevant, concentrations of granisetron the 7-hydroxy metabolite predominated. Rates of granisetron 7-hydroxylation varied over 100-fold in the human livers investigated. 3. Enzyme kinetics demonstrated the involvement of at least two enzymes contributing to the 7-hydroxylation of granisetron, one of which was a high affinity component with a Km of 4 microM. A single, low affinity, enzyme was responsible for the 9'-desmethylation of granisetron. 4. Granisetron caused no inhibition of any of the cytochrome P450 activities investigated (CYP1A2, CYP2A6, CYP2B6, CYP2C9/8, CYP2C19, CYP2D6, CYP2E1 and CYP3A), at concentrations up to 250 microM. 5. Studies using chemical inhibitors selective for individual P450 enzymes indicated the involvement of cytochrome P450 3A (CYP3A), both pathways of granisetron metabolism being very sensitive to ketoconazole inhibition. Correlation data were consistent with the role of CYP3A3/4 in granisetron 9'-desmethylation but indicated that a different enzyme was involved in the 7-hydroxylation. PMID:7888294

Evaluating the potential effect on fetal tissue after exposure to granisetron during pregnancy.

PubMed

Smith, Judith A; Julius, Justin M; Gaikwad, Anjali; Berens, Pamela D; Alcorn, Joseph; Moise, Kenneth J; Refuerzo, Jerrie S

2015-06-01

The objective of this study was to elucidate the possible toxic effects on the fetal tissues after exposure to two clinically relevant concentrations of granisetron. Primary cells were isolated from human fetal organs of 16-19 weeks gestational age and treated with 3 ng/mL or 30 ng/mL of granisetron. Cell cycle progression was evaluated by flow cytometry. ELISA was used to detect alterations in major apoptotic proteins. Up to 10% apoptosis in cardiac tissue was observed following treatment with 30 ng/mL granisetron. Neither concentration of granisetron caused alteration in cell cycle progression or alterations in apoptotic proteins in any of the other tissues. At 30 ng/mL granisetron concentration had the potential to induce up to 10% apoptosis in cardiac tissue; clinical significance needs further evaluation. At granisetron 3 ng/mL there was no detectable toxicity or on any fetal tissue in this study. Further research is needed to confirm these preliminary findings and determine if clinically significant. Copyright © 2015 Elsevier Inc. All rights reserved.

Carbon monoxide contributes to the constipating effects of granisetron in rat colon.

PubMed

Nacci, Carmela; Fanelli, Margherita; Potenza, Maria Assunta; Leo, Valentina; Montagnani, Monica; De Salvia, Maria Antonietta

2016-11-14

To investigate the mechanisms underlying the potential contribution of the heme oxygenase/carbon monoxide (HO/CO) pathway in the constipating effects of granisetron. For in vivo studies, gastrointestinal motility was evaluated in male rats acutely treated with granisetron [25, 50, 75 μg/kg/subcutaneous (sc)], zinc protoporphyrin IX [ZnPPIX, 50 μg/kg/intraperitoneal (ip)] and hemin (50 μmol/L/kg/ip), alone or in combination. For in vitro studies, the contractile neurogenic response to electrical field stimulation (EFS, 3, 5, 10 Hz, 14 V, 1 ms, pulse trains lasting 10 s), as well as the contractile myogenic response to acetylcholine (ACh, 0.1-100 μmol/L) were evaluated on colon specimens incubated with granisetron (3 μmol/L, 15 min), ZnPPIX (10 μmol/L, 60 min) or CO-releasing molecule-3 (CORM-3, 100, 200, 400 μmol/L) alone or in combination. These experiments were performed under co-treatment with or without atropine (3 μmol/L, a muscarinic receptor antagonist) or N G -nitro-L-Arginine (L-NNA, 100 μmol/L, a nitric oxide synthase inhibitor). Administration of granisetron (50, 75 μg/kg) in vivo significantly increased the time to first defecation ( P = 0.045 vs vehicle-treated rats), clearly suggesting a constipating effect of this drug. Although administration of ZnPPIX or hemin alone had no effect on this gastrointestinal motility parameter, ZnPPIX co-administered with granisetron abolished the granisetron-induced constipation. On the other hand, co-administration of hemin and granisetron did not modify the increased constipation observed under granisetron alone. When administered in vitro , granisetron alone (3 μmol/L) did not significantly modify the colon's contractile response to either EFS or ACh. Incubation with ZnPPIX alone (10 μmol/L) significantly reduced the colon's contractile response to EFS ( P = 0.016) but had no effect on contractile response to ACh. Co-administration of ZnPPIX and atropine (3 μmol/L) abolished the ZnPPIX-mediated decrease

Carbon monoxide contributes to the constipating effects of granisetron in rat colon

PubMed Central

Nacci, Carmela; Fanelli, Margherita; Potenza, Maria Assunta; Leo, Valentina; Montagnani, Monica; De Salvia, Maria Antonietta

2016-01-01

AIM To investigate the mechanisms underlying the potential contribution of the heme oxygenase/carbon monoxide (HO/CO) pathway in the constipating effects of granisetron. METHODS For in vivo studies, gastrointestinal motility was evaluated in male rats acutely treated with granisetron [25, 50, 75 μg/kg/subcutaneous (sc)], zinc protoporphyrin IX [ZnPPIX, 50 μg/kg/intraperitoneal (ip)] and hemin (50 μmol/L/kg/ip), alone or in combination. For in vitro studies, the contractile neurogenic response to electrical field stimulation (EFS, 3, 5, 10 Hz, 14 V, 1 ms, pulse trains lasting 10 s), as well as the contractile myogenic response to acetylcholine (ACh, 0.1-100 μmol/L) were evaluated on colon specimens incubated with granisetron (3 μmol/L, 15 min), ZnPPIX (10 μmol/L, 60 min) or CO-releasing molecule-3 (CORM-3, 100, 200, 400 μmol/L) alone or in combination. These experiments were performed under co-treatment with or without atropine (3 μmol/L, a muscarinic receptor antagonist) or NG-nitro-L-Arginine (L-NNA, 100 μmol/L, a nitric oxide synthase inhibitor). RESULTS Administration of granisetron (50, 75 μg/kg) in vivo significantly increased the time to first defecation (P = 0.045 vs vehicle-treated rats), clearly suggesting a constipating effect of this drug. Although administration of ZnPPIX or hemin alone had no effect on this gastrointestinal motility parameter, ZnPPIX co-administered with granisetron abolished the granisetron-induced constipation. On the other hand, co-administration of hemin and granisetron did not modify the increased constipation observed under granisetron alone. When administered in vitro, granisetron alone (3 μmol/L) did not significantly modify the colon’s contractile response to either EFS or ACh. Incubation with ZnPPIX alone (10 μmol/L) significantly reduced the colon’s contractile response to EFS (P = 0.016) but had no effect on contractile response to ACh. Co-administration of ZnPPIX and atropine (3 μmol/L) abolished the Zn

Codeine

MedlinePlus

... with other medications, to reduce coughing. Codeine will help relieve symptoms but will not treat the cause ... granisetron (Kytril), ondansetron (Zofran, Zuplenz), or palonosetron (Aloxi); selective serotonin-reuptake inhibitors such as citalopram (Celexa), escitalopram ( ...

Comparison the Effect of Granisetron and Dexamethasone on Intravenous Propofol Pain.

PubMed

Adinehmehr, Leili; Salimi, Sohrab; Sane, Shahryar; Sina, Venous; Najafizadeh, Rana

2018-01-01

The incidence of propofol injection pain during induction of general anesthesia varies from 28% to 90%. This prospective, randomized, double-blind, placebo-controlled study evaluated the effect of dexamethasone and granisetron for reducing the incidence and severity of propofol injection pain. A total of 227 female subjects received 5 mL of preservative-free saline, 1 mg granisetron (5 ml), or 0.15 mg/kg of dexamethasone (5 ml), intravenously, following exsanguination and occlusion of the veins of the arm. This was followed by a 0.5 mg/kg injection of propofol. Pain scores and intensity of pain recorded immediately following the injection of propofol. Hemodynamic parameters and O 2 sat were recorded 1, 3, 5, and 10 min after propofol injection. The incidence pain following the injection of propofol was significantly decreased with both granisetron and dexamethasone (50.7% and 49.4%). Mean pain score in granisetron group was 3.16 ± 1.23, dexamethasone was 2.73 ± 1.03, and in saline group was 4.82 ± 1.73 ( P = 0.001). Mean pain intensity in granisetron group was 1.16 ± 0.18, dexamethasone was 1.26 ± 0.14, and in saline group was 2.2 ± 0.99 ( P = 0.001). There were no differences in either mean arterial pressure or O 2 Sate at any time point after drugs injection among the groups. There was a significant difference in pulse rate in third minutes between three groups and in the group who received granisetron was lesser ( P = 0.04). Pretreatment with intravenous granisetron (1 mg) and dexamethasone (0.15 mg/kg) before injection of propofol is effective and safe in reducing the incidence and severity of pain due to propofol injection.

Comparison the Effect of Granisetron and Dexamethasone on Intravenous Propofol Pain

PubMed Central

Adinehmehr, Leili; Salimi, Sohrab; Sane, Shahryar; Sina, Venous; Najafizadeh, Rana

2018-01-01

Background: The incidence of propofol injection pain during induction of general anesthesia varies from 28% to 90%. This prospective, randomized, double-blind, placebo-controlled study evaluated the effect of dexamethasone and granisetron for reducing the incidence and severity of propofol injection pain. Materials and Methods: A total of 227 female subjects received 5 mL of preservative-free saline, 1 mg granisetron (5 ml), or 0.15 mg/kg of dexamethasone (5 ml), intravenously, following exsanguination and occlusion of the veins of the arm. This was followed by a 0.5 mg/kg injection of propofol. Pain scores and intensity of pain recorded immediately following the injection of propofol. Hemodynamic parameters and O2 sat were recorded 1, 3, 5, and 10 min after propofol injection. Results: The incidence pain following the injection of propofol was significantly decreased with both granisetron and dexamethasone (50.7% and 49.4%). Mean pain score in granisetron group was 3.16 ± 1.23, dexamethasone was 2.73 ± 1.03, and in saline group was 4.82 ± 1.73 (P = 0.001). Mean pain intensity in granisetron group was 1.16 ± 0.18, dexamethasone was 1.26 ± 0.14, and in saline group was 2.2 ± 0.99 (P = 0.001). There were no differences in either mean arterial pressure or O2 Sate at any time point after drugs injection among the groups. There was a significant difference in pulse rate in third minutes between three groups and in the group who received granisetron was lesser (P = 0.04). Conclusion: Pretreatment with intravenous granisetron (1 mg) and dexamethasone (0.15 mg/kg) before injection of propofol is effective and safe in reducing the incidence and severity of pain due to propofol injection. PMID:29862223

Transdermal granisetron: a guide to its use in preventing nausea and vomiting induced by chemotherapy.

PubMed

Keating, Gillian M; Duggan, Sean T; Curran, Monique P

2012-09-01

Transdermal granisetron (Sancuso®) is effective in the prevention of nausea and vomiting in patients with cancer who are receiving moderately or highly emetogenic chemotherapy for 3-5 days. Transdermal granisetron is noninferior to oral granisetron in this indication, and is generally well tolerated in this indication. Thus, transdermal granisetron provides a convenient option for the prevention of chemotherapy-induced nausea and vomiting, with the potential to improve patient compliance.

[Effects of granisetron/lidocaine combination on propofol injection-induced pain: a double-blind randomized clinical trial].

PubMed

Ma, Yu-shan; Lin, Xue-mei; Zhou, Jun

2009-05-01

To investigate the alleviation effect of vein pretreatment and granisetron/lidocaine combination on propofol injection-induced pain. Two hundreds patients scheduled for gynaecological laparoscopic operations were randomly divided into four groups: control group (group I), lidocaine group (group II), granisetron group (group III) and granisetron/lidocaine combination group (group IV), with 50 patients in each group. The patients in the above four groups received placebo (saline), lidocaine 20 mg, granisetron 2 mg and granisetron 2 mg plus lidocaine intravenously respectively. The patients were injected with one-forth of scheduled propofol via a dorsal hand vein after one minute of venous occlusion. The pain during the injection of propofol was evaluated. Pain occurred in 84% of patients in the control group, 46% in the lidocaine group, 52% in the granisetron group and 24% in the granisetron/lidocaine combination group. There was a significant reduction in pain incidence in the three experimental groups compared with the control group (P<0.05). The incidence of pain, nausea, vomiting and shivering was less in the granisetron/lidocaine combination group than in the control group (P<0.05). Pretreatment with granisetron/lidocaine may be effective not only in attenuating pains during i.v. injection of propofol, but also in preventing postoperative nausea, vomiting and shivering.

Comparison of antiemetic effects of granisetron and palonosetron in patients receiving bendamustine-based chemotherapy.

PubMed

Uchida, M; Nakamura, T; Makihara, Y; Suetsugu, K; Ikesue, H; Mori, Y; Kato, K; Shiratsuchi, M; Hosohata, K; Miyamoto, T; Akashi, K

2018-05-01

The antiemetic effects and safety of granisetron and palonosetron against chemotherapy-induced nausea and vomiting (CINV) were retrospectively evaluated in patients with non-Hodgkin lymphoma receiving bendamustine-based chemotherapy. A total of 61 patients were eligible for this study. Before starting the bendamustine-based chemotherapy, granisetron or palonosetron were intravenously administered with or without aprepitant and/or dexamethasone. The proportions of patients with complete control (CC) during the overall (during the 6 days after the start of the chemotherapy), acute (up to 2 days), and delayed (3 to 6 days) phases were assessed. CC was defined as complete response with only grade 0-1 nausea, no vomiting, and no use of antiemetic rescue medication. Granisetron or palonosetron alone were administered to 9 and 19 patients, respectively. Aprepitant and/or dexamethasone were combined with granisetron and palonosetron in 28 and 5 patients, respectively. Acute CINV was completely controlled in all patients. Both granisetron monotherapy and palonosetron combination therapy could provide good control of delayed CINV, although the CC rates during the delayed and overall phases were not significantly different among mono- and combination therapy of the antiemetics. There was no significant difference in the frequencies of adverse drug events between the granisetron and palonosetron treatment groups. The present study showed that the antiemetic efficacy and safety of granisetron-based therapy were non-inferior to those of palonosetron-based therapy. Taken together with treatment costs, granisetron monotherapy would be adequate to prevent CINV in patients with non-Hodgkin lymphoma receiving bendamustine-based chemotherapy.

Off-Label Use of Ondansetron in Pregnancy in Western Australia

PubMed Central

Colvin, Lyn; Gill, Andrew W.; Slack-Smith, Linda; Stanley, Fiona J.; Bower, Carol

2013-01-01

Aims. Nausea and vomiting of pregnancy is the most common medical condition in pregnancy. There is an increasing trend to prescribe ondansetron although its safety for use in pregnancy has not been established. Methods. Exposed pregnancies were all births in Western Australia, 2002–2005, where the mother was dispensed ondansetron under the Australian Pharmaceutical Benefits Scheme, compared with all other births during the same period. Outcomes investigated include maternal and child characteristics, birth defects, pregnancy, and delivery characteristics. Results. There were 96,968 births from 2002 to 2005. Ondansetron was dispensed to 251 pregnant women during this period. The women dispensed ondansetron were more likely to be privately insured (OR: 5.8; 95% CI: 4.3–7.9), to be Caucasian (3.3; 1.9–5.7), not to smoke during their pregnancy (2.9; 1.8–4.7), to have a multiple birth (2.7; 1.5–5.0), and to have used fertility treatment (1.8; 1.0–3.4). There was a small but not significantly increased risk of a major birth defect with first trimester exposure (1.2; 0.6–2.2). Conclusions. Our study did not detect any adverse outcomes from the use of ondansetron in pregnancy but could not conclude that ondansetron is safe to use in pregnancy. PMID:24396830

Pharmacokinetics and repolarization effects of intravenous and transdermal granisetron.

PubMed

Mason, Jay W; Selness, Daniel S; Moon, Thomas E; O'Mahony, Bridget; Donachie, Peter; Howell, Julian

2012-05-15

The need for greater clarity about the effects of 5-HT(3) receptor antagonists on cardiac repolarization is apparent in the changing product labeling across this therapeutic class. This study assessed the repolarization effects of granisetron, a 5-HT(3) receptor antagonist antiemetic, administered intravenously and by a granisetron transdermal system (GTDS). In a parallel four-arm study, healthy subjects were randomized to receive intravenous granisetron, GTDS, placebo, or oral moxifloxacin (active control). The primary endpoint was difference in change from baseline in mean Fridericia-corrected QT interval (QTcF) between GTDS and placebo (ddQTcF) on days 3 and 5. A total of 240 subjects were enrolled, 60 in each group. Adequate sensitivity for detection of QTc change was shown by a 5.75 ms lower bound of the 90% confidence interval (CI) for moxifloxacin versus placebo at 2 hours postdose on day 3. Day 3 ddQTcF values varied between 0.2 and 1.9 ms for GTDS (maximum upper bound of 90% CI, 6.88 ms), between -1.2 and 1.6 ms for i.v. granisetron (maximum upper bound of 90% CI, 5.86 ms), and between -3.4 and 4.7 ms for moxifloxacin (maximum upper bound of 90% CI, 13.45 ms). Day 5 findings were similar. Pharmacokinetic-ddQTcF modeling showed a minimally positive slope of 0.157 ms/(ng/mL), but a very low correlation (r = 0.090). GTDS was not associated with statistically or clinically significant effects on QTcF or other electrocardiographic variables. This study provides useful clarification on the effect of granisetron delivered by GTDS on cardiac repolarization. ©2012 AACR.

Pharmacodynamics of transdermal granisetron in women with nausea and vomiting of pregnancy.

PubMed

Caritis, Steve; Zhao, Yang; Chen, Hui-Jun; Venkataramanan, Raman

2016-07-01

Limited options exist for women with nausea and vomiting of pregnancy (NVP) who cannot tolerate oral intake. Transdermal delivery of granisetron, a 5-hydroxytryptamine-3 receptor antagonist, provides an effective alternative for such patients. The objective of this study was to evaluate the pharmacodynamics of granisetron administered intravenously (IV) and as a sustained release transdermal patch in women with NVP. We recruited 16 women with singleton gestation between 12 0/7-18 6/7 weeks who were receiving treatment for NVP and had a Pregnancy Unique Quantification of Emesis and Nausea (PUQE) score of ≥6. All consenting subjects received 1 mg of granisetron as an IV infusion over 5 minutes and blood was obtained prior to the infusion and at 10, 20, 30, and 60 minutes and at 2, 4, 6, 8, 12, and 24 hours after the start of the infusion. After a minimum washout of 48 hours after initiation of IV granisetron, a 52-cm(2) granisetron patch (34.3 mg) was placed on the upper arm of all subjects for 7 days. Blood was drawn prior to patch placement and daily thereafter for 9 days. The subjects were evaluated daily. The PUQE score was obtained from these subjects prior to the IV infusion and daily for 2 days after and again prior to and daily for 9 days after patch placement. Complete data were available in 15 women after IV administration and 13 women after patch placement. One woman stopped participation during the IV infusion while data were not available in 2 additional women after patch placement due to noncompliance. Peak plasma granisetron concentrations after IV and transdermal administration were similar (∼10 ng/mL). Prior to IV administration of granisetron, the PUQE score was 8.6 ± 1.8 (mean ± SD). The PUQE scores were significantly reduced for the ensuing 2 days (P < .01). The PUQE score prior to patch placement was 7.6 ± 2.4. Scores were significantly (P < .001) reduced within 1 day of patch placement and stayed significantly reduced during the ensuing 6

Ondansetron or droperidol for prophylaxis of nausea and vomiting after intrathecal morphine.

PubMed

Peixoto, A J; Celich, M F; Zardo, L; Peixoto Filho, A J

2006-08-01

There is a controversy regarding the best drug for prevention of nausea and vomiting in patients receiving intrathecal morphine. The aim of this study was to examine efficacy and tolerability of droperidol compared with ondansetron for the prevention of morphine-induced nausea and vomiting. In a randomized, placebo-controlled trial, 120 women undergoing Caesarean section under spinal anaesthesia with intrathecal morphine 0.1 mg received intravenous ondansetron 4 mg (n = 40), droperidol 1.25 mg (n = 40) or saline (n = 40) immediately after umbilical-cord clamping. Nausea and vomiting were graded according to intensity at 1, 2, 4, 6, 12 and 24 h. Nausea or vomiting occurred in 14 patients (35%) in the placebo group, 4 (10%) in the ondansetron group and 10 (25%) in the droperidol group; the difference between ondansetron and placebo was statistically significant (P = 0.007). Eleven of the 14 placebo patients (27.5%) vomited, compared with none of the 4 ondansetron patients (vs. placebo, P = 0.0004) and 5 of the droperidol patients (vs. placebo, P = 0.18). Three of the 14 placebo patients (7.5%) were nauseous, compared with 4 (10%) receiving ondansetron and 5 (12.5%) receiving droperidol. Ondansetron was effective in reducing the incidence of nausea and vomiting in patients receiving intrathecal morphine for Caesarean section.

Ondansetron Suppositories: Extemporaneous Preparation, Drug Release, Stability and Flux through Rabbit Rectal Membrane.

PubMed

Tenjarla, S N; Ward, E S; Fox, J L

1998-01-01

The objective of this study was to determine the feasibility and develop a formulation for an extemporaneously prepared ondansetron suppository form Zofran 8-mg tablets. The stability of the formulation over 28 days of refrigerated storage and the initial and poststorage drug-release profiles were evaluated. The ondansetron flux in an in vitro model (a rabbit rectal membrane) from each formulation was determined. Suppositories containing 8 or 16 mg ondansetron were made using commercially available hydrophobic and hydrophilic suppository bases. A sensitive, stability-indication high-performance liquid chromatography assay was used for the analysis of ondansetron. The partition coefficient (octanol/water) of ondansetron and the displacement factor of tablets with each of the two bases were determined . The suppositories, formed in disposable molds, were kept in plastic wwrap and stored at 5 deg C in the refrigerator. The effect of storage on ondansetron release from the suppository base and the stability of ondansetron in the two suppository bases were evaluated over a period of 28 days. The dissolution study provided data on the release profile of the drug over 28 days, as well as the stabilty of the drug during the storage period. Ondansetron flux through rabbit rectal membrane from the various formulations was determined in vitro using modified Franz diffusion cells. Greater than 90% of the intiial amount (8 or 16 mg) of ondansetron was retained in the suppositories after 28-day storage at 5 deg C for both hydrophilic and hydrophobic formulations. There was no statistically siginificant difference in the drug-release profiles during this period. Ondansetron flux through the rabbit rectal membrane from 8- and 16-mg hydrophobic suppositories was 393 +/- 58 and 76.2 +/- 13.8 micrograms per centimeters squared -hour, respectively (n=6). The corresponding flux from 8- and 16-mg hydrophilic suppositories was 37.8 +/- 16 and 81.7 +/- 22.9 micrograms per centimeter

Effect of casting solvent on crystallinity of ondansetron in transdermal films.

PubMed

Pattnaik, Satyanarayan; Swain, Kalpana; Mallick, Subrata; Lin, Zhiqun

2011-03-15

The purpose of the present investigation is to assess the influence of casting solvent on crystallinity of ondansetron hydrochloride in transdermal polymeric matrix films fabricated using povidone and ethyl cellulose as matrix forming polymers. Various casting solvents like chloroform (CHL), dichloromethane (DCM), methanol (MET); and mixture of chloroform and ethanol (C-ETH) were used for fabrication of the transdermal films. Analytical tools like scanning electron microscopy (SEM), X-ray diffraction (XRD) studies, differential scanning calorimetry (DSC), etc. were utilized to characterize the crystalline state of ondansetron in the film. Recrystallisation was observed in all the transdermal films fabricated using the casting solvents other than chloroform. Long thin slab-looking, long wire-like or spherulite-looking crystals with beautiful impinged boundaries were observed in SEM. Moreover, XRD revealed no crystalline peaks of ondansetron hydrochloride in the transdermal films prepared using chloroform as casting solvent. The significantly decreased intensity and sharpness of the DSC endothermic peaks corresponding to the melting point of ondansetron in the formulation (specifically in CHL) indicated partial dissolution of ondansetron crystals in the polymeric films. The employed analytical tools suggested chloroform as a preferred casting solvent with minimum or practically absence of recrystallization indicating a relatively amorphous state of ondansetron in transdermal films. Copyright © 2011 Elsevier B.V. All rights reserved.

Granisetron plus dexamethasone for prevention of postoperative nausea and vomiting in patients undergoing laparoscopic surgery: A meta-analysis

PubMed Central

Zhu, Min; Zhou, Chengmao; Huang, Bing; Ruan, Lin; Liang, Rui

2017-01-01

Objective This study was designed to compare the effectiveness of granisetron plus dexamethasone for preventing postoperative nausea and vomiting (PONV) in patients undergoing laparoscopic surgery. Methods We searched the literature in the Cochrane Library, PubMed, EMBASE, and CNKI. Results In total, 11 randomized controlled trials were enrolled in this analysis. The meta-analysis showed that granisetron in combination with dexamethasone was significantly more effective than granisetron alone in preventing PONV in patients undergoing laparoscopy surgery. No significant differences in adverse reactions (dizziness and headache) were found in association with dexamethasone. Conclusion Granisetron in combination with dexamethasone was significantly more effective than granisetron alone in preventing PONV in patients undergoing laparoscopic surgery, with no difference in adverse reactions between the two groups. Granisetron alone or granisetron plus dexamethasone can be used to prevent PONV in patients undergoing laparoscopic surgery. PMID:28436248

Granisetron plus dexamethasone for prevention of postoperative nausea and vomiting in patients undergoing laparoscopic surgery: A meta-analysis.

PubMed

Zhu, Min; Zhou, Chengmao; Huang, Bing; Ruan, Lin; Liang, Rui

2017-06-01

Objective This study was designed to compare the effectiveness of granisetron plus dexamethasone for preventing postoperative nausea and vomiting (PONV) in patients undergoing laparoscopic surgery. Methods We searched the literature in the Cochrane Library, PubMed, EMBASE, and CNKI. Results In total, 11 randomized controlled trials were enrolled in this analysis. The meta-analysis showed that granisetron in combination with dexamethasone was significantly more effective than granisetron alone in preventing PONV in patients undergoing laparoscopy surgery. No significant differences in adverse reactions (dizziness and headache) were found in association with dexamethasone. Conclusion Granisetron in combination with dexamethasone was significantly more effective than granisetron alone in preventing PONV in patients undergoing laparoscopic surgery, with no difference in adverse reactions between the two groups. Granisetron alone or granisetron plus dexamethasone can be used to prevent PONV in patients undergoing laparoscopic surgery.

Ondansetron can enhance cisplatin-induced nephrotoxicity via inhibition of multiple toxin and extrusion proteins (MATEs)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Qing; Institute of Clinical Pharmacology, Central South University, Hunan 410078; Guo, Dong

2013-11-15

The nephrotoxicity limits the clinical application of cisplatin. Human organic cation transporter 2 (OCT2) and multidrug and toxin extrusion proteins (MATEs) work in concert in the elimination of cationic drugs such as cisplatin from the kidney. We hypothesized that co-administration of ondansetron would have an effect on cisplatin nephrotoxicity by altering the function of cisplatin transporters. The inhibitory potencies of ondansetron on metformin accumulation mediated by OCT2 and MATEs were determined in the stable HEK-293 cells expressing these transporters. The effects of ondansetron on drug disposition in vivo were examined by conducting the pharmacokinetics of metformin, a classical substrate formore » OCTs and MATEs, in wild-type and Mate1−/− mice. The nephrotoxicity was assessed in the wild-type and Mate1−/− mice received cisplatin with and without ondansetron. Both MATEs, including human MATE1, human MATE2-K, and mouse Mate1, and OCT2 (human and mouse) were subject to ondansetron inhibition, with much greater potencies by ondansetron on MATEs. Ondansetron significantly increased tissue accumulation and pharmacokinetic exposure of metformin in wild-type but not in Mate1−/− mice. Moreover, ondansetron treatment significantly enhanced renal accumulation of cisplatin and cisplatin-induced nephrotoxicity which were indicated by increased levels of biochemical and molecular biomarkers and more severe pathohistological changes in mice. Similar increases in nephrotoxicity were caused by genetic deficiency of MATE function in mice. Therefore, the potent inhibition of MATEs by ondansetron enhances the nephrotoxicity associated with cisplatin treatment in mice. Potential nephrotoxic effects of combining the chemotherapeutic cisplatin and the antiemetic 5-hydroxytryptamine-3 (5-HT{sub 3}) receptor antagonists, such as ondansetron, should be investigated in patients. - Highlights: • Nephrotoxicity significantly limits clinical use of the

Enhanced tolerability of the 5-hydroxytryptophane challenge test combined with granisetron.

PubMed

Jacobs, G E; Kamerling, I M C; de Kam, M L; Derijk, R H; van Pelt, J; Zitman, F G; van Gerven, J M A

2010-01-01

A recently developed oral serotonergic challenge test consisting of 5-Hydroxytryptophane (5-HTP, 200 mg) combined with carbidopa (CBD, 100 mg + 50 mg) exhibited dose-related neuroendocrine responsiveness and predictable pharmacokinetics. However, its applicability is limited by nausea and vomiting. A randomized, double-blind, placebo-controlled, four-way crossover trial was performed in 12 healthy male volunteers. The 5-HTP/CBD-challenge was combined with two oral anti-emetics (granisetron, 2 mg or domperidone, 10 mg) to investigate its reliability when side-effects are suppressed. The neuroendocrine response (serum cortisol and prolactin), the side-effect profile [Visual Analogue Scale Nausea (VAS)] and vomiting subjects per treatment were the main outcome measures. Compared to 5-HTP/CBD/placebo, 5-HTP/CBD/ granisetron had no impact on cortisol [% change with 95% confidence interval: -7.1% (18.9; 6.5)] or prolactin levels [-9.6% (-25.1; 9.1)]; 5-HTP/CBD/domperidone increased cortisol [+13.0% (-4.2; 33.4)], and increased prolactin extensively [+336.8% (245.7; 451.9)]. Compared to placebo, VAS Nausea increased non-significantly with granisetron [+7.6 mm (-1.3; 16.5)], as opposed to domperidone [+16.2 mm (7.2; 25.2)] and 5-HTP/CBD/placebo [+14.7 mm (5.5; 23.8)]. No subjects vomited with granisetron, compared to two subjects treated with 5-HTP/CBD/placebo and five subjects with domperidone. Compared with 5-HTP/CBD/placebo, granisetron addition decreased C(max) of 5-HTP statistically significantly different (from 1483 to 1272 ng/ml) without influencing AUC(0- infinity). Addition of granisetron to the combined 5-HTP/CBD challenge suppresses nausea and vomiting without influencing the neuroendocrine response or pharmacokinetics, enhancing its clinical applicability in future psychiatric research and drug development.

Ramosetron compared with granisetron for the prevention of vomiting following strabismus surgery in children

PubMed Central

Fujii, Y.; Tanaka, H.; Ito, M.

2001-01-01

BACKGROUND/AIMS—Postoperative vomiting occurs frequently after strabismus surgery in children. Granisetron, a selective 5-hydroxytryptamine type 3 receptor antagonist, is effective for the prevention of vomiting following paediatric strabismus surgery. Ramosetron, another new antagonist of 5-hydroxytryptamine type 3 receptor, has more potent and longer acting properties than granisetron against cisplatin induced emesis. This study was undertaken to compare the efficacy and safety of granisetron and ramosetron for the prevention of vomiting following strabismus surgery in children.
METHODS—In a randomised, double blinded manner 80 children, aged 4-10 years, received intravenously granisetron 40 µg/kg or ramosetron 6 µg/kg (n=40 each) at the end of surgery. A standard general anaesthetic technique and postoperative analgesia were used. Emetic episodes and safety assessment were performed during the first 24 hours and the next 24 hours after anaesthesia.
RESULTS—The percentage of patients who were emesis free during 0-24 hours after anaesthesia was 85% with granisetron and 90% with ramosetron, respectively (p = 0.369); the corresponding rate during 24-48 hours after anaesthesia was 70% and 95% (p = 0.003). No clinically serious adverse events caused by the study drug were observed in any of the groups.
CONCLUSION—Prophylactic antiemetic therapy with ramosetron is comparable with granisetron for the prevention of vomiting during 0-24 hours after anaesthesia in children undergoing strabismus surgery. During 24-48 hours after anaesthesia, ramosetron is more effective than granisetron for prophylaxis against postoperative vomiting.

 PMID:11371485

Granisetron in the treatment of chemotherapy-induced nausea and vomiting (CINV) - is there still a role after comparison with palonosetron?

PubMed

Doggrell, Sheila A

2017-07-01

Chemotherapy-induced nausea and vomiting (CINV) has a negative impact on the lives of subjects receiving chemotherapy. In 2009, the second generation 5-HT 3 -receptor antagonist, palonosetron, which is longer-acting than granisetron, was shown, as part of dual therapy with dexamethasone, to be superior to intravenous granisetron in the delayed phase of CINV. Area covered: In an attempt to maintain plasma levels of granisetron during the delayed phase of CINV, longer-acting preparations of granisetron have been manufactured. In addition to comparing intravenous/oral granisetron with palonosetron, this review considers the new longer-acting preparations of granisetron (transdermal and subcutanous) with emphasis on whether they are effective in the delayed phase of CINV. Expert opinion: Comparison of intravenous/oral granisetron and palonosetron, as part of triple therapy against the delayed phase of CINV, do not give clear-cut results as to non-inferiority or superiority of either agent. Subcutaneous granisetron is more convenient to use than transdermal granisetron, and has been shown to be non-inferior to palonosetron, as part of dual therapy, in the treatment of the acute and delayed phases of CINV. At present, it seems likely that there will be ongoing roles for intravenous and subcutaneous granisetron in CINV, but further data is required to ascertain the future of transdermal granisetron.

A single-blind study of the efficacy and safety of intravenous granisetron compared with alizapride plus dexamethasone in the prophylaxis and control of emesis in patients receiving 5-day cytostatic therapy. The Granisetron Study Group.

PubMed

Bremer, K

1992-01-01

200 cancer patients who were due to receive fractionated chemotherapy (cisplatin greater than or equal to 15, ifosfamide greater than or equal to 1.2 or etoposide greater than or equal to 120, all mg/m2 per day) for 5 days, entered a multicentre study. Patients were randomised single-blind to receive either prophylactic intravenous granisetron (40 micrograms/kg) or alizapride (4 mg/kg followed by 4 mg/kg at 4 and 8 h post-treatment) plus dexamethasone 8 mg. Granistron was superior to the combination in preventing nausea and vomiting (54% vs. 43% complete responders). The differences were in the cisplatin-treated group. The time to first episode of moderate to severe nausea was significantly longer in the granisetron group (P = 0.03). Dosing with granisetron was more simple, with over 85% of patients requiring only a single prophylactic dose. Fewer patients receiving granisetron experienced adverse events (48% vs. 62%, P = 0.047). The frequency of constipation was, as expected, significantly higher in the granisetron group. Extrapyramidal effects, which were not noted by any granisetron patient, occurred in 5.3% of comparator patients.

Provesicular granisetron hydrochloride buccal formulations: in vitro evaluation and preliminary investigation of in vivo performance.

PubMed

Ahmed, Sami; El-Setouhy, Doaa Ahmed; El-Latif Badawi, Alia Abd; El-Nabarawi, Mohamed Ahmed

2014-08-18

Granisetron hydrochloride (granisetron) is a potent antiemetic that has been proven to be effective in acute and delayed emesis in cancer chemotherapy. Granisetron suffers from reduced oral bioavailability (≈60%) due to hepatic metabolism. In this study the combined advantage of provesicular carriers and buccal drug delivery has been explored aiming to sustain effect and improve bioavailability of granisetron via development of granisetron provesicular buccoadhesive tablets with suitable quality characteristics (hardness, drug content, in vitro release pattern, exvivo bioadhesion and in vivo bioadhesion behavior). Composition of the reconstituted niosomes from different prepared provesicular carriers regarding type of surfactant used and cholesterol concentration significantly affected both entrapment efficiency (%EE) and vesicle size. Span 80 proniosome-derived niosomes exhibited higher encapsulation efficiency and smaller particle size than those derived from span 20. Also, the effect of %EE and bioadhesive polymer type on in vitro drug release and in vivo performance of buccoadhesive tablets was investigated. Based on achievement of required in vitro release pattern (20-30% at 2h, 40-65% at 6h and 80-95% at 12h), in vivo swelling behavior, and in vivo adhesion time (>14 h) granisetron formulation (F19, 1.4 mg) comprising HPMC:carbopol 974P (7:3) and maltodextrin coated with the vesicular precursors span 80 and cholesterol (9:1) was chosen for in vivo study. In vivo pharmacokinetic study revealed higher bioavailability of buccal formulation relative to conventional oral formulation of granisetron (AUC0-∞ is 89.97 and 38.18 ng h/ml for buccal and oral formulation, respectively). A significantly lower and delayed Cmax (12.09±4.47 ng/ml, at 8h) was observed after buccal application compared to conventional oral tablet (31.66±10.15 ng/ml, at 0.5 h). The prepared provesicular buccoadhesive tablet of granisetron (F19) might help bypass hepatic first

Involvement of nitric oxide in granisetron improving effect on scopolamine-induced memory impairment in mice.

PubMed

Javadi-Paydar, Mehrak; Zakeri, Marjan; Norouzi, Abbas; Rastegar, Hossein; Mirazi, Naser; Dehpour, Ahmad Reza

2012-01-06

Granisetron, a serotonin 5-HT(3) receptor antagonist, widely used as an antiemetic drug following chemotherapy, has been found to improve learning and memory. In this study, effects of granisetron on spatial recognition memory and fear memory and the involvement of nitric oxide (NO) have been determined in a Y-maze and passive avoidance test. Granisetron (3, 10mg/kg, intraperitoneally) was administered to scopolamine-induced memory-impaired mice prior to acquisition, consolidation and retrieval phases, either in the presence or in the absence of a non-specific NO synthase inhibitor, l-NAME (3, 10mg/kg, intraperitoneally); a specific inducible NO synthase (iNOS) inhibitor, aminoguanidine (100mg/kg); and a NO precursor, l-arginine (750 mg/kg). It is demonstrated that granisetron improved memory acquisition in a dose-dependent manner, but it was ineffective on consolidation and retrieval phases of memory. The beneficial effect of granisetron (10mg/kg) on memory acquisition was significantly reversed by l-NAME (10mg/kg) and aminoguanidine (100mg/kg); however, l-arginine (750 mg/kg) did not potentiate the effect of sub-effective dose of granisetron (3mg/kg) in memory acquisition phase. It is concluded that nitric oxide is probably involved in improvement of memory acquisition by granisetron in both spatial recognition memory and fear memory. This article is part of a Special Issue entitled The Cognitive Neuroscience. Copyright © 2011 Elsevier B.V. All rights reserved.

Granistron and dexamethasone provide more improved prevention of postoperative emesis than granisetron alone in children.

PubMed

Fujii, Y; Tanaka, H; Toyooka, H

1996-12-01

Dexamethasone decreases chemotherapy-induced emesis when added to antiemetic regimens. This study was designed to compare the effectiveness of granisetron and dexamethasone with granisetron alone in the prevention of post-operative vomiting after strabismus repair, tonsillectomy with or without adenoidectomy in children. In a randomized, double-blind study, 60 healthy children, 4-10 yr of age, received either granisetron 40 micrograms.kg-1 and saline (Group S) or granisetron 40 micrograms.kg-1 and dexamethasone 4 mg (Group D) iv immediately after the induction of anaesthesia. All subjects received anaesthetics consisting of sevoflurane and nitrous oxide in oxygen Postoperative pain was treated with acetaminophen pr or pentazocine iv. Postoperatively, during the first 24 hr after anaesthesia, the frequencies of retching and vomiting, and the incidence of adverse events were recorded by nursing staff. There were no differences between the treatment groups with regard to demographics, surgical procedure, anaesthetic administered or analgesics used for postoperative pain. The frequency of the symptoms was 27% and 7% in Groups S and D, respectively (P < 0.05). The incidence of adverse events was comparable in the two groups. The prophylactic administration of granisetron and dexamethasone was more effective than granisetron alone in the prevention of postoperative vomiting in paediatric subjects undergoing strabismus repair, tonsillectomy and adenoidectomy.

Granisetron and carvedilol can protect experimental rats againstadjuvant-induced arthritis.

PubMed

Ahmed, Yasmin Moustafa; Messiha, Basim Anwar Shehata; Abo-Saif, Ali Ahmed

2017-04-01

Rheumatoid arthritis (RA), a disabling autoimmune disorder of the joints as well as other organs, affects about 1% of population. Unfortunately, all current treatments of RA cause severe gastrointestinal, renal and other complications. We aimed to evaluate the possible antiarthritic effects of a serotonin 5-HT 3 receptor blocker, granisetron, and a nonselective adrenergic receptor blocker, carvedilol, on complete Freund's adjuvant-induced RA in adult female albino rats. Rats were allocated into a normal control group, an arthritis control group, two reference treatment groups receiving dexamethasone (1.5 mg/kg/day) and methotrexate (1 mg/kg/day), and two treatment groups receiving granisetron (2.5 mg/kg/day) and carvedilol (10 mg/kg/day). Serum-specific rheumatoid, immunological, inflammatory and oxidative stress biomarkers were assessed. A confirmatory histopathological study on joints and spleens was performed. Granisetron administration significantly improved all the measured biomarkers, with the values of rheumatoid factor, matrix metalloproteinase-3, cartilage oligomeric matrix protein, immunoglobulin G, antinuclear antibody and myeloperoxidase being restored back to normal levels. Carvedilol administration significantly improved all biomarkers, with serum MPO value restored back to normal levels. Serotonin 5-HT 3 receptor blockers and adrenergic receptor blockers, represented by granisetron and carvedilol, may represent new promising protective strategies against RA, at least owing to immune-modulator, anti-inflammatory and antioxidant potentials.

Ondansetron: design and development of oral pharmaceutical suspensions.

PubMed

Gallardo Lara, V; Gallardo, M Lopez-Viota; Morales Hernandez, Ma E; Ruiz Martinez, Ma A

2009-02-01

Ondansetron is a carbazol with antiemetic properties that acts as a competitive and selective antagonist for the 5 HT3 serotonin receptors. It is used primarily to control nausea and vomiting caused by cytotoxic chemotherapy and radiotherapy, as well as in postoperative vomiting in gynecological surgery. The main aim of this work was to obtain a stable, long-acting oral suspension of ondansetron. To prolong the action, latexes are used as transport vehicles, specifically we tested, Aquateric, which comprises mainly cellulose acetophthalate. We prepared a complex drug-polymer, and the release profile of ondansetron was evaluated at acid, basic and acid-basic pH. This complex is additioned to a vehicle with xanthan gum and sodium carboxymethylcellulose (CMCNa) as thickeners to retard as much as possible particle sedimentation and thus increase physical stability of the suspension. The results obtained for sediment volume and degree of flocculation suggest that xanthan gum provides the best results, with better organolepticcharacteristics, appearance, physical stability and easy redispersability.

Premedication with granisetron reduces shivering during spinal anaesthesia in children.

PubMed

Eldaba, Ahmed A; Amr, Yasser M

2012-01-01

This study evaluates the effect of prophylactic granisetron on the incidence of postoperative shivering after spinal anaesthesia in children. Eighty children, American Society of Anesthesiologists physical status I to II and aged two to five years were scheduled for surgery of the lower limb under spinal anaesthesia. The children were randomised to receive 10 µg/kg granisetron diluted in 10 ml saline 0.9% intravenously (group 1, n=40) or placebo (10 ml 0.9% saline, group 2, n=40) to be given over five minutes just before spinal puncture. Shivering, core temperature and the levels of motor and sensory block were assessed. No patients shivered in group 1. However, six patients shivered in Group 2 (P=0.025). There were no significant differences in the other measured variables between the groups. Granisetron is an effective agent to prevent shivering after spinal anaesthesia in children from two to five years of age.

Ondansetron Can Enhance Cisplatin-Induced Nephrotoxicity via Inhibition of Multiple Toxin and Extrusion Proteins (MATEs)

PubMed Central

Li, Qing; Guo, Dong; Dong, Zhongqi; Zhang, Wei; Zhang, Lei K.; Huang, Shiew-Mei; Polli, James E.; Shu, Yan

2013-01-01

The nephrotoxicity limits the clinical application of cisplatin. Human organic cation transporter 2 (OCT2) and multidrug and toxin extrusion proteins (MATEs) work in concert in the elimination of cationic drugs such as cisplatin from the kidney. We hypothesized that co-administration of ondansetron would have an effect on cisplatin nephrotoxicity by altering the function of cisplatin transporters. The inhibitory potencies of ondansetron on metformin accumulation mediated by OCT2 and MATEs were determined in the stable HEK-293 cells expressing these transporters. The effects of ondansetron on drug disposition in vivo were examined by conducting the pharmacokinetics of metformin, a classical substrate for OCTs and MATEs, in wild-type and Mate1−/− mice. The nephrotoxicity was assessed in the wild-type and Mate1−/− mice received cisplatin with and without ondansetron. Both MATEs, including human MATE1, human MATE2-K, and mouse Mate1, and OCT2 (human and mouse) were subject to ondansetron inhibition, with much greater potencies by ondansetron on MATEs. Ondansetron significantly increased tissue accumulation and pharmacokinetic exposure of metformin in wild-type but not in Mate1−/− mice. Moreover, ondansetron treatment significantly enhanced renal accumulation of cisplatin and cisplatin-induced nephrotoxicity which were indicated by increased levels of biochemical and molecular biomarkers and more severe pathohistological changes in mice. Similar increases in nephrotoxicity were caused by genetic deficiency of MATE function in mice. Therefore, the potent inhibition of MATEs by ondansetron enhances the nephrotoxicity associated with cisplatin treatment in mice. Potential nephrotoxic effects of combining the chemotherapeutic cisplatin and the antiemetic 5-hydroxytryptamine-3 (5-HT3) receptor antagonists, such as ondansetron, should be investigated in patients. PMID:24001450

Dose finding study of granisetron in patients receiving high-dose cisplatin chemotherapy. The Granisetron Study Group.

PubMed Central

Riviere, A.

1994-01-01

The efficacy and safety of three different doses of granisetron (2 micrograms kg-1, group A; 10 micrograms kg-1, group B; 40 micrograms kg-1, group C) were compared in a randomised, double-blind study of 157 patients due to receive high-dose cisplatin therapy (mean dose > 97 mg m-2). In each group, up to two 3 mg rescue doses of granisetron were allowed if more than mild nausea or vomiting occurred. In group A 30.8%, in group B 61.5% and in group C 67.9% of patients were complete responders (i.e. no vomiting or nothing worse than mild nausea) during the first 24 h. These differences are significant between groups A and B, and A and C. There were no statistically significant differences in any efficacy variable between the 10 micrograms kg-1 and 40 micrograms kg-1 groups, although in each case the trend favoured the higher dose. Additional rescue doses resulted in resolved or improved symptoms in 95.3% for the first rescue dose and 93.3% for the second. Over the 7 days of the study, 82.7%, 82.7% and 86.8% of patients in groups A, B and C respectively were treated with granisetron alone. Headache was the most common side-effect, reported by 9.6% of patients; the majority of headaches were mild. There was no difference between the treatment groups regarding the adverse event rate. We concluded that prophylactic doses of 10 or 40 micrograms kg-1 lead to a safe and satisfactory degree of control of nausea and vomiting induced by high-dose cisplatin. PMID:8180032

Pharmacokinetics of a granisetron transdermal system for the treatment of chemotherapy-induced nausea and vomiting.

PubMed

Howell, Julian; Smeets, Jean; Drenth, Henk-Jan; Gill, David

2009-12-01

To determine the pharmacokinetic (PK) profile of granisetron transdermal formulation and examine its possible relationship with age, gender, and renal function. This article describes a Phase I PK study and a post hoc pooled population PK analysis. The Phase I study was a randomized, cross-over study that assessed PK parameters of three granisetron patch sizes and oral granisetron. The pooled population PK analysis included data from three trials in healthy subjects (n = 48) and from Phase II and III studies in patients with cancer (n = 793). The population PK model was used to investigate granisetron exposure and its possible relationship with age, gender, and renal function. Following oral dosing, plasma granisetron concentration was quantifiable at 1 h, and maximal mean concentration (4.7 ng/mL) was reached 2 h after administration. With transdermal application, maximal concentration was reached 48 h post-application; t(1/2) was 36 h. With oral dosing, overall exposure after 5 days was 306 ng/mL.h, and C(avg) 2.6 ng/mL. This corresponded to an AUC(0-infinity) for the 52 cm(2) patch of 420 ng/mL.h and C(avg) 2.2 ng/mL over 6 days. Clearance was not affected by age, gender, weight, or renal function. The 52 cm( 2) granisetron patch achieves a similar exposure to that of a 2 mg oral dose and provides continuous delivery of granisetron over 6 days. The patch may have utility in treating chemotherapy-induced nausea and vomiting where prolonged drug delivery is advantageous. No dose adjustments would be needed based on age or renal function.

Prophylactic antiemetic effects of Midazolam, Ondansetron, and their combination after middle ear surgery.

PubMed

Honarmand, Azim; Safavi, Mohammadreza; Chegeni, Mansoureh; Hirmanpour, Anahita; Nazem, Masoud; Sarizdi, Seyyad Hamid

2016-01-01

The purpose of the present study was to evaluate the efficacy of midazolam-ondansetron combination in prevention of postoperative nausea and vomiting (PONV) after middle ear surgery and its comparison with using midazolam or ondansetron alone. One hundred and forty patients were enrolled in four groups to receive midazolam 0.75 mg/kg in group M, ondansetron 4 mg in group O, midazolam 0.75 mg/kg and ondansetron 4 mg in group MO, and saline 0.90% in group S intravenously just before anesthesia. Assessment of nausea, vomiting, rescue antiemetic, and side effects of study drugs such as headache and dizziness was carried out postoperatively for 24 h. The incidence of PONV was significantly smaller in group MO than group M and group O, while there was no significant difference between group M and group O during the first 24 h postoperatively. Requirement to the additional antiemetic was significantly more in group S (71.4%) compared to other groups, while in group MO (11.4%) was lower than group M (31.4%) and group O (34.3%). Our study showed that prophylactic administration of midazolam 0.75 mg/kg combined with ondansetron 4 mg was more effective than using midazolam or ondansetron alone in prevention of PONV after middle ear surgery.

Does granisetron eliminate the gag reflex? A crossover, double-blind, placebo-controlled pilot study.

PubMed

Barenboim, Silvina Friedlander; Dvoyris, Vladislav; Kaufman, Eliezer

2009-01-01

Although gagging is a frequent problem that, when severe, can jeopardize the dental procedure, no single protocol is used to alleviate this phenomenon. Selective 5-HT3 antagonists, such as granisetron, may attenuate gagging. In this study, granisetron and placebo were administered intravenously, in a crossover, double-blind manner, to 25 healthy volunteers in 2 different sessions. Gagging levels were recorded before and after administration, as were BP, pulse, and O2 saturation. Recorded results were analyzed with the use of tests for nonparametric values (P = .05). A significant increase in the depth of swab insertion was noted after administration of both placebo and drug. The increase in drug effectiveness correlated with decreased body weight. The true efficacy of granisetron in gagger patients with this treatment protocol has yet to be fully established, although it has been theorized that an increased dosage of granisetron may have a better effect.

Does Granisetron Eliminate the Gag Reflex? A Crossover, Double-Blind, Placebo-Controlled Pilot Study

PubMed Central

Friedlander Barenboim, Silvina; Dvoyris, Vladislav; Kaufman, Eliezer

2009-01-01

Although gagging is a frequent problem that, when severe, can jeopardize the dental procedure, no single protocol is used to alleviate this phenomenon. Selective 5-HT3 antagonists, such as granisetron, may attenuate gagging. In this study, granisetron and placebo were administered intravenously, in a crossover, double-blind manner, to 25 healthy volunteers in 2 different sessions. Gagging levels were recorded before and after administration, as were BP, pulse, and O2 saturation. Recorded results were analyzed with the use of tests for nonparametric values (P = .05). A significant increase in the depth of swab insertion was noted after administration of both placebo and drug. The increase in drug effectiveness correlated with decreased body weight. The true efficacy of granisetron in gagger patients with this treatment protocol has yet to be fully established, although it has been theorized that an increased dosage of granisetron may have a better effect. PMID:19562886

Ondansetron in acute food protein-induced enterocolitis syndrome, a retrospective case-control study.

PubMed

Miceli Sopo, S; Bersani, G; Monaco, S; Cerchiara, G; Lee, E; Campbell, D; Mehr, S

2017-04-01

Therapy for moderate to severe acute food protein-induced enterocolitis syndrome (FPIES) typically consists of intravenous fluids and corticosteroids (traditional therapy). Ondansetron has been suggested as an adjunctive treatment. We aimed to evaluate the efficacy of the parenteral (intravenous or intramuscular) ondansetron vs traditional therapy to resolve the symptoms of acute FPIES. Cases of FPIES who had a positive oral food challenge (OFC) were retrospectively examined at two major hospitals over a two-year period (Rome, Italy; and Sydney, Australia). The efficacy of therapy, based on the percentage of cases who stopped vomiting, was compared in cases who received parenteral ondansetron and in cases who received traditional therapy or no pharmacological therapy. A total of 66 patients were included: 37 had parenteral ondansetron, 14 were treated with traditional therapy, and 15 did not receive any pharmacological therapy. Nineteen percentage of children treated with ondansetron continued vomiting after the administration of the therapy vs 93% of children who received traditional therapy (P < 0.05, relative risk = 0.2). Children who received ondansetron or no therapy were less likely to require an admission overnight compared with those who received traditional therapy (P < 0.05). Parenteral ondansetron is significantly more effective than traditional therapy in resolving acute symptoms of FPIES. The relative risk = 0.2 greatly reduces the bias linked to the lack of randomization. These findings suggest an effective treatment for vomiting in positive FPIES OFCs and allow for more confidence in performing OFCs. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Antiemetic Therapy With or Without Olanzapine in Preventing Chemotherapy-Induced Nausea and Vomiting in Patients With Cancer Receiving Highly Emetogenic Chemotherapy | Division of Cancer Prevention

Cancer.gov

This randomized phase III trial studies antiemetic therapy with olanzapine to see how well they work compared to antiemetic therapy alone in preventing chemotherapy-induced nausea and vomiting in patients with cancer receiving highly emetogenic (causes vomiting) chemotherapy. Antiemetic drugs, such as palonosetron hydrochloride, ondansetron, and granisetron hydrochloride, may

Development and evaluation of a sublingual film of the antiemetic granisetron hydrochloride.

PubMed

Kalia, Vani; Garg, Tarun; Rath, Gautam; Goyal, Amit Kumar

2016-05-01

The objective of this study was to develop an oral transmucosal formulation of an antiemetic drug that can not only serve in the active form but also provide a controlled release profile. In this study, sublingual films based on the biodegradable and water-soluble polymers, that is HPMCK-4M and PVPK-30, were developed by the solvent casting method, and were loaded with the antiemetic drug granisetron hydrochloride (granisetron HCl). The entrapment efficiency of the developed formulation was found to be 86%. The in vitro profile showed an instant release of the drug from the sublingual film, in a pattern following the first order kinetics array. The in vivo studies showed that granisetron HCl was delivered in its active state and showed effective results, as compared to its activity in the marketed formulation.

Toward biophysical probes for the 5-HT3 receptor: structure-activity relationship study of granisetron derivatives.

PubMed

Vernekar, Sanjeev Kumar V; Hallaq, Hasan Y; Clarkson, Guy; Thompson, Andrew J; Silvestri, Linda; Lummis, Sarah C R; Lochner, Martin

2010-03-11

This report describes the synthesis and biological characterization of novel granisetron derivatives that are antagonists of the human serotonin (5-HT(3)A) receptor. Some of these substituted granisetron derivatives showed low nanomolar binding affinity and allowed the identification of positions on the granisetron core that might be used as attachment points for biophysical tags. A BODIPY fluorophore was appended to one such position and specifically bound to 5-HT(3)A receptors in mammalian cells.

Toward Biophysical Probes for the 5-HT3 Receptor: Structure−Activity Relationship Study of Granisetron Derivatives

PubMed Central

2010-01-01

This report describes the synthesis and biological characterization of novel granisetron derivatives that are antagonists of the human serotonin (5-HT3A) receptor. Some of these substituted granisetron derivatives showed low nanomolar binding affinity and allowed the identification of positions on the granisetron core that might be used as attachment points for biophysical tags. A BODIPY fluorophore was appended to one such position and specifically bound to 5-HT3A receptors in mammalian cells. PMID:20146481

Prophylactic antiemetic effects of Midazolam, Ondansetron, and their combination after middle ear surgery

PubMed Central

Honarmand, Azim; Safavi, Mohammadreza; Chegeni, Mansoureh; Hirmanpour, Anahita; Nazem, Masoud; Sarizdi, Seyyad Hamid

2016-01-01

Objective: The purpose of the present study was to evaluate the efficacy of midazolam-ondansetron combination in prevention of postoperative nausea and vomiting (PONV) after middle ear surgery and its comparison with using midazolam or ondansetron alone. Methods: One hundred and forty patients were enrolled in four groups to receive midazolam 0.75 mg/kg in group M, ondansetron 4 mg in group O, midazolam 0.75 mg/kg and ondansetron 4 mg in group MO, and saline 0.90% in group S intravenously just before anesthesia. Assessment of nausea, vomiting, rescue antiemetic, and side effects of study drugs such as headache and dizziness was carried out postoperatively for 24 h. Findings: The incidence of PONV was significantly smaller in group MO than group M and group O, while there was no significant difference between group M and group O during the first 24 h postoperatively. Requirement to the additional antiemetic was significantly more in group S (71.4%) compared to other groups, while in group MO (11.4%) was lower than group M (31.4%) and group O (34.3%). Conclusion: Our study showed that prophylactic administration of midazolam 0.75 mg/kg combined with ondansetron 4 mg was more effective than using midazolam or ondansetron alone in prevention of PONV after middle ear surgery. PMID:26985431

Effectiveness of granisetron in controlling pediatric gastroenteritis-related vomiting after discharge from the ED.

PubMed

Qazi, Khajista; BinSalleeh, Hashim M; Shah, Ubaid H; AlGhamedi, Najwa; Tamim, Hani; Mubasher, Mohamed; Alrasheed, Faris; Alkanhal, Abdulrahman; AlTamimi, Saleh A

2014-09-01

The objective of the study is to determine the efficacy of oral granisetron (a long-acting 5-HT3 receptor antagonist) in stopping vomiting subsequent to discharge from emergency department (ED), in 6-month-old to 8-year-old patients with gastroenteritis-related vomiting and dehydration, who had failed an initial trial of oral rehydration (ORT). Eligible patients were offered ORT on a slowly advancing schedule. Patients who tolerated the initial ORT were discharged home. Patients who vomited were randomized to receive either 40 μg/kg of granisetron or placebo, and ORT was resumed. Patients who tolerated the postrandomization ORT were discharged home with another dose of the study drug. Parents were contacted by telephone every 24 hours until complete resolution of symptoms. The primary outcome was the proportion of patients with vomiting at 24 hours. Of the 900 eligible patients, 537 (60%) tolerated the initial ORT and were discharged home. Of the patients who vomited during the initial ORT, 165 were included in the final study sample (placebo, n = 82; granisetron, n = 83). There was no statistically significant difference in the proportion of patients with vomiting at 24 hours (granisetron, n = 38; placebo, n = 45; odds ratio, 0.64; 95% confidence interval, 0.34-1.19; P = .16). A similar trend in the proportion of patients with vomiting was noted for the entire follow-up period (granisetron, n = 43; placebo, n = 47; odds ratio, 0.73; P = .33; 95% confidence interval, 0.39-1.36). Granisetron was not effective in controlling gastroenteritis-related vomiting subsequent to discharge from ED. It did not change the expected course of the illness. Copyright © 2014 Elsevier Inc. All rights reserved.

Relative bioavailability of an extemporaneous ondansetron 4-mg capsule formulation versus solution.

PubMed

Lam, Y W Francis; Javors, Martin A; Ait-Daoud, Nassima; Roache, John D; Johnson, Bankole A

2004-04-01

To compare the relative bioavailability of an extemporaneous ondansetron capsule formulation with that of an identical dose of the commercially available solution formulation. Open-label, randomized, two-way crossover study. University-affiliated research laboratory. Sixteen (eight men, eight women) healthy, nonsmoking volunteers. Participants were randomly assigned to receive a 4-mg dose of either the commercially available ondansetron solution or the extemporaneous ondansetron capsule formulation. Blood sampling was performed over 12 hours after dosing. After a washout period of at least 3 days, each participant was switched to the alternate formulation, and blood sampling was repeated. Ondansetron was well absorbed after administration of both formulations, with the solution achieving a faster rate of drug absorption over the first hour of dosing. After the peak plasma concentration was achieved, the plasma concentration-time curves of both formulations declined at a similar steady rate. There were no significant differences in pharmacokinetic parameters between the two formulations, and the relative bioavailability of the capsule versus the solution formulation was 101%. Similar concentration-time curves and pharmacokinetic parameters were achieved with the two formulations. The commercially available solution would be a useful alternative formulation for administration of low-dose ondansetron in research and clinical settings.

[Anti-emetic effect of granisetron in patients undergoing cranial and craniospinal radiotherapy].

PubMed

Yamasaki, Fumiyuki; Watanabe, Yosuke; Nosaka, Ryo; Kenjo, Masahiro; Nakamura, Kazuhiro; Takayasu, Takeshi; Saito, Taiichi; Tominaga, Atsushi; Sugiyama, Kazuhiko; Kurisu, Kaoru

2014-01-01

Approximately 30-59% of patients undergoing cranial or craniospinal radiotherapy experience nausea and/or vomiting. Here, we evaluated the effectiveness of granisetron for controlling emesis in patients treated with cranial or craniospinal radiotherapy. Between December 2011 and January 2013, 34 patients(19 males, 15 females;age range, 3-80 years)received cranial or craniospinal radiotherapy at our department. All but one male patient, who developed meningitis during the irradiation period were enrolled in this retrospective study. Patients who experienced irradiation-induced vomiting(grade 1)or nausea(grade 2)were treated with granisetron as a rescue anti-emetic. Episodes were graded as(1)no vomiting, no nausea, no anti-emetic;(2)no vomiting, nausea, no anti-emetic;(3)no vomiting, nausea with anti-emetic;and(4)vomiting. Of the 9 patients who underwent whole-brain or whole neural-axis irradiation, 5(55.6%)experienced grade 2 nausea or vomiting. Two of 6 patients(33.3%)treated with whole ventricle irradiation experienced grade 2 nausea or vomiting. Three of 18 patients(16.7%)who underwent local-field irradiation experienced grade 2 nausea or vomiting. Patients who underwent wide-field irradiation experienced nausea, vomiting, and anorexia(p<0.05). Complete response(no vomiting, no additional rescue anti-emetic, and no nausea)was observed in 5 of 9 patients treated with granisetron. Four of 9 patients(44.4%)treated with granisetron experienced constipation(grade 1 or 2);its administration had no major adverse effects in our study population. Rescue therapy with granisetron is safe and effective to treat nausea and vomiting in patients subjected to cranial or craniospinal irradiation.

Effect of casopitant, a novel NK-1 antagonist, on the pharmacokinetics of dolasetron and granisetron.

PubMed

Adams, Laurel M; Johnson, Brendan; Zhang, Ke; Yue, Lin; Kirby, Lyndon C; Lebowitz, Peter; Stoltz, Randall

2009-09-01

The objective of this study was to characterize the impact of casopitant, a novel neurokinin-1 receptor antagonist under investigation for the prevention of postoperative and chemotherapy-induced nausea and vomiting, on the pharmacokinetics of the commonly prescribed 5-hydroxytryptamine receptor 3 receptor antagonists, dolasetron or granisetron. In a phase I, open-label, two-part, two-period, single-sequence study, two cohorts of healthy subjects received either oral dolasetron (100 mg once daily for 3 days) or oral granisetron (2 mg once daily for 3 days) alone (period 1) and combined with oral casopitant, 150 mg day 1, 50 mg days 2 and 3 (period 2). Pharmacokinetics of hydrodolasetron and granisetron were assessed on days 1 and 3 of each period. Log-transformed area under the curve (AUC) and Cmax were statistically analyzed by performing an analysis of variance. Eighteen subjects were enrolled in the dolasetron cohort; nine subjects were CYP2D6 extensive metabolizers (EMs) and nine subjects were CYP2D6 poor metabolizers. Nineteen subjects were enrolled in the granisetron cohort. The largest changes in hydrodolasetron exposure after coadministration with casopitant were seen in CYP2D6 EMs, with a 24% increase in hydrodolasetron AUC on day 1 and 30% increase in Cmax on days 1 and 3. All other changes in hydrodolasetron exposure were <20%, and granisetron exposure was not altered to any relevant extent (<11%). None of the changes observed are considered clinically meaningful, and coadministration of casopitant with dolasetron or granisetron was well tolerated.

A Comparative Study Between Palonosetron and Granisetron to Prevent Postoperative Nausea and Vomiting after Laparoscopic Cholecystectomy

PubMed Central

Bhattacharjee, Dhurjoti Prosad; Dawn, Satrajit; Nayak, Sushil; Roy, Pramod Ranjan; Acharya, Amita; Dey, Ramkrishna

2010-01-01

Background: Postoperative nausea and vomiting (PONV) is commonly seen after laparoscopic surgery. In this randomized double blind prospective clinical study, we investigated and compared the efficacy of palonosetron and granisetron to prevent postoperative nausea and vomiting after laparoscopic cholecystectomy. Patients & Methods: Sixty female patients (18-65 yrs of age) undergoing elective laparoscopic cholecystectomy were randomly allocated one of the two groups containing 30 patients each. Group P received palonosetron 75 μg intravenously as a bolus before induction of anaesthesia. Group G received granisetron 2.5 mg intravenously as a bolus before induction. Results: The incidence of a complete response (no PONV, no rescue medication) during 0-3 hour in the postoperative period was 86.6% with granisetron and 90% with palonosetron, the incidence during 3-24 hour postoperatively was 83.3% with granisetron and 90% with palonosetron. During 24-48 hour, the incidence was 66.6% and 90% respectively (p<0.05). The incidence of adverse effects were statistically insignificant between the groups. Conclusion: Prophylactic therapy with palonosetron is more effective than granisetron for long term prevention of postoperative nausea and vomiting after laparoscopic cholecystectomy. PMID:21547174

Influence of intramuscular granisetron on experimentally induced muscle pain by acidic saline.

PubMed

Louca, S; Ernberg, M; Christidis, N

2013-06-01

The aim of this study was to investigate whether intramuscular administration of the 5-HT(3) receptor antagonist granisetron reduces experimental muscle pain induced by repeated intramuscular injections of acidic saline into the masseter muscles. Twenty-eight healthy and pain-free volunteers, fourteen women and fourteen men participated in this randomized, double-blind and placebo-controlled study. After a screening examination and registration of the baseline pressure-pain threshold (PPT), the first simultaneous bilateral injections of 0·5 mL acidic saline (9 mg mL(-1) , pH 3·3) into the masseter muscles were performed. Two days later, PPT and pain (VAS) were re-assessed. The masseter muscle was then pre-treated with 0·5 mL granisetron (Kytril(®) 1 mg mL(-1) pH 5·3) on one side and control substance (isotonic saline, 9 mg mL(-1) pH 6) on the contralateral side. Two minutes thereafter a bilateral simultaneous injection of 0·5 mL acidic saline followed. The evoked pain intensity, pain duration, pain area and PPT were assessed. The volunteers returned 1 week later to re-assess VAS and PPT. On the side pre-treated with granisetron, the induced pain had significantly lower intensity and shorter duration (P < 0·05) compared with the side pre-treated with control. A subgroup analysis showed that the effect of granisetron on pain duration was significant only in women (P < 0·001), while the effect on peak pain and pain area were significant in both sexes. The results showed no significant change in PPT. In conclusion, these results indicate that granisetron has a pain-reducing effect on experimentally induced muscle pain by repeated acidic saline injection. © 2013 John Wiley & Sons Ltd.

Emergency department treatment of viral gastritis using intravenous ondansetron or dexamethasone in children.

PubMed

Stork, Christine M; Brown, Kathleen M; Reilly, Tracey H; Secreti, LaLaina; Brown, Lawrence H

2006-10-01

To compare the efficacy of intravenous ondansetron or dexamethasone compared with intravenous fluid therapy alone in children presenting to the emergency department with refractory vomiting from viral gastritis who had failed attempts at oral hydration. This double-blind, randomized, controlled trial was performed in a tertiary care pediatric emergency department. Children aged 6 months to 12 years presenting with more than three episodes of vomiting in the past 24 hours, mild/moderate dehydration, and failed oral hydration were included. Patients with other medical causes were excluded. Subjects were randomized to dexamethasone 1 mg/kg (15 mg maximum), ondansetron 0.15 mg/kg, or placebo (normal saline [NS], 10 mL). All subjects also received intravenous NS at 10-20 mL/kg/hr. Oral fluid tolerance was evaluated at two and four hours. Those not tolerating oral fluids at four hours were admitted. Discharged patients were evaluated at 24 and 72 hours for vomiting and repeat health care visits. The primary study outcome was hospitalization rates between the groups. Data were analyzed using chi-square test, Kruskal-Wallis test, Mantel-Haenszel test, and analysis of variance, with p < 0.05 considered significant. A total of 166 subjects were enrolled; data for analysis were available for 44 NS-treated patients, 46 ondansetron-treated patients, and 47 dexamethasone-treated patients. Hospital admission occurred in nine patients (20.5%) receiving placebo (NS alone), two patients (4.4%) receiving ondansetron, and seven patients (14.9%) receiving dexamethasone, with ondansetron significantly different from placebo (p = 0.02). Similarly, at two hours, more ondansetron-treated patients (39 [86.6%]) tolerated oral hydration than NS-treated patients (29 [67.4%]; relative risk, 1.28; 95% confidence interval = 1.02 to 1.68). There were no differences in number of mean episodes of vomiting or repeat visits to health care at 24 and 72 hours in the ondansetron, dexamethasone, or NS

Pharmacokinetic profile and clinical efficacy of a once-daily ondansetron suppository in cyclophosphamide-induced emesis: a double blind comparative study with ondansetron tablets.

PubMed Central

de Wit, R.; Beijnen, J. H.; van Tellingen, O.; Schellens, J. H.; de Boer-Dennert, M.; Verweij, J.

1996-01-01

We investigated the pharmacokinetic profile and the efficacy of ondansetron (day 1) given as 16 mg suppository once a day, as compared with ondansetron 8 mg tablets twice daily, in patients receiving moderately emetogenic chemotherapy. The study was primarily aimed at investigating the pharmacokinetics and was part of a large multinational, randomised, double-blind, double-dummy efficacy trial. Pharmacokinetic data were obtained in a total of 20 patients, 11 of whom had received a suppository containing ondansetron, and nine patients had received the oral formulation. The median area under the plasma concentration curve (AUC) obtained with the oral formulation was 226 ng ml-1h-1 (range 91-750), and the median maximum plasma level (Cmax) was 50.5 ng ml-1 (range 24.7-199.6) after a dose of 8 mg. For the ondansetron suppository the median AUC was 140 ng ml-1h-1 range (77-405) and the median Cmax was 17.1 ng ml-1 (range 13-48.3) after a dose of 16 mg. The systemic exposure after correction for the dose difference after the suppository was on average 70% lower than after the tablet. The median time to reach the maximum level (Tmax) was 60 min (range 28-120) with the oral formulation and 209 min (range 90-420) with the suppository. For both the tablet and suppository, there was no apparent relationship between either Cmax or AUC, and efficacy. Although the patient numbers were too small for a formal exposure-response relationship to be derived, the slightly poorer pharmacokinetic performance of the suppository did not appear to be associated with a lessening of control of emesis following chemotherapy. The study demonstrates that the pharmacokinetic analysis of a once-daily 16 mg ondansetron suppository results in appropriate plasma concentrations and AUC, and that this rectal formulation is effective in the protection against nausea and vomiting associated with cyclophosphamide chemotherapy. This formulation will provide a useful alternative to the currently available

Pharmacokinetic profile and clinical efficacy of a once-daily ondansetron suppository in cyclophosphamide-induced emesis: a double blind comparative study with ondansetron tablets.

PubMed

de Wit, R; Beijnen, J H; van Tellingen, O; Schellens, J H; de Boer-Dennert, M; Verweij, J

1996-07-01

We investigated the pharmacokinetic profile and the efficacy of ondansetron (day 1) given as 16 mg suppository once a day, as compared with ondansetron 8 mg tablets twice daily, in patients receiving moderately emetogenic chemotherapy. The study was primarily aimed at investigating the pharmacokinetics and was part of a large multinational, randomised, double-blind, double-dummy efficacy trial. Pharmacokinetic data were obtained in a total of 20 patients, 11 of whom had received a suppository containing ondansetron, and nine patients had received the oral formulation. The median area under the plasma concentration curve (AUC) obtained with the oral formulation was 226 ng ml-1h-1 (range 91-750), and the median maximum plasma level (Cmax) was 50.5 ng ml-1 (range 24.7-199.6) after a dose of 8 mg. For the ondansetron suppository the median AUC was 140 ng ml-1h-1 range (77-405) and the median Cmax was 17.1 ng ml-1 (range 13-48.3) after a dose of 16 mg. The systemic exposure after correction for the dose difference after the suppository was on average 70% lower than after the tablet. The median time to reach the maximum level (Tmax) was 60 min (range 28-120) with the oral formulation and 209 min (range 90-420) with the suppository. For both the tablet and suppository, there was no apparent relationship between either Cmax or AUC, and efficacy. Although the patient numbers were too small for a formal exposure-response relationship to be derived, the slightly poorer pharmacokinetic performance of the suppository did not appear to be associated with a lessening of control of emesis following chemotherapy. The study demonstrates that the pharmacokinetic analysis of a once-daily 16 mg ondansetron suppository results in appropriate plasma concentrations and AUC, and that this rectal formulation is effective in the protection against nausea and vomiting associated with cyclophosphamide chemotherapy. This formulation will provide a useful alternative to the currently available

Preparation and the in vitro evaluation of nanoemulsion system for the transdermal delivery of granisetron hydrochloride.

PubMed

Zheng, Wen-wu; Zhao, Ling; Wei, Yu-meng; Ye, Yun; Xiao, Shun-han

2010-08-01

The objective of this study was to develop and evaluate nanoemulsion system for transdermal delivery of granisetron hydrochloride. Pseudo-ternary phase diagram was constructed to ascertain the concentration range of components of nanoemulsion composed of isopropyl myristate (IPM) as an oil phase, tween 85 as surfactant, ethanol as cosurfactant, water as aqueous phase. The effects of the content of IPM as an oil phase and n-methyl pyrrolidone (NMP) as transdermal enhancer on rat skin permeation of granisetron hydrochloride nanoemulsion were studied in vitro. The results showed that the mean particle size of nanoemulsion ranged from 50.4+/-1.5 to 82.4+/-0.9 nm with homogeneous size distribution. The resulted optimum formulation composed of 2.5% granisetron hydrochloride, 4% IPM, 40% tween 85/ethanol (1 : 1) and 10% NMP showed that the skin permeation rate was the highest (85.39+/-2.90 microg/cm(2)/h) and enhancement of drug permeability was 4.1-fold for transdermal delivery of granisetron hydrochloridein comparison with the control group (20% of tween 85 and 20% of ethanol micelle solution containing 2.5% of granisetron hydrochloride without IPM), and cumulative permeation amount was the highest (891.8+/-2.86 microg/cm(2)) with the shortest lag time (0.11+/-0.02 h) and was stable for at least 12 months. Therefore, the nanoemulsion system developed in this study offers a promising vehicle for the transdermal delivery system of granisetron hydrochloride, which may be as effective as oral or intravenous dosage forms and avoid some difficulties associated with these dosage forms.

Haloperidol Versus Ondansetron for Treatment of Established Nausea and Vomiting Following General Anesthesia: A Randomized Clinical Trial.

PubMed

Yazbeck-Karam, Vanda G; Siddik-Sayyid, Sahar M; Barakat, Hanane B; Korjian, Serge; Aouad, Marie T

2017-02-01

Haloperidol is an antipsychotic. At low doses, it is a useful agent for the prophylaxis of postoperative nausea and vomiting (PONV). However, its use for treating established PONV has not been well studied. This randomized double-blinded trial tested whether haloperidol is noninferior to ondansetron for the early treatment of established PONV in adult patients undergoing general anesthesia. The primary outcome is whether patients were PONV free during the first 4 hours. The noninferiority margin was set at 15%. One hundred twenty patients with PONV received either haloperidol 1 mg intravenously (n = 60) or ondansetron 4 mg intravenously (n = 60). Data from 112 patients (59 in the haloperidol group and 53 in the ondansetron group) were analyzed. Thirty-five patients (52%) in the haloperidol group received 1 or 2 prophylactic antiemetics compared with 42 (79%) in the ondansetron group. Haloperidol was noninferior to ondansetron for the end point of complete response to treatment (defined as the rate of PONV-free patients) for the early (0-4 hour) and the 0- to 24-hour postoperative periods by both the per-protocol and intention-to-treat analyses. In the per-protocol analysis, complete responses in the early period were noted in 35 of 59 patients (59%) and 29 of 53 patients (55%) for the haloperidol and ondansetron groups, respectively (difference 5%; 95% confidence interval [CI]: -13% to 22 %), and in the 0- to 24-hour period in 31 of 59 patients (53%) and 26 of 53 patients (49%) for the haloperidol and ondansetron groups, respectively (difference 4%; 95% CI of the difference: -15% to 21%). In the intention-to-treat analysis, complete responses in the early period were noted in 35 of 60 patients (58%) and 29 of 60 patients (48%) for the haloperidol and ondansetron groups, respectively (difference 10%; 95% CI of difference: -8% to 27%) and in the 0- to 24-hour period in 31 of 60 patients (52%) and 26 of 60 patients (43%) for the haloperidol and ondansetron groups

Enhanced Patient Expectant and Antiemetic Drug Efficacy

DTIC Science & Technology

1999-07-01

Breast Cancer Nausea and Vomiting Expectancy Patient Information Antiemetic Side Effect 15. NUMBER OF PAGES 15 16. PRICE CODE 17. SECURITY ...CLASSIFICATION OF REPORT Unclassified 18. SECURITY CLASSIFICATION OF THIS PAGE Unclassified 19. SECURITY CLASSIFICATION OF ABSTRACT...5-HT3 receptor antagonist class of antiemetics (ondansetron, granisetron , tropisitron) have greatly reduced chemotherapy-related vomiting, this has

First derivative spectrophotometric determination of granisetron hydrochloride in presence of its hydrolytic products and preservative and application to pharmaceutical preparations.

PubMed

Hewala, Ismail I; Bedair, Mona M; Shousha, Sherif M

2013-04-01

Granisetron is a selective 5-HT3 receptor antagonist used in prevention and treatment of chemotherapy-induced nausea and vomiting. The drug is available in tablet dosage form and parenteral dosage form containing benzyl alcohol as a preservative. The main route of degradation of granisetron is through hydrolysis. The present work describes the development of a simple, rapid, and reliable first derivative spectrophotometric method for the determination of granisetron in presence of its hydrolytic products as well as the formulations adjuvant and benzyl alcohol. The method is based on the measurement of the first derivative response of granisetron at 290 nm where the interference of the hydrolytic products, the co-formulated adjuvant and benzyl alcohol is completely eliminated. The proposed method was validated with respect to specificity, linearity, selectivity, accuracy, precision, robustness, detection, and quantification limits. Regression analysis showed good correlation between the first derivative response and the concentration of granisetron over a range of 8-16 μg ml(-1) . Statistical analysis proved the accuracy of the proposed method compared with a reference stability indicating high performance liquid chromatography method. The described method was successfully applied to the determination of granisetron in different batches of tablets and ampoules. The assay results obtained in this study strongly encourage us to apply the validated method for the quality control and routine analysis of tablets and parenteral preparations containing granisetron. Copyright © 2012 John Wiley & Sons, Ltd.

Evaluation of the maternal-fetal transfer of granisetron in an ex vivo placenta perfusion model.

PubMed

Julius, Justin M; Tindall, Andrew; Moise, Kenneth J; Refuerzo, Jerrie S; Berens, Pamela D; Smith, Judith A

2014-11-01

The objective of this study was to estimate maternal-fetal transplacental passage of granisetron in an ex vivo placental perfusion model. Term human placentas (N=8) were collected immediately after delivery. A single cotyledon from each placenta was perfused granisetron concentration to mimic systemic maternal peak plasma concentrations following either IV (50ng/mL) or transdermal administration (5ng/mL). To assess drug transfer and accumulation, samples were collected from maternal and fetal compartments. In the 50ng/mL open model, the mean transport fraction was 0.21±0.08 with clearance index of 0.53±0.66. Fetal peak concentrations achieved was 5.6±6.6ng/mL with mean accumulation of 5.35±6.4ng/mL. No drug was detected in the fetal compartment with the 5ng/mL models. Transplacental passage of granisetron was inconsistent at the 50ng/mL concentration that achieved with IV dosing. However, there consistently was no detectable passage in all the placentas evaluated of the granisetron at 5ng/mL concentration that would be achieved after transdermal patch administration. Copyright © 2014 Elsevier Inc. All rights reserved.

Changes of hypertonic saline-induced masseter muscle pain characteristics, by an infusion of the serotonin receptor type 3 antagonist granisetron.

PubMed

Christidis, Nikolaos; Ioannidou, Kiriaki; Milosevic, Milena; Segerdahl, Märta; Ernberg, Malin

2008-10-01

This study aimed to investigate whether granisetron reduces masseter muscle pain and allodynia induced by hypertonic saline. Fifteen healthy women and 15 age-matched healthy men participated in this randomized, placebo-controlled, double-blinded study. They first received bilateral injections of hypertonic saline into the masseter muscles (internal control). The evoked pain intensity and the pressure-pain threshold (PPT) were recorded during 30 minutes. Granisetron was then injected on one side and placebo (normal saline) on the contralateral side. Two minutes thereafter, the hypertonic saline injections were repeated. Pain and PPT were again recorded. The first injection of hypertonic saline induced pain of similar intensity, duration, and pain area on both sides, but with larger pain area in the women (P = .017). The PPT did not change significantly. The second injection of hypertonic saline induced considerably less pain (62.5%), of shorter duration (44.1%), and of smaller area (77.4%) on the side pretreated with granisetron (P = .005). The PPT was increased on the granisetron side in the men (P = .002). The results of this study show that local injection of a single dose of granisetron attenuates masseter muscle pain induced by hypertonic saline. This article presents the changes of hypertonic saline-induced masseter muscle pain characteristics by infusion of granisetron. It appears that the pain-inducing effect in this experimental pain model is partly due to activation of 5-HT3-receptors. Hence, the results indicate that granisetron might offer a new treatment approach for localized myofascial pain.

Enhanced Patient Expectation and Antiemetic Drug Efficacy

DTIC Science & Technology

1999-07-01

NUMBER OF PAGES 15 Breast Cancer Expectancy Antiemetic Nausea and Vomiting Patient Information Side Effect 16. PRICE CODE 17. SECURITY CLASSIFICATION 18... SECURITY CLASSIFICATION OF THIS 19. SECURITY CLASSIFICATION 20. LIMITATION OF ABSTRACT OF REPORT PAGE OF ABSTRACT Unclassified Unclassified...by the introduction of the 5-HT 3 receptor antagonist class of antiemetics (ondansetron, granisetron , tropisitron) have greatly reduced chemotherapy

Development of chitosan-based ondansetron buccal delivery system for the treatment of emesis.

PubMed

Park, Dong-Min; Song, Yun-Kyoung; Jee, Jun-Pil; Kim, Hyung Tae; Kim, Chong-Kook

2012-09-01

For the buccal drug delivery, chitosan (CS) can be used to improve drug absorption and reduce application frequency and drug amount. The aim of this study is to develop and evaluate mucoadhesive ondansetron buccal films for the treatment of emesis using CS as a mucoadhesive polymer. The film prepared by solvent casting method was comprised of ondansetron (approximately 65 μg)-loaded mucoadhesive gels containing 1, 2 or 3% CS and impermeable backing layer. Rheological property of the gels, physiochemical properties of the films (weight, thickness, drug content, swelling ratio, adhesion time and mucoadhesive force) and in vitro ondansetron release profile from the films were determined to evaluate the formulation. The films containing 3% CS (diameter: 0.5 cm; thickness: 170 μm) was selected as the novel formulation, and were used for the in vivo study. Comparative pharmacokinetic studies of ondansetron with this film and oral solution were performed at the same dose in hamsters. The mean values of T(max) and C(max) of the film and oral solution were similar. However, the half-life, mean residence time and AUC(0-24 h) of the film were about 1.7, 1.4 and 2.0-fold higher than those of the oral solution, respectively. The film showed enhanced bioavailability and prolonged efficacy compared to the oral solution. The mucoadhesive ondansetron buccal film may be a potential alternative to the marketed oral formulation, parenterals and solid suppositories with better patient compliance and higher bioavailability for the treatment of emesis.

Randomized, double-blind, crossover study of palonosetron compared with granisetron for the prevention of chemotherapy-induced nausea and vomiting in a Chinese population.

PubMed

Tian, Weihua; Wang, Zhiqiang; Zhou, Juntian; Zhang, Shucai; Wang, Jinghui; Chen, Qiang; Huang, Cheng; Pan, Liangxi; Zhang, Lili; Huang, Jianjin; Shen, Hong; Lin, Tongyu

2011-03-01

The objective of this study was to compare the efficacy and tolerability of palonosetron and granisetron in a Chinese population receiving highly emetogenic cisplatin-based chemotherapy or moderately emetogenic chemotherapy. Patients were stratified by chemotherapy with cisplatin (yes/no) and then randomly assigned to receive either palonosetron (0.25 mg i.v.) in the first cycle followed by granisetron (3 mg i.v.) in the second cycle or vice versa. The primary efficacy endpoint was the proportion of patients with complete response 0-24 h post-chemotherapy administration. The proportions of patients with complete response 24-120 and 0-120 h following chemotherapy were also compared. Of the 144 patients randomized, 36 (25%) received 60-80 mg/m(2) cisplatin; 66 of 72 patients in the palonosetron to granisetron group and 56 of 72 patients in the granisetron to palonosetron group completed treatment with both antiemetics. The efficacy and safety analyses included 128 palonosetron treatments and 138 granisetron treatments. Palonosetron consistently produced numerically higher complete response rates than granisetron in the acute phase (0-24 h, 71.09 vs. 65.22%), the delayed phase (24-120 h, 60.16 vs. 55.80%), and overall (0-120 h, 53.13 vs. 50.00%) though the differences were not significant. Both palonosetron and granisetron were well tolerated. Palonosetron was well tolerated and effective in preventing acute and delayed chemotherapy-induced nausea and vomiting in a Chinese population. When used as monotherapy, 0.25-mg palonosetron was not inferior to 3-mg granisetron for preventing vomiting following highly or moderately emetogenic chemotherapy.

Ondansetron Pharmacokinetics in Pregnant Women and Neonates: Towards a New Treatment for Neonatal Abstinence Syndrome

PubMed Central

Elkomy, Mohammed H.; Sultan, Pervez; Carvalho, Brendan; Peltz, Gary; Wu, Manhong; Clavijo, Claudia; Galinkin, Jeffery L.; Drover, David R.

2014-01-01

Ondansetron is the drug of choice to prevent nausea in women undergoing cesarean surgery and can be used to prevent neonatal abstinence syndrome (NAS). Pharmacokinetics of ondansetron has not been characterized in pregnant women or in newborns. A nonlinear mixed-effects modeling approach was used to analyze plasma samples obtained from 20 non-pregnant and 40 pregnant women following single administration of 4 or 8 mg ondansetron, from umbilical cord blood at delivery, and from neonates after birth. The analysis indicates that: ondansetron disposition is not affected by pregnancy (p>0.05), but influenced by dose (p<0.05), and is characterized by rapid transplacental transfer and longer elimination half-life in neonates compared to their mother. A dosing regimen for prevention of NAS was designed based on the model. The regimen involves IV administration of 4 mg to the mothers shortly before cord clamping, or oral administration of 0.07 mg/kg (or equivalently 0.04 mg/kg IV) to neonates. PMID:25670522

Granisetron: a review of pharmacokinetics and clinical experience in chemotherapy induced - nausea and vomiting.

PubMed

Spartinou, Anastasia; Nyktari, Vasileia; Papaioannou, Alexandra

2017-12-01

Chemotherapy induced nausea and vomiting (CINV) are major side effects of chemotherapy and a great burden to patients' quality of life. Serotonin and substance P are the major neurotransmitters involved in the pathophysiology of CINV, but in spite of new antiemetics no completely effective regime exists for its prevention or treatment. Areas covered: In this review the authors provide a detailed description of granisetron's chemistry pharmacokinetics, pharmacodynamics, toxicity and a brief review of clinical trials involving granisetron and the management of CINV. We searched reviews, meta-analysis and randomized controlled trials (Medline, Embase and article reference lists). Expert opinion: According to current literature, granisetron 2 mg orally or 0,01mg/kg (1 mg) intravenously per day, co-administered with dexamethasone and NK-1 antagonists is the recommended regime for highly emetogenic chemotherapy. In the future the role of transdermal and subcutaneous formulations against delayed CINV will be clarified and probably enhance patients' convenience.

Cost-effectiveness analysis of granisetron-based versus standard antiemetic regimens in low-emetogenic chemotherapy: a hospital-based perspective from Malaysia.

PubMed

Keat, Chan Huan; Ghani, Norazila Abdul

2013-01-01

In a prospective cohort study of antiemetic therapy conducted in Malaysia, a total of 94 patients received low emetogenic chemotherapy (LEC) with or without granisetron injections as the primary prophylaxis for chemotherapy-induced nausea and vomiting (CINV). This study is a retrospective cost analysis of two antiemetic regimens from the payer perspective. This cost evaluation refers to 2011, the year in which the observation was conducted. Direct costs incurred by hospitals including the drug acquisition, materials and time spent for clinical activities from prescribing to dispensing of home medications were evaluated (MYR 1=$0.32 USD). As reported to be significantly different between two regimens (96.1% vs 81.0%; p=0.017), the complete response rate of acute emesis which was defined as a patient successfully treated without any emesis episode within 24 hours after LEC was used as the main indicator for effectiveness. Antiemetic drug acquisition cost per patient was 40.7 times higher for the granisetron-based regimen than for the standard regimen (MYR 64.3 vs 1.58). When both the costs for materials and clinical activities were included, the total cost per patient was 8.68 times higher for the granisetron-based regimen (MYR 73.5 vs 8.47). Considering the complete response rates, the mean cost per successfully treated patient in granisetron group was 7.31 times higher (MYR 76.5 vs 10.5). The incremental cost-effectiveness ratio (ICER) with granisetron-based regimen, relative to the standard regimen, was MYR 430.7. It was found to be most sensitive to the change of antiemetic effects of granisetron-based regimen. While providing a better efficacy in acute emesis control, the low incidence of acute emesis and high ICER makes use of granisetron as primary prophylaxis in LEC controversial.

The effects of 5HT3 receptor antagonist granisetron on inflammatory parameters and angiogenesis in the air-pouch model of inflammation.

PubMed

Maleki-Dizaji, Nasrin; Eteraf-Oskouei, Tahereh; Fakhrjou, Ashraf; Maljaie, Seyyed Hadi; Garjani, Alireza

2010-09-01

The antagonists of 5HT(3) receptors have shown impressive efficacy in rheumatoid arthritis, osteoarthritis or fibromyalgia. The mechanistic relationships between 5HT(3) receptors, angiogenesis and sequence of cytokine expression, and leukocyte recruitment during inflammation are not clear. We evaluate the effects of granisetron on inflammatory parameters and angiogenesis in rat air-pouch model. Male Wistar rats were anesthetized, and then 20 ml and 10 ml of sterile air were injected subcutaneously in the back on day 0 and day 3, respectively. On day 6, inflammation was induced by injection of 1 ml of carrageenan 1% into pouches. After 6 and 72 h, the rats were sacrificed; pouch fluid was collected in order to determine exudate volume, the number of accumulated cells and TNFalpha/PGE(2) concentration. Pouches were dissected out and weighed. Angiogenesis of granulomatous tissue was assayed using a hemoglobin kit. Leukocyte accumulation was dose-dependently inhibited by granisetron both at 6 and 72 h after induction of inflammation. All doses of granisetron decreased hemoglobin level in the whole granulation tissue in a bell-shaped manner. Vascular network formation was also inhibited by granisetron. Granisetron increased PGE(2) level at a lower dose (50 microg/pouch) but higher doses (100 and 200 microg/pouch) inhibited the release. At the same time, TNFalpha production was decreased by the lower dose and increased by higher doses of granisetron in a reciprocal fashion. Anti-inflammatory activities of 5HT(3) receptor antagonist, granisetron probably are mediated through modulation of TNFalpha/PGE(2) production and leukocyte infiltration. (c) 2010 Elsevier B.V. All rights reserved.

In vitro percutaneous absorption enhancement of granisetron by chemical penetration enhancers.

PubMed

Zhao, Nanxi; Cun, Dongmei; Li, Wei; Ma, Xu; Sun, Lin; Xi, Honglei; Li, Li; Fang, Liang

2013-04-01

Granisetron (GRN), a potent antiemetic agent, is frequently used to prevent nausea and vomiting induced by cancer cytotoxic chemotherapy and radiation therapy. As part of our efforts to further modify the physicochemical properties of this market drug, with the ultimate goal to formulate a better dosage form for GRN, this work was carried out to improve its permeability in vitro. The permeation behavior of GRN in isopropyl myristate (IPM) was investigated across excised rabbit abdominal skin and the enhancing activities of three novel O-acylmenthol derivatives synthesized in our laboratory as well as five well-known chemical enhancers were evaluated. It was found that the steady-state flux of granisetron free base (GRN-B) was about 26-fold higher than that of granisetron hydrochloride (GRN-H). The novel enhancer, 2-isopropyl-5-methylcyclohexyl heptanoate (M-HEP), was observed to provide the most significant enhancement for the absorption of GRN-B. When incorporated in the donor solution with the optimal enhancer M-HEP, the steady-state flux of GRN-B increased from (196.44 ± 12.03) μg·cm⁻²·h⁻¹ to (1044.95 ± 71.99) μg·cm⁻²·h⁻¹ (P < 0.01). These findings indicated that the application of chemical enhancers was an effective approach to increase the percutaneous absorption of GRN in vitro.

Repeated tender point injections of granisetron alleviate chronic myofascial pain--a randomized, controlled, double-blinded trial.

PubMed

Christidis, Nikolaos; Omrani, Shahin; Fredriksson, Lars; Gjelset, Mattias; Louca, Sofia; Hedenberg-Magnusson, Britt; Ernberg, Malin

2015-01-01

Serotonin (5-HT) mediates pain by peripheral 5-HT3-receptors. Results from a few studies indicate that intramuscular injections of 5-HT3-antagonists may reduce musculoskeletal pain. The aim of this study was to investigate if repeated intramuscular tender-point injections of the 5-HT3-antagonist granisetron alleviate pain in patients with myofascial temporomandibular disorders (M-TMD). This prospective, randomized, controlled, double blind, parallel-arm trial (RCT) was carried out during at two centers in Stockholm, Sweden. The randomization was performed by a researcher who did not participate in data collection with an internet-based application ( www.randomization.com ). 40 patients with a diagnose of M-TMD according to the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) were randomized to receive repeated injections, one week apart, with either granisetron (GRA; 3 mg) or isotonic saline as control (CTR). The median weekly pain intensities decreased significantly at all follow-ups (1-, 2-, 6-months) in the GRA-group (Friedman test; P < 0.05), but not in the CTR-group (Friedman-test; P > 0.075). The numbers needed to treat (NNT) were 4 at the 1- and 6-month follow-ups, and 3.3 at the 2-month follow-up in favor of granisetron. Repeated intramuscular tender-point injections with granisetron provide a new pharmacological treatment possibility for myofascial pain patients with repeated intramuscular tender-point injections with the serotonin type 3 antagonist granisetron. It showed a clinically relevant pain reducing effect in the temporomandibular region, both in a short- and long-term aspect. European Clinical Trials Database 2005-006042-41 as well as at Clinical Trials NCT02230371 .

Acute Radiation Sickness Amelioration Analysis

DTIC Science & Technology

1994-05-01

Emetic Drugs 16. PRICE CODE Antagonists 17. SECURITY CLASSIFICATION 18. SECURITY CLASSIFICATION 19, SECURITY CLASSIFICATION 20. LIMITATION OF ABSTRACT OF...102 UNCLASSIFIED mcuIw IA IIIcaIIin or Isis PAW CLASSFIED BY: N/A since Unclassified. DECLASSIFY ON: N/A since Unclassified. SECURITY CLASSIFICATION OF...Approximately 2000 documents relevant to the development of the candidate anti-emetic drugs ondansetron (Zofran, Glaxo Pharmaceuticals) and granisetron

Ramosetron versus ondansetron for the prevention of postoperative nausea and vomiting after laparoscopic cholecystectomy.

PubMed

Ryu, Junghee; So, Yun-Mi; Hwang, Jungwon; Do, Sang-Hwan

2010-04-01

Patients undergoing general anesthesia for laparoscopic cholecystectomy are at high risk for postoperative nausea and vomiting (PONV). This study compared ramosetron and ondansetron in terms of efficacy for PONV prevention after laparoscopic cholecystectomy. For this study, 120 patients scheduled to undergo laparoscopic cholecystectomy were randomized (in double-blind fashion) to receive 4 mg of ondansetron (group O4, n = 40), 8 mg of ondansetron (group O8, n = 40), or 0.3 mg of ramosetron (group R, n = 40) intravenously after surgery. Postoperative nausea, retching, vomiting, pain, and side effects were assessed at 2 h, 24 h, and 48 h after surgery. No statistical differences were observed among the three groups with regard to patient characteristics and information on surgery and anesthesia. The ratio of complete response (no PONV for 2 h) was higher for groups O8 and R than for group O4 as follows: 80% (n = 32) for groups O8 and R versus 58% (n = 23) for group O4 during the first postoperative 2 h (p = 0.04), 90% (n = 36) for groups O8 and R versus 76% (n = 30) for group O4 over 24 h (2-24 h) (p = 0.09), and 98% (n = 38) for groups O4 and O8 versus 100% (n = 40) for group R over the next 24 h (24-48 h) after surgery (p = 0.36). During the first 2 h after surgery, rescue antiemetics were used for significantly fewer patients in groups O8 and R (20%) than in group O4 (42.5%) (p = 0.04). Postoperative pain and the use of rescue analgesics were comparable among the groups. There was no clinically serious adverse event due to the study drugs. Ramosetron 0.3 mg and ondansetron 8 mg are more effective than ondansetron 4 mg for the prevention of PONV (2 h). Ramosetron 0.3 mg is as effective as ondansetron 8 mg for the prophylaxis of PONV after laparoscopic cholecystectomy.

The effect of ondansetron on analgesic efficacy of acetaminophen after hysterectomy: A randomized double blinded placebo controlled trial.

PubMed

Koyuncu, Onur; Leung, Steve; You, Jing; Oksar, Menekse; Turhanoglu, Selim; Akkurt, Cagla; Dolapcioglu, Kenan; Sahin, Hanifi; Sessler, Daniel I; Turan, Alparslan

2017-08-01

To determine that perioperative ondansetron reduces the analgesic efficacy of acetaminophen. Randomized, double-blinded study. 120 patients ASA I-II who underwent abdominal hysterectomy. All the patients were given 1g acetaminophen at skin closure. Patients were divided into two groups; ondansetron HCl (8mg, 2ml IV) (Group I, N=60) and saline (2ml IV) (Group II, N=60) at the skin closure. Postoperative pain scores (VAS) while resting in bed and sitting, total opioid consumption were noted. Patients randomized to ondansetron had significantly worse pain scores upon arrival to the recovery unit [by 1.7 (99.7% CI: 0.75, 2.59) cm] and at 1h [by 1.3 (0.5, 2.1) cm] while resting in bed. Pain scores while sitting were also significantly greater in ondansetron group at arrival in PACU by 0.6 (99.7% CI: 0.1, 1.0) cm. Thereafter, pain scores did not differ significantly. Median total opioid (tramadol) consumption was 441 [Q1, Q3: 280, 578] mg in the ondansetron group and 412 [309, 574] mg in the placebo group, P=0.95. Ondansetron significantly decreased the analgesic effect of acetaminophen during the initial postoperative period. Our results thus confirm that acetaminophen analgesia is partially mediated by serotonin receptors. However, the reduction was of marginal clinical importance and short-lived. Copyright © 2017 Elsevier Inc. All rights reserved.

Physical characteristics of polymer complexes in suspension obtained from cellulosic latexes with ondansetron.

PubMed

Ruiz, A; Llácer, J M; Morales, E; Gallardo, V

2004-06-01

Ondansetron is a carbazol with antiemetic properties. It is used primarily to control nausea and vomiting caused by cytotoxic chemotherapy and radiotherapy, as well as in postoperative vomiting in gynecological surgery. Ondansetron has a half-life of approximately 4 h, hence it is a matter of great interest to determine the ideal conditions for the formation of a drug-polymer complex in order to prolong the duration of the therapeutic action. A stability study of the active drug was first carried out on each of the polymers (Aquateric and Aquacoat). The adsorption of ondansetron on the lattices was determined with respect to time, pH and concentration. The results obtained suggest that both polymers are suitable as drug carriers for the controlled-release formulations obtained. We conclude that an acid pH is evidently fundamental in the adsorption process of this drug in the latexes. Moreover, the Aquateric latex would seem to be the best-suited polymer to use as a vehicle for drug delivery.

Efficacy and tolerability of transdermal granisetron for the control of chemotherapy-induced nausea and vomiting associated with moderately and highly emetogenic multi-day chemotherapy: a randomized, double-blind, phase III study.

PubMed

Boccia, Ralph V; Gordan, Lucio N; Clark, Gemma; Howell, Julian D; Grunberg, Steven M

2011-10-01

A novel transdermal formulation of granisetron (the granisetron transdermal delivery system (GTDS)) has been developed to deliver granisetron continuously over 7 days. This double-blind, phase III, non-inferiority study compared the efficacy and tolerability of the GTDS to daily oral granisetron for the control of chemotherapy-induced nausea and vomiting (CINV). Six hundred forty-one patients were randomized to oral (2 mg/day, 3-5 days) or transdermal granisetron (one GTDS patch, 7 days), before receiving multi-day chemotherapy. The primary endpoint was complete control of CINV (no vomiting/retching, no more than mild nausea, no rescue medication) from chemotherapy initiation until 24 h after final administration. The prespecified non-inferiority margin was 15%. Five hundred eighty-two patients were included in the per protocol analysis. The GTDS displayed non-inferiority to oral granisetron: complete control was achieved by 60% of patients in the GTDS group, and 65% in the oral granisetron group (treatment difference, -5%; 95% confidence interval, -13-3). Both treatments were well tolerated, the most common adverse event being constipation. The GTDS provides effective, well-tolerated control of CINV associated with moderately or highly emetogenic multi-day chemotherapy. It offers a convenient alternative route for delivering granisetron for up to 7 days that is as effective as oral granisetron.

Aromatherapy Versus Oral Ondansetron for Antiemetic Therapy Among Adult Emergency Department Patients: A Randomized Controlled Trial.

PubMed

April, Michael D; Oliver, Joshua J; Davis, William T; Ong, David; Simon, Erica M; Ng, Patrick C; Hunter, Curtis J

2018-02-17

We compare aromatherapy with inhaled isopropyl alcohol versus oral ondansetron for treating nausea among emergency department (ED) patients not requiring immediate intravenous access. In a randomized, blinded, placebo-controlled trial, we enrolled a convenience sample of adults presenting to an urban tertiary care ED with chief complaints including nausea or vomiting. We randomized subjects to 1 of 3 arms: inhaled isopropyl alcohol and 4 mg oral ondansetron, inhaled isopropyl alcohol and oral placebo, and inhaled saline solution placebo and 4 mg oral ondansetron. The primary outcome was mean nausea reduction measured by a 0- to 100-mm visual analog scale from enrollment to 30 minutes postintervention. Secondary outcomes included receipt of rescue antiemetic medications and adverse events. We enrolled 122 subjects, of whom 120 (98.3%) completed the study. Of randomized subjects, 40 received inhaled isopropyl alcohol and oral ondansetron, 41 received inhaled isopropyl alcohol and oral placebo, and 41 received inhaled saline solution placebo and oral ondansetron. The mean decrease in nausea visual analog scale score in each arm was 30 mm (95% confidence interval [CI] 22 to 37 mm), 32 mm (95% CI 25 to 39 mm), and 9 mm (95% CI 5 to 14 mm), respectively. The proportions of subjects who received rescue antiemetic therapy in each arm were 27.5% (95% CI 14.6% to 43.9%), 25.0% (95% CI 12.7% to 41.2%), and 45.0% (95% CI 29.3% to 61.5%), respectively. There were no adverse events. Among ED patients with acute nausea and not requiring immediate intravenous access, aromatherapy with or without oral ondansetron provides greater nausea relief than oral ondansetron alone. Copyright © 2018 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.

X-ray analysis of the effect of the 5-HT3 receptor antagonist granisetron on gastrointestinal motility in rats repeatedly treated with the antitumoral drug cisplatin.

PubMed

Vera, Gema; López-Pérez, Ana Esther; Martínez-Villaluenga, María; Cabezos, Pablo Antonio; Abalo, Raquel

2014-08-01

Cancer chemotherapy is associated with the development of numerous adverse effects, including nausea, emesis and other alterations in gastrointestinal (GI) motility. The administration of 5-HT3 receptor antagonists has provided a clinical advance in the treatment of chemotherapy-induced vomiting but these drugs lose efficacy throughout chronic treatment. The effects of these drugs in experimental animals under chronic administration are not well known. Our aim was to study, using radiographic methods, the effect of the 5-HT3 receptor antagonist granisetron on GI dysmotility induced in the rat by repeated cisplatin administration. First, invasive methods were used to select a dose of granisetron capable of reducing increased stomach weight due to acute cisplatin administration (6 mg/kg, ip). Second, rats received two intraperitoneal (ip) injections once a week for 4 weeks: granisetron (1 mg/kg, ip) or saline and, thirty min later, saline or cisplatin (2 mg/kg, ip). Body weight gain was measured throughout treatment. Radiological techniques were used to determine the acute (after first dose) and chronic (after last dose) effects of cisplatin and/or granisetron on GI motility. Repeated cisplatin-induced weight loss which granisetron did not prevent. Gastric emptying was delayed after the first cisplatin administration. Granisetron completely prevented this effect. After weekly administration, cisplatin-induced gastric dysmotility was enhanced and granisetron was not capable of completely preventing this effect. Granisetron prevents gastric emptying alterations, but its efficacy decreases throughout antineoplastic treatment. This might be due to the enhanced effect of cisplatin.

Comparison between Antiemetic Effects of Palonosetron and Granisetron on Chemotherapy-Induced Nausea and Vomiting in Japanese Patients Treated with R-CHOP.

PubMed

Uchida, Mayako; Mori, Yasuo; Nakamura, Tsutomu; Kato, Koji; Kamezaki, Kenjiro; Takenaka, Katsuto; Shiratsuchi, Motoaki; Kadoyama, Kaori; Miyamoto, Toshihiro; Akashi, Koichi

2017-01-01

In the present study, the antiemetic effect of palonosetron, not combined with dexamethasone and aprepitant, on chemotherapy-induced nausea and vomiting was evaluated in patients with malignant lymphoma receiving first-line rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy, and was compared to that of granisetron. A total of 74 patients with non-Hodgkin lymphoma were included in this study (April 2007 to December 2015). Palonosetron (0.75 mg) or granisetron (3 mg) was intravenously administered before R-CHOP therapy. The proportions of patients with complete response (CR) during the overall (0-120 h after the start of R-CHOP therapy), acute (0-24 h) and delayed (24-120 h) phases were evaluated. CR was defined as no vomiting and no use of antiemetic rescue medication. A total of 32 and 42 patients were treated with palonosetron and granisetron, respectively. The CR rate in the palonosetron group was significantly higher than that in the granisetron group during the delayed phase (90.6 and 61.9%, respectively; p=0.007). Logistic regression analysis showed that use of palonosetron improved the CR rate during the delayed phase, compared to use of granisetron. Female sex, age less than 60 years, no habitual alcohol intake, and Eastern Cooperative Oncology Group performance status (ECOG-PS) score of 1 were significant risk factors associated with non-CR. The findings of this study suggested the superiority of palonosetron to granisetron, without accompanying dexamethasone and aprepitant, for chemotherapy-induced nausea and vomiting in patients with malignant lymphoma.

Can granisetron injection used as primary prophylaxis improve the control of nausea and vomiting with low- emetogenic chemotherapy?

PubMed

Keat, Chan Huan; Phua, Gillian; Abdul Kassim, Mohd Shainol; Poh, Wong Kar; Sriraman, Malathi

2013-01-01

The purpose of this study is to examine the risk of uncontrolled chemotherapy-induced nausea and vomiting (CINV) among patients receiving low emetogenic chemotherapy (LEC) with and without granisetron injection as the primary prophylaxis in addition to dexamethasone and metochlopramide. This was a single-centre, prospective cohort study. A total of 96 patients receiving LEC (52 with and 42 without granisetron) were randomly selected from the full patient list generated using the e-Hospital Information System (e-His). The rates of complete control (no CINV from days 1 to 5) and complete response (no nausea or vomiting in both acute and delayed phases) were identified through patient diaries which were adapted from the MASCC Antiemesis Tool (MAT). Selected covariates including gender, age, active alcohol consumption, morning sickness and previous chemotherapy history were controlled using the multiple logistic regression analyses. Both groups showed significant difference with LEC regimens (p<0.001). No differences were found in age, gender, ethnic group and other baseline characteristics. The granisetron group indicated a higher complete response rate in acute emesis (adjusted OR: 0.1; 95%CI 0.02-0.85; p=0.034) than did the non-granisetron group. Both groups showed similar complete control and complete response rates for acute nausea, delayed nausea and delayed emesis. Granisetron injection used as the primary prophylaxis in LEC demonstrated limited roles in CINV control. Optimization of the guideline-recommended antiemetic regimens may serve as a less costly alternative to protect patients from uncontrolled acute emesis.

Influence of serotonin on the analgesic effect of granisetron on temporomandibular joint arthritis.

PubMed Central

Voog, Ulle; Alstergren, Per; Leibur, Edvitar; Kallikorm, Riina; Kopp, Sigvard

2004-01-01

The influence of circulating serotonin (5-HT) on the effects of intra-articular administration of granisetron on temporomandibular joint (TMJ) pain was investigated in 11 patients with chronic polyarthritides. An analgesic effect superior to placebo has been shown previously. The change in TMJ movement pain intensity was negatively correlated to circulating 5-HT; that is, the higher the 5-HT before injection, the greater the reduction of pain intensity. The resting pain intensity reduction was not related to 5-HT. In conclusion, this study indicates a stronger short-term analgesic effect on TMJ movement pain by intra-articular administration of the 5-HT3 receptor antagonist granisetron in patients with high levels of circulating 5-HT. PMID:15770056

Polymorphisms in CYP1A1 and CYP3A5 Genes Contribute to the Variability in Granisetron Clearance and Exposure in Pregnant Women with Nausea and Vomiting.

PubMed

Bustos, Martha L; Zhao, Yang; Chen, Huijun; Caritis, Steve N; Venkataramanan, Raman

2016-12-01

Nausea and vomiting affect up to 90% of pregnant women. Granisetron is a potent and highly selective serotonin receptor antagonist and is an effective antiemetic. Findings from a prior study in pregnant women demonstrated a large interindividual variability in granisetron exposure. Granisetron is primarily metabolized by the cytochrome P450 (CYP) enzymes CYP1A1 and CYP3A and is likely a substrate of the ABCB1 transporter. Single-nucleotide polymorphisms (SNPs) in CYP3A, CYP1A1, and ABCB1 can alter drug metabolism. This study evaluated the influence of polymorphisms in CYP3A4, CYP3A5, CYP1A1, and ABCB1 on the pharmacokinetic properties of granisetron in pregnant women. The study enrolled 16 pregnant women (gestational age of 12-19 wks). All patients had nausea and vomiting and were treated with granisetron 1 mg. Granisetron plasma concentrations were determined using liquid chromatography tandem-mass spectrometry. The patients' genotype was determined using TaqMan SNP Genotyping Assays. The Hardy-Weinberg equilibrium was assessed by comparing observed and expected genotype frequencies, using the exact test. Intravenous granisetron clearance was used as the dependent variable for analysis of associations. Of 16 patients, 25% were homozygous for the allele variant CYP3A5*3 and had a significantly lower granisetron clearance and increased area under the plasma concentration-versus-time curve (AUC) compared with nonhomozygous patients. Approximately one-third of patients (n=5) were carriers for the allele variant CYP1A1*2A and had a significantly higher granisetron clearance and decreased AUC. We did not find significant differences in the AUC or clearance for any SNPs in CYP3A4 and ABCB1 genes. Polymorphisms in CYP3A5 and CYP1A1 account for some of the variability in systemic clearance and exposure of granisetron in pregnant women. © 2016 Pharmacotherapy Publications, Inc.

Compatibility of butorphanol with granisetron in 0.9% sodium chloride injection packaged in glass bottles or polyolefin bags.

PubMed

Chen, Fu-Chao; Xiong, Hui; Liu, Hui-Min; Fang, Bao-Xia; Li, Peng

2015-08-15

The stability of admixtures containing butorphanol and granisetron in polyolefin bags and glass bottles stored at 4 and 25 °C was studied. Commercial solutions of butorphanol tartrate and granisetron hydrochloride were combined and further diluted with 0.9% sodium chloride injection to final concentrations of butorphanol tartrate 0.08 mg/mL and granisetron 0.03 or 0.06 mg/mL; the resulting mixtures were packaged in polyolefin bags and glass bottles. The admixtures were assessed for periods of up to 48 hours after storage at 25 °C without protection from room light and up to 14 days at 4 °C with protection from room light. The chemical stability of the admixtures was evaluated by a validated high-performance liquid chromatography (HPLC) method and by measurement of pH values. Solution appearance and color were assessed by observing the samples against room light and dark backgrounds. HPLC analysis demonstrated that the percentages of the initial concentrations of butorphanol and granisetron in the various solutions remained above 97% during the testing period. No changes in color or turbidity were observed in any of the prepared solutions. Throughout this period, pH values remained stable. Admixtures of butorphanol tartrate 0.08 mg/mL and granisetron 0.03 or 0.06 mg/mL in 0.9% sodium chloride injection in polyolefin bags or glass bottles remained stable for 48 hours when stored at 25 °C exposed to room light and for 14 days when stored at 4 °C protected from room light. Copyright © 2015 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

Comparative trial of two intravenous doses of granisetron (1 versus 3 mg) in the prevention of chemotherapy-induced acute emesis: a double-blind, randomized, non-inferiority trial.

PubMed

Tsuji, Daiki; Kim, Yong-Il; Taku, Keisei; Nakagaki, Shigeru; Ikematsu, Yoshito; Tsubota, Hiromi; Maeda, Masato; Hashimoto, Naoya; Kimura, Masayuki; Daimon, Takashi

2012-05-01

A single 3 mg or 40 μg/kg intravenous dose of granisetron combined with dexamethasone is routinely used in several countries, although the antiemetic guidelines have recommended granisetron at the dose of 1 mg or 10 μg/kg. A randomized, multicenter trial was conducted to determine the optimal intravenous granisetron dose, 1 or 3 mg, in cancer patients receiving emetogenic chemotherapy. We enrolled 365 patients and randomly assigned them to receive intravenous granisetron 3 mg (3-mg group) or 1 mg (1-mg group), combined with dexamethasone at an adequate dose fixed as per the emetic risk category. The primary end point was the proportion of patients with a complete response during the first 24 h after chemotherapy. The study demonstrated that 1 mg of granisetron was not inferior in effect to 3 mg. For the primary end point, 359 patients were evaluable according to the modified intention-to-treat (ITT) analysis. Complete protection was achieved in the modified ITT population, 90.6% and 88.8% for the 3- and 1-mg groups, respectively (p < 0.01 for non-inferiority). This study showed that 1 mg granisetron is not inferior to 3 mg when both doses are combined with dexamethasone. Therefore, 1-mg dose of intravenous granisetron should be the recommended prophylactic regimen for the prevention of acute emesis.

Combination of haloperidol, dexamethasone, and ondansetron reduces nausea and pain intensity and morphine consumption after laparoscopic sleeve gastrectomy.

PubMed

Benevides, Márcio Luiz; Oliveira, Sérgio de Souza; Aguilar-Nascimento, José Eduardo

2013-01-01

Postoperative nausea and vomiting (PONV) occur frequently after laparoscopic bariatric surgery. The combination of haloperidol, dexamethasone, and ondansetron may reduce these undesirable events. The aim of this study was to evaluate the intensity of nausea and pain, the number of vomiting episodes, and morphine consumption in postoperative (PO) obese patients undergoing laparoscopic sleeve gastrectomy (LSG). A clinical, randomized, controlled, double-blind study conducted with 90 patients with body mass index ≥ 35 kg.cm-2. Patients were divided into three groups of 30 individuals to receive ondansetron 8 mg (Group O); ondansetron 8 mg and dexamethasone 8 mg (Group OD); and ondansetron 8 mg, dexamethasone 8 mg, and haloperidol 2 mg (Group HDO). We evaluated the intensity of nausea and pain using the verbal numeric scale, cumulative number of vomiting episodes, and morphine consumption in the period of 0-2, 2-12, 12-24, and 24-36 hours postoperatively. Nausea intensity was lower in Group HDO compared to Group O (p = 0.001), pain intensity was lower in Group HDO compared to Group O (p = 0.046), and morphine consumption was lower in Group HDO compared to Group O (p = 0.037). There was no difference between groups regarding the number of vomiting episodes (p = 0.052). The combination of haloperidol, ondansetron, and dexamethasone reduced nausea and pain intensity and morphine consumption in postoperative obese patients undergoing LSG.

Management of chemotherapy-induced nausea and vomiting in patients receiving multiple-day highly or moderately emetogenic chemotherapy: role of transdermal granisetron.

PubMed

Coluzzi, Flaminia; Mattia, Consalvo

2016-08-01

Granisetron transdermal delivery system (GTDS) is the first 5-HT3 drug to be transdermally delivered and represents a convenient alternative to oral and intravenous antiemetics for the treatment of chemotherapy-induced nausea and vomiting. GTDS is effective and well tolerated in patients receiving multiple-day moderate-to-highly emetogenic chemotherapy. In this setting noninferiority studies showed similar efficacy when GTDS was compared with intravenous and oral granisetron and intravenous palonosetron. GTDS has shown good cardiovascular safety; however, special caution is needed in patients at risk for developing excessive QTc interval prolongation and arrhythmias. So far, GTDS has been investigated for intravenous prevention in comparison with granisetron and palonosetron; however, further prospects open the route to future clinical investigations.

Dexamethasone, ondansetron, and their combination and postoperative nausea and vomiting in children undergoing strabismus surgery: a meta-analysis of randomized controlled trials.

PubMed

Shen, Yun-Dun; Chen, Chien-Yu; Wu, Chih-Hsiung; Cherng, Yih-Giun; Tam, Ka-Wai

2014-05-01

Postoperative nausea and vomiting (PONV) is a common complication after pediatric strabismus surgery. Steroids and ondansetron (a 5-HT3 antagonist) can effectively reduce nausea, vomiting, and pain and thus might be useful agents for the prevention of PONV in pediatric patients. The aim of this study was to conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the prophylactic effects of dexamethasone and ondansetron on PONV after strabismus surgery in pediatric patients. A comprehensive literature search was conducted to identify RCTs that investigated the efficacy and safety of intravenous dexamethasone or ondansetron on PONV in pediatric strabismus surgical patients. The primary outcome was the incidence of PONV during the initial 24 postoperative hours. The secondary outcomes were number of patients requiring a rescue antiemetic and complications. We included 13 RCTs that evaluated 2006 patients. In the two studies that compared dexamethasone and placebo treatments, POV occurred in 34.3% (23/67) of the patients in the dexamethasone group and in 68.2% (45/66) of the patients in the placebo group. The difference between the two groups was significant (RR 0.50; 95% confidence interval (CI) 0.34-0.72). Similarly, seven studies that compared ondansetron and a placebo identified a relatively lower incidence of PONV in the ondansetron group (103/277, 37.2%) than in the placebo group (177/270, 65.6%). The difference between the two groups was also significant (RR 0.58; 95% CI 0.43-0.79). The combination of dexamethasone and ondansetron was significantly more effective at reducing the incidence of POV than dexamethasone or ondansetron alone. In all included RCTs, experimental drug-related complications, such as facial flushing and headache, were limited. Surgeons and anesthesiologists are recommended to administer the combination of dexamethasone and ondansetron to pediatric patients undergoing strabismus surgery. © 2014 John

The incidence of anticipatory nausea and vomiting after repeat cycle chemotherapy: the effect of granisetron.

PubMed Central

Aapro, M. S.; Kirchner, V.; Terrey, J. P.

1994-01-01

Anticipatory nausea and vomiting (ANV) after repeated cycles of cytotoxic chemotherapy is thought to be a conditioned response to a conditioning stimulus. Good control of acute and delayed emesis may result in a lower incidence of ANV. We have analysed data from 574 chemotherapy patients who received granisetron as their antiemetic treatment during repeat cycle chemotherapy. Per treatment cycle, less than 10% of patients displayed symptoms of anticipatory nausea and 2% or less had symptoms of anticipatory vomiting. It is concluded that the use of granisetron as an antiemetic during the acute phase of chemotherapy may result in a lower incidence of ANV in patients undergoing repeat cycle chemotherapy. PMID:8180031

The effect of ondansetron, a 5-HT3 receptor antagonist, in chronic fatigue syndrome: a randomized controlled trial.

PubMed

The, Gerard K H; Bleijenberg, Gijs; Buitelaar, Jan K; van der Meer, Jos W M

2010-05-01

Accumulating data support the involvement of the serotonin (5-hydroxytryptamine [5-HT]) system in the pathophysiology of chronic fatigue syndrome. Neuropharmacologic studies point to a hyperactive 5-HT system, and open-label treatment studies with 5-HT(3) receptor antagonists have shown promising results. In this randomized controlled clinical trial, the effect of ondansetron, a 5-HT(3) receptor antagonist, was assessed on fatigue severity and functional impairment in adult patients with chronic fatigue syndrome. A randomized, placebo-controlled, double-blind clinical trial was conducted at Radboud University Nijmegen Medical Centre, The Netherlands. Sixty-seven adult patients who fulfilled the US Centers for Disease Control and Prevention (CDC) criteria for chronic fatigue syndrome and who were free from current psychiatric comorbidity participated in the clinical trial. Participants received either ondansetron 16 mg per day or placebo for 10 weeks. The primary outcome variables were fatigue severity (Checklist Individual Strength fatigue severity subscale [CIS-fatigue]) and functional impairment (Sickness Impact Profile-8 [SIP-8]). The effect of ondansetron was assessed by analysis of covariance. Data were analyzed on an intention-to-treat basis. All patients were recruited between June 2003 and March 2006. Thirty-three patients were allocated to the ondansetron condition, 34 to the placebo condition. The 2 groups were well matched in terms of age, sex, fatigue severity, functional impairment, and CDC symptoms. Analysis of covariance showed no significant differences between the ondansetron- and placebo-treated groups during the 10-week treatment period in fatigue severity and functional impairment. This clinical trial demonstrates no benefit of ondansetron compared to placebo in the treatment of chronic fatigue syndrome. www.trialregister.nl: ISRCTN02536681. ©Copyright 2010 Physicians Postgraduate Press, Inc.

Prevention of dimethylsulfoxide-related nausea and vomiting by prophylactic administration of ondansetron for patients receiving autologous cryopreserved peripheral blood stem cells.

PubMed

Eisenberg, Seth; Wickline, Mihkaila; Linenberger, Michael; Gooley, Ted; Holmberg, Leona

2013-05-01

To evaluate the effectiveness of ondansetron for the prevention of nausea and vomiting from dimethylsulfoxide (DMSO) during autologous stem cell transplantation (ASCT) infusion. Nonrandomized cohort using historical control. Comprehensive cancer center outpatient infusion department. 50 patients receiving ASCT in the outpatient setting. Patients were assessed for nausea and vomiting on their infusion day using the Multinational Association of Supportive Care in Cancer Antiemesis Tool (MAT) at arrival, pre-ASCT infusion, pre-ondansetron administration, prior to the first bag, and after each bag of stem cells. A standard script was used to ensure consistency. Ondansetron, 16 mg IV, was administered 30-90 minutes prior to each ASCT infusion. Number and volume of stem cells bags, as well as infusion rate and emesis episodes, were recorded. Nausea scores and vomiting episodes were compared to historical data. Subjectivity of nausea, potential Hawthorne Effect. Forty-five percent of patients had an MAT score greater than 2 on arrival, decreasing to 18% after receiving ondansetron before the first bag. Twenty-four percent had MAT increases of more than two points by infusion end compared to 58% in the historic control group. Eighteen percent of patients vomited compared to 28% of historic controls. The administration of 16 mg of IV ondansetron significantly reduced DMSO-related nausea and episodes of vomiting in patients receiving ASCT. Prophylactic administration of ondansetron had a positive effect on reducing nausea symptoms and episodes of vomiting during ASCT infusions. These results prompted a change in clinical practice. More research is required to determine whether the inclusion of other antiemetic agents would provide even greater benefit. To date, no other published studies have explored the benefits of premedicating patients with ondansetron prior to ASCT infusions. This study is the first to establish efficacy of ondansetron for an unlabeled indication. These

Ondansetron reduces naturalistic drinking in non-treatment seeking alcohol dependent individuals with the LL 5′-HTTLPR genotype: a laboratory study

PubMed Central

Kenna, George A.; Zywiak, William H.; Swift, Robert M.; McGeary, John E.; Clifford, James S.; Shoaff, Jessica R.; Vuittonet, Cynthia; Fricchione, Samuel; Brickley, Michael; Beaucage, Kayla; Haass-Koffler, Carolina L.; Leggio, Lorenzo

2014-01-01

Background One hypothesis suggests that the differential response to ondansetron and serotonin specific re-uptake inhibitors (SSRIs) may be due to a functional polymorphism of the 5′-HTTLPR promoter region in SLC6A4, the gene that codes for the serotonin transporter (5-HTT). The LL 5′-HTTLPR genotype is postulated to be specifically sensitive to the effects of ondansetron with SS/SL 5′-HTTLPR genotypes sensitive to SSRIs. This study tests this hypothesis by matching non-treatment seeking alcohol dependent (AD) individuals with LL genotype to ondansetron and SS/SL genotypes to the SSRI sertraline, and mis-matching them assessing naturalistic and bar-laboratory alcohol drinking. Methods Seventy-seven AD individuals were randomized to one of two counterbalanced arms to receive sertraline 200mg/day or ondansetron 0.5 mg/day for three weeks followed by an alcohol self-administration experiment (ASAE), then received placebo for three weeks followed by a second ASAE. Individuals then received the alternate drug for three weeks followed by a third ASAE. Drinks per drinking day (DDD with drinks in SDUs) for 7 days prior to each ASAE and milliliters consumed during each ASAE were the primary outcomes. Results Fifty-five participants completed the study. The genotype x order interaction was significant [F(1,47) = 8.42, p = .006] for DDD. Three ANCOVAs were conducted for DDD during the week before each ASAE. Ondansetron compared to sertraline resulted in a significant reduction in DDD during the week before the first [F(1,47) = 7.64, p = .008] but not the third ASAE. There was no difference in milliliters consumed during each ASAE. Conclusion This study modestly supports the hypothesis that ondansetron may reduce DDD in AD individuals with the LL genotype as measured naturalistically. By contrast there was no support that ondansetron reduces drinking during the ASAEs or that sertraline reduces alcohol use in individuals who have SS/SL genotypes. We provide limited

A double-blind, crossover, randomized comparison of granisetron and ramosetron for the prevention of acute and delayed cisplatin-induced emesis in patients with gastrointestinal cancer: is patient preference a better primary endpoint?

PubMed

Koizumi, Wasaburo; Tanabe, Satoshi; Nagaba, Shizuka; Higuchi, Katsuhiko; Nakayama, Norisuke; Saigenji, Katsunori; Nonaka, Miwa; Yago, Kazuo

2003-12-01

Serotonin receptor antagonists are recommended by the American Society of Clinical Oncology for the prevention of acute and delayed chemotherapy-induced emesis. However, the most effective agent in this class of antiemetic drugs for preventing emesis has not been clearly defined. We therefore performed a double-blind, crossover, randomized, controlled trial comparing the efficacy of granisetron and ramosetron, using patient preference as the primary endpoint. Thirty patients receiving two courses of combined chemotherapy (including > or =60 mg/m(2) cisplatin) for gastric or esophageal cancer were randomly assigned to the granisetron-ramosetron group (treatment phase 1: granisetron, 3 mg; treatment phase 2: ramosetron, 0.3 mg) or the ramosetron-granisetron group (treatment phase 1: ramosetron, 0.3 mg; treatment phase 2: granisetron, 3 mg). All patients received methylprednisolone sodium, 250 mg i.v., during each treatment phase. The efficacy of granisetron and ramosetron was similar in terms of the suppression of emesis and appetite status. However, the majority of patients (19/30, 63.3%) expressed a preference for granisetron, as compared with 9 patients (30.0%) who preferred ramosetron; 2 patients (6.7%) had no preference (chi(2) test: p = 0.008; Fisher's exact test: p = 0.015). (1) A significant proportion of patients prefer granisetron over ramosetron for the prevention of chemotherapy-induced emesis. (2) Granisetron and ramosetron possess similar effectiveness for the suppression of emesis. (3) The variable of 'patient preference' should be accepted as a primary endpoint of antiemetic drug efficacy. Copyright 2003 S. Karger AG, Basel

Oral Ondansetron versus Domperidone for Acute Gastroenteritis in Pediatric Emergency Departments: Multicenter Double Blind Randomized Controlled Trial

PubMed Central

Bonati, Maurizio; Maestro, Alessandra; Zanon, Davide; Rovere, Francesca; Arrighini, Alberto; Barbi, Egidio; Bertolani, Paolo; Biban, Paolo; Da Dalt, Liviana; Guala, Andrea; Mazzoni, Elisa; Pazzaglia, Anna; Perri, Paolo Francesco; Reale, Antonino; Renna, Salvatore; Urbino, Antonio Francesco; Valletta, Enrico; Vitale, Antonio; Zangardi, Tiziana; Clavenna, Antonio

2016-01-01

The use of antiemetics for vomiting in acute gastroenteritis in children is still a matter of debate. We conducted a double-blind randomized trial to evaluate whether a single oral dose of ondansetron vs domperidone or placebo improves outcomes in children with gastroenteritis. After failure of initial oral rehydration administration, children aged 1–6 years admitted for gastroenteritis to the pediatric emergency departments of 15 hospitals in Italy were randomized to receive one oral dose of ondansetron (0.15 mg/kg) or domperidone (0.5 mg/kg) or placebo. The primary outcome was the percentage of children receiving nasogastric or intravenous rehydration. A p value of 0.014 was used to indicate statistical significance (and 98.6% CI were calculated) as a result of having carried out two interim analyses. 1,313 children were eligible for the first attempt with oral rehydration solution, which was successful for 832 (63.4%); 356 underwent randomization (the parents of 125 children did not give consent): 118 to placebo, 119 to domperidone, and 119 to ondansetron. Fourteen (11.8%) needed intravenous rehydration in the ondansetron group vs 30 (25.2%) and 34 (28.8%) in the domperidone and placebo groups, respectively. Ondansetron reduced the risk of intravenous rehydration by over 50%, both vs placebo (RR 0.41, 98.6% CI 0.20–0.83) and domperidone (RR 0.47, 98.6% CI 0.23–0.97). No differences for adverse events were seen among groups. In a context of emergency care, 6 out of 10 children aged 1–6 years with vomiting due to gastroenteritis and without severe dehydration can be managed effectively with administration of oral rehydration solution alone. In children who fail oral rehydration, a single oral dose of ondansetron reduces the need for intravenous rehydration and the percentage of children who continue to vomit, thereby facilitating the success of oral rehydration. Domperidone was not effective for the symptomatic treatment of vomiting during acute

Oral Ondansetron versus Domperidone for Acute Gastroenteritis in Pediatric Emergency Departments: Multicenter Double Blind Randomized Controlled Trial.

PubMed

Marchetti, Federico; Bonati, Maurizio; Maestro, Alessandra; Zanon, Davide; Rovere, Francesca; Arrighini, Alberto; Barbi, Egidio; Bertolani, Paolo; Biban, Paolo; Da Dalt, Liviana; Guala, Andrea; Mazzoni, Elisa; Pazzaglia, Anna; Perri, Paolo Francesco; Reale, Antonino; Renna, Salvatore; Urbino, Antonio Francesco; Valletta, Enrico; Vitale, Antonio; Zangardi, Tiziana; Clavenna, Antonio; Ronfani, Luca

2016-01-01

The use of antiemetics for vomiting in acute gastroenteritis in children is still a matter of debate. We conducted a double-blind randomized trial to evaluate whether a single oral dose of ondansetron vs domperidone or placebo improves outcomes in children with gastroenteritis. After failure of initial oral rehydration administration, children aged 1-6 years admitted for gastroenteritis to the pediatric emergency departments of 15 hospitals in Italy were randomized to receive one oral dose of ondansetron (0.15 mg/kg) or domperidone (0.5 mg/kg) or placebo. The primary outcome was the percentage of children receiving nasogastric or intravenous rehydration. A p value of 0.014 was used to indicate statistical significance (and 98.6% CI were calculated) as a result of having carried out two interim analyses. 1,313 children were eligible for the first attempt with oral rehydration solution, which was successful for 832 (63.4%); 356 underwent randomization (the parents of 125 children did not give consent): 118 to placebo, 119 to domperidone, and 119 to ondansetron. Fourteen (11.8%) needed intravenous rehydration in the ondansetron group vs 30 (25.2%) and 34 (28.8%) in the domperidone and placebo groups, respectively. Ondansetron reduced the risk of intravenous rehydration by over 50%, both vs placebo (RR 0.41, 98.6% CI 0.20-0.83) and domperidone (RR 0.47, 98.6% CI 0.23-0.97). No differences for adverse events were seen among groups. In a context of emergency care, 6 out of 10 children aged 1-6 years with vomiting due to gastroenteritis and without severe dehydration can be managed effectively with administration of oral rehydration solution alone. In children who fail oral rehydration, a single oral dose of ondansetron reduces the need for intravenous rehydration and the percentage of children who continue to vomit, thereby facilitating the success of oral rehydration. Domperidone was not effective for the symptomatic treatment of vomiting during acute gastroenteritis.

Oral Ondansetron in Management of Dehydrating Diarrhea with Vomiting in Children Aged 3 Months to 5 Years: A Randomized Controlled Trial.

PubMed

Danewa, Arun Singh; Shah, Dheeraj; Batra, Prerna; Bhattacharya, Swapan Kumar; Gupta, Piyush

2016-02-01

To evaluate the role of oral ondansetron in facilitating successful rehydration of under-5-year-old children suffering from acute diarrhea with vomiting and some dehydration. Children (n = 170) aged 3 months to 5 years with acute diarrhea with vomiting and some dehydration were enrolled in this double blind, randomized, placebo-controlled trial. The participants were randomized to receive either single dose of oral ondansetron (n = 85) or placebo (n = 85) in addition to standard management of dehydration according to World Health Organization guidelines. Failure of oral rehydration therapy (ORT), administration of unscheduled intravenous fluids, and amount of oral rehydration solution intake in 4 hours were the primary outcomes. Secondary outcome measures included duration of dehydration correction, number of vomiting episodes, adverse effects, and caregiver satisfaction. Failure of ORT was significantly less in children receiving ondansetron compared with those receiving placebo (31% vs 62%; P < .001; relative risk 0.50, 95% CI 0.35-0.72). Almost one-half of the children in the ondansetron group received intravenous fluids compared with those in the placebo group, but it was not statistically significant (P = .074; relative risk 0.56, 95% CI 0.30-1.07). The oral rehydration solution consumption was significantly more in the ondansetron group (645 mL vs 554 mL; mean difference 91 mL; 95% CI: 35-148 mL). Patients in the ondansetron group also showed faster rehydration, lesser number of vomiting episodes, and better caregiver satisfaction. A single oral dose of ondansetron, given before starting ORT to children <5 years of age with acute diarrhea and vomiting results in better oral rehydration. Clinical Trial Registry of India: CTRI-2011/07/001916. Copyright © 2016 Elsevier Inc. All rights reserved.

Ondansetron for reduction of drinking among biologically predisposed alcoholic patients: A randomized controlled trial.

PubMed

Johnson, B A; Roache, J D; Javors, M A; DiClemente, C C; Cloninger, C R; Prihoda, T J; Bordnick, P S; Ait-Daoud, N; Hensler, J

Early-onset alcoholism differs from late-onset alcoholism by its association with greater serotonergic abnormality and antisocial behaviors. Thus, individuals with early-onset alcoholism may be responsive to treatment with a selective serotonergic agent. To test the hypothesis that drinking outcomes associated with early vs late-onset alcoholism are differentially improved by the selective 5-HT(3) (serotonin) antagonist ondansetron. Double-blind, randomized, placebo-controlled clinical trial. University of Texas Health Science Center in Houston (April 1995-June 1998) and University of Texas Health Science Center in San Antonio (July 1998-December 1999). A total of 321 patients with diagnosed alcoholism (mean age, 40.6 years; 70.5% male; 78.6% white) were enrolled, 271 of whom proceeded to randomization. After 1 lead-in week of single-blind placebo, patients were randomly assigned to receive 11 weeks of treatment with ondansetron, 1 microg/kg (n = 67), 4 microg/kg (n = 77), or 16 microg/kg (n = 71) twice per day; or identical placebo (n = 56). All patients also participated in weekly standardized group cognitive behavioral therapy. Self-reported alcohol consumption (drinks per day, drinks per drinking day, percentage of days abstinent, and total days abstinent per study week); and plasma carbohydrate deficient transferrin (CDT) level, an objective and sensitive marker of transient alcohol consumption. Patients with early-onset alcoholism who received ondansetron (1, 4, and 16 microg/kg twice per day) compared with those who were administered placebo, had fewer drinks per day (1.89, 1.56, and 1.87 vs 3.30; P =.03, P =.01, and P =.02, respectively) and drinks per drinking day (4.75, 4.28, and 5.18 vs 6.90; P =.03, P =.004, and P =.03, respectively). Ondansetron, 4 microg/kg twice per day, was superior to placebo in increasing percentage of days abstinent (70.10 vs 50.20; P =.02) and total days abstinent per study week (6.74 vs 5.92; P =.03). Among patients with early

Ondansetron does not prevent physical dependence in patients taking opioid medications chronically for pain control.

PubMed

Chu, Larry F; Rico, Tom; Cornell, Erika; Obasi, Hannah; Encisco, Ellen M; Vertelney, Haley; Gamble, Jamison G; Crawford, Clayton W; Sun, John; Clemenson, Anna; Erlendson, Matthew J; Okada, Robin; Carroll, Ian; Clark, J David

2018-02-01

In this study, we investigated the co-administration of ondansetron with morphine, and whether it could prevent the development of physical dependence in patients taking opioids for the treatment of chronic pain. A total of 48 chronic back pain patients (N = 48) participated in this double-blinded, placebo-controlled, randomized study. Patients were titrated onto sustained-release oral morphine and randomized to take 8 mg ondansetron or placebo three times daily concurrently with morphine during the 30-day titration. Following titration, patients underwent Naloxone induced opioid withdrawal. Opioid withdrawal signs and symptoms were then assessed by a blinded research assistant (objective opioid withdrawal score: OOWS) and by the research participant (subjective opioid withdrawal score: SOWS). We observed clinically significant signs of naloxone-precipitated opioid withdrawal in all participants (ΔOOWS = 4.3 ± 2.4, p < 0.0001; ΔSOWS = 14.1 ± 11.7, p < 0.0001), however no significant differences in withdrawal scores were detected between treatment groups. We hypothesized that ondansetron would prevent the development of physical dependence in human subjects when co-administered with opioids, but found no difference in naloxone-precipitated opioid withdrawal scores between ondansetron and placebo treatment groups. These results suggest that further studies are needed to determine if 5HT 3 receptor antagonists are useful in preventing opioid physical dependence. Copyright © 2017 Elsevier B.V. All rights reserved.

Double-blind comparison of granisetron, promethazine, or a combination of both for the prevention of postoperative nausea and vomiting in females undergoing outpatient laparoscopies.

PubMed

Gan, Tong J; Candiotti, Keith A; Klein, Stephen M; Rodriguez, Yiliam; Nielsen, Karen C; White, William D; Habib, Ashraf S

2009-11-01

Postoperative nausea and vomiting (PONV) and postdischarge nausea and vomiting (PDNV) are common problems after surgery. Prophylactic combination antiemetic therapy is recommended for patients at high risk for developing PONV and PDNV. Granisetron, a serotonin antagonist, is an effective antiemetic that is devoid of sedative side effect. Although promethazine is effective, commonly used doses are associated with sedation. This study investigates the combination of low doses of granisetron and promethazine for the prevention of PONV. Women undergoing ambulatory gynecological laparoscopy were enrolled. A standard general anesthetic regimen was prescribed. Fifteen minutes before the expected end of surgery, the patients were randomly assigned to receive granisetron 0.1 mg iv, promethazine 6.25 mg iv, or a combination of the two drugs. Prophylaxis with oral promethazine 12.5 mg, granisetron 1 mg, or both was started in the respective groups 12 hr after the end of surgery and continued every 12 hr until postoperative day 3 (a total of five oral doses). The following outcomes were recorded: total response rate (defined as no vomiting, no more than mild nausea, and no use of rescue antiemetic); incidence of nausea, vomiting, and use of rescue antiemetics; severity of nausea; patient activity level; and patient satisfaction with PONV management. Patients in the combination group had a higher total response rate at 6, 24, 48, and 72 hr after surgery compared with those who received promethazine alone (at 24 hr, Combination 69.6%, Promethazine 36.2%, Granisetron 53.3%; P = 0.0079). The maximum nausea scores were also lower in the combination group at 6, 24, 48, and 72 hr (Combination 1.7 +/- 2.2, Promethazine 4.0 +/- 3.6, Granisetron 3.1 +/- 3.2 at 24 hr; P < 0.05). There was no difference in the sedation scores, incidence of drowsiness, patient activity level, and satisfaction with PONV management. Low-dose granisetron and promethazine combination was more effective in

Design and evaluation of ondansetron liquid suppository for the treatment of emesis.

PubMed

Ban, Eunmi; Kim, Chong-Kook

2013-05-01

The thermosensitive-mucoadhesive ondansetron liquid suppository (tmOLS) was developed to enhance patient compliance and bioavailability in high-risk patients receiving highly emetogenic therapy and having difficulty in swallowing, The thermosensitive-mucoadhesive liquid suppository bases were formulated using poloxamers (P407 and P188) and hydroxypropylmethyl cellulose (HPMC). The physicochemical properties of the liquid suppository bases were characterized by their gelation temperature, mucoadhesive force, rheological properties, and in vitro release. Rectal mucosal damage following rectal administration of tmOLS in rats was assessed using microscopy. Pharmacokinetic analyses were performed to compare tmOLS administered via the rectal route to ondansetron solution administered orally. The liquid suppository base of tmOLS contained P407, P188, and HPMC in the ratio 18:20:0.8, was in the liquid state at room temperature, underwent gelation at body temperature. Area under the curve and half-life (t1/2) of ondansetron were significantly higher in the tmOLS-treated group, indicating that the formulation bypassed the first-pass metabolism and that it was released slowly from the tmOLS because of the formation of mucoadhesive gel state. Furthermore, the t1/2 of tmOLS was two-fold that of the oral solution. Thus, tmOLS could be administered to patients who have difficulty in swallowing; however, adjustments in dosing interval may be needed.

The inhibition of cholera toxin-induced 5-HT release by the 5-HT3 receptor antagonist, granisetron, in the rat

PubMed Central

Turvill, J L; Connor, P; Farthing, M J G

2000-01-01

The secretagogue 5-hydroxytryptamine (5-HT) is implicated in the pathophysiology of cholera. 5-HT released from enterochromaffin cells after cholera toxin exposure is thought to activate non-neuronally (5-HT2 dependent) and neuronally (5-HT3 dependent) mediated water and electrolyte secretion. CT-secretion can be reduced by preventing the release of 5-HT. Enterochromaffin cells possess numerous receptors that, under basal conditions, modulate 5-HT release. These include basolateral 5-HT3 receptors, the activation of which is known to enhance 5-HT release. Until now, 5-HT3 receptor antagonists (e.g. granisetron) have been thought to inhibit cholera toxin-induced fluid secretion by blockading 5-HT3 receptors on secretory enteric neurones. Instead we postulated that they act by inhibiting cholera toxin-induced enterochromaffin cell degranulation. Isolated intestinal segments in anaesthetized male Wistar rats, pre-treated with granisetron 75 μg kg−1, lidoocaine 6 mg kg−1 or saline, were instilled with a supramaximal dose of cholera toxin or saline. Net fluid movement was determined by small intestinal perfusion or gravimetry and small intestinal and luminal fluid 5-HT levels were determined by HPLC with fluorimetric detection. Intraluminal 5-HT release was proportional to the reduction in tissue 5-HT levels and to the onset of water and electrolyte secretion, suggesting that luminal 5-HT levels reflect enterochromaffin cell activity. Both lidocaine and granisetron inhibited fluid secretion. However, granisetron alone, and proportionately, reduced 5-HT release. The simultaneous inhibition of 5-HT release and fluid secretion by granisetron suggests that 5-HT release from enterochromaffin cells is potentiated by endogenous 5-HT3 receptors. The accentuated 5-HT release promotes cholera toxin-induced fluid secretion. PMID:10882387

Transdermal granisetron for the prevention of nausea and vomiting following moderately or highly emetogenic chemotherapy in Chinese patients: a randomized, double-blind, phase III study.

PubMed

Yang, Liu-Qing; Sun, Xin-Chen; Qin, Shu-Kui; Chen, Ying-Xia; Zhang, He-Long; Cheng, Ying; Chen, Zhen-Dong; Shi, Jian-Hua; Wu, Qiong; Bai, Yu-Xian; Han, Bao-Hui; Liu, Wei; Ouyang, Xue-Nong; Liu, Ji-Wei; Zhang, Zhi-Hui; Li, Yong-Qiang; Xu, Jian-Ming; Yu, Shi-Ying

2016-12-01

The granisetron transdermal delivery system (GTDS) has been demonstrated effectiveness in the control of chemotherapy-induced nausea and vomiting (CINV) in previous studies. This is the first phase III study to evaluate the efficacy and tolerability of GTDS in patients receiving moderately emetogenic chemotherapy (MEC) or highly emetogenic chemotherapy (HEC) in China. A total of 313 patients were randomized into the GTDS group (one transdermal granisetron patch, 7 days) or the oral granisetron group (granisetron oral 2 mg/day, ≥2 days). The primary endpoint was the percentage of patients achieving complete control (CC) from chemotherapy initiation until 24 h after final administration (PEEP). Chi-square test and Fisher's exact test were used for statistical analysis. Two hundred eighty-one patients were included in the per protocol analysis. During PEEP, CC was achieved by 67 (47.52%) patients in the GTDS group and 83 (59.29%) patients in the oral granisetron group. There was no statistical significance between the groups (P=0.0559). However, the difference of the CC percentage mainly occurred on the first day of chemotherapy between the groups. The CC was 70.13% on day 1 in the GTDS group, which was significantly lower than that of 91.03% in the oral granisetron group in the full analysis set. In the following days of chemotherapy, the CC was similar between the groups. In terms of cisplatin-contained regimen and female, there was statistical significance between the groups. Both treatments were well tolerated and safe. The most common adverse event was constipation. GTDS provided effective and well-tolerated control of CINV in Chinese patients, especially to non-cisplatin-contained regimen.

A randomized controlled non-inferiority study comparing the antiemetic effect between intravenous granisetron and oral azasetron based on estimated 5-HT3 receptor occupancy.

PubMed

Endo, Junki; Iihara, Hirotoshi; Yamada, Maya; Yanase, Koumei; Kamiya, Fumihiko; Ito, Fumitaka; Funaguchi, Norihiko; Ohno, Yasushi; Minatoguchi, Shinya; Itoh, Yoshinori

2012-09-01

The acute antiemetic effect was compared between oral azasetron and intravenous granisetron based on the 5-hydroxytryptamine(3) (5-HT(3)) receptor occupancy theory. Receptor occupancy was estimated from reported data on plasma concentrations and affinity constants to 5-HT(3) receptor. A randomized non-inferiority study comparing acute antiemetic effects between oral azasetron and intravenous granisetron was performed in 105 patients receiving the first course of carboplatin-based chemotherapy for lung cancer. Azasetron exhibited the highest 5-HT(3) receptor occupancy among various first-generation 5-HT(3) antagonists. The complete response to oral azasetron was shown to be non-inferior to that of intravenous granisetron, in which the risk difference was 0.0004 (95% confidence interval: -0.0519-0.0527). The lower limit of the confidence intervals did not exceed the negative non-inferiority margin (-0.1). The complete response during the overall period was not different (68% versus 67%). Oral azasetron was found to be non-inferior to intravenous granisetron in the acute antiemetic effect against moderately emetogenic chemotherapy.

Pharmacokinetics of three formulations of ondansetron hydrochloride in healthy volunteers: 24-mg oral tablet, rectal suppository, and i.v. infusion.

PubMed

VanDenBerg, C M; Kazmi, Y; Stewart, J; Weidler, D J; Tenjarla, S N; Ward, E S; Jann, M W

2000-06-01

The absolute bioavailability and pharmacokinetics of three formulations of ondansetron hydrochloride 24 mg--an oral tablet, an intravenous solution, and an extemporaneous rectal suppository--were studied. Twelve healthy, nonsmoking volunteers (six men and six women) were given ondansetron in a study with a three-way cross-over design. All subjects received each dosage form on the same day in the following order: oral tablet, rectal suppository, and intravenous infusion. Administrations were separated by one week. Blood sampling times varied, depending on the administration route. Mean absolute bioavailability for the oral tablet and the rectal suppository differed significantly. Absorption of ondansetron was prolonged when it was administered as the rectal suppository. Absolute bioavailability for the 24-mg tablet was similar to that for other tablet strengths in previous studies. All subjects completed the study without significant adverse effects. Absorption of ondansetron from the rectal suppository was prolonged compared with the oral tablet and the i.v. infusion. Bioavailability for the 24-mg suppository formulation was considerably lower than for the 24-mg tablet.

Ondansetron Oral Dissolve Tab vs. Oral Solution in Children Presenting to the Emergency Department with Gastroenteritis.

PubMed

Thompson, Graham C; Morrison, Ellen L; Chaulk, David; Wobma, Holly; Kwong, Simon; Johnson, David W

2016-11-01

Ondansetron is often used in the emergency department (ED) to promote oral rehydration in children with acute gastroenteritis (AGE), yet medication solutions administered orally may be poorly tolerated in this population. We compared the tolerability of ondansetron oral dissolve tab (ODT) to oral solution (OS) in children presenting to the ED with AGE. Using alternate-day controlled clinical trial design, children aged 3 months to 10 years received either ondansetron ODT or OS. Our primary outcome was early vomiting (within 15 min of drug administration). The secondary outcome was intravenous (i.v.) fluid administration. There were 462/534 eligible children who met study criteria. Demographics, severity, and duration of illness were similar between groups. Using intention-to-treat analysis, early vomiting occurred in 8/209 ODT vs. 19/253 OS children (3.8% vs. 7.5%; odds ratio [OR] 0.49; 95% confidence interval [CI] 0.18-1.21). Using as-treated analysis, 6/222 (2.7%) children receiving ODT experienced early vomiting, compared with 21/221 (9.5%) of the OS group (OR 0.26; 95% CI 0.09-0.70). The proportion of children discharged without i.v. fluids was not different (intention-to-treat: ODT = 91.4% (191/209), OS = 94.1% (238/253), OR 1.49, 95% CI 0.69-3.28; as-treated: ODT = 92.3% (205/222), OS = 93.2% (206/221), OR 0.88, 95% CI 0.40-1.93). Using a conservative intention-to-treat analysis, we found that children presenting to an ED with AGE did not have statistically less early vomiting with ondansetron ODT as compared with OS. However, our as-treated analysis demonstrates that children receiving ondansetron ODT experienced early vomiting approximately one-third as often as those receiving OS. The rate of i.v. fluid administration was no different between groups regardless of the type of analysis used. Copyright © 2016 Elsevier Inc. All rights reserved.

Ondansetron attenuates depression co-morbid with obesity in obese mice subjected to chronic unpredictable mild stress; an approach using behavioral battery tests.

PubMed

Kurhe, Yeshwant; Radhakrishnan, Mahesh; Gupta, Deepali

2014-09-01

The aim of the present work was to investigate the role of ondansetron on the high fat diet (HFD) induced obese mice for behavioral and biochemical alterations using chronic unpredictable mild stress (CUMS) model of depression. Animals were fed with high fat diet for 14 weeks and subjected to different stress procedures for 4 weeks. Treatment with ondansetron was started on day 15. After day 28 behavioral assays and biochemical estimations were performed. Behavioral paradigms viz. sucrose preference test, locomotor score, forced swim test (FST) and elevated plus maze (EPM), whereas biochemical parameters like plasma glucose, total cholesterol, triglycerides and total proteins were estimated. Results examines that in behavioral assays, ondansetron significantly (P < 0.05) increased sucrose consumption, reduced immobility time in FST, increased the percent entries and time in open arm in EPM. In biochemical assessments elevated plasma glucose, total cholesterol, triglycerides and total proteins were significantly (P < 0.05) reversed by ondansetron treatment in HFD obese animals subjected to CUMS. The study indicates that the obese mice subjected to CUMS exhibited severe depressive-like symptoms and ondansetron significantly reversed the behavioral and biochemical alterations. In the present study the plasma glucose level indicates that, it could be "altered glucose level" playing an important role in depression co-morbid with obesity. Ondansetron through allosteric modulation of serotonergic system elevates the serotonin level and thereby regulates the insulin secretion and hence, reversing the "altered glucose level", could be the possible antidepressive-like mechanism against depression co-morbid with obesity.

Inadvertent Provocative Oral Ondansetron use Leading to Toxic Epidermal Necrolysis in an HIV-infected Patient

PubMed Central

Saraogi, Punit P; Nayak, Chitra S; Pereira, Rickson R; Dhurat, Rachita S

2012-01-01

Toxic epidermal necrolysis (TEN) is a severe cutaneous adverse reaction to drugs, characterized by extensive detachment of epidermis and mucous membranes with a mortality of 30-40%. An increased occurrence of cutaneous drug reactions is seen in patients with human immunodeficiency virus (HIV) infection. We present this case of TEN caused by ondansetron in an HIV-infected patient. A 24-year-old HIV-1-infected man on antitubercular therapy and cotrimoxazole, presented with extensive and confluent erosions involving the face, trunk, extremities and mucous membranes following the intake of oral ondansetron, ofloxacin and ornidazole. All the drugs were withdrawn and he was treated with intravenous dexamethasone and antibiotics with consequent healing of the erosions. However, the lesions recurred on inadvertent intake of oral ondansetron. He was treated with intravenous antibiotics, fluid resuscitation and supportive care. The skin lesions healed completely over 2 months with postinflammatory depigmentation and scarring, and the eye lesions healed with corneal opacities. We would like to emphasize that the drug most frequently associated with adverse drug reactions may be innocent in a given patient and the physician dealing with a suspected drug reaction must always remain unbiased regarding the causative drug. PMID:23248379

Development and application of a validated stability-indicating high-performance liquid chromatographic method using photodiode array detection for simultaneous determination of granisetron, methylparaben, propylparaben, sodium benzoate, and their main degradation products in oral pharmaceutical preparations.

PubMed

Hewala, Ismail; El-Fatatry, Hamed; Emam, Ehab; Mabrouk, Mokhtar

2011-01-01

A simple, rapid, and sensitive RP-HPLC method using photodiode array detection was developed and validated for the simultaneous determination of granisetron hydrochloride, 1-methyl-1H-indazole-3-carboxylic acid (the main degradation product of granisetron), sodium benzoate, methylparaben, propylparaben, and 4-hydroxybenzoic acid (the main degradation product of parabens) in granisetron oral drops and solutions. The separation of the compounds was achieved within 8 min on a SymmetryShield RP18 column (100 x 4.6 mm id, 3.5 microm particle size) using the mobile phase acetonitrile--0.05 M KH2PO4 buffered to pH 3 using H3PO4 (3+7, v/v). The photodiode array detector was used to test the purity of the peaks, and the chromatograms were extracted at 240 nm. The method was validated, and validation acceptance criteria were met in all cases. The robust method was successfully applied to the determination of granisetron and preservatives, as well as their degradation products in different batches of granisetron oral drops and solutions. The method proved to be sensitive for determination down to 0.04% (w/w) of granisetron degradation product relative to granisetron and 0.03% (w/w) 4-hydroxybenzoic acid relative to total parabens.

Effect of naltrexone and ondansetron on alcohol cue-induced activation of the ventral striatum in alcohol-dependent people.

PubMed

Myrick, Hugh; Anton, Raymond F; Li, Xingbao; Henderson, Scott; Randall, Patrick K; Voronin, Konstantin

2008-04-01

Medication for the treatment of alcoholism is currently not particularly robust. Neuroimaging techniques might predict which medications could be useful in the treatment of alcohol dependence. To explore the effect of naltrexone, ondansetron hydrochloride, or the combination of these medications on cue-induced craving and ventral striatum activation. Functional brain imaging was conducted during alcohol cue presentation. Participants were recruited from the general community following media advertisement. Experimental procedures were performed in the magnetic resonance imaging suite of a major training hospital and medical research institute. Ninety non-treatment-seeking alcohol-dependent (by DSM-IV criteria) and 17 social drinking (< 14 drinks per week) paid volunteers recruited through advertisements at an academic center. A taste of alcohol and a series of alcohol-related pictures, neutral beverage pictures, and visual control images were provided to volunteers after 7 days of double-blind randomly assigned daily dosing with 50 mg of naltrexone (n = 23), 0.50 mg of ondansetron hydrochloride (n = 23), the combination of the 2 medications (n = 20), or matching placebos (n = 24). Difference in brain blood oxygen level-dependent magnetic resonance when viewing alcohol pictures vs neutral beverage pictures with a particular focus on ventral striatum activity comparison across medication groups. Self-ratings of alcohol craving. The combination treatment decreased craving for alcohol. Naltrexone with (P = .02) or without (P = .049) ondansetron decreased alcohol cue-induced activation of the ventral striatum. Ondansetron by itself was similar to naltrexone and the combination in the overall analysis but intermediate in a region-specific analysis. Consistent with animal data that suggest that both naltrexone and ondansetron reduce alcohol-stimulated dopamine output in the ventral striatum, the current study found evidence that these medications, alone or in combination

The efficacy and safety of palonosetron compared with granisetron in preventing highly emetogenic chemotherapy-induced vomiting in the Chinese cancer patients: a phase II, multicenter, randomized, double-blind, parallel, comparative clinical trial.

PubMed

Yu, Zhaocai; Liu, Wenchao; Wang, Ling; Liang, Houjie; Huang, Ying; Si, Xiaoming; Zhang, Helong; Liu, Duhu; Zhang, Hongmei

2009-01-01

This clinical trial was conducted to evaluate the efficacy and safety of Palonosetron in preventing chemotherapy-induced vomiting (CIV) among the Chinese cancer patients. Two hundred and forty patients were scheduled to be enrolled and randomized to receive a single intravenous dose of palonosetron 0.25 mg, or granisetron 3 mg, 30 min before receiving highly emetogenic chemotherapy. The primary efficacy endpoint was the complete response (CR) rate for acute CIV (during the 0-24-h interval after chemotherapy). Secondary endpoints included the CR rates for delayed CIV (more than 24 h after chemotherapy). Two hundred and eight patients were accrued and received study medication. CR rates for acute CIV were 82.69% for palonosetron and 72.12% for granisetron, which demonstrated that palonosetron was not inferior to granisetron in preventing acute CIV. Comparisons of CR rates for delayed CIV yielded no statistical difference between palonosetron and granisetron groups and did not reveal non-inferiority of palonosetron to granisetron. Adverse events were mostly mild to moderate, with quite low rates among the two groups. A single dose (0.25 mg) of palonosetron is not inferior to a single dose (3 mg) of granisetron in preventing CIV and possesses an acceptable safety profile in the Chinese population.

Sodium Dodecyl Sulphate-Supported Nanocomposite as Drug Carrier System for Controlled Delivery of Ondansetron.

PubMed

Sharma, Gaurav; Naushad, Mu; Thakur, Bharti; Kumar, Amit; Negi, Poonam; Saini, Reena; Chahal, Anterpreet; Kumar, Ashok; Stadler, Florian J; Aqil, U M H

2018-02-27

Sodium dodecyl sulphate-supported iron silicophosphate (SDS/FeSP) nanocomposite was successfully fabricated by the co-precipitation method. The SDS/FeSP nanocomposite was investigated as a drug carrier for ondansetron. The cumulative drug release of ondansetron was observed at various pH values for different time intervals, i.e., from 20 min to 48 h. A ranking of the drug release was observed at different pHs; pH 2.2 > saline (pH 5.5) > pH 7.4 > pH 9.4 > distilled water. Maximum release of encapsulated drug was found to be about 45.38% at pH 2.2. The cell viability tests of SDS/FeSP nanocomposite concluded that SDS/FeSP nanocomposite was non-cytotoxic in nature.

Ondansetron, orally disintegrating tablets versus intravenous injection for prevention of intrathecal morphine-induced nausea, vomiting, and pruritus in young males.

PubMed

Pirat, Arash; Tuncay, Senay F; Torgay, Adnan; Candan, Selim; Arslan, Gulnaz

2005-11-01

In this study we compared the efficacy of orally disintegrating tablets (ODT) and IV ondansetron for preventing spinal morphine-induced pruritus and postoperative nausea and vomiting (PONV) in healthy young male patients. Patients who received bupivacaine with 0.20 mg morphine for spinal anesthesia were randomly assigned to the ODT group (ODT ondansetron 8 mg, n = 50), the IV group (4 mg ondansetron IV, n = 50), or the placebo group (n = 50). Each individual was assessed for pruritus, postoperative nausea and vomiting, and pain at 0, 2, 6, 12, 18, and 24 h after surgery using three distinct visual analog scales. The frequencies of postoperative nausea and vomiting and frequencies of requirement for rescue antiemetic and antipruritic were recorded. There were no significant differences among the three groups with respect to incidence or severity of PONV or postoperative pain visual analog scale scores. The incidences of pruritus in the ODT (56%) and IV (66%) groups were significantly different from that in the placebo group (86%) (P < 0.02 for both). Only the ODT group had significantly lower mean pruritus visual analog scale scores at 0, 2, 6, and 12 h postsurgery than the placebo group (P < 0.023 for all). The frequency of requirement for rescue antipruritic was significantly less in the ODT group than the placebo group (P = 0.013). Both ODT ondansetron 8 mg and IV ondansetron 4 mg are more effective than placebo for preventing spinal morphine-induced pruritus, but neither form of this agent reduces spinal morphine-induced postoperative nausea and vomiting in this patient group.

Effects of a 5-HT(3) antagonist, ondansetron, on fasting and postprandial small bowel water content assessed by magnetic resonance imaging.

PubMed

Marciani, L; Wright, J; Foley, S; Hoad, C L; Totman, J J; Bush, D; Hartley, C; Armstrong, A; Manby, P; Blackshaw, E; Perkins, A C; Gowland, P A; Spiller, R C

2010-09-01

5-HT(3) antagonists have been shown to be effective in relieving the symptoms of irritable bowel syndrome with diarrhoea (IBS-D). Using a recently validated magnetic resonance imaging (MRI) method, we have demonstrated reduced fasting small bowel water content (SBWC) in IBS-D associated with accelerated small bowel transit. We hypothesized that slowing of transit with ondansetron would lead to an increase in SBWC by inhibiting fasting motility. To assess the effects of ondansetron compared with placebo in healthy volunteers on SBWC and motility in two different groups of subjects, one studied using MRI and another using manometry. Healthy volunteers were given either a placebo or ondansetron on the day prior to and on the study day. Sixteen volunteers underwent baseline fasting and postprandial MRI scans for 270 min. In a second study, a separate group of n = 18 volunteers were intubated and overnight migrating motor complex (MMC) recorded. Baseline MRI scans were carried out after the tube was removed. Fasting SBWC was markedly increased by ondansetron (P < 0.0007). Ondansetron reduced the overall antroduodenal Motility Index (P < 0.04). The subjects who were intubated had significantly lower fasting SBWC (P < 0.0002) compared with the group of subjects who were not intubated. The 5-HT(3) receptor antagonism increased fasting small bowel water. This was associated with reduced fasting antroduodenal Motility Index which may explain the clinical benefit of such drugs. 2010 Blackwell Publishing Ltd.

Comparative safety and effectiveness of serotonin receptor antagonists in patients undergoing chemotherapy: a systematic review and network meta-analysis.

PubMed

Tricco, Andrea C; Blondal, Erik; Veroniki, Areti Angeliki; Soobiah, Charlene; Vafaei, Afshin; Ivory, John; Strifler, Lisa; Cardoso, Roberta; Reynen, Emily; Nincic, Vera; Ashoor, Huda; Ho, Joanne; Ng, Carmen; Johnson, Christy; Lillie, Erin; Antony, Jesmin; Roberts, Derek J; Hemmelgarn, Brenda R; Straus, Sharon E

2016-12-23

Although serotonin (5-HT 3 ) receptor antagonists are effective in reducing nausea and vomiting, they may be associated with increased cardiac risk. Our objective was to examine the comparative safety and effectiveness of 5-HT 3 receptor antagonists (e.g., dolasetron, granisetron, ondansetron, palonosetron, tropisetron) alone or combined with steroids for patients undergoing chemotherapy. We searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials from inception until December 2015 for studies comparing 5-HT 3 receptor antagonists with each other or placebo in chemotherapy patients. The search results were screened, data were abstracted, and risk of bias was appraised by pairs of reviewers, independently. Random-effects meta-analyses and network meta-analyses (NMAs) were conducted. After screening 9226 citations and 970 full-text articles, we included 299 studies (n = 58,412 patients). None of the included studies reported harms for active treatment versus placebo. For NMAs on the risk of arrhythmia (primary outcome; three randomized controlled trials [RCTs], 627 adults) and mortality (secondary outcome; eight RCTs, 4823 adults), no statistically significant differences were observed between agents. A NMA on the risk of QTc prolongation showed a significantly greater risk for dolasetron + dexamethasone versus ondansetron + dexamethasone (four RCTs, 3358 children and adults, odds ratio 2.94, 95% confidence interval 2.13-4.17). For NMAs on the number of patients without nausea (44 RCTs, 11,664 adults, 12 treatments), number of patients without vomiting (63 RCTs, 15,460 adults, 12 treatments), and number of patients without chemotherapy-induced nausea or vomiting (27 RCTs, 10,924 adults, nine treatments), all agents were significantly superior to placebo. For a NMA on severe vomiting (10 RCTs, 917 adults), all treatments decreased the risk, but only ondansetron and ramosetron were significantly superior to placebo. According to a

A Randomized Double-Blind, Double-Dummy, Multicenter Trial of Azasetron versus Ondansetron to Evaluate Efficacy and Safety in the Prevention of Delayed Nausea and Vomiting Induced by Chemotherapy

PubMed Central

Lee, Hee Yeon; Lee, Kyung Hee; Kim, Bong-Seog; Song, Hong Suk; Yang, Sung Hyun; Kim, Joon Hee; Kim, Yeul Hong; Kim, Jong Gwang; Kim, Sang-We; Kim, Dong-Wan; Kim, Si-Young; Park, Hee Sook

2014-01-01

Purpose This study was conducted to evaluate the efficacy and safety of azasetron compared to ondansetron in the prevention of delayed chemotherapy-induced nausea and vomiting. Materials and Methods This study was a multi-center, prospective, randomized, double-dummy, double-blind and parallel-group trial involving 12 institutions in Korea between May 2005 and December 2005. A total of 265 patients with moderately and highly emetogenic chemotherapy were included and randomly assigned to either the azasetron or ondansetron group. All patients received azasetron (10 mg intravenously) and dexamethasone (20 mg intravenously) on day 1 and dexamethasone (4 mg orally every 12 hours) on days 2-4. The azasetron group received azasetron (10 mg orally) with placebo of ondansetron (orally every 12 hours), and the ondansetron group received ondansetron (8 mg orally every 12 hours) with placebo of azasetron (orally) on days 2-6. Results Over days 2-6, the effective ratio of complete response in the azasetron and ondansetron groups was 45% and 54.5%, respectively (95% confidence interval, -21.4 to 2.5%). Thus, the non-inferiority of azasetron compared with ondansetron in delayed chemotherapy-induced nausea and vomiting was not proven in the present study. All treatments were well tolerated and no unexpected drug-related adverse events were reported. The most common adverse events related to the treatment were constipation and hiccups, and there were no differences in the overall incidence of adverse events. Conclusion In the present study, azasetron showed inferiority in the control of delayed chemotherapy-induced nausea and vomiting compared with ondansetron whereas safety profiles were similar between the two groups. PMID:24520219

Comparison of palonosetron, granisetron, and ramosetron for the prevention of postoperative nausea and vomiting after laparoscopic gynecologic surgery: a prospective randomized trial.

PubMed

Lee, Won-Suk; Lee, Kwang-Beom; Lim, Soyi; Chang, Young Gin

2015-09-03

Selective 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists are reported to have potent antiemetic effects for postoperative nausea and vomiting (PONV). The purpose of this study was to prospectively evaluate the efficacy of palonosetron, granisetron, and ramosetron for the prevention of PONV in patients undergoing laparoscopic gynecologic surgery. In this prospective, randomized observational study, 105 healthy female patients who were undergoing laparocopic hystectomy under general anaesthesia were enrolled (clinical trial number: NCT01752374, www.clinicaltrials.gov ). Patients were divided into three groups: the palonostron (0.075 mg i.v.; n = 35), the granisetron group (3 mg i.v.; n = 35), and the ramosetron group (0.3 mg i.v.; n = 35). The treatments were given before the end of surgery. The incidence of PONV, severity of nausea/vomiting, and the use of rescue antiemetic requirements during the first 48 h after surgery were evaluated. The overall incidence of PONV was 33.3 % for this series. The number of complete responders at 48 h after the surgery was 21 (60.0 %) for palonosetron, 24 (68.6 %) for granisetron, and 26 (71.4 %) for ramosetron, representing no statistical difference (P = 0.086). There were no significant differences in the overall incidence of postoperative nausea and vomiting and complete responders for palonosetron, granisetron and ramosetron group. NCT01752374 , www.clinicaltrials.gov .

Scary Science: Ondansetron Safety in Pregnancy-Two Opposing Results From the Same Danish Registry.

PubMed

Koren, Gideon

2014-01-09

While perceived safe in pregnancy, several recent studies raise concerns about both fetal and maternal safety of ondansetron. Until more data are available, it should not be a first-line medication for morning sickness.

[Efficacy of granisetron for preventing chemotherapy-induced nausea and vomiting in patients with acute myelogenous leukemia treated with a combination of anthracycline and cytarabine].

PubMed

Goto, Takashi; Tanimoto, Kazuki; Ishibashi, Makoto; Okamura, Seiichi

2012-08-01

In Japan, the combination of anthracycline and cytarabine(Ara-C)is a standard therapy for acute myelogenous leukemia(AML). Chemotherapy-induced nausea and vomiting(CINV)are frequently reported as side effects related to the administration of these regimens. In our hospital, patients received prophylactic granisetron at a dose of 3 mg daily during chemotherapy. However, granisetron is known to induce constipation as a side effect. The present study evaluated the efficacy of a single dose of granisetron administered throughout the entire period of chemotherapy in AML patients receiving anthracycline and Ara-C combination therapy, and also examined the incidence of constipation during chemotherapy. From July 2008 to December 2010, all patients with AML treated using anthracycline and Ara-C combination therapy were registered in the study. This retrospective study investigated the patients' background and the incidence of CINV and constipation from the patients' records. The efficacy of granisetron was measured on each day using the complete regression(no vomiting and no rescue medication; CR)rate. A total of 45 patients were included in the study(27 male; 18 female), and received a total 68 courses(56 of induction therapy; 12 of consolidation therapy)of the regimens. The CR rate and the incidence of constipation on the final day of chemotherapy were 61. 8% and 63. 2%, respectively. As the duration of chemotherapy increased, the CR rate tended to decrease, whereas the incidence of constipation tended to increase. The CR rate in this study was 61. 8%, thus indicating that there is still room for improvement. The combination of dexamethasone and a neurokinin-1 receptor antagonist, or the changeover from granisetron to palonosetron could therefore increase the CR rate.

Transdermal scopolamine: an alternative to ondansetron and droperidol for the prevention of postoperative and postdischarge emetic symptoms.

PubMed

White, Paul F; Tang, Jun; Song, Dajun; Coleman, Jayne E; Wender, Ronald H; Ogunnaike, Babatunde; Sloninsky, Alexander; Kapu, Rajani; Shah, Mary; Webb, Tom

2007-01-01

Given the controversy regarding the use of droperidol and the high cost of the 5-HT3 antagonists, a cost-effective alternative for routine use as a prophylactic antiemetic would be desirable. We designed two parallel, randomized, double-blind sham and placebo-controlled studies to compare the early and late antiemetic efficacy and adverse event profile of transdermal scopolamine (TDS) 1.5 mg, to ondansetron 4 mg IV, and droperidol 1.25 mg IV for antiemetic prophylaxis as part of a multimodal regimen in "at risk" surgical populations. A total of 150 patients undergoing major laparoscopic (n = 80) or plastic (n = 70) surgery procedures received either an active TDS patch (containing scopolamine 1.5 mg) or a similar appearing sham patch 60 min before entering the operating room. All patients received a standardized general anesthetic technique. A second study medication was administered in a 2-mL numbered syringe containing either saline (for the two active TDS groups), droperidol, 1.25 mg, or ondansetron, 4 mg (for the sham patch groups), and was administered IV near the end of the procedure. The occurrence of postoperative nausea and vomiting/retching, need for rescue antiemetics, and the complete response rates (i.e., absence of protracted nausea or repeated episodes of emesis requiring antiemetic rescue medication) was reported. In addition, complaints of visual disturbances, dry mouth, drowsiness, and restlessness were noted up to 72 h after surgery. There were no significant differences in any of the emetic outcomes or need for rescue antiemetics among the TDS, droperidol, and ondansetron groups in the first 72 h after surgery. The complete response rates varied from 41% to 51%, and did not significantly differ among the treatment groups. The overall incidence of dry mouth was significantly more frequent in the TDS groups than in the droperidol and ondansetron groups (21% vs 3%). Premedication with TDS was as effective as droperidol (1.25 mg) or ondansetron (4

Initial high anti-emetic efficacy of granisetron with dexamethasone is not maintained over repeated cycles.

PubMed Central

de Wit, R.; van den Berg, H.; Burghouts, J.; Nortier, J.; Slee, P.; Rodenburg, C.; Keizer, J.; Fonteyn, M.; Verweij, J.; Wils, J.

1998-01-01

We have reported previously that the anti-emetic efficacy of single agent 5HT3 antagonists is not maintained when analysed with the measurement of cumulative probabilities. Presently, the most effective anti-emetic regimen is a combination of a 5HT3 antagonist plus dexamethasone. We, therefore, assessed the sustainment of efficacy of such a combination in 125 patients, scheduled to receive cisplatin > or = 70 mg m(-2) either alone or in combination with other cytotoxic drugs. Anti-emetic therapy was initiated with 10 mg of dexamethasone and 3 mg of granisetron intravenously, before cisplatin. On days 1-6, patients received 8 mg of dexamethasone and 1 mg of granisetron twice daily by oral administration. Protection was assessed during all cycles and calculated based on cumulative probability analyses using the method of Kaplan-Meier and a model for transitional probabilities. Irrespective of the type of analysis used, the anti-emetic efficacy of granisetron/dexamethasone decreased over cycles. The initial complete acute emesis protection rate of 66% decreased to 30% according to the method of Kaplan-Meier and to 39% using the model for transitional probabilities. For delayed emesis, the initial complete protection rate of 52% decreased to 21% (Kaplan-Meier) and to 43% (transitional probabilities). In addition, we observed that protection failure in the delayed emesis period adversely influenced the acute emesis protection in the next cycle. We conclude that the anti-emetic efficacy of a 5HT3 antagonist plus dexamethasone is not maintained over multiple cycles of highly emetogenic chemotherapy, and that the acute emesis protection is adversely influenced by protection failure in the delayed emesis phase. PMID:9652766

The inhibitory effect of granisetron on ventrolateral medulla neuron responses to colorectal distension in rats.

PubMed

Panteleev, Sergey S; Martseva, Alexandra А; Lyubashina, Olga А

2015-02-15

Irritable bowel syndrome (IBS) is one of the most widespread functional gastrointestinal disorders characterized by abdominal pain. A key pathophysiological mechanism of abdominal pain is associated with disturbances of serotonergic transmission in feedback control loops of endogenous pain modulation in which the ventrolateral medulla (VLM) plays an important role. The receptors to serotonin (5-HT), and particularly the serotonin 3 (5-HT3) receptors have been extensively used as a potential target for abdominal pain treatment of IBS patients due to antinociceptive features of the 5-HT3 receptor antagonists. The precise mechanisms underlying the antinociceptive action of these antagonists remain unclear. The main objective of our study was to evaluate the involvement of the 5-HT3 receptors in abdominal pain transmission within the VLM. Experiments were carried out on urethane-anaesthetized rats using the animal model of abdominal pain. Noxious colorectal distension (CRD) with a pressure of 80mmHg induced a significant increase in VLM neuron-evoked activity and depressor reactions (171.1±12.7% and 64±1.8% to baseline, accordingly). Selective blockade of the 5-HT3 receptors with granisetron at doses of 1.0 or 2.0mg/kg (i.v) resulted in long-lasting (90min) dose-dependent inhibition of VLM neuron-evoked activity and depressor reactions. When brainstem dorsal surface applications of granisetron (10 or 20µM) were used, the changes were more pronounced. These results suggest involvement of the 5-HT3 receptors in abdominal pain transmission within the VLM, which will be discussed in relation to the central antinociceptive effect of granisetron. Copyright © 2015 Elsevier B.V. All rights reserved.

Early post-natal neuroactive steroid manipulation modulates ondansetron effects on initial periods of alcohol consumption in rats.

PubMed

Bartolomé, Iris; Llidó, Anna; Darbra, Sònia; Pallarès, Marc

2018-06-21

Neuroactive steroids (NS) such as allopregnanolone are crucial for brain development and adult behaviour. Early post-natal alterations of NS by administering finasteride induce a decrease in the sensitivity to stimulant effects of low alcohol doses, an increase in alcohol consumption, and a decrease in ventrostriatal dopamine and serotonin levels. The aim of the present study is to observe if the effects of the 5HT3 receptor antagonist ondansetron on initial alcohol consumption are modulated by post-natal NS manipulation. For this purpose, allopregnanolone, finasteride, or vehicle was injected from day 5 to 9. In adulthood, a novel object preference test was carried out in order to detect a possible novelty-seeking pattern in our animals, which has been related to vulnerability to drug abuse. The subjects then had access to two bottles (alcohol or control solutions) one hour daily for two consecutive weeks. Ondansetron (0.01 mg/kg, 0.1 mg/kg or vehicle) was administered before the hour of consumption in the initial phase (days 1, 2, 3) of the procedure, and after prolonged alcohol intake (days 11, 12, 13). Results indicated that finasteride animals showed a higher preference to explore the new object, as well as a higher alcohol consumption than the rest of the groups. Moreover, 0.1 mg/kg of ondansetron decreased alcohol consumption, but only in the post-natal finasteride group, suggesting a possible increase in 5HT3 receptor sensitivity in these animals. In conclusion, NS manipulation in crucial stages of development, such as early post-natal periods, seems to play an important role on the effects of ondansetron on alcohol intake and in the vulnerability to develop drug use or abuse. Copyright © 2018. Published by Elsevier Inc.

Studies on optimizing in vitro transdermal permeation of ondansetron hydrochloride using nerodilol, carvone, and limonene as penetration enhancers.

PubMed

Krishnaiah, Yellela S R; Raju, Vengaladasu; Shiva Kumar, Mantri; Rama, Bukka; Raghumurthy, Vanambattina; Ramana Murthy, Kolapalli V

2008-01-01

The present investigation was carried out to formulate a terpene-based hydroxypropyl cellulose (HPC) gel drug reservoir system for its optimal transdermal permeation of ondansetron hydrochloride. The HPC gel formulations containing ondansetron hydrochloride (3% w/w) and selected concentrations of either nerodilol (0% w/w, 1% w/w, 2% w/w, 3% w/w, and 4% w/w), carvone (0% w/w, 2% w/w, 4% w/w, 8% w/w, and 10% w/w), or limonene (0% w/w, 2% w/w, 3% w/w, and 4% w/w) were prepared and subjected to in vitro permeation of the drug across rat epidermis. All the 3 terpene enhancers increased the transdermal permeation of ondansetron hydrochloride. The optimal transdermal permeation was observed with 3% w/w of nerodilol (175.3 +/- 3.1 microg/cm(2.)h), 8% w/w of carvone (87.4 +/- 1.6 microg/cm(2.)h), or 3% w/w of limonene (181.9 +/- 0.9 microg/cm(2.)h). The enhancement ratio (ER) in drug permeability with 3% w/w nerodilol, 8% w/w carvone, and 3% w/w limonene were 21.6, 10.8, and 22.5, respectively, when compared with that obtained without a terpene enhancer (control). However, there was 1.04-, 2.09-, and 2.17-fold increase in the optimal drug flux obtained with carvone, nerodilol, and limonene, respectively, when compared with the desired drug flux (84 microg/cm(2.)h). It was concluded that the HPC gel drug reservoir systems containing either 3% w/w nerodilol or 3% w/w limonene act as optimal formulations for use in the design of membrane-controlled transdermal therapeutic system (TTS) of ondansetron hydrochloride.

[Comparison of 1 mg/body and 3 mg/body of intravenous granisetron for the prevention of chemotherapy-induced nausea and vomiting and adverse events in hematological malignancy patients].

PubMed

Motohashi, Shinya; Hori, Katsuhito; Ono, Takaaki; Ohnishi, Kazunori; Kawakami, Junichi

2012-01-01

Granisetron is a selective 5-hydroxy tryptamine3 receptor antagonist and widely used for chemotherapy-induced nausea and vomiting (CINV). Recommended dose of intravenous granisetron in the USA and Europe has been set at 0.01 mg/kg (1 mg/body) in the antiemetic treatment guidelines established by the American Society of Clinical Oncology and National Comprehension Cancer Network. In contrast, the approved dose in Japan is 0.04 mg/kg (3 mg/body). Randomized controlled trials (RCTs) which compared 1 mg/body with 3 mg/body of intravenous granisetron for CINV had been reported in Japan. In these RCTs, however, hematological malignancy patients were excluded. We performed observational retrospective study to compare 1 mg/body with 3 mg/body of intravenous granisetron for the prevention of CINV and adverse events in hematological malignancy patients. Number of the patients and chemotherapy courses were 15 and 30 in the 1 mg/body group, and 15 and 27 in the 3 mg/body group, respectively. No nausea rates in the 1 and 3 mg/body group were 83% and 89% of courses, respectively. No vomiting rates in the 1 and 3 mg/body group were 97% and 100% of courses, respectively. The incidences of constipation in the 1 and 3 mg/body group were 34% and 45% of courses, respectively. Anaphylaxis and headache did not occur in both groups. Our findings suggested that 1 mg/body of intravenous granisetron can prevent from CINV in hematological malignancy patients, as well as 3 mg/body.

Development and application of a validated stability-indicating HPLC method for simultaneous determination of granisetron hydrochloride, benzyl alcohol and their main degradation products in parenteral dosage forms.

PubMed

Hewala, Ismail; El-Fatatre, Hamed; Emam, Ehab; Mubrouk, Mokhtar

2010-06-30

A simple, rapid and sensitive reversed phase high performance liquid chromatographic method using photodiode array detection was developed and validated for the simultaneous determination of granisetron hydrochloride, benzyl alcohol, 1-methyl-1H-indazole-3-carboxylic acid (the main degradation product of granisetron) and benzaldehyde (the main degradation product of benzyl alcohol) in granisetron injections. The separation was achieved on Hypersil BDS C8 (250 mm x 4.6 mm i.d., 5 microm particle diameter) column using a mobile phase consisted of acetonitrile:0.05 M KH(2)PO(4):triethylamine (22:100:0.15) adjusted to pH 4.8. The column was maintained at 25 degrees C and 20 microL of solutions was injected. Photodiode array detector was used to test the peak purity and the chromatograms were extracted at 210 nm. Naphazoline hydrochloride was used as internal standard. The method was validated with respect to specificity, linearity, accuracy, precision, limit of quantitation and limit of detection. The validation acceptance criteria were met in all cases. Identification of the pure peaks was carried out using library match programmer and wavelengths of derivative optima of the spectrograms of the peaks. The method was successfully applied to the determination of the investigated drugs and their degradation products in different batches of granisetron injections. The method was proved to be sensitive for the determination down to 0.03 and 0.01% of granisetron degradation product and benzaldehyde, respectively, which are far below the compendia limits for testing these degradation products in their corresponding intact drugs. Copyright 2010 Elsevier B.V. All rights reserved.

Effects of Preoperative Serotonin-Receptor-Antagonist Administration in Spinal Anesthesia-Induced Hypotension: A Randomized, Double-blind Comparison Study of Ramosetron and Ondansetron.

PubMed

Shin, Hyun-Jung; Choi, Eun-Su; Lee, Gwan-Woo; Do, Sang-Hwan

2015-01-01

The adverse effects of spinal anesthesia (SA) include arterial hypotension and bradycardia. The aim of this study was to compare the effects of 2 type 3 serotonin receptor antagonists in SA-induced adverse effects. Specifically, we assessed whether ramosetron was more effective than ondansetron in reducing SA-induced decreases in blood pressure (BP) and heart rate (HR). A total of 117 patients undergoing orthopedic surgery and receiving SA were intravenously administered 0.3 mg of ramosetron (n = 39, group R), 4 mg of ondansetron (n = 39, group O4), or 8 mg of ondansetron (n = 39, group O8). Systolic BP (SBP), diastolic BP (DBP), mean BP (MBP), HR, and the lowest SBP, DBP, MBP, and HR values were measured preoperatively (baseline) and intraoperatively. The incidence of postoperative nausea and vomiting, the need for rescue antiemetics, the amount of patient-controlled analgesia consumption, and pain score in the first 48 hours after surgery were determined. Baseline values did not significantly differ among the 3 groups. After SA, SBP, DBP, MBP, and HR were lower than their baseline values in all 3 groups. The differences between the baseline and the lowest values were significantly less in group R than in groups O4 and O8 with respect to SBP (P < 0.001), DBP (P = 0.001), and MBP (P < 0.001) less in group R than in group O4 with respect to HR (P = 0.032). Intergroup differences were not significant for postoperative nausea and vomiting, the need for rescue antiemetics, patient-controlled analgesia consumption, or pain score. The administration of ramosetron (0.3 mg) significantly attenuated the SA-induced decrease in BP compared with 4 or 8 mg of ondansetron and HR compared with 4 mg of ondansetron.

High-performance liquid chromatographic method optimization for ondansetron assay in extemporaneous topical gel and in marketed products.

PubMed

Quamrun, Masuda; Mamoon, Rashid; Nasheed, Shams; Randy, Mullins

2014-01-01

The compounding and evaluation of ondansetron hydrochloride dihydrate topical gel, 2.5% w/w, were conducted in this study. The gelling agent was Carbopol 940. Ethanol 70% in purified water was used to dissolve the drug and disperse the gelling agent. A gel was formed by adding drops of 0.1 N sodium hydroxide solution. To assay this gel, we developed a simple and reproducible stability--indicating high-performance liquid chromatographic method. This method was validated for specificity, accuracy, and precision. The compounded gel was assayed in triplicate, and the average recovery was 98.3%. Ondansetron marketed products were analyzed for comparison with the compounded formulation. Assay, accuracy, and precision data of the compounded topical gel were comparable to the marketed products.

Effect of PEG6000 on the in vitro and in vivo transdermal permeation of ondansetron hydrochloride from EVA1802 membranes.

PubMed

Krishnaiah, Yellela S R; Rama, Bukka; Raghumurthy, Vanambattina; Ramanamurthy, Kolapalli V; Satyanarayana, Vemulapalli

2009-01-01

The objective was to evaluate ethylene vinyl acetate (EVA) copolymer membranes with vinyl acetate content of 18% w/w (EVA1802) for transdermal delivery of ondansetron hydrochloride. The EVA1802 membranes containing selected concentrations (0, 5, 10 and 15% w/w) of PEG6000 were prepared, and subjected to in vitro permeation studies from a nerodilol-based drug reservoir. Flux of ondansetron from EVA1802 membranes without PEG6000 was 64.1 +/- 0.6 microg/cm(2.)h, and with 10%w/w of PEG6000 (EVA1802-PEG6000-10) it increased to 194.9 +/- 4.6 microg/cm(2.)h. However, with 15%w/w of PEG6000, EVA1802 membranes produced a burst release of drug which in turn decreased drug flux. The EVA1802-PEG6000-10 membrane was coated with an adhesive emulsion, applied to rat epidermis and subjected to in vitro permeation studies against controls. Flux of ondansetron from transdermal patch across rat epidermis was 111.7 +/- 1.3 microg/cm(2.)h, which is about 1.3 times the required flux. A TTS was fabricated using adhesive-coated EVA1802-PEG6000-10 membrane and other TTS components, and subjected to in vivo delivery in human volunteers against a control. It was concluded from the comparative pharmacokinetic study that TTS of ondansetron, prepared with EVA1802-PEG6000-10 membrane, provided average steady-state plasma concentration on par with multiple-dosed oral tablets, but with a low percent of peak-to-trough fluctuation.

Using transdermal iontophoresis to increase granisetron delivery across skin in vitro and in vivo: effect of experimental conditions and a comparison with other enhancement strategies.

PubMed

Cázares-Delgadillo, Jennyfer; Ganem-Rondero, Adriana; Quintanar-Guerrero, David; López-Castellano, Alicia C; Merino, Virginia; Kalia, Yogeshvar N

2010-03-18

The objectives of the study were (i) to investigate the effect of experimental parameters on the iontophoretic transport of granisetron, (ii) to identify the relative contributions of electromigration (EM) and electroosmosis (EO), (iii) to determine the feasibility of delivering therapeutic amounts of drug for the treatment of chemotherapy-induced nausea and vomiting and (iv) to test the in vitro results in a simple animal model in vivo. Preliminary in vitro studies using aqueous granisetron formulations investigating the effect of drug concentration (5, 10, 20 and 40 mM) and current density (0.1, 0.2, 0.3 mA cm(-2)) were performed using porcine ear skin. As expected, cumulative delivery in vitro at the 20 and 40 mM concentrations was significantly greater than that at 5 and 10mM, which were not statistically different (p<0.05). Increasing the applied current density from 0.1 to 0.3 mA cm(-2) resulted in a approximately 4.2-fold increase in iontophoretic flux. Furthermore, in the absence of Na(+) in the formulation, no dependence of iontophoretic flux on drug concentration was reported (at a granisetron concentration of 40 mM, the transport rate was 2.93+/-0.62 microg cm(-2)min(-1)). Co-iontophoresis of acetaminophen was used to show that EM was the predominant transport mechanism accounting for 71-86% of total granisetron delivery. In vivo studies in Wistar rats (40 mM granisetron; application of 0.3 mA cm(-2) for 5h with Ag/AgCl electrodes and salt bridges) showed an average iontophoretic input rate (k(input)) of 0.83+/-0.26 microg min(-1) and a maximum plasma concentration (C(max)) of 0.092+/-0.004 microg ml(-1). Based on these results and given the known pharmacokinetics, transdermal iontophoresis could achieve therapeutic drug levels for the management of chemotherapy-induced emesis using a reasonably sized (4-6 cm(2)) patch. Copyright 2010 Elsevier B.V. All rights reserved.

Influence of Polymorphisms in the HTR3A and HTR3B Genes on Experimental Pain and the Effect of the 5-HT3 Antagonist Granisetron.

PubMed

Louca Jounger, Sofia; Christidis, Nikolaos; Hedenberg-Magnusson, Britt; List, Thomas; Svensson, Peter; Schalling, Martin; Ernberg, Malin

2016-01-01

The aim of this study was to investigate experimentally if 5-HT3 single nucleotide polymorphisms (SNP) contribute to pain perception and efficacy of the 5-HT3-antagonist granisetron and sex differences. Sixty healthy participants were genotyped regarding HTR3A (rs1062613) and HTR3B (rs1176744). First, pain was induced by bilateral hypertonic saline injections (HS, 5.5%, 0.2 mL) into the masseter muscles. Thirty min later the masseter muscle on one side was pretreated with 0.5 mL granisetron (1 mg/mL) and on the other side with 0.5 mL placebo (isotonic saline) followed by another HS injection (0.2 mL). Pain intensity, pain duration, pain area and pressure pain thresholds (PPTs) were assessed after each injection. HS evoked moderate pain, with higher intensity in the women (P = 0.023), but had no effect on PPTs. None of the SNPs influenced any pain variable in general, but compared to men, the pain area was larger in women carrying the C/C (HTR3A) (P = 0.015) and pain intensity higher in women with the A/C alleles (HTR3B) (P = 0.019). Pre-treatment with granisetron reduced pain intensity, duration and area to a lesser degree in women (P < 0.05), but the SNPs did not in general influence the efficacy of granisetron. Women carrying the C/T & T/T (HTR3A) genotype had less reduction of pain intensity (P = 0.041) and area (P = 0.005), and women with the C/C genotype (HTR3B) had less reduction of pain intensity (P = 0.030), duration (P = 0.030) and area compared to men (P = 0.017). In conclusion, SNPs did not influence experimental muscle pain or the effect of granisetron on pain variables in general, but there were some sex differences in pain variables that seem to be influenced by genotypes. However, due to the small sample size further research is needed before any firm conclusions can be drawn.

Influence of Polymorphisms in the HTR3A and HTR3B Genes on Experimental Pain and the Effect of the 5-HT3 Antagonist Granisetron

PubMed Central

Hedenberg-Magnusson, Britt; List, Thomas; Svensson, Peter; Schalling, Martin

2016-01-01

The aim of this study was to investigate experimentally if 5-HT3 single nucleotide polymorphisms (SNP) contribute to pain perception and efficacy of the 5-HT3-antagonist granisetron and sex differences. Sixty healthy participants were genotyped regarding HTR3A (rs1062613) and HTR3B (rs1176744). First, pain was induced by bilateral hypertonic saline injections (HS, 5.5%, 0.2 mL) into the masseter muscles. Thirty min later the masseter muscle on one side was pretreated with 0.5 mL granisetron (1 mg/mL) and on the other side with 0.5 mL placebo (isotonic saline) followed by another HS injection (0.2 mL). Pain intensity, pain duration, pain area and pressure pain thresholds (PPTs) were assessed after each injection. HS evoked moderate pain, with higher intensity in the women (P = 0.023), but had no effect on PPTs. None of the SNPs influenced any pain variable in general, but compared to men, the pain area was larger in women carrying the C/C (HTR3A) (P = 0.015) and pain intensity higher in women with the A/C alleles (HTR3B) (P = 0.019). Pre-treatment with granisetron reduced pain intensity, duration and area to a lesser degree in women (P < 0.05), but the SNPs did not in general influence the efficacy of granisetron. Women carrying the C/T & T/T (HTR3A) genotype had less reduction of pain intensity (P = 0.041) and area (P = 0.005), and women with the C/C genotype (HTR3B) had less reduction of pain intensity (P = 0.030), duration (P = 0.030) and area compared to men (P = 0.017). In conclusion, SNPs did not influence experimental muscle pain or the effect of granisetron on pain variables in general, but there were some sex differences in pain variables that seem to be influenced by genotypes. However, due to the small sample size further research is needed before any firm conclusions can be drawn. PMID:28002447

Compatibility and Stability of VARUBI (Rolapitant) Injectable Emulsion Admixed with Intravenous Granisetron Hydrochloride.

PubMed

Wu, George; Powers, Dan; Yeung, Stanley; Chen, Frank; Neelon, Kelly

2018-01-01

Prophylaxis or therapy with a combination of a neurokinin 1 (NK-1) receptor antagonist (RA), a 5-hydroxytryptamine- 3 (5-HT3) RA, and dexamethasone is recommended by international antiemesis guidelines for the prevention of chemotherapy-induced nausea and vomiting for patients receiving highly emetogenic chemotherapy and for select patients receiving moderately emetogenic chemotherapy. VARUBI (rolapitant) is a substance P/NK-1 RA that was recently approved by the U.S. Food and Drug Administration as an injectable emulsion in combination with other antiemetic agents in adults for the prevention of delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy. Granisetron Hydrochloride Injection USP is one of the 5-HT3 RAs indicated for the prevention of nausea and/or vomiting associated with initial and repeat courses of emetogenic cancer therapy, including high-dose cisplatin. Herein, we describe the physical and chemical compatibility and stability of VARUBI (rolapitant) injectable emulsion (166.5 mg/92.5 mL [1.8 mg/mL], equivalent to 185 mg of rolapitant hydrochloride) admixed with Granisetron Hydrochloride Injection USP (1.0 mg/mL, equivalent to 1.12 mg/mL hydrochloride). Binary admixtures of VARUBI injectable emulsion and Granisetron Hydrochloride Injection USP were prepared and stored in VARUBI ready-to-use glass vials and in four types of commonly used intravenous administration (tubing) sets. Evaluation of the physical and chemical compatibility and stability of the admixtures in the VARUBI ready-to-use vials stored at room temperature (20°C to 25°C) under fluorescent light and under refrigeration (2°C to 8°C protected from light) was conducted at 0, 1, 6, 24, and 48 hours, and that of the admixtures in the intravenous tubing sets was evaluated at 0, 2, and 6 hours of storage at 20°C to 25°C. Physical stability was evaluated by visual examination

A randomized study of the efficacy and safety of transdermal granisetron in the control of nausea and vomiting induced by moderately emetogenic chemotherapy in Korean patients.

PubMed

Kim, Jeong Eun; Hong, Yong Sang; Lee, Jae-Lyun; Kim, Kyu-Pyo; Park, Seong Joon; Sym, Sun Jin; Shin, Dong Bok; Lee, Jeeyun; Park, Young Suk; Ahn, Jin Seok; Kim, Tae Won

2015-06-01

The granisetron transdermal system (GTS) showed non-inferior efficacy to oral granisetron to control chemotherapy-induced nausea and vomiting (CINV) during multiday chemotherapy. We compared the efficacy and safety of GTS with that of intravenous and oral granisetron in Korean patients receiving moderately emetogenic chemotherapy (MEC). A total of 276 patients were randomized into GTS (n = 139, one patch on days 1-4) or control group (n = 137, intravenous on day 1 and oral on days 2-4). The primary endpoint was the percentage of patients achieving complete response (CR) from chemotherapy initiation until 24 h after the final administration. Out of 234 patients (112 in GTS and 122 in control group) included in the per protocol analysis, 97.9 % had gastrointestinal cancer and 76.9 % received 3-day chemotherapy. The GTS showed non-inferior efficacy achieving CR in 75.0 % of the patients; 74.6 % of the patients in the control group achieved CR (95 % confidence interval -10.73 to 11.55 %). The CR rate did not change after subgroup analyses by sex, age, and chemotherapy naivety and analysis per day and overall days of treatment. The GTS group showed sustained CR from day 1 to day 4. Patients' satisfaction, assessed using Functional Living Index-Emesis (FLI-E), showed no difference. Both treatments were well tolerated and safe. The GTS showed non-inferior efficacy to intravenous and oral granisetron. The safety, tolerability, and FLI-E scores of the GTS were comparable to those of control group. The GTS offers a convenient alternative option for relieving CINV in patients receiving MEC.

Efficacy of triplet regimen antiemetic therapy for chemotherapy-induced nausea and vomiting (CINV) in bone and soft tissue sarcoma patients receiving highly emetogenic chemotherapy, and an efficacy comparison of single-shot palonosetron and consecutive-day granisetron for CINV in a randomized, single-blinded crossover study

PubMed Central

Kimura, Hiroaki; Yamamoto, Norio; Shirai, Toshiharu; Nishida, Hideji; Hayashi, Katsuhiro; Tanzawa, Yoshikazu; Takeuchi, Akihiko; Igarashi, Kentaro; Inatani, Hiroyuki; Shimozaki, Shingo; Kato, Takashi; Aoki, Yu; Higuchi, Takashi; Tsuchiya, Hiroyuki

2015-01-01

The first aim of this study was to evaluate combination antiemetic therapy consisting of 5-HT3 receptor antagonists, neurokinin-1 receptor antagonists (NK-1RAs), and dexamethasone for multiple high emetogenic risk (HER) anticancer agents in bone and soft tissue sarcoma. The second aim was to compare the effectiveness of single-shot palonosetron and consecutive-day granisetron in a randomized, single-blinded crossover study. A single randomization method was used to assign eligible patients to the palonosetron or granisetron arm. Patients in the palonosetron arm received a palonosetron regimen during the first and third chemotherapy courses and a granisetron regimen during the second and fourth courses. All patients received NK-1RA and dexamethasone. Patients receiving the palonosetron regimen were administered 0.75 mg palonosetron on day 1, and patients receiving the granisetron regimen were administered 3 mg granisetron twice daily on days 1 through 5. All 24 patients in this study received at least 4 chemotherapy courses. A total of 96 courses of antiemetic therapy were evaluated. Overall, the complete response CR rate (no emetic episodes and no rescue medication use) was 34%, while the total control rate (a CR plus no nausea) was 7%. No significant differences were observed between single-shot palonosetron and consecutive-day granisetron. Antiemetic therapy with a 3-drug combination was not sufficient to control chemotherapy-induced nausea and vomiting (CINV) during chemotherapy with multiple HER agents for bone and soft tissue sarcoma. This study also demonstrated that consecutive-day granisetron was not inferior to single-shot palonosetron for treating CINV. PMID:25533447

Taste masking of ondansetron hydrochloride by polymer carrier system and formulation of rapid-disintegrating tablets.

PubMed

Khan, Shagufta; Kataria, Prashant; Nakhat, Premchand; Yeole, Pramod

2007-06-22

The purpose of this research was to mask the intensely bitter taste of ondansetron HCl and to formulate a rapid-disintegrating tablet (RDT) of the taste-masked drug. Taste masking was done by complexing ondansetron HCl with aminoalkyl methacrylate copolymer (Eudragit EPO) in different ratios by the precipitation method. Drug-polymer complexes (DPCs) were tested for drug content, in vitro taste in simulated salivary fluid (SSF) of pH 6.2, and molecular property. Complex that did not release drug in SSF was considered taste-masked and selected for formulation RDTs. The complex with drug-polymer ratio of 8:2 did not show drug release in SSF; therefore, it was selected. The properties of tablets such as tensile strength, wetting time, water absorption ratio, in vitro disintegration time, and disintegration in the oral cavity were investigated to elucidate the wetting and disintegration characteristics of tablets. Polyplasdone XL-10 7% wt/wt gave the minimum disintegration time. Tablets of batch F4 containing spray-dried mannitol and microcrystalline cellulose in the ratio 1:1 and 7% wt/wt Polyplasdone XL-10 showed faster disintegration, within 12.5 seconds, than the marketed tablet (112 seconds). Good correlation between in vitro disintegration behavior and in the oral cavity was recognized. Taste evaluation of RDT in human volunteers revealed considerable taste masking with the degree of bitterness below threshold value (0.5) ultimately reaching to 0 within 15 minutes, whereas ondansetron HCl was rated intensely bitter with a score of 3 for 10 minutes. Tablets of batch F4 also revealed rapid drug release (t(90), 60 seconds) in SGF compared with marketed formulation (t(90), 240 seconds; P < .01). Thus, results conclusively demonstrated successful masking of taste and rapid disintegration of the formulated tablets in the oral cavity.

Ondansetron rapidly dissolving film for the prophylactic treatment of radiation-induced nausea and vomiting-a pilot study.

PubMed

Wong, E; Pulenzas, N; Bedard, G; DeAngelis, C; Zhang, L; Tsao, M; Danjoux, C; Thavarajah, N; Lechner, B; McDonald, R; Cheon, P M; Chow, E

2015-06-01

The purpose of the present study was to investigate the efficacy of an ondansetron rapidly dissolving film (rdf) in the prophylaxis of radiation-induced nausea and vomiting (rinv). Rapidly dissolving film formulations facilitate drug delivery in circumstances in which swallowing the medication might be difficult for the patient. Patients undergoing palliative radiotherapy at risk for rinv were prescribed ondansetron rdf 8 mg twice daily while on treatment and were asked to complete a nausea and vomiting-specific daily diary, the Functional Living Index-Emesis (flie), and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C15 Palliative (qlq-C15-pal). Patients were categorized as receiving primary or secondary prophylaxis based on whether they had already experienced emetic episodes. "Overall control" was defined as a maximum increase of 2 episodes of nausea or vomiting from baseline. "Acute phase" was defined as the days during radiation until the first day after radiation; "delayed phase" was defined as days 2-10 after radiation. The study accrued 30 patients. Rates of overall control for nausea and for vomiting during the acute phase in the primary prophylaxis group were 88% and 93% respectively; during the delayed phase, they were 73% and 75%. Rates of overall control for nausea and for vomiting during the acute phase in the secondary prophylaxis group were both 100%; during the delayed phase, they were 50%. The number of nausea and vomiting episodes was found to be significantly correlated with the flie and qlq-C15-pal questionnaires. Ondansetron rdf is effective for the prophylaxis of rinv.

Efficacy of triplet regimen antiemetic therapy for chemotherapy-induced nausea and vomiting (CINV) in bone and soft tissue sarcoma patients receiving highly emetogenic chemotherapy, and an efficacy comparison of single-shot palonosetron and consecutive-day granisetron for CINV in a randomized, single-blinded crossover study.

PubMed

Kimura, Hiroaki; Yamamoto, Norio; Shirai, Toshiharu; Nishida, Hideji; Hayashi, Katsuhiro; Tanzawa, Yoshikazu; Takeuchi, Akihiko; Igarashi, Kentaro; Inatani, Hiroyuki; Shimozaki, Shingo; Kato, Takashi; Aoki, Yu; Higuchi, Takashi; Tsuchiya, Hiroyuki

2015-03-01

The first aim of this study was to evaluate combination antiemetic therapy consisting of 5-HT3 receptor antagonists, neurokinin-1 receptor antagonists (NK-1RAs), and dexamethasone for multiple high emetogenic risk (HER) anticancer agents in bone and soft tissue sarcoma. The second aim was to compare the effectiveness of single-shot palonosetron and consecutive-day granisetron in a randomized, single-blinded crossover study. A single randomization method was used to assign eligible patients to the palonosetron or granisetron arm. Patients in the palonosetron arm received a palonosetron regimen during the first and third chemotherapy courses and a granisetron regimen during the second and fourth courses. All patients received NK-1RA and dexamethasone. Patients receiving the palonosetron regimen were administered 0.75 mg palonosetron on day 1, and patients receiving the granisetron regimen were administered 3 mg granisetron twice daily on days 1 through 5. All 24 patients in this study received at least 4 chemotherapy courses. A total of 96 courses of antiemetic therapy were evaluated. Overall, the complete response CR rate (no emetic episodes and no rescue medication use) was 34%, while the total control rate (a CR plus no nausea) was 7%. No significant differences were observed between single-shot palonosetron and consecutive-day granisetron. Antiemetic therapy with a 3-drug combination was not sufficient to control chemotherapy-induced nausea and vomiting (CINV) during chemotherapy with multiple HER agents for bone and soft tissue sarcoma. This study also demonstrated that consecutive-day granisetron was not inferior to single-shot palonosetron for treating CINV. © 2014 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Ondansetron and sertraline may interact with 5-HTTLPR and DRD4 polymorphisms to reduce drinking in non-treatment seeking alcohol dependent women: exploratory findings

PubMed Central

Kenna, George A.; Zywiak, William H.; Swift, Robert M.; McGeary, John E.; Clifford, James S.; Shoaff, Jessica R.; Fricchione, Samuel; Brickley, Michael; Beaucage, Kayla; Haass-Koffler, Carolina L.; Leggio, Lorenzo

2014-01-01

The purpose of this exploratory study was to examine the interaction of 5-HTTLPR and DRD4 exon III polymorphisms with gender in non-treatment seeking alcohol dependent (AD) individuals while alternately taking ondansetron and sertraline. Evidence suggests that alcohol dependence may be influenced by a genetic interaction that may be gender specific with temporal changes making pharmacological treatment with serotonergic drugs complex. The main trial was a within-subject double-blind placebo-controlled human laboratory study with 77 non-treatment-seeking AD individuals randomized (55 completed, 49 complete data) to receive 200mg/day of sertraline or 0.5mg/day of ondansetron for 3-weeks followed by an alcohol self-administration experiment (ASAE), then placebo for three weeks followed by a second ASAE, then receive the alternate drug, in a counterbalanced order, for three weeks followed by a third ASAE. Results for men were not significant. Women with the LL 5-HTTLPR genotype receiving ondansetron and SS/SL 5-HTTLPR genotypes receiving sertraline (matched), drank significantly fewer drinks per drinking day (DDD) during the 7-days prior to the first and third ASAEs than women receiving the mismatched medication (i.e. sertraline to LL and ondansetron to SS/SL). In a three-way interaction, 5-HTTLPR alleles by DRD4 alleles by medications, women with the LL genotype who received ondansetron and had DRD4 ≥7 exon III repeats drank significantly fewer DDD as did SS/SL women who received sertraline but conversely had DRD4 <7-repeats in the 7-day period leading up to the first and third ASAEs. Consistent with these data was a significant reduction of milliliters consumed ad lib during these same ASAEs. These exploratory findings add possible support to gender and genetic differences among AD individuals in response to serotonergic pharmacotherapies. Future trials should be powerful enough to take into account that endophenotypes and a targeting of serotonergic interactions

CNS drug development: lessons from the development of ondansetron, aprepitant, ramelteon, varenicline, lorcaserin, and suvorexant. Part I.

PubMed

Preskorn, Sheldon H

2014-11-01

This column is the first in a two-part series exploring lessons for psychiatric drug development that can be learned from the development of six central nervous system drugs with novel mechanisms of action over the past 25 years. Part 1 presents a brief overview of the neuroscience that supported the development of each drug, including the rationale for selecting a) the target, which in each case was a receptor for a specific neurotransmitter system, and b) the indication, which was based on an understanding of the role that target played in a specific neural circuit in the brain. The neurotransmitter systems on which the development of these agents were based included serotonin for ondansetron and lorcaserin, dopamine for varenicline, substance P (or neurokinin) for aprepitant, melatonin for ramelteon, and orexin for suvorexant. The indications were chemotherapy-induced nausea and vomiting for ondansetron and aprepitant, smoking cessation for varenicline, weight loss for lorcaserin, and insomnia for suvorexant and ramelteon.

Daily Palonosetron Is Superior to Ondansetron in the Prevention of Delayed Chemotherapy-Induced Nausea and Vomiting in Patients With Acute Myelogenous Leukemia

PubMed Central

Mattiuzzi, Gloria N.; Cortes, Jorge E.; Blamble, Deborah A.; Bekele, B. Nebiyou; Xiao, Lianchun; Cabanillas, Maria; Borthakur, Gautam; O’Brien, Susan; Kantarjian, Hagop

2014-01-01

BACKGROUND Nausea and vomiting in patients with acute myelogenous leukemia (AML) can be from various causes, including the use of high-dose cytarabine. METHODS The authors compared 2 schedules of palonosetron versus ondansetron in the treatment of chemotherapy-induced nausea and vomiting (CINV) in patients with AML receiving high-dose cytarabine. Patients were randomized to: 1) ondansetron, 8 mg intravenously (IV), followed by 24 mg continuous infusion 30 minutes before high-dose cytarabine and until 12 hours after the high-dose cytarabine infusion ended; 2) palonosetron, 0.25 mg IV 30 minutes before chemotherapy, daily from Day 1 of high-dose cytarabine up to Day 5; or 3) palonosetron, 0.25 mg IV 30 minutes before high-dose cytarabine on Days 1, 3, and 5. RESULTS Forty-seven patients on ondansetron and 48 patients on each of the palonosetron arms were evaluable for efficacy. Patients in the palonosetron arms achieved higher complete response rates (no emetic episodes plus no rescue medication), but the difference was not statistically significant (ondansetron, 21%; palonosetron on Days 1–5, 31%; palonosetron on Days 1, 3, and 5, 35%; P = .32). Greater than 77% of patients in each arm were free of nausea on Day 1; however, on Days 2 through 5, the proportion of patients without nausea declined similarly in all 3 groups. On Days 6 and 7, significantly more patients receiving palonosetron on Days 1 to 5 were free of nausea (P = .001 and P = .0247, respectively). CONCLUSIONS The daily assessments of emesis did not show significant differences between the study arms. Patients receiving palonosetron on Days 1 to 5 had significantly less severe nausea and experienced significantly less impact of CINV on daily activities on Days 6 and 7. PMID:21218459

Physical and Chemical Compatibility of Injectable Acetaminophen During Simulated Y-Site Administration

PubMed Central

Anderson, Collin; Boehme, Sabrina; Ouellette, Jacquelyn; Stidham, Chanelle; MacKay, Mark

2014-01-01

Purpose: The physical and chemical compatibility of intravenous acetaminophen with commonly administered injectable medications was evaluated. Methods: Simulated Y-site evaluation was accomplished by mixing 2 mL of acetaminophen (10 mg/mL) with 2 mL of an alternative intravenous medication and subsequently storing the mixture in a polypropylene syringe for 4 hours. The aliquot solutions were visually inspected and evaluated for crystal content at 4 hours by infusing 4 mL of the medication mixture through a 0.45-μm nitrocellulose filter disc. Medication mixtures that were selected for chemical stability testing were analyzed by high-performance liquid chromatography at 0, 1, and 4 hours using a Zorbax Eclipse Plus C18, 4.6 x 100 mm, 3.5-μm column for separation of analytes with subsequent diode-array detection. Medications were considered chemically compatible if the concentrations of all components were >90% of the original concentrations during the 4 hour simulated Y-site compatibility test. Results: U.S. Pharmacopeial Convention (USP) standards for physical particle counts were met for acetaminophen injection (10 mg/mL) when combined with cefoxitin, ceftriaxone, clindamycin, dexamethasone, diphenhydramine, dolasetron, fentanyl, granisetron, hydrocortisone, hydromorphone, ketorolac, meperidine, methylprednisolone, midazolam, morphine, nalbuphine, ondansetron, piperacillin/tazobactam, ranitidine, and vancomycin. Injectable acetaminophen is incompatible with acyclovir and diazepam and therefore should not be administered concomitantly with either of these products. Further testing confirmed the chemical compatibility of acetaminophen with ceftriaxone, diphenhydramine, granisetron, ketorolac, nalbuphine, ondansetron, piperacillin/tazobactam, and vancomycin. Conclusion: All medications tested with acetaminophen were physically compatible except for acyclovir and diazepam. All 8 medications tested for chemical compatibility with acetaminophen were stable over the 4

A randomized, blinded, controlled trial of the antiemetic effect of ondansetron on dexmedetomidine-induced emesis in cats.

PubMed

Santos, Luiz Cesar P; Ludders, John W; Erb, Hollis N; Martin-Flores, Manuel; Basher, Karen L; Kirch, Pati

2011-07-01

To determine the effect of ondansetron on the incidence of vomiting in cats pre-medicated with dexmedetomidine and buprenorphine. Randomized, blinded, controlled trial. Eighty-nine female domestic shorthair cats, aged 3-60 months (median, 12 months) and weighing 1.2-5.1 kg. Each cat received dexmedetomidine (40 μg kg(-1)) plus buprenorphine (20 μg kg(-1)), intramuscularly as pre-anesthetic medication. Cats were assigned to three treatment groups: ondansetron (0.22 mg kg(-1), intramuscular [IM]), either 30 minutes before the pre-anesthetic medication (ONDA group, n = 31) or with the pre-anesthetic medication (OPM group, n = 30) mixed with the pre-anesthetic medications in the same syringe, or not to receive the antiemetic (control group, n = 28). Emesis was recorded as an all-or-none response. The number of episodes of emesis and the time until onset of the first emetic episode were recorded for each cat. Clinical signs of nausea were recorded whenever they occurred, and a numerical rating scale was used to quantify these signs. Data were analyzed using Kruskal-Wallis and Chi-square test; a Bonferroni correction was made for six comparisons; thus, the two-sided p for significance was 0.05/6 = 0.008. There was a significant reduction in the number of cats vomiting, in the episodes of vomiting/cat, the time elapsed between the premedication and the first vomiting and the severity of nausea in the OPM group compared to the ONDA and control groups. In cats, the administration of ondansetron (0.22 mg kg(-1)) ameliorates and reduced the severity of dexmedetomidine-induced nausea and vomiting only when it was administered in association with this drug. © 2011 The Authors. Veterinary Anaesthesia and Analgesia. © 2011 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesiologists.

Palonosetron versus granisetron in combination with aprepitant for the prevention of chemotherapy-induced nausea and vomiting in patients with gynecologic cancer.

PubMed

Fujiwara, Satoe; Terai, Yoshito; Tsunetoh, Satoshi; Sasaki, Hiroshi; Kanemura, Masanori; Ohmichi, Masahide

2015-10-01

There is no research regarding the appropriate antiemetic agents for female patients, especially those receiving moderately emetogenic chemotherapy (MEC). We evaluated the antiemetic efficacy of a combination of 5-HT₃ receptor with/without aprepitant in patients with gynecological cancer treated with the TC (paclitaxel and carboplatin) regimen of MEC. We enrolled 38 patients diagnosed with gynecologic cancer and scheduled to receive the TC regimen. The patients were randomly assigned to receive a 5-HT₃ receptor antagonist, either palonosetron in the first cycle followed by granisetron in the second cycle or vice versa. In the third cycle, all patients received a combination of the 5-HT₃ receptor and dexamethasone with/without aprepitant. When three drugs were administered, palonosetron consistently produced an equivalent complete response (CR) rate to granisetron in the acute phase (89.5% vs. 86.8%, p=0.87) and delayed phase (60.5% vs. 65.8%, p=0.79). With regard to the change in dietary intake, palonosetron exhibited similar efficacy to granisetron in the acute phase (92.1% vs. 89.4%, p=0.19) and delayed phase (65.7% vs. 68.4%, p=0.14). However, in the delayed phase, the addition of aprepitant therapy with a 5-HT₃ receptor antagonist and dexamethasone produced a higher CR rate than a 5-HT₃ receptor antagonist with dexamethasone (93.3% vs. 47.8%, p<0.001) and allowed the patients to maintain a higher level of dietary intake (93.3% vs. 56.5%, p<0.001). The addition of aprepitant therapy was more effective than the control therapy of a 5-HT₃ receptor antagonist, and dexamethasone in gynecological cancer patients treated with the TC regimen.

Oral ondansetron versus domperidone for symptomatic treatment of vomiting during acute gastroenteritis in children: multicentre randomized controlled trial

PubMed Central

2011-01-01

Background Vomiting in children with acute gastroenteritis (AG) is not only a direct cause of fluid loss but it is also a major factor of failure of oral rehydration therapy (ORT). Physicians who provide care to paediatric patients in the emergency department (ED) usually prescribe intravenous fluid therapy (IVT) for mild or moderate dehydration when vomiting is the major symptom. Thus, effective symptomatic treatment of vomiting would lead to an important reduction in the use of IVT and, consequently, of the duration of hospital stay and of frequency of hospital admission. Available evidence on symptomatic treatment of vomiting shows the efficacy of the most recently registered molecule (ondansetron) but a proper evaluation of antiemetics drugs largely used in clinical practice, such as domperidone, is lacking. Objectives To compare the efficacy of ondansetron and domperidone for the symptomatic treatment of vomiting in children with AG who have failed ORT. Methods/Design Multicentre, double-blind randomized controlled trial conducted in paediatric EDs. Children aged from 1 to 6 years who vomiting, with a presumptive clinical diagnosis of AG, and without severe dehydration will be included. After the failure of a initial ORS administration in ED, eligible children will be randomized to receive: 1) ondansetron syrup (0,15 mg/Kg of body weight); 2) domperidone syrup (0,5 mg/Kg of body weight); 3) placebo. The main study outcome will be the percentage of patients needing nasogastric or IVT after symptomatic oral treatment failure, defined as vomiting or fluid refusal after a second attempt of ORT. Data relative to study outcomes will be collected at 30 minute intervals for a minimum of 6 hours. A telephone follow up call will be made 48 hours after discharge. A total number of 540 children (i.e. 180 patients in each arm) will be enrolled. Discussion The trial results would provide evidence on the efficacy of domperidone, which is largely used in clinical practice

Oral ondansetron versus domperidone for symptomatic treatment of vomiting during acute gastroenteritis in children: multicentre randomized controlled trial.

PubMed

Marchetti, Federico; Maestro, Alessandra; Rovere, Francesca; Zanon, Davide; Arrighini, Alberto; Bertolani, Paolo; Biban, Paolo; Da Dalt, Liviana; Di Pietro, Pasquale; Renna, Salvatore; Guala, Andrea; Mannelli, Francesco; Pazzaglia, Anna; Messi, Gianni; Perri, Francesco; Reale, Antonino; Urbino, Antonio Francesco; Valletta, Enrico; Vitale, Antonio; Zangardi, Tiziana; Tondelli, Maria Teresa; Clavenna, Antonio; Bonati, Maurizio; Ronfani, Luca

2011-02-10

Vomiting in children with acute gastroenteritis (AG) is not only a direct cause of fluid loss but it is also a major factor of failure of oral rehydration therapy (ORT). Physicians who provide care to paediatric patients in the emergency department (ED) usually prescribe intravenous fluid therapy (IVT) for mild or moderate dehydration when vomiting is the major symptom. Thus, effective symptomatic treatment of vomiting would lead to an important reduction in the use of IVT and, consequently, of the duration of hospital stay and of frequency of hospital admission. Available evidence on symptomatic treatment of vomiting shows the efficacy of the most recently registered molecule (ondansetron) but a proper evaluation of antiemetics drugs largely used in clinical practice, such as domperidone, is lacking. To compare the efficacy of ondansetron and domperidone for the symptomatic treatment of vomiting in children with AG who have failed ORT. Multicentre, double-blind randomized controlled trial conducted in paediatric EDs. Children aged from 1 to 6 years who vomiting, with a presumptive clinical diagnosis of AG, and without severe dehydration will be included. After the failure of a initial ORS administration in ED, eligible children will be randomized to receive: 1) ondansetron syrup (0,15 mg/Kg of body weight); 2) domperidone syrup (0,5 mg/Kg of body weight); 3) placebo. The main study outcome will be the percentage of patients needing nasogastric or IVT after symptomatic oral treatment failure, defined as vomiting or fluid refusal after a second attempt of ORT. Data relative to study outcomes will be collected at 30 minute intervals for a minimum of 6 hours. A telephone follow up call will be made 48 hours after discharge. A total number of 540 children (i.e. 180 patients in each arm) will be enrolled. The trial results would provide evidence on the efficacy of domperidone, which is largely used in clinical practice despite the lack of proper evaluation and a

Relative bioavailability of ondansetron 8-mg oral tablets versus two extemporaneous 16-mg suppositories: formulation and gender differences.

PubMed

Jann, M W; ZumBrunnen, T L; Tenjarla, S N; Ward, E S; Weidler, D J

1998-01-01

To compare the relative bioavailability of two 16-mg extemporaneously prepared suppository formulations with that of an 8-mg commercially available oral tablet. Prospective, crossover bioavailability study. Inpatient clinical research center. Sixteen young, nonsmoking, healthy volunteers. Blood samples were obtained 24 and 48 hours after administration of an 8-mg oral ondansetron tablet and 16-mg suppository, respectively. Two 16-mg suppository formulations were compounded using commercially available Fattibase and Polybase. Ondansetron was well absorbed by both routes of administration. The following pharmacokinetic parameters (mean+/-SEM) were obtained for the 8-mg tablet, 16-mg Fattibase suppository, and 16-mg Polybase suppository, respectively: area under the curve (AUC) in men 154.2+/-21.77, 253.4+/-72.3, 304.8+/-62.2 ng x hr/ml; AUC in women 353.6+/-32.7, 561.6+/-103.6, and 768.7+/-117.9 ng x hr/ml; maximum concentration (Cmax) in men 45.5+/-7.0, 40.6+/-10.4, and 51.2+/-6.7 ng/ml; Cmax in women 51.4+/-.8, 47.1+/-3.9, and 82.9+/-6.6 ng/ml. Times to Cmax (Tmax; mean+/-SEM) for men were 1.5+/-0.3, 4.4+/-0.5, and 2.9+/-0.3 hours; Tmax for women were 1.8+/-0.3, 4.1+/-0.4, and 4.4+/-0.6 hours for the three formulations, respectively. Women had a consistently higher AUC for all three formulations than men (p<0.05). With the exception of the 16-mg Polybase formulation in women, the two suppositories closely approximated the pharmacokinetics of the 8-mg oral tablet. These results suggest that gender may be a significant factor in ondansetron's disposition.

Palonosetron versus granisetron in combination with aprepitant for the prevention of chemotherapy-induced nausea and vomiting in patients with gynecologic cancer

PubMed Central

Fujiwara, Satoe; Tsunetoh, Satoshi; Sasaki, Hiroshi; Kanemura, Masanori; Ohmichi, Masahide

2015-01-01

Objective There is no research regarding the appropriate antiemetic agents for female patients, especially those receiving moderately emetogenic chemotherapy (MEC). We evaluated the antiemetic efficacy of a combination of 5-HT3 receptor with/without aprepitant in patients with gynecological cancer treated with the TC (paclitaxel and carboplatin) regimen of MEC. Methods We enrolled 38 patients diagnosed with gynecologic cancer and scheduled to receive the TC regimen. The patients were randomly assigned to receive a 5-HT3 receptor antagonist, either palonosetron in the first cycle followed by granisetron in the second cycle or vice versa. In the third cycle, all patients received a combination of the 5-HT3 receptor and dexamethasone with/without aprepitant. Results When three drugs were administered, palonosetron consistently produced an equivalent complete response (CR) rate to granisetron in the acute phase (89.5% vs. 86.8%, p=0.87) and delayed phase (60.5% vs. 65.8%, p=0.79). With regard to the change in dietary intake, palonosetron exhibited similar efficacy to granisetron in the acute phase (92.1% vs. 89.4%, p=0.19) and delayed phase (65.7% vs. 68.4%, p=0.14). However, in the delayed phase, the addition of aprepitant therapy with a 5-HT3 receptor antagonist and dexamethasone produced a higher CR rate than a 5-HT3 receptor antagonist with dexamethasone (93.3% vs. 47.8%, p<0.001) and allowed the patients to maintain a higher level of dietary intake (93.3% vs. 56.5%, p<0.001). Conclusion The addition of aprepitant therapy was more effective than the control therapy of a 5-HT3 receptor antagonist, and dexamethasone in gynecological cancer patients treated with the TC regimen. PMID:26197776

Periodic modulation-based stochastic resonance algorithm applied to quantitative analysis for weak liquid chromatography-mass spectrometry signal of granisetron in plasma

NASA Astrophysics Data System (ADS)

Xiang, Suyun; Wang, Wei; Xiang, Bingren; Deng, Haishan; Xie, Shaofei

2007-05-01

The periodic modulation-based stochastic resonance algorithm (PSRA) was used to amplify and detect the weak liquid chromatography-mass spectrometry (LC-MS) signal of granisetron in plasma. In the algorithm, the stochastic resonance (SR) was achieved by introducing an external periodic force to the nonlinear system. The optimization of parameters was carried out in two steps to give attention to both the signal-to-noise ratio (S/N) and the peak shape of output signal. By applying PSRA with the optimized parameters, the signal-to-noise ratio of LC-MS peak was enhanced significantly and distorted peak shape that often appeared in the traditional stochastic resonance algorithm was corrected by the added periodic force. Using the signals enhanced by PSRA, this method extended the limit of detection (LOD) and limit of quantification (LOQ) of granisetron in plasma from 0.05 and 0.2 ng/mL, respectively, to 0.01 and 0.02 ng/mL, and exhibited good linearity, accuracy and precision, which ensure accurate determination of the target analyte.

Efficacy of prophylactic droperidol, ondansetron or both in the prevention of postoperative nausea and vomiting in major gynaecological surgery. A prospective, randomized, double-blind clinical trial.

PubMed

Peixoto, A J; Peixoto Filho, A J; Leães, L F; Celich, M F; Barros, M A

2000-10-01

We conducted a prospective, randomized, double-blind clinical trial comparing droperidol 1.25 mg intravenously (i.v.) (group 1, n = 30), ondansetron 4 mg i.v. (group 2, n = 30), or both (group 3, n = 30) in the prevention of postoperative nausea and vomiting (PONV) in the first 24 h following major gynaecological procedures under combined general and epidural anaesthesia. PONV was analysed by a linear nausea/vomiting score, incidence of nausea and vomiting, and the need for antiemetic rescue. Our results showed a similar incidence of nausea and vomiting in all groups (G1 33%, G2 40%, G3 43%). However, when comparisons were made according to the time of assessment, combination therapy resulted in significantly lower PONV than droperidol in the first hour (0% vs. 13%, P < 0.05) and second hour (0% vs. 13%, P < 0.05), and than ondansetron on the first hour (0% vs. 13%, P < 0.05). A trend persisted up to the fourth hour but was not statistically significant in either group. In conclusion, droperidol and ondansetron are effective agents in the prevention of PONV, and their combination seems to provide slightly better results than either drug alone.

Association of ABCB1 polymorphisms with the antiemetic efficacy of granisetron plus dexamethasone in breast cancer patients.

PubMed

Tsuji, Daiki; Kim, Yong-Il; Nakamichi, Hidenori; Daimon, Takashi; Suwa, Kaori; Iwabe, Yutaro; Hayashi, Hideki; Inoue, Kazuyuki; Yoshida, Masayuki; Itoh, Kunihiko

2013-01-01

Resistance to antiemetic treatment with 5-hydroxytryptamine 3 receptor antagonists is a problem, with 20-30% of patients showing unsatisfactory responses. Efflux transport by P-glycoprotein, encoded by the ATP-binding cassette ABCB1 gene in the blood-brain barrier, has been the suggested resistance mechanism. We evaluated the association between the antiemetic efficacy of granisetron plus dexamethasone and ABCB1 polymorphisms 3435C>T and 2677G>T/A. Sixty-four breast cancer patients treated with doxorubicin plus cyclophosphamide were evaluated for their responses to antiemetic therapy. Genotyping of patient DNA samples for ABCB1 single nucleotide polymorphisms was performed; the genotypes were then investigated for their association with the efficacy of prophylactic antiemetics. The acute phase complete response rate was 83% in GG subjects (n = 12), and 69% (n = 35) and 41% (n = 17) in heterozygous and homozygous carriers of the 2677T/A allele, respectively (p = 0.047). The ABCB1 2677 TT genotype group showed significantly lower rates of complete control of acute emesis than the group with GG genotypes (p = 0.045). No significant association with complete response was found for 3435C>T (p = 0.190). ABCB1 polymorphisms may influence the extent of acute emesis control in granisetron-treated patients, making the ABCB1 genotype a predictor of prophylactic antiemetic response.

Palonosetron versus ondansetron for prevention of chemotherapy-induced nausea and vomiting in paediatric patients with cancer receiving moderately or highly emetogenic chemotherapy: a randomised, phase 3, double-blind, double-dummy, non-inferiority study.

PubMed

Kovács, Gábor; Wachtel, Antonio E; Basharova, Elena V; Spinelli, Tulla; Nicolas, Pierre; Kabickova, Edita

2016-03-01

Palonosetron has shown efficacy in the prevention of chemotherapy-induced nausea and vomiting in adults undergoing moderately or highly emetogenic chemotherapy. We assessed the efficacy and safety of palonosetron versus ondansetron in the prevention of chemotherapy-induced nausea and vomiting in paediatric patients. In this multicentre, multinational, double-blind, double-dummy, phase 3 study, paediatric patients aged between 0 and younger than 17 years, who were naive or non-naive to chemotherapy, and scheduled to undergo moderately or highly emetogenic chemotherapy for the treatment of malignant disease were randomised centrally (1:1:1) to receive up to four cycles of 10 μg/kg or 20 μg/kg palonosetron on day 1, or three 150 μg/kg doses of ondansetron on day 1, scheduled 4 h apart, according to a static central permuted block randomisation scheme by an interactive web response system. Randomisation was stratified according to age and emetogenicity. Treatment allocation was masked to project team members involved in data collection and analysis, and members of the investigator's team. The primary endpoint was complete response (no vomiting, retching, or use of rescue drugs) during the acute phase (0-24 h post-chemotherapy) of the first on-study chemotherapy cycle, as assessed in the population of randomly assigned patients who received moderately or highly emetogenic chemotherapy and an active study drug. The primary efficacy objective was to show the non-inferiority of palonosetron versus ondansetron during the acute phase (0-24 h post-chemotherapy) of the first on-study chemotherapy cycle through comparison of the difference in the proportions of patients who achieved a complete response with palonosetron (πT) minus ondansetron (πR) versus a preset non-inferiority margin (δ -15%). To be considered as non-inferior to ondansetron, for at least one of the doses of palonosetron, the lower limit of the 97·5% CI for the weighted sum of the differences in

Prevention of cisplatin-based chemotherapy-induced delayed nausea and vomiting using triple antiemetic regimens: a mixed treatment comparison

PubMed Central

Li, Hongjia; Le, Qiqi; Liu, Shanshan; Zong, Shaoqi; Zheng, Leizhen; Hou, Fenggang

2016-01-01

A variety of triple antiemetic regimens are being used to prevent cisplatin-based chemotherapy induced delayed emesis and nausea in cancer patients. We performed a network meta-analysis to compare the efficacies of the different regimens. Electronic searches of the PubMed, Cochrane Library and MEDLINE databases were performed to identify randomized controlled trials, and data were analyzed using JAGS, Stata 14.0 and R project. The primary outcome was a complete response (CR). The secondary outcomes were no vomiting (NV) and no nausea (NN). Among the 398 studies identified, 10 were eligible and included, providing data on nine regimens. In the CR analysis, the absolute rank of netupitant + palonosetron + dexamethasone (NEPA) was 0.8579. In the NV and NN analyses, NEPA's absolute ranks were 0.8631 and 0.7902, respectively. The compliance of patients treated with rolapitant + granisetron + dexamethasone (RGD) was the best due to a low incidence of adverse events, and good compliance was also observed with NEPA. It was difficult to achieve good compliance with aprepitant + granisetron + dexamethasone (AGD). Overall, NEPA was the best regimen, and aprepitant + ondansetron + dexamethasone (AOD) is also worthy of recommendation because of its low cost and good effect. For patients with severe constipation, hiccups, asthenia and/or delayed nausea, RGD is worthy of consideration. PMID:27015550

Prophylactic effects of intrathecal Meperidine and intravenous Ondansetron on shivering in patients undergoing lower extremity orthopedic surgery under spinal anesthesia

PubMed Central

Safavi, Mohammadreza; Honarmand, Azim; Negahban, Maryam; Attari, Mohammadali

2014-01-01

Objective: Intraoperative hypothermia is a common problem with anesthesia. Spinal anesthesia, the same as general anesthesia, affects the process of temperature regulation. The aim of this study was to compare the prophylactic effect of intravenous (IV) ondansetron with intrathecal (IT) meperidine on prevention of shivering during spinal anesthesia in patients underwent orthopedic surgery of the lower limb. Methods: In this study, 120 patients with American Society of Anesthesiologists physical status I to II, between the ages 16 and 65 were randomized into three groups. Group O and Group M were given IV ondansetron 8 mg and IT meperidine 0.2 mg/kg, before spinal anesthesia, respectively. Group C received IV saline 0.9%. The core and ambient temperatures, the incidence and intensity of shivering, blood pressure, heart rate, and maximum level of sensory block were recorded. Findings: Shivering was observed in 15%, 2.5%, and 37.5% of patients in Groups O, M, and C, respectively. There was a significant difference between Group O and M compared to Group C (P = 0.023 for Group O vs. Group C, P < 0.001 for Group M vs. Group C, P = 0.049 for Group M vs. Group O). Shivering incidence and intensity in Group M was significantly lower than Group O (P = 0.049 and P = 0.047, respectively). Twenty-two patients required additional IV meperidine among which 15 patients were from Group C (37.5%), six patients from Group O (15%) and one patient from Group M (2.5%). Conclusion: We concluded that IT meperidine and IV ondansetron comparably can decrease intensity and incidence of shivering compared to control group as well as decreasing the requirement to additional doses of meperidine for shivering the control without any hemodynamic side effect. PMID:25328899

A prospective, randomized, double-blind, and multicenter trial of prophylactic effects of ramosetronon postoperative nausea and vomiting (PONV) after craniotomy: comparison with ondansetron

PubMed Central

2014-01-01

Background Craniotomy patients have a high incidence of postoperative nausea and vomiting (PONV). This prospective, randomized, double-blind, multi-center study was performed to evaluate the efficacy of prophylactic ramosetron in preventing PONV compared with ondansetron after elective craniotomy in adult patients. Methods A total of 160 American Society of Anesthesiologists physical status I–II patients aged 19–65 years who were scheduled to undergo elective craniotomy for various intracranial lesions were enrolled in this study. All patients received total intravenous anesthesia (TIVA) with propofol and remifentanil. Patients were randomly allocated into three groups to receive ondansetron (4 mg; group A, n  =  55), ondansetron (8 mg; group B, n  =  54), or ramosetron (0.3 mg; group C, n  =  51) intravenously at the time of dural closure. The incidence of PONV, the need for rescue antiemetics, pain score, patient-controlled analgesia (PCA) consumption, and adverse events were recorded 48 h postoperatively. Results Among the initial 160 patients, 127 completed the study and were included in the final analysis. The incidences of PONV were lower (nausea, 14% vs. 59% and 41%, respectively; P  <  0.001; vomiting, P  =  0.048) and the incidence of complete response was higher (83% vs. 37% and 59%, respectively; P  <  0.001) in group C than in groups A and B at 48 h postoperatively. There were no significant differences in the incidence of PONV or need for rescue antiemetics 0–2 h postoperatively, but significant differences were observed in the incidence of PONV and complete response among the three groups 2–48 h postoperatively. No statistically significant intergroup differences were observed in postoperative pain, PCA consumption, or adverse events. Conclusion Intravenous administration of ramosetron at 0.3 mg reduced the incidence of PONV and rescue antiemetic requirement in craniotomy patients

Prophylactic use of intravenous ondansetron versus ketamine - midazolam combination for prevention of shivering during spinal anesthesia: A randomized double-blind placebo-controlled trial

PubMed Central

Safavi, Mohammadreza; Honarmand, Azim; Mohammadsadeqie, Sara

2015-01-01

Background: The aim of this study was to compare the efficacy intravenous (IV) ondansetron with ketamine plus midazolam for the prevention of shivering during spinal anesthesia (SA). Materials and Methods: Ninety patients, aged 18–65 years, undergoing lower extremity orthopedic surgery were included in the present study. SA was performed in all patients with hyperbaric bupivacaine 15 mg. The patients were randomly allocated to receive normal saline (Group C), ondansetron 8 mg IV (Group O) or ketamine 0.25 mg/kg IV plus midazolam 37.5 μg/kg IV (Group KM) immediately after SA. During surgery, shivering scores were recorded at 5 min intervals. The operating room temperature was maintained at 24°C. Results: The incidences of shivering were 18 (60%) in Group C, 6 (20%) in Group KM and 8 (26.6%) in Group O. The difference between Groups O and Group KM with Group C was statistically significant (P < 0.05). No significant difference was noted between Groups KM with Group O in this regard (P > 0.05). Peripheral and core temperature changes throughout surgery were not significantly different among three groups (P > 0.05). Incidence (%) of hallucination was not significantly different between the three groups (0, 3.3, 0 in Group O, Group KM, Group C respectively, P > 0.05). Conclusion: Prophylactic use of ondansetron 8 mg IV was comparable to ketamine 0.25 mg/kg IV plus midazolam 37.5 μg/kg IV in preventing shivering during SA. PMID:26605236

Transdermal granisetron versus palonosetron for prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: a multicenter, randomized, open-label, cross-over, active-controlled, and phase IV study.

PubMed

Seol, Young Mi; Kim, Hyo Jeong; Choi, Young Jin; Lee, Eun Mi; Kim, Yang Soo; Oh, Sung Yong; Koh, Su Jin; Baek, Jin Ho; Lee, Won Sik; Joo, Young Don; Lee, Hyun Gi; Yun, Eun Young; Chung, Joo Seop

2016-02-01

Palonosetron is the second-generation 5-hydroxytryptamine 3 receptor antagonist (5-HT3RA) that has shown better efficacy than the first-generation 5-HT3RA for prevention of chemotherapy-induced nausea and vomiting (CINV) in patients receiving moderately emetogenic chemotherapy (MEC). Granisetron transdermal delivery system (GTDS), a novel transdermal formulation, was developed to deliver granisetron continuously over 7 days. This study compared the efficacy and tolerability of the GTDS to palonosetron for the control of CINV following MEC. A total of 196 patients were randomized to GP or PG group. In this multicenter, randomized, open-label, cross-over, active-controlled, Phase IV study, GP group was assigned to receive transdermal granisetron (one GTDS patch, 7 days) in the first chemotherapy cycle, palonosetron (iv 0.25 mg/day, 1 days) in the second chemotherapy cycle before receiving MEC, and PG group was assigned to receive palonosetron in the first cycle and GTDS in the second cycle. Primary endpoint was the percentage of chemotherapy cycles achieving complete response (CR; defined as no emetic episodes and no rescue medication use) during the acute phase (0-24 h in post-chemotherapy; non-inferiority comparison with palonosetron). Total 333 cycles (165 in GTDS and 168 in palonosetron) were included in the per protocol analysis. The GTDS cycles showed non-inferiority to palonosetron cycles during the acute phase: CR was achieved by 124 (75.2 %) patients in the GTDS cycles and 134 (79.8 %) patients in the palonosetron cycles (treatment difference, -4.6 %; 95 % confidence interval, -13.6-4.4). There was no significant difference in CR rate during acute phase after the end of the first and second chemotherapy cycle between GP and PG group (p = 0.405, p = 0.074). Patients' satisfaction, assessed using Functional Living Index-Emesis (FLI-E), GTDS cycle were higher than those of palonosetron cycle in GP group (FLI-E score; median 1549.5 in GTDS cycle, median 1670

A novel lipid nanoemulsion system for improved permeation of granisetron.

PubMed

Doh, Hea-Jeong; Jung, Yunjin; Balakrishnan, Prabagar; Cho, Hyun-Jong; Kim, Dae-Duk

2013-01-01

A new lipid nanoemulsion (LNE) system containing granisetron (GRN) was developed and its in vitro permeation-enhancing effect was evaluated using Caco-2 cell monolayers. Particle size, polydispersity index (PI) and stability of the prepared GRN-loaded LNE systems were also characterized. The mean diameters of prepared LNEs were around 50 nm with PI<0.2. Developed LNEs were stable at 4°C in the dark place over a period of 12 weeks. In vitro drug dissolution and cytotoxicity studies of GRN-loaded LNEs were performed. GRN-loaded LNEs exhibited significantly higher drug dissolution than GRN suspension at pH 6.8 for 2h (P<0.05). In vitro permeation study in Caco-2 cell monolayers showed that the LNEs significantly enhanced the drug permeation compared to GRN powder. The in vivo toxicity study in the rat jejunum revealed that the prepared GRN-loaded LNE was as safe as the commercial formulation (Kytril). These results suggest that LNE could be used as a potential oral liquid formulation of GRN for anti-emetic treatment on the post-operative and chemotherapeutic patients. Copyright © 2012 Elsevier B.V. All rights reserved.

Nanoethosomes for transdermal delivery of tropisetron HCl: multi-factorial predictive modeling, characterization, and ex vivo skin permeation.

PubMed

Abdel Messih, Hanaa A; Ishak, Rania A H; Geneidi, Ahmed S; Mansour, Samar

2017-06-01

The aim of the present work is to exclusively optimize and model the effect of phospholipid type either egg phosphatidylcholine (EPC) or soybean phosphatidylcholine (SPC), together with other formulation variables, on the development of nano-ethosomal systems for transdermal delivery of a water-soluble antiemetic drug. Tropisetron HCl (TRO) is available as hard gelatin capsules and IV injections. The transdermal delivery of TRO is considered as a novel alternative route supposing to improve BAV as well as patient convenience. TRO-loaded ethanolic vesicular systems were prepared by hot technique. The effect of formulation variables were optimized through a response surface methodology using 3 × 2 2 -level full factorial design. The concentrations of both PC (A) and ethanol (B) and PC type (C) were the factors, while entrapment efficiency (Y 1 ), vesicle size (Y 2 ), polydispersity index (Y 3 ), and zeta potential (Y 4 ) were the responses. The drug permeation across rat skin from selected formulae was studied. Particle morphology, drug-excipient interactions, and vesicle stability were also investigated. The results proved the critical role of all formulation variables on ethosomal characteristics. The suggested models for all responses showed good predictability. Only the concentration of phospholipid, irrespective to PC type, had a significant effect on the transdermal flux (p < 0.01). The ethosomal vesicles were unilamellar with a nearly spherical shape. EPC-based ethosomes proved good stability. The study suggests the applicability of statistical modeling as a promising tool for prediction of ethosomal characteristics. The ethanolic vesicles were considered as novel potential nanocarriers for accentuated transdermal TRO delivery.

Successful control of intractable nausea and vomiting requiring combined ondansetron and haloperidol in a patient with advanced cancer.

PubMed

Cole, R M; Robinson, F; Harvey, L; Trethowan, K; Murdoch, V

1994-01-01

Chemically induced nausea and vomiting is a common symptom of advanced cancer effected through stimulation of dopamine (D2) or serotonin (5-HT3) receptors located in the chemoreceptor trigger zone (CTZ). These may be blocked by therapeutic doses of haloperidol and ondansetron, respectively. This case, reporting on a single patient acting as her own control, establishes that combined blockade of these receptors is sometimes required to relieve intractable nausea and vomiting. It also demonstrates the value of clinical review, audit of care, and quality assurance in the palliative care setting.

Hydrophilic interaction liquid chromatography in analysis of granisetron HCl and its related substances. Retention mechanisms and method development.

PubMed

Maksić, Jelena; Tumpa, Anja; Stajić, Ana; Jovanović, Marko; Rakić, Tijana; Jančić-Stojanović, Biljana

2016-05-10

In this paper separation of granisetron and its two related substances in HILIC mode is presented. Separation was done on silica column derivatized with sulfoalkylbetaine groups (ZIC-HILIC). Firstly, retention mechanisms were assessed whereby retention factors of substances were followed in wide range of acetonitrile content (80-97%), at constant concentration of aqueous buffer (10mM) as well as at constant pH value of 3.0. Further, in order to developed optimal HILIC method, Design of Experiments (DoE) methodology was applied. For optimization full factorial design 3(2) was employed. Influence of acetonitrile content and ammonium acetate concentration were investigated while pH of the water phase was kept at 3.3. Adequacy of obtained mathematical models was confirmed by ANOVA. Optimization goals (α>1.15 and minimal run time) were accomplished with 94.7% of acetonitrile in mobile phase and 70 mM of ammonium acetate in water phase. Optimal point was in the middle of defined Design Space. In the next phase, robustness was experimetally tested by Rechtschaffen design. The investigated factors and their levels were: acetonitrile content (±1%), ammonium acetate molarity in water phase (±2 mM), pH value of water phase (±0.2) and column temperature (±4 °C). The validation scope included selectivity, linearity, accuracy and precision as well as determination of limit of detection (LOD) and limit of quantification (LOQ) for the related substances. Additionally, the validation acceptance criteria were met in all cases. Finally, the proposed method could be successfully utilized for estimation of granisetron HCl and its related substances in tablets and parenteral dosage forms, as well as for monitoring degradation under various stress conditions. Copyright © 2016 Elsevier B.V. All rights reserved.

Enhanced transdermal delivery of ondansetron using nanovesicular systems: Fabrication, characterization, optimization and ex-vivo permeation study-Box-Cox transformation practical example.

PubMed

Habib, Basant A; Sayed, Sinar; Elsayed, Ghada M

2018-03-30

This study aimed to formulate suitable nanovesicles (NVs) for transdermal delivery of Ondansetron. It also illustrated a practical example for the importance of Box-Cox transformation. A 2 3 full factorial design was used to enable testing transfersomes, ethosomes, and transethosomes of Ondansetron simultaneously. The independent variables (IVs) studied were sodium taurocholate amount, ethanol volume in hydration medium and sonication time. The studied dependent variables (DVs) were: particle size (PS), zeta potential (ZP) and entrapment efficiency (EE). Polynomial equations were used to study the influence of IVs on each DV. Numerical multiple response optimization was applied to select an optimized formula (OF) with the goals of minimizing PS and maximizing ZP absolute value and EE. Box-Cox transformation was adopted to enable modeling PS raised to the power of 1.2 with an excellent prediction R 2 of 1.000. ZP and EE were adequately represented directly with prediction R 2 of 0.9549 and 0.9892 respectively. Response surface plots helped in explaining the influence of IVs on each DV. Two-sided 95% prediction interval test and percent deviation of actual values from predicted ones proved the validity of the elucidated models. The OF was a transfersomal formula with desirability of 0.866 and showed promising results in ex-vivo permeation study. Copyright © 2018 Elsevier B.V. All rights reserved.

A high-performance liquid chromatography-tandem mass spectrometry method coupled with protein precipitation for determination of granisetron in human plasma and its application to a comparative pharmacokinetic study.

PubMed

Zhou, Ying; Jiang, Ji; Hu, Pei; Wang, Hongyun

2014-12-01

A rapid, simple and validated method based on liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) has been developed for the determination of granisetron in human plasma. Plasma samples were pre-purified by protein precipitation procedure. The chromatographic separation was achieved with Synergi Polar-RP (75 × 2 mm, 4 µm) column using a mixture of 5 mm pH4.0 ammonium formate and methanol (300:316, v/v) under isocratic conditions at a flow rate of 0.3 mL/min. The detection was performed on a triple quadrupole tandem mass spectrometer in multiple reaction monitoring mode using positive electrospray ionization. The analysis time was about 2.5 min. The method was fully validated over the concentration range 0.1-10 ng/mL. The lower limit of quantification was 0.1 ng/mL. Inter- and intra-batch precision was <6.1% and the accuracy was within 95.6-100.0%. The mean extraction recovery was 96.3%. Selectivity, matrix effect and stability were also validated. The method was applied to the comparative pharmacokinetic study of granisetron in Chinese healthy subjects. Copyright © 2014 John Wiley & Sons, Ltd.

Synthesis and Pharmacological Evaluation of [11C]Granisetron and [18F]Fluoropalonosetron as PET Probes for 5-HT3 Receptor Imaging.

PubMed

Mu, Linjing; Müller Herde, Adrienne; Rüefli, Pascal M; Sladojevich, Filippo; Milicevic Sephton, Selena; Krämer, Stefanie D; Thompson, Andrew J; Schibli, Roger; Ametamey, Simon M; Lochner, Martin

2016-11-16

Serotonin-gated ionotropic 5-HT 3 receptors are the major pharmacological targets for antiemetic compounds. Furthermore, they have become a focus for the treatment of irritable bowel syndrome (IBS) and there is some evidence that pharmacological modulation of 5-HT 3 receptors might alleviate symptoms of other neurological disorders. Highly selective, high-affinity antagonists, such as granisetron (Kytril) and palonosetron (Aloxi), belong to a family of drugs (the "setrons") that are well established for clinical use. To enable us to better understand the actions of these drugs in vivo, we report the synthesis of 8-fluoropalonosetron (15) that has a binding affinity (K i = 0.26 ± 0.05 nM) similar to the parent drug (K i = 0.21 ± 0.03 nM). We radiolabeled 15 by nucleophilic 18 F-fluorination of an unsymmetrical diaryliodonium palonosetron precursor and achieved the radiosynthesis of 1-(methyl- 11 C)-N-granisetron ([ 11 C]2) through N-alkylation with [ 11 C]CH 3 I, respectively. Both compounds [ 18 F]15 (chemical and radiochemical purity >95%, specific activity 41 GBq/μmol) and [ 11 C]2 (chemical and radiochemical purity ≥99%, specific activity 170 GBq/μmol) were evaluated for their utility as positron emission tomography (PET) probes. Using mouse and rat brain slices, in vitro autoradiography with both [ 18 F]15 and [ 11 C]2 revealed a heterogeneous and displaceable binding in cortical and hippocampal regions that are known to express 5-HT 3 receptors at significant levels. Subsequent PET experiments suggested that [ 18 F]15 and [ 11 C]2 are of limited utility for the PET imaging of brain 5-HT 3 receptors in vivo.

The Impact of 5-HT3RA Use on Cost and Utilization in Patients with Chemotherapy-Induced Nausea and Vomiting: Systematic Review of the Literature

PubMed Central

Broder, Michael S.; Faria, Claudio; Powers, Annette; Sunderji, Jehangeer; Cherepanov, Dasha

2014-01-01

Background Individual studies have assessed the impact of standard prophylactic therapy with 5-hydroxytryptamine receptor antagonists (5-HT3RAs) for chemotherapy-induced nausea and vomiting (CINV) on cost and utilization, but no synthesis of the findings exists. Objective To systematically review published literature on costs and utilization associated with CINV prophylaxis with palonosetron and other 5-HT3RAs. Methods PubMed and the National Institute for Health Research Centre for Reviews and Dissemination databases, conferences of 4 organizations (ie, Academy of Managed Care Pharmacy, American Society of Clinical Oncology, International Society for Pharmacoeconomics and Outcomes Research, and Multinational Association of Supportive Care in Cancer), and the bibliographies of relevant articles were queried for the medical subject headings and key terms of “ondansetron,” “granisetron,” “palonosetron,” “dolasetron mesylate,” “costs,” “cost analysis,” and “economics.” We included records published (full-length articles after 1997 and conference presentations after 2010) in English and with human patients, reporting data on cost and utilization (rescue medication, outpatient and inpatient services) associated with the use of 5-HT3RAs for the treatment or prevention of CINV. Results Of the 434 identified studies, 32 are included in the current analysis: 7 studies report costs, 18 report utilization, and 7 studies report both. The costs are reported in US dollars (7 studies), in Euros (5 studies), and in Canadian dollars (2 studies). The studies vary in designs, patients, 5-HT3RA regimens, and the definition of outcomes. The US studies report higher drug costs for CINV prophylaxis with palonosetron compared with ondansetron, lower medical outpatient and inpatient costs for palonosetron versus other 5-HT3RAs, and higher acquisition costs for palonosetron versus ondansetron or other 5-HT3RAs. Fewer patients receiving palonosetron versus with

Granisetron transdermal system improves refractory nausea and vomiting in gastroparesis.

PubMed

Simmons, Kellie; Parkman, Henry P

2014-06-01

Symptoms of gastroparesis include nausea and vomiting, which can markedly diminish quality of life. Nausea and vomiting can also make treatment with oral antiemetics problematic. Our aim was to determine whether treatment-resistant nausea and vomiting in patients with gastroparesis improve after granisetron transdermal patch (GTP) therapy. In an open-label pilot study, patients with gastroparesis and symptoms of nausea and vomiting refractory to conventional treatment were treated with GTP. After 2 weeks, patients were asked to assess their therapeutic response using the Clinical Patient Grading Assessment Scale (CPGAS; +7 = completely better; 0 = no change; -7 = very considerably worse). Responders were defined as CPGAS score >0, non-responders as ≤0. Patients (n = 36) were treated with GTP. Of these 36 patients, one patient discontinued treatment due to the GTP not adhering to the skin. Of the remaining 35 patients, 18 improved, 15 remained the same, and two worsened. The average CPGAS score was +1.8 ± 0.4 (SEM) (P < 0.05 vs 0). Of the 18 patients with improvement, the average CPGAS score was +3.7 ± 0.3 (SEM), corresponding to "somewhat" to "moderately better" improvement in nausea/vomiting. Side effects occurred in nine patients: four developed constipation, three patients had skin rash, and two reported headaches. GTP was moderately effective in reducing refractory symptoms of nausea and/or vomiting from gastroparesis in 50% of patients. Mild side effects were reported by 25% of patients. GTP may be an effective treatment for nausea and vomiting in gastroparesis, and further study is warranted.

Delta-9-tetrahydrocannabinol and cannabidiol, but not ondansetron, interfere with conditioned retching reactions elicited by a lithium-paired context in Suncus murinus: An animal model of anticipatory nausea and vomiting.

PubMed

Parker, Linda A; Kwiatkowska, Magdalena; Mechoulam, Raphael

2006-01-30

Chemotherapy patients report not only acute nausea and vomiting during the treatment itself, but also report anticipatory nausea and vomiting upon re-exposure to the cues associated with the treatment. We present a model of anticipatory nausea based on the emetic reactions of the Suncus murinus (musk shrew). Following three pairings of a novel distinctive contextual cue with the emetic effects of an injection of lithium chloride, the context acquired the potential to elicit conditioned retching in the absence of the toxin. The expression of this conditioned retching reaction was completely suppressed by pretreatment with each of the principal cannabinoids found in marijuana, Delta(9)-tetrahydrocannabinol or cannabidiol, at a dose that did not suppress general activity. On the other hand, pretreatment with a dose of ondansetron (a 5-HT(3) antagonist) that interferes with acute vomiting in this species, did not suppress the expression of conditioned retching during re-exposure to the lithium-paired context. These results support anecdotal claims that marijuana, but not ondansetron, may suppress the expression of anticipatory nausea.

Ondansetron and promethazine have differential effects on hypothermic responses to lithium chloride administration and to provocative motion in rats

PubMed Central

Guimaraes, Drielle D; Andrews, Paul L R; Rudd, John A; Braga, Valdir A; Nalivaiko, Eugene

2015-01-01

We recently reported that provocative motion (rotation in a home cage) causes hypothermic responses in rats, similar to the hypothermic responses associated with motion sickness in humans. Many stimuli inducing emesis in species with an emetic reflex also provoke hypothermia in the rat, therefore we hypothesized that a fall in body temperature may reflect a “nausea-like” state in these animals. As rats do not possess an emetic reflex, we employed a pharmacological approach to test this hypothesis. In humans, motion- and chemically-induced nausea have differential sensitivity to anti-emetics. We thus tested whether the hypothermia induced in rats by provocative motion (rotation at 0.7 Hz) and by the emetic LiCl (63 mg/kg i.p.) have a similar differential pharmacological sensitivity. Both provocations caused a comparable robust fall in core body temperature (−1.9 ± 0.3°C and −2.0 ± 0.2°C for chemical and motion provocations, respectively). LiCl−induced hypothermia was completely prevented by ondansetron (2mg/kg, i.p., a 5-HT3 receptor antagonist that reduces cancer chemotherapy-induced nausea and vomiting), but was insensitive to promethazine (10 mg/kg, i.p., a predominantly histamine-H1 and muscarinic receptor antagonist that is commonly used to treat motion sickness). Conversely, motion-induced hypothermia was unaffected by ondansetron but promethazine reduced the rate of temperature decline from 0.20 ± 0.02 to 0.11 ± 0.03°C/min (P < 0.05) with a trend to decrease the magnitude. We conclude that this differential pharmacological sensitivity of the hypothermic responses of vestibular vs. chemical etiology in rats mirrors the observations in other pre-clinical models and humans, and thus supports the idea that a “nausea-like” state in rodents is associated with disturbances in thermoregulation. PMID:27227074

Triple Therapy with Scopolamine, Ondansetron, and Dexamethasone for Prevention of Postoperative Nausea and Vomiting in Moderate to High-Risk Patients Undergoing Craniotomy Under General Anesthesia: A Pilot Study.

PubMed

Bergese, Sergio D; Antor, Maria A; Uribe, Alberto A; Yildiz, Vedat; Werner, Joseph

2015-01-01

Postoperative nausea and vomiting (PONV) is one of the most common complaints from patients and clinicians after a surgical procedure. According to the current Society of Ambulatory Anesthesia Consensus Guidelines, the general incidence of vomiting and nausea is around 30 and 50%, respectively; and up to 80% in high-risk patients. In previous studies, the reported incidence of PONV at 24 h after craniotomy was 43-70%. The transdermal scopolamine (TDS) delivery system contains a 1.5-mg drug reservoir, which is designed to deliver a continuous slow release of scopolamine through intact skin during the first 72 h of patch application. Therefore, we designed this single arm, non-randomized, pilot study to assess the efficacy and safety of triple therapy with scopolamine, ondansetron, and dexamethasone to prevent PONV. In the preoperative area, subjects received an active TDS 1.5 mg that was applied to a hairless patch of skin in the mastoid area approximately 2 h prior to the operation. Immediately after anesthesia induction, all patients received a single 4 mg dose of ondansetron IV and a single 10 mg dose of dexamethasone IV. Patients who experienced nausea and/or vomiting received ondansetron 4 mg IV as the initial rescue medication. Postoperative nausea and vomiting assessments were performed for up to 120 h after surgery. A total of 36 subjects were analyzed. The overall incidence of PONV during the first 24 h after neurological surgery was 33% (n = 12). The incidence of nausea and emesis during the first 24 h after surgery was recorded as 33% (n = 12) and 16% (n = 6), respectively. Our data showed that this triple therapy regimen may be an efficient alternative regimen for PONV prophylaxis in patients undergoing neurological surgery with general anesthesia. Further studies using regimens affecting different receptor pathways should be performed to better prove the efficacy and safety in the prevention or delay of PONV.

Formulation of Convenient, Easily Scalable, and Efficient Granisetron HCl Intranasal Droppable Gels.

PubMed

Ibrahim, Howida K; Abdel Malak, Nevine S; Abdel Halim, Sally A

2015-06-01

Deacetylated gellan gum and two sodium alginate polymer types were used each at three concentrations in the suitable range for their sol-gel transition. The prepared nine droppable gels were evaluated in vitro, ex vivo through sheep nasal mucosa, as well as in vivo in comparison to drug solution given intravenously and orally at the same dose. The prepared formulas gelled instantaneously in simulated nasal fluid and the obtained gels sustained their shear thinning and thixotropic behavior up to 48 h. Polymer type and concentration had significant effects on the apparent viscosities and the in vitro release profile of granisetron from the prepared gels. The drug release data best fitted a modified Higuchi equation with initial burst and followed Fickian diffusion mechanism. A 0.5% gellan-gum-based formula sustained the in vitro drug release up to 3 h and enhanced the drug permeation without need for an enhancer. The histopatholgical study revealed the safety of the tested formula. Intranasal delivery recorded double the drug bioavailabilty in comparison to the oral route. It had an absolute bioavailability of 0.6539 and the maximum plasma drug concentration reached after 1.5 h. The developed formula could be promising for the management of chemotherapy-induced nausea and vomiting regarding its improved bioavailability, patient acceptability, and ease of production.

Aprepitant plus granisetron and dexamethasone for prevention of chemotherapy-induced nausea and vomiting in patients with gastric cancer treated with S-1 plus cisplatin.

PubMed

Oyama, Katsunobu; Fushida, Sachio; Kaji, Masahide; Takeda, Toshiya; Kinami, Shinichi; Hirono, Yasuo; Yoshimoto, Katsuhiro; Yabushita, Kazuhisa; Hirosawa, Hisashi; Takai, Yuki; Nakano, Tatsuo; Kimura, Hironobu; Yasui, Toshiaki; Tsuneda, Atsushi; Tsukada, Tomoya; Kinoshita, Jun; Fujimura, Takashi; Ohta, Tetsuo

2013-11-01

We aimed to evaluate the efficacy of a new combination antiemetic therapy comprising aprepitant, granisetron, and dexamethasone in gastric cancer patients undergoing chemotherapy with cisplatin and S-1. Gastric cancer patients scheduled to receive their first course of chemotherapy with cisplatin (60 mg/m(2)) and S-1 (80 mg/m(2)) were treated with a new combination antiemetic therapy aprepitant, granisetron, and dexamethasone on day 1; aprepitant and dexamethasone on days 2 and 3; and dexamethasone on day 4. The patients reported vomiting, nausea, use of rescue therapy, and change in the amount of diet intake, and completed the Functional Living Index-Emesis (FLIE) questionnaire. The primary endpoint was complete response (CR; no emesis and use of no rescue antiemetics) during the overall study phase (0-120 h after cisplatin administration). The secondary endpoints included complete protection (CP; CR plus no significant nausea); change in the amount of diet intake; and the impact of chemotherapy-induced nausea and vomiting (CINV) on daily life during the overall, acute (0-24 h), and delayed (24-120 h) phases. Fifty-three patients were included. CR was achieved in 88.7, 98.1, and 88.7% of patients in the overall, acute, and delayed phases, respectively. The corresponding rates of CP were 67.9, 96.2, and 67.9%. Approximately half of the patients had some degree of anorexia. FLIE results indicated that 79.5% of patients reported "minimal or no impact of CINV on daily life". Addition of aprepitant to standard antiemetic therapy was effective in gastric cancer patients undergoing treatment with cisplatin and S-1.

Evidence that the atypical 5-HT3 receptor ligand, [3H]-BRL46470, labels additional 5-HT3 binding sites compared to [3H]-granisetron.

PubMed Central

Steward, L. J.; Ge, J.; Bentley, K. R.; Barber, P. C.; Hope, A. G.; Lambert, J. J.; Peters, J. A.; Blackburn, T. P.; Barnes, N. M.

1995-01-01

1. The radioligand binding characteristics of the 3H-derivative of the novel 5-HT3 receptor antagonist BRL46470 were investigated and directly compared to the well characterized 5-HT3 receptor radioligand [3H]-granisetron, in tissue homogenates prepared from rat cerebral cortex/hippocampus, rat ileum, NG108-15 cells, HEK-5-HT3As cells and human putamen. 2. In rat cerebral cortex/hippocampus, rat ileum, NG108-15 cell and HEK-5-HT3As cell homogenates, [3H]-BRL46470 bound with high affinity (Kd (nM): 1.57 +/- 0.18, 2.49 +/- 0.30, 1.84 +/- 0.27, 3.46 +/- 0.36, respectively; mean +/- s.e. mean, n = 3-4) to an apparently homogeneous saturable population of sites (Bmax (fmol mg-1 protein): 102 +/- 16, 44 +/- 4, 968 +/- 32 and 2055 +/- 105, respectively; mean +/- s.e. mean, n = 3-4) but failed to display specific binding in human putamen homogenates. 3. In the same homogenates of rat cerebral cortex/hippocampus, rat ileum, NG108-15 cells, HEK-5-HT3As cells and human putamen as used for the [3H]-BRL46470 studies, [3H]-granisetron also bound with high affinity (Kd (nM): 1.55 +/- 0.61, 2.31 +/- 0.44, 1.89 +/- 0.36, 2.03 +/- 0.42 and 6.46 +/- 2.58 respectively; mean +/- s.e. mean, n = 3-4) to an apparently homogeneous saturable population of sites (Bmax (fmol mg-1 protein): 39 +/- 4, 20 +/- 2, 521 +/- 47, 870 +/- 69 and 18 +/- 2, respectively; mean +/- s.e. mean, n = 3-4).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8528560

Slow-release granisetron (APF530) versus palonosetron for chemotherapy-induced nausea/vomiting: analysis by American Society of Clinical Oncology emetogenicity criteria.

PubMed

Raftopoulos, Harry; Boccia, Ralph; Cooper, William; O'Boyle, Erin; Gralla, Richard J

2015-09-01

APF530 is a novel sustained-release formulation of granisetron. In a Phase III trial, APF530 500 mg was noninferior to palonosetron 0.25 mg in preventing acute chemotherapy-induced nausea and vomiting (CINV) after moderately (MEC) or highly emetogenic chemotherapy (HEC) and delayed CINV after MEC, but not superior in preventing delayed CINV after HEC. Emetogenicity was classified by Hesketh criteria; this reanalysis uses newer American Society of Clinical Oncology criteria. Complete responses (no emesis or rescue medication) after cycle one were reanalyzed after reclassification of MEC and HEC by American Society of Clinical Oncology criteria. APF530 maintained noninferiority to palonosetron. Single-dose APF530 is a promising alternative to palonosetron for preventing acute and delayed CINV after MEC or HEC. The Clinicaltrials.gov identifier for this study is NCT00343460.

A combination of nonionic surfactants and iontophoresis to enhance the transdermal drug delivery of ondansetron HCl and diltiazem HCl.

PubMed

Silva, Sérgio M C; Hu, Longsheng; Sousa, João J S; Pais, Alberto A C C; Michniak-Kohn, Bozena B

2012-04-01

The present work reports the evaluation of three nonionic ether-monohydroxyl surfactants (C(12)E(1), C(12)E(5,) and C(12)E(8)) as skin permeation enhancers in the transdermal drug delivery of two drugs: ondansetron hydrochloride and diltiazem hydrochloride, formulated as hydrogels. The enhancers are used alone, or in combination with iontophoresis (0.3 mA - 8h). After 1h of pre-treatment with 0.16 M enhancer solutions in propylene glycol (PG), passive and iontophoretic 24 h in vitro studies across dermatomed porcine skin were performed using vertical Franz diffusion cells. Data obtained showed that the nonionic surfactant C(12)E(5) was the most effective permeation enhancer, both for the passive process as well as for samples subjected to iontophoresis, resulting in cumulative amounts of ondansetron HCl after 24h of approximately 93 μg/cm(2) and 336 μg/cm(2), respectively. Data obtained using diltiazem HCl showed a similar trend. The use of the nonionic surfactant C(12)E(5) resulted in higher enhancement ratios (ER) in passive studies, but C(12)E(8) yielded slightly higher values of drug permeated (2678 μg/cm(2)) than C(12)E(5) (2530 μg/cm(2)) when iontophoresis was also employed. Skin integrity studies were performed to assess potential harmful effects on the tissues resulting from the compounds applied and/or from the methodology employed. Skin samples used in permeation studies visualized by light microscopy and Scanning Electron Microscopy (SEM) at different levels of magnification did not show significant morphological and structural changes, when compared to untreated samples. Complementary studies were performed to gain information regarding the relative cytotoxicity of the penetration enhancers on skin cells. MTS assay data using human epidermal keratinocytes (HEK) and human dermal fibroblasts (HDF) indicated that HEK are more sensitive to the presence of the enhancers than HDF and that the toxicity of these compounds is enhancer molecular weight

Efficacy of tropisetron in patients with advanced non-small-cell lung cancer receiving adjuvant chemotherapy with carboplatin and taxanes.

PubMed

Tsavaris, N; Kosmas, C; Kopterides, P; Vadiaka, M; Kosmas, N; Skopelitis, H; Karadima, D; Kolliokosta, G; Tzima, E; Loukeris, D; Pagouni, E; Batziou, E; Xyla, V; Koufos, C

2008-03-01

Even though significant progress has been made, chemotherapy-induced emesis remains a challenging problem. Few studies focus on emesis in patients treated with carboplatin and the observation period is limited to the initial 24 h following chemotherapy. Thus, we investigated if tropisetron (T) monotherapy can adequately prevent acute and delayed emesis in non-small-cell lung cancer (NSCLC) patients receiving a moderately emetogenic chemotherapy (MEC) (carboplatin-containing) regimen. Furthermore, we explored the merits of adding dexamethasone (D) or alprazolam (A) to T, especially in the setting of a pre-existing high level of stress. We studied 60 patients with advanced NSCLC receiving carboplatin and taxanes in three consecutive cycles. During the first cycle, patients received 5 mg of T intravenously before chemotherapy and the same dose per os on each of the following 3 days. In the second cycle, T was co-administered with 8 mg of D once a day, while, during the third cycle, T was combined with per os A 0.25 mg every 12 h and continued over the following 3 days. Finally, we evaluated the impact of stress on the anti-emetic response achieved with the previously described regimens. The combination of T + A was superior to T monotherapy and the combination of T + D, regarding the prevention of acute and delayed emesis. Both T + A and T + D combinations led to appetite improvement, while patients receiving T + A experienced sedation more frequently. Interestingly, subgroup analysis revealed that patients without underlying stress obtained no further benefit by the addition of A or D, while both T + A and T + D combinations led to a better anti-emetic response in patients with stress. In conclusion, T monotherapy provides a satisfactory result in controlling nausea and emesis caused by a MEC regimen in patients without stress. However, the addition of D and, mainly, A improves its anti-emetic effect in patients with obvious stress.

A Prospective, Randomized, Double-Blinded, Double-Dummy Pilot Study to Assess the Preemptive Effect of Triple Therapy with Aprepitant, Dexamethasone, and Promethazine versus Ondansetron, Dexamethasone and Promethazine on Reducing the Incidence of Postoperative Nausea and Vomiting Experienced by Patients Undergoing Craniotomy Under General Anesthesia.

PubMed

Bergese, Sergio Daniel; Puente, Erika G; Antor, Maria A; Viloria, Adolfo L; Yildiz, Vedat; Kumar, Nicolas Alexander; Uribe, Alberto A

2016-01-01

Postoperative nausea and vomiting (PONV) is among the most common distressing complications of surgery under anesthesia. Previous studies have demonstrated that patients who undergo craniotomy have incidences of nausea and vomiting as high as 50-70%. The main purpose of this pilot study is to assess the incidence of PONV by using two different prophylactic regimens in subjects undergoing a craniotomy. Thus, we designed this study to assess the efficacy and safety of triple therapy with the combination of dexamethasone, promethazine, and aprepitant versus ondansetron to reduce the incidence of PONV in patients undergoing craniotomy. This is a prospective, single center, two-armed, randomized, double-dummy, double-blind, pilot study. Subjects were randomly assigned to one of the two treatment groups. Subjects received 40 mg of aprepitant pill (or matching placebo pill) 30-60 min before induction of anesthesia and 4 mg of ondansetron IV (or 2 ml of placebo saline solution) at induction of anesthesia. In addition, all subjects received 25 mg of promethazine IV and 10 mg of dexamethasone IV at induction of anesthesia. Assessments of PONV commenced for the first 24 h after surgery and were subsequently assessed for up to 5 days. The overall incidence of PONV during the first 24 h after surgery was 31.0% (n = 15) in the aprepitant group and 36.2% (n = 17) for the ondansetron group. The median times to first emetic and significant nausea episodes were 7.6 (2.9, 48.7) and 14.3 (4.4, 30.7) hours, respectively, for the aprepitant group and 6.0 (2.2, 29.5) and 9.6 (0.7, 35.2) hours, respectively, for the ondansetron group. There were no statistically significant differences between these groups. No adverse events directly related to study medications were found. This pilot study showed similar effectiveness when comparing the two PONV prophylaxis regimens. Our data showed that both treatments could be effective regimens to prevent PONV in patients

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

NASA Astrophysics Data System (ADS)

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

2013-03-01

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.

Aprepitant, granisetron, and dexamethasone versus palonosetron and dexamethasone for prophylaxis of cisplatin-induced nausea and vomiting in patients with upper gastrointestinal cancer: a randomized crossover phase II trial (KDOG 1002).

PubMed

Ishido, Kenji; Higuchi, Katsuhiko; Azuma, Mizutomo; Sasaki, Tohru; Tanabe, Satoshi; Katada, Chikatoshi; Yano, Takafumi; Wada, Takuya; Koizumi, Wasaburo

2016-10-01

We conducted a randomized trial to compare the safety and effectiveness of aprepitant, granisetron, and dexamethasone (AGD) with those of palonosetron and dexamethasone (PD) in patients who received highly emetogenic chemotherapy (HEC). Patients with esophageal or gastric cancer who were scheduled to receive HEC including at least 60 mg/m of cisplatin as the first-line treatment were randomly assigned to receive AGD (oral aprepitant 125 mg on day 1 and 80 mg on days 2-3; intravenous granisetron 3 mg on day 1; intravenous dexamethasone 6.6 mg on day 1 and oral dexamethasone 4 mg on days 2-3) or PD (intravenous palonosetron 0.75 mg on day 1; intravenous dexamethasone 13.2 mg on day 1 and oral dexamethasone 8 mg on days 2-3). The primary endpoint was a complete response during the overall study period (0-120 h after the start of chemotherapy) in the first cycle. Eighty-five patients were enrolled, and 84 were eligible. The complete response rate did not differ between the treatment groups, but the proportion of patients with no vomiting was significantly higher in the AGD group than in the PD group (81.4 vs. 58.5%; P=0.031). The results of a quality-of-life survey indicated that the proportion of patients with no or minimal impact on daily life in the vomiting domain was significantly higher in the AGD group (79.1 vs. 53.7%; P=0.020). The primary endpoint of complete response was not achieved, but AGD seems to be more effective than PD for the prevention of HEC-induced vomiting.

[Preparation of ondansetron hydrochloride osmotic pump tablets and their in vitro drug release].

PubMed

Zheng, Hang-sheng; Bi, Dian-zhou

2005-12-01

To prepare ondansetron hydrochloride osmotic pump tablets (OND-OPT) and investigate their in vitro drug release behavior. OND-OPT were prepared with a single punch press and pan coating technique. Osmotic active agents and plasticizer of coating film were chosen by drug release tests. The effects of the number, position and direction of drug release orifice on release behavior were investigated. The relation between drug release duration and thickness of coating film, PEG content of coating film and size of drug release orifice was established by uniform design experiment. The surface morphological change of coating film before and after drug release test was observed by scanning electron microscopy. The osmotic pumping release mechanism of OND-OPT was confirmed by drug release test with high osmotic pressure medium. Lactose-mannitol (1:2) was chosen as osmotic active agents and PEG400 as plasticizer of coating film. The direction of drug release orifice had great effect on the drug release of OND-OPT without HPMC, and had no effect on the drug release of OND-OPT with HPMC. The OND-OPT with one drug release orifice at the centre of the coating film on one surface of tablet released their drug with little fluctuation. The drug release duration of OND-OPT correlated with thickness of coating film and PEG content of coating film, and didn't correlate significantly with the size of drug release orifice. OND-OPT released their drug with osmotic pumping mechanism predominantly. OND-OPT are able to realize ideal controlled drug release.

Design and evaluation of buccal films as paediatric dosage form for transmucosal delivery of ondansetron.

PubMed

Trastullo, Ramona; Abruzzo, Angela; Saladini, Bruno; Gallucci, Maria Caterina; Cerchiara, Teresa; Luppi, Barbara; Bigucci, Federica

2016-08-01

In the process of implementation and innovation of paediatric dosage forms, buccal films for transmucosal administration of drug represent one of the most interesting approach. In fact, films are able to provide an extended duration of activity allowing minimal dosage and frequency and offer an exact and flexible dose, associated with ease of handling. The objective of the present study was to develop polymeric films for the sustained release of ondansetron hydrochloride, a selective inhibitor of 5-HT3 receptors indicated in paediatrics for the prevention and treatment of nausea and vomiting caused by cytotoxic chemotherapy or radiotherapy and postoperatively. Films were prepared by casting and drying of aqueous solutions containing different weight ratios of hydroxypropylmethylcellulose (HPMC) with chitosan (CH) or sodium hyaluronate (HA) or gelatin (GEL) and characterized for their physico-chemical and functional properties. The presence of HA, GEL and CH did not improve the mucoadhesive properties of HPMC film. The inclusion of GEL and CH in HPMC film increased in vitro drug release with respect to the inclusion of HA, although films containing HA showed the highest water uptake. Moreover in agreement with the release behaviour, the inclusion of CH and GEL provided higher drug permeation through porcine buccal mucosa with respect to HPMC film and ensured linear permeation profiles of drug. Copyright © 2016 Elsevier B.V. All rights reserved.

Long-term stability of dexamethasone and alizapride or ondansetron in sodium chloride 0.9% polyolefin bag at 5±3°C.

PubMed

Simar, J; Godet, M; Hecq, J-D; Closset, M; Gillet, P; Langhendries, C; Bihin, B; Jamart, J; Galanti, L

2017-01-01

The aim of the study was to investigate the long-term stability of dexamethasone 10mg associated with alizapride 100mg or ondansetron 8mg in 100mL of 0.9% sodium chloride solution stored at 5±3°C. Solutions of 0.9% sodium chloride 100mL in polyolefin bags (n=5) containing approximately dexamethasone (DEX) 10mg associated with alizapride (ALI) 100mg or ondansetron (OND) 8mg were prepared under aseptic conditions and stored about 30 days at 5±3°C. ALI, DEX and OND concentrations were measured by high-performance liquid chromatography (HPLC). Optic density measurement at different wavelengths, pH measurement and optic microscope observations were performed periodically during the storage. A forced degradation test with HCL 5M and NaOH 5M before and after heating at 100°C was also performed. Solutions were considered stable if the 95% one-sided lower confidence limit of the concentration remains superior to 90% of the initial concentration or 95% of the initial concentration when any signs of physical instability exist as recently recommend. The calibration was linear over the following range from 20 to 1.25mg/100mL for DEX, from 200 to 12.5mg/100mL for ALI and from 20 to 1.25mg/100mL for OND with a calculated correlation coefficient (r 2 ) of 0.998, 0.999 and 0.999, respectively. The inter- and intra-assay precision was below 10% for both mixtures. All formulations were physically stable during the storage. The lower confidence limit of the concentration for these solutions remains superior to 90% of the initial concentration at this date as recommended by the Food and Drug Administration (FDA) until 30 days. The HPLC method is specific and reproducible and can easily be adopted for monitoring the quality control in the production of DEX-ALI and DEX-OND bags. Solutions of DEX-ALI and DEX-OND were physically and chemically stable for 30 days in polyolefin bags stored at 5±3°C and could therefore be prepared in advance. Copyright © 2016 Académie Nationale de

Clinical roundtable monograph: New data in emerging treatment options for chemotherapy-induced nausea and vomiting.

PubMed

Morrow, Gary R; Navari, Rudolph M; Rugo, Hope S

2014-03-01

Chemotherapy-induced nausea and vomiting (CINV) has long been one of the most troublesome adverse effects of chemotherapy, leading to significant detriments in quality of life and functioning, increased economic costs, and, in some cases, the discontinuation of effective cancer therapy. The past 2 decades have witnessed a dramatic increase in the number of effective antiemetic agents, with the introduction of the serotonin (5-hydroxytryptamine [5-HT₃]) receptor antagonists (ondansetron, granisetron, and palonosetron), the neurokinin-1 (NK₁) receptor antagonists (aprepitant and fosaprepitant), and the identification of other agents that have demonstrated efficacy against CINV, including corticosteroids. These agents often provide excellent control of emesis. Nausea, however, has proven more intractable, particularly in the days after administration of chemotherapy. Newer antiemetic agents under study may provide additional CINV control, particularly against delayed nausea. New agents undergoing review by the US Food and Drug Administration for the prevention of CINV include the novel NK₁ receptor antagonist rolapitant and a fixed-dose combination consisting of the novel NK₁ receptor antagonist netupitant and palonosetron (NEPA). Adherence to clinical practice guidelines has been shown to significantly improve CINV control. As antiemetic therapy continues to evolve, it will be important for clinicians to stay informed of new developments and changes in guidelines.

Randomized, double-blind, phase III trial of palonosetron versus granisetron in the triplet regimen for preventing chemotherapy-induced nausea and vomiting after highly emetogenic chemotherapy: TRIPLE study.

PubMed

Suzuki, K; Yamanaka, T; Hashimoto, H; Shimada, Y; Arata, K; Matsui, R; Goto, K; Takiguchi, T; Ohyanagi, F; Kogure, Y; Nogami, N; Nakao, M; Takeda, K; Azuma, K; Nagase, S; Hayashi, T; Fujiwara, K; Shimada, T; Seki, N; Yamamoto, N

2016-08-01

There has been no phase III study of comparing the efficacy of first- and second-generation 5-HT3 receptor antagonists in the triplet regimen with dexamethasone and aprepitant for preventing chemotherapy-induced nausea and vomiting after highly emetogenic chemotherapy (HEC). Patients with a malignant solid tumor who would receive HEC containing 50 mg/m(2) or more cisplatin were randomly assigned to either palonosetron (0.75 mg) arm (Arm P) or granisetron (1 mg) arm (Arm G), on day 1, both arms with dexamethasone (12 mg on day 1 and 8 mg on days 2-4) and aprepitant (125 mg on day 1 and 80 mg on days 2-3). The primary end point was complete response (CR; no vomiting/retching and no rescue medication) at the 0-120 h period and secondary end points included complete control (CC; no vomiting/retching, no rescue medication, and no more than mild nausea) and total control (TC; no vomiting/retching, no rescue medication, and no nausea). Between July 2011 and June 2012, 842 patients were enrolled. Of 827 evaluable, 272 of 414 patients (65.7%) in Arm P had a CR at the 0-120 h period when compared with 244 of 413 (59.1%) in Arm G (P = 0.0539). Both arms had the same CR rate of 91.8% at the acute (0-24 h) period, while at the delayed (24-120 h) period, Arm P had a significantly higher CR rate than Arm G (67.2% versus 59.1%; P = 0.0142). In secondary end points, Arm P had significantly higher rates than Arm G at the 0-120 h period (CC rate: 63.8% versus 55.9%, P = 0.0234; TC rate: 47.6% versus 40.7%, P = 0.0369) and delayed periods (CC rate: 65.2% versus 55.9%, P = 0.0053; TC rate: 48.6% versus 41.4%, P = 0.0369). The present study did not show the superiority of palonosetron when compared with granisetron in the triplet regimen regarding the primary end point. UMIN000004863. © The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Aprepitant, granisetron, and dexamethasone for prevention of chemotherapy-induced nausea and vomiting after high-dose melphalan in autologous transplantation for multiple myeloma: results of a randomized, placebo-controlled phase III trial.

PubMed

Schmitt, Thomas; Goldschmidt, Hartmut; Neben, Kai; Freiberger, Anja; Hüsing, Johannes; Gronkowski, Martina; Thalheimer, Markus; Pelzl, Le Hang; Mikus, Gerd; Burhenne, Jürgen; Ho, Anthony D; Egerer, Gerlinde

2014-10-20

The optimal regimen to prevent chemotherapy-induced nausea and vomiting (CINV) for patients undergoing high-dose chemotherapy and autologous stem-cell transplantation (ASCT) is unclear. To evaluate the effect of aprepitant in addition to a standard regimen, we conducted this randomized, placebo-controlled phase III trial. Patients with multiple myeloma were randomly assigned at a one-to-one ratio to receive either aprepitant (125 mg orally on day 1 and 80 mg orally on days 2 to 4), granisetron (2 mg orally on days 1 to 4), and dexamethasone (4 mg orally on day 1 and 2 mg orally on days 2 to 3) or matching placebo, granisetron (2 mg orally on days 1 to 4), and dexamethasone (8 mg orally on day 1 and 4 mg orally on days 2 to 3). Melphalan 100 mg/m(2) was administered intravenously on days 1 to 2. ASCT was performed on day 4. The primary end point (complete response) was defined as no emesis and no rescue therapy within 120 hours of melphalan administration. Quality of life was assessed by modified Functional Living Index-Emesis (FLIE) questionnaire on days -1 and 6. Overall, 362 patients were available for the efficacy analysis (181 in each treatment arm). Significantly more patients receiving aprepitant reached the primary end point (58% v 41%; odds ratio [OR], 1.92; 95% CI, 1.23 to 3.00; P = .0042). Absence of major nausea (94% v 88%; OR, 2.37; 95% CI, 1.09 to 5.15; P = .026) and emesis (78% v 65%; OR, 1.99; 95% CI, 1.25 to 3.18; P = .0036) within 120 hours was increased by aprepitant. Mean total FLIE score (± standard deviation) was 114 ± 18 for aprepitant and 106 ± 26 for placebo (P < .001). The addition of aprepitant resulted in significantly less CINV and had a positive effect on quality of life. © 2014 by American Society of Clinical Oncology.

Characterization and in vitro evaluation of freeze-dried microparticles composed of granisetron-cyclodextrin complex and carboxymethylcellulose for intranasal delivery.

PubMed

Cho, Hyun-Jong; Balakrishnan, Prabagar; Shim, Won-Sik; Chung, Suk-Jae; Shim, Chang-Koo; Kim, Dae-Duk

2010-11-15

The aim of this study was to prepare microparticles (MPs) of granisetron (GRN) in combination with hydroxypropyl-β-cyclodextrin (HP-β-CD) and sodium carboxymethylcellulose (CMC-Na) by the simple freeze-drying method for intranasal delivery. The composition of MPs was determined from the phase-solubility study of GRN in various CDs. Fourier transform infrared spectroscopy (FT-IR), powder X-ray diffraction (PXRD) analysis and differential scanning calorimetry (DSC) studies were performed to evaluate possible interactions between GRN and excipients. The results indicated the formation of inclusion complex between GRN and CD, and the conversion of drug into amorphous state. The in vitro release of GRN from MPs was determined in phosphate buffered saline (pH 6.4) at 37°C. Cytotoxicity of the MPs and in vitro permeation study were conducted by using primary human nasal epithelial (HNE) cells and their monolayer system cultured by air-liquid interface (ALI) method, respectively. The MPs showed significantly higher GRN release profile compared to pure GRN. Moreover, the prepared MPs showed significantly lower cytotoxicity and higher permeation profile than that of GRN powder (p<0.05). These results suggested that the MPs composed of GRN, HP-β-CD and CMC-Na represent a simple and new GRN intranasal delivery system as an alternative to the oral and intravenous administration of GRN. Copyright © 2010 Elsevier B.V. All rights reserved.

Prospective trial of efficacy and safety of ondansetron and fluoxetine in patients with obstructive sleep apnea syndrome.

PubMed

Prasad, Bharati; Radulovacki, Miodrag; Olopade, Christopher; Herdegen, James J; Logan, Thomas; Carley, David W

2010-07-01

Incremental withdrawal of serotonin during wake to sleep transition is postulated as a key mechanism that renders the pharyngeal airway collapsible. While serotonin promotion with reuptake inhibitors have demonstrated modest beneficial effects during NREM sleep on obstructive sleep apnea (OSA), animal studies suggest a potential therapeutic role for selective serotonin receptor antagonists (5-HT3) in REM sleep. We aimed to test the hypothesis that a combination of ondansetron (Ond) and fluoxetine (Fl) may effectively reduce expression of disordered breathing during REM and NREM sleep in patients with OSA. A prospective, parallel-groups, single-center trial in patients with OSA. 35 adults with apnea hypopnea index (AHI) > 10; range 10-98. Subjects were randomized to placebo, n = 7; Ond (24 mg QD), n = 9; Fl (5 mg QD) + Ond (12 mg QD), n = 9; and Fl (10 mg QD) + Ond (24 mg QD), n = 10. AHI was measured by in-lab polysomnography after a 7-day no-treatment period (Baseline) and on days 14 and 28 of treatment. The primary endpoint was AHI reduction at days 14 and 28. OND+FL resulted in approximately 40% reduction of baseline AHI at days 14 and 28 (unadjusted P < 0.03 for each) and improved oximetry trends. This treatment-associated relative reduction in AHI was also observed in REM and supine sleep. Combined treatment with OND+FL is well-tolerated and reduces AHI, yielding a potentially therapeutic response in some subjects with OSA.

Gateways to clinical trials.

PubMed

Bayes, M; Rabasseda, X; Prous, J R

2002-05-01

Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables can be retrieved from the Clinical Studies knowledge area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: Abacavir sulfate, abarelix, abciximab, acarbose, alefacept, alteplase, amisulpride, amoxicillin trihydrate, apomorphine hydrochloride, aprepitant, argatroban monohydrate, aspirin, atenolol; Betamethasone dipropionate, betamethasone valerate, bicalutamide, bleomycin sulfate; Calcium carbonate, candesartan cilexetil, celecoxib, cetirizine hydrochloride, cisplatin, clarithromycin, clavulanate potassium, clomethiazole edisilate, clopidogrel hydrogensulfate, cyclophosphamide, chorionic gonadotropin (human); Dalteparin sodium, desloratadine, dexamethasone, doxorubicin, DPC-083; Efalizumab, efavirenz, enoxaparin sodium, eprosartan mesilate, etanercept, etoposide, ezetimibe; Faropenem daloxate, fenofibrate, fluocinolone acetonide, flutamide, fluvastatin sodium, follitropin beta, fondaparinux sodium; Gabapentin, glibenclamide, goserelin, granisetron hydrochloride; Haloperidol, hydrochlorothiazide; Imiquimod, interferon beta-1a, irbesartan, iseganan hydrochloride; L-758298, lamivudine, lanoteplase, leflunomide, leuprorelin acetate, loratadine, losartan potassium; Melagatran, metformin hydrochloride, methotrexate, metronidazole, micafungin sodium, mitoxantrone hydrochloride; Nelfinavir mesilate, neutral insulin injection, nizatidine; Olopatadine hydrochloride, omeprazole, ondansetron hydrochloride; Pamidronate sodium, paracetamol, paroxetine hydrochloride, perindopril, pimecrolimus, pioglitazone hydrochloride, piroxicam, pleconaril, pralmorelin, pravastatin sodium, prednisolone, prednisone, propofol; Raloxifene hydrochloride, ranpirnase, remifentanil hydrochloride, risedronate sodium, risperidone, rofecoxib, ropinirole

Marijuana to prevent nausea and vomiting in cancer patients: a survey of clinical oncologists.

PubMed

Schwartz, R H; Voth, E A; Sheridan, M J

1997-02-01

Marijuana, if rescheduled by the Drug Enforcement Agency, would be the only Food and Drug Administration (FDA)-approved drug to be administered by smoking. American physicians need timely, factual information about probable usage patterns and potential adverse effects of medical marijuana, and a factual complete review of the literature on the subject. We mailed a survey to 1,500 American clinical oncologists. Of particular interest was whether and how often in the past 24 months these physicians recommended smoked marijuana, synthetic tetrahydrocannabinol, or 5-HT3 (serotonin) antagonists (ondansetron [Zofran], granisetron [Kytril]) for their patients. We also inquired whether and how often the oncologists would prescribe marijuana in the form of cigarettes, were it to be FDA-approved. Completed surveys were received from 1,122 (75%) of the oncologists. The percentages of oncologists who prescribed or recommended selected antiemetics more than five times between 1992 and 1994 were 98% for 5-HT, antagonists, 6% for dronabinol (Marinol), and 1% for smoked marijuana. We also found that 332 (30%) of the oncologist-respondents to this nationwide survey supported rescheduling of marijuana for medical purposes; however, two thirds (67%) of the 332 respondents who were in favor of rescheduling estimated that they would write less than one prescription per month for marijuana cigarettes. A comprehensive literature review failed to provide persuasive evidence to recommend marijuana as a needed antiemetic medicine.

Comparison of an extended-release formulation of granisetron (APF530) versus palonosetron for the prevention of chemotherapy-induced nausea and vomiting associated with moderately or highly emetogenic chemotherapy: results of a prospective, randomized, double-blind, noninferiority phase 3 trial.

PubMed

Raftopoulos, Harry; Cooper, William; O'Boyle, Erin; Gabrail, Nashat; Boccia, Ralph; Gralla, Richard J

2015-03-01

Subcutaneous APF530 provides controlled sustained release of granisetron to prevent acute (0-24 h) and delayed (24-120 h) chemotherapy-induced nausea and vomiting (CINV). This randomized, double-blind phase 3 trial compared APF530 and palonosetron in preventing acute and delayed CINV after moderately (MEC) or highly emetogenic chemotherapy (HEC). Patients receiving single-day MEC or HEC received single-dose APF530 250 or 500 mg subcutaneously (SC) (granisetron 5 or 10 mg) or intravenous palonosetron 0.25 mg. Primary objectives were to establish APF530 noninferiority to palonosetron for preventing acute CINV following MEC or HEC and delayed CINV following MEC and to determine APF530 superiority to palonosetron for preventing delayed CINV following HEC. The primary efficacy end point was complete response (CR [using CI difference for APF530-palonosetron]). A lower confidence bound greater than -15 % indicated noninferiority. In the modified intent-to-treat population (MEC = 634; HEC = 707), both APF530 doses were noninferior to palonosetron in preventing acute CINV after MEC (CRs 74.8 % [-9.8, 9.3] and 76.9 % [-7.5, 11.4], respectively, vs. 75.0 % palonosetron) and after HEC (CRs 77.7 % [-11.5, 5.5] and 81.3 % [-7.7, 8.7], respectively, vs. 80.7 % palonosetron). APF530 500 mg was noninferior to palonosetron in preventing delayed CINV after MEC (CR 58.5 % [-9.5, 12.1] vs. 57.2 % palonosetron) but not superior in preventing delayed CINV after HEC. Adverse events were generally mild and unrelated to treatment, the most common (excluding injection-site reactions) being constipation. A single subcutaneous APF530 injection offers a convenient alternative to palonosetron for preventing acute and delayed CINV after MEC or HEC.

Synthesis of a novel superdisintegrant by starch derivatization with polysuccinimide and its application for the development of Ondansetron fast dissolving tablet.

PubMed

Sadeghi, Mozhgan; Hemmati, Salar; Hamishehkar, Hamed

2016-01-01

Disintegrants are the key excipients administered in tablet formulations to boost the decomposition of the tablet into smaller pieces in the gastrointestinal environment, thereby increasing the available surface area and enhancing a more rapid release of the active ingredient. Polysuccinimide (PSI), a biodegradable polymer synthesized from aspartic acid, was reacted with starch and fully assessed by CHN, (1)H-NMR, and FTIR. PSI-grafted starch (PSI-St) was synthesized and applied as a disintegrant in the formulation of a rapidly disintegrating tablet of Ondansetron, a nausea and vomiting medicine. The tablet formulated with the newly developed superdisintegrant was evaluated for hardness, friability, disintegration time, and dissolution rate, and the results were compared with tablets formulated with an identical composition of test formulation differing only in type of disintegrant. Tablets prepared with starch and tablets prepared with sodium starch glycolate (SSG) were used as negative and positive controls, respectively. Dissolution study results indicated that although the onset of disintegration action was faster for SSG than PSI-St, higher amounts of drug were released from tablets formulated from PSI-St than from those formulated from SSG during 10 min. It was concluded that the novel synthesized superdisintegrant has an appropriate potential for the application in the formulation of fast dissolving tablets.

Synthesis of a novel superdisintegrant by starch derivatization with polysuccinimide and its application for the development of Ondansetron fast dissolving tablet.

PubMed

Sadeghi, Mozhgan; Hemmati, Salar; Hamishehkar, Hamed

2016-05-01

Disintegrants are the key excipients administered in tablet formulations to boost the decomposition of the tablet into smaller pieces in the gastrointestinal environment, thereby increasing the available surface area and enhancing a more rapid release of the active ingredient. Polysuccinimide (PSI), a biodegradable polymer synthesized from aspartic acid, was reacted with starch and fully assessed by CHN, 1 H-NMR, and FTIR. PSI-grafted starch (PSI-St) was synthesized and applied as a disintegrant in the formulation of a rapidly disintegrating tablet of Ondansetron, a nausea and vomiting medicine. The tablet formulated with the newly developed superdisintegrant was evaluated for hardness, friability, disintegration time, and dissolution rate, and the results were compared with tablets formulated with an identical composition of test formulation differing only in type of disintegrant. Tablets prepared with starch and tablets prepared with sodium starch glycolate (SSG) were used as negative and positive controls, respectively. Dissolution study results indicated that although the onset of disintegration action was faster for SSG than PSI-St, higher amounts of drug were released from tablets formulated from PSI-St than from those formulated from SSG during 10 min. It was concluded that the novel synthesized superdisintegrant has an appropriate potential for the application in the formulation of fast dissolving tablets.

Ondansetron blocks LiCl-induced conditioned place avoidance but not conditioned taste/flavor avoidance in rats

PubMed Central

Rinaman, Linda; Saboury, Mitra; Litvina, Elizabeth

2009-01-01

The ability of an experimental agent to support conditioned taste/flavor avoidance (CT/FA) in rats often is interpreted as sufficient evidence that the agent produced a state of malaise or nausea. Paradoxically, however, CT/FA also is induced by certain drugs that support conditioned preferences in rats, suggesting that CT/FA is insufficient to reveal a negative hedonic state. The present study tested the hypothesis that the anti-nausea drug ondansetron (OND) would block the ability of nauseogenic lithium chloride (LiCl) to support conditioned place avoidance (CPA), without attenuating LiCl-induced CT/FA. After pre-treatment with either OND or vehicle, rats were conditioned with i.p. injection of 0.15M LiCl containing 2% saccharin (LiCl+sac) on conditioning day 1, and with 0.15M NaCl alone on conditioning day 2. Rats were confined to a distinct chamber of a CPA apparatus after each conditioning injection. In other rats, OND or vehicle pre-treatment was followed by NaCl+sac on conditioning day 1, and LiCl alone on day 2. Subsequent testing revealed that OND blocked the ability of LiCl to support CPA. Conversely, in the same rats, OND did not alter the ability of LiCl to condition avoidance of 0.2% sac solution during a 60 min bottle test. In a separate experiment, a sensitive 2-bottle choice test was used to confirm that OND pretreatment does not reduce the ability of LiCl to support CT/FA. These results support the view that CPA is an additional useful tool to reveal the experience of malaise and nausea in rats, whereas CT/FA demonstrated in bottle intake tests is insufficient for this purpose. PMID:19583975

Development of novel bioadhesive granisetron hydrochloride spanlastic gel and insert for brain targeting and study their effects on rats.

PubMed

Abdelmonem, Rehab; El Nabarawi, Mohamed; Attia, Alshaimaa

2018-11-01

The aim of this study was to formulate granisetron hydrochloride (GH) spanlastic in mucoadhesive gels and lyophilized inserts for intranasal administration to improve GH bioavailability and brain targeting. Carpapol 934 and HPMC were incorporated in GH spanlastic in nasal gels (GHSpNGs). Gelatin and HPMC as matrix former, glycine as a collapse protecting and mannitol as an insert filler and sweeting agent were used to prepare GH spanlastic loaded in lyophilized inserts (GHSpNIs). The prepared GHSpNGs were characterized for pH measurement, drug content, rheology, and in vitro drug release. The prepared GHSpNIs were characterized for drug content, surface pH, GH release, and mucoadhesion. Biological investigations including pharmacokinetics studies and brain drug targeting efficiency dimensions were performed on rats (LC-MS/MS). The results showed thixotropic pseudoplastic gels and white insert with pH values in a physiological range, drug content (89.9-98.6%), (82.4-98.38%) for gel and insert, respectively and rapid release rate of GH. Biological studies showed that C max and AUC 0-6 h in brain and plasma after intranasal administration of gel and insert were higher compared to IV administration of GH solution. A high brain targeting efficiency (199.3%, 230%) for gel and insert, respectively and a direct nose to brain transport (49.8%, 56.95%) for gel and insert, respectively confirmed that there is a direct nose to brain transport of GH following nasal administration of GH spanlastic loaded in nasal gel and insert. GHSpNIs can be considered as potential novel drug delivery system intended for brain targeting via the nasal rout of administration than GHSpNGs.

New approaches to chemotherapy-induced nausea and vomiting: from neuropharmacology to clinical investigations.

PubMed

Rubenstein, Edward B; Slusher, Barbara S; Rojas, Camilo; Navari, Rudolph M

2006-01-01

Nausea and vomiting are considered to be among the most distressing consequences of cytotoxic chemotherapies. Currently, there are several novel 5-HT(3) receptor antagonists for the treatment of chemotherapy-induced nausea and vomiting (CINV), including ondansetron, granisetron, and dolasetron. These agents provide significant improvement in the management of acute emesis but are ineffective at preventing delayed emesis. In 2003, a new 5-HT(3) receptor antagonist, palonosetron HCL (Aloxi), was introduced to the U.S. market. Palonosetron was found to be effective in preventing delayed CINV. Indeed, palonosetron was the first and only 5-HT(3) receptor antagonist approved by the FDA for the prevention of both acute and delayed CINV. More recently, studies on the role of substance P in the emetic process led to the development of aprepitant (Emend) for the prevention of delayed emesis in combination with 5-HT(3) receptor antagonists. Despite these major advances, CINV remains uncontrolled in some patients. Current efforts are focused on treating refractory emesis and include both the clinical evaluation of compounds marketed for other indications and the preclinical evaluation of novel molecules targeting other transmitters in the emetic pathway. Ongoing work in pharmacogenomics has postulated several candidate genes that could be involved in emetic sensitivity and responsiveness to antiemetic therapy. Investigations into the pharmacogenomics of CINV may someday be able to aid in the identification of high risk patients and patients unlikely to respond to conventional therapies.

Pretreatment of patients requiring oral contrast abdominal computed tomography with antiemetics: a randomized controlled trial of efficacy.

PubMed

Garra, Gregory; Singer, Adam J; Bamber, Danny; Chohan, Jasmine; Troxell, Regina; Thode, Henry C

2009-04-01

Ingestion of diatrizoate meglumine before abdominal computed tomography (CT) is time consuming. We hypothesized that pretreatment with metoclopramide or ondansetron would result in faster ingestion of diatrizoate meglumine than placebo. The study was a double-blind, randomized controlled trial on adults requiring oral contrast abdominal CT. Patients were randomized to placebo, metoclopramide 10 mg, or ondansetron 4 mg intravenously 15 minutes before ingesting 2 L of diatrizoate meglumine. The primary outcome was time to complete diatrizoate meglumine ingestion. Secondary outcome measures included volume of diatrizoate meglumine ingested, 100-mm visual analog scale for nausea at 15-minute intervals, time to CT, vomiting, and use of rescue antiemetics. The study was powered to detect a 60-minute difference in diatrizoate meglumine ingestion time between saline and medication groups. One hundred six patients were randomized; placebo (36), metoclopramide (35), and ondansetron (35). Groups were similar in baseline characteristics. Median (interquartile range) times for diatrizoate meglumine ingestion were placebo 109 minutes (82 to 135 minutes); metoclopramide 105 minutes (75 to 135 minutes); and ondansetron 110 minutes (79 to 140 minutes) (P=.67). Vomiting was less frequent with metoclopramide (3%) than placebo (18%) or ondansetron (9%) (P=.11). The visual analog scale for nausea at each point was not significantly different between groups (P=.11). The need for rescue antiemetics was lowest for metoclopramide (3%) compared with placebo (27%) and ondansetron (12%) (P=.02). Pretreatment with ondansetron or metoclopramide does not reduce oral contrast solution ingestion time.

Structural basis of ligand recognition in 5-HT3 receptors

PubMed Central

Kesters, Divya; Thompson, Andrew J; Brams, Marijke; van Elk, René; Spurny, Radovan; Geitmann, Matthis; Villalgordo, Jose M; Guskov, Albert; Helena Danielson, U; Lummis, Sarah C R; Smit, August B; Ulens, Chris

2013-01-01

The 5-HT3 receptor is a pentameric serotonin-gated ion channel, which mediates rapid excitatory neurotransmission and is the target of a therapeutically important class of anti-emetic drugs, such as granisetron. We report crystal structures of a binding protein engineered to recognize the agonist serotonin and the antagonist granisetron with affinities comparable to the 5-HT3 receptor. In the serotonin-bound structure, we observe hydrophilic interactions with loop E-binding site residues, which might enable transitions to channel opening. In the granisetron-bound structure, we observe a critical cation–π interaction between the indazole moiety of the ligand and a cationic centre in loop D, which is uniquely present in the 5-HT3 receptor. We use a series of chemically tuned granisetron analogues to demonstrate the energetic contribution of this electrostatic interaction to high-affinity ligand binding in the human 5-HT3 receptor. Our study offers the first structural perspective on recognition of serotonin and antagonism by anti-emetics in the 5-HT3 receptor. PMID:23196367

[Comparison of antiemesis effects of granisetron, aprepitant and dexamethasone to palonosetron, aprepitant and dexamethasone in treatment of high-emetic risk chemotherapy-induced nausea and vomiting - a retrospective study for efficacy and safety in a single institute].

PubMed

Osawa, Hiroshi; Goto, Hiroaki; Myojo, Tomohiro

2013-05-01

Nausea and vomiting are among the most problematic symptoms experienced by patients with cancer who are receiving chemotherapy. 5-hydroxytryptamine 3(5-HT3)-receptor antagonists, NK1 receptor antagonists(aprepitant)and dexamethasone are now the standard therapies for preventing chemotherapy-induced nausea and vomiting(CINV)that follow highly emetogenic chemotherapy, such as cisplatin and anthracycline. However, since it is not cleared which 5-HT3-recepter antagonist is a proper treatment for combined use with aprepitant and dexamethasone, we conducted a questionnaire survey, which used the numerical rating scale(NRS), for comparing palonosetron with granisetron in the same patient. Palonosetron showed a significant improvement of nausea for both acute(within 24 hours)and delayed phase(24-120 hours later), regardless of the type of chemotherapy(cisplatin or anthracycline-based regimen). Furthermore, palonosetron had a tolerable safety profile. Our study suggests that palonosetron-based antiemetic treatment will be a preferred choice for preventing CINV following highly emetogenic chemotherapy.

Ondansetron

MedlinePlus

... by your doctor.If you are taking the rapidly disintegrating tablet, remove the tablet from the package just before ... of reach of children. Store the tablets and rapidly disintegrating tablets away from light, at room temperature or in ...

A Randomized Cross‐over Study of High‐dose Metoclopramide plus Dexamethasone versus Granisetron plus Dexamethasone in Patients Receiving Chemotherapy with High‐dose Cisplatin

PubMed Central

Eguchi, Kenji; Shinkai, Tetsu; Tamura, Tomohide; Ohe, Yuichiro; Nisio, Masato; Kunikane, Hiroshi; Arioka, Hitoshi; Karato, Atsuya; Nakashima, Hajime; Sasaki, Yasutsuna; Tajima, Kinuko; Tada, Noriko; Saijo, Nagahiro

1994-01-01

We carried out a randomized, single‐blind, cross‐over trial to compare the antiemetic effect, for both acute and delayed emesis, of granisetron plus dexamethasone (GRN+Dx) with that of high‐dose metoclopramide plus dexamethasone (HDMP + Dx). Fifty‐four patients with primary or metastatic lung cancer, given single‐dose cisplatin (> 80 mg/m2) chemotherapy more than twice, were enrolled in this study. They were treated with both HDMP+Dx and GRN+Dx in two consecutive chemotherapy courses. On day 1, patients experienced a mean of 2.5 (SD=4.3) and 0,1 (SD = 0.4) episodes of vomiting in the HDMP+Dx and the GRN + Dx groups, respectively (P=0.0008). Complete response rate on day 1 was 45 and 90% in the HDMP+Dx and the GRN+Dx groups, respectively (P= 0.0001). Patients treated with GRN+Dx had a tendency to suffer more episodes of vomiting than the HDMP+Dx group on days 2–5, but it was not statistically significant. Twenty‐four patients (57%) preferred the GRN+Dx treatment and 14 patients (33%), HDMP + Dx. In the HDMP + Dx group, nine patients (21%) had an extrapyramidal reaction, and 5 patients (12%) had constipation that lasted for at least two days. In contrast, no patients had extrapyramidal reactions, and IS patients (43%) had constipation in the GRN+Dx group (P < 0.01). GRN+Dx was more effective than HDMP+Dx only in preventing the acute emesis induced by cisplatin. An effective treatment for delayed emesis is still needed. PMID:7829401

Granisetron

MedlinePlus

... 5-HT3 receptor antagonists. It works by blocking serotonin, a natural substance in the body that causes ... Eldepryl, Emsam, Zelapar), and tranylcypromine (Parnate); phenobarbital; selective serotonin reuptake inhibitors (SSRIs) such as citalopram (Celexa), escitalopram ( ...

Efficacy of palonosetron and 1-day dexamethasone in moderately emetogenic chemotherapy compared with fosaprepitant, granisetron, and dexamethasone: a prospective randomized crossover study.

PubMed

Kitayama, Hiromitsu; Tsuji, Yasushi; Sugiyama, Junko; Doi, Ayako; Kondo, Tomohiro; Hirayama, Michiaki

2015-12-01

Although palonosetron (PALO) and NK1 receptor antagonist both reduce chemotherapy-induced nausea and vomiting, no comparison trial in moderately emetogenic chemotherapy (MEC) had been reported. The purpose of this study was to find out which drug combinations are preferable for patients receiving MEC. Chemotherapy-naive patients receiving MEC were randomized to two groups; group A first received PALO therapy [PALO plus 1-day dexamethasone (DEX)], and group B first received fosaprepitant (FAPR) therapy [FAPR, granisetron (GRAN), and DEX]. Patients were re-allocated to the other therapy, respectively, for the second cycle of chemotherapy. We administered intravenous PALO (0.75 mg) and DEX (9.9 mg) to the PALO therapy group, and FAPR (150 mg), DEX (4.95 mg), and GRAN (3 mg) to the FAPR therapy group, on Day 1. Complete response (CR) was the primary endpoint; complete control (CC), total control (CT), and the therapy chosen by the patients for their third and following cycles of antiemetic therapy were the secondary endpoints. We evaluated CR, CC, and TC in the acute phase, in the delayed phase, and over the whole period. A total of 35 patients and 70 cycles of therapy was evaluable for analysis. No significant difference was found at all evaluation points. Overall CR rates for PALO and FAPR therapy were 74 vs 69 % (P = 0.567), CC rates 66 vs 69 % (P = 0.521), and TC rates 46 vs 60 % (P = 0.235), respectively. Patients also showed no clear preference for their third and following cycles of chemotherapy, choosing both regimens almost equally often (PALO 10 vs FAPR 13). PALO and 1-day DEX is almost equivalent to FAPR, GRAN, and DEX for MEC.

Evaluation of aprepitant for acute chemotherapy-induced nausea and vomiting in children and adolescents with acute lymphoblastic leukemia receiving high-dose methotrexate.

PubMed

Felix-Ukwu, Femi; Reichert, Kate; Bernhardt, M Brooke; Schafer, Eric S; Berger, Amanda

2018-02-01

Chemotherapy-induced nausea and vomiting (CINV) negatively impacts patients' quality of life. The emetogenicity of high-dose methotrexate in children and adolescents with cancer is incompletely characterized. At our institution, a number of patients with acute lymphoblastic leukemia (ALL) have received aprepitant with courses of high-dose methotrexate after poor CINV control with prior courses. We conducted a retrospective cohort analysis on patients with ALL who received methotrexate 5 g/m 2 /dose with and without concomitant aprepitant at Texas. Children's Hospital between October 1, 2010 and January 31, 2016. We identified 16 patients who received a total of 69 courses of methotrexate. An enhanced antiemetic regimen containing aprepitant was administered with 42 methotrexate courses and resulted in a 54% reduction in the use of as-needed antiemetics (P = 0.002, 95% CI: 21-89%). There were no statistically significant differences in methotrexate area under the curve values (2,209 μM⋅hr/l ± 151 vs. 2,051 μM⋅hr/l ± 94, P = 0.355) or end-infusion methotrexate concentrations (80.5 μM ± 5.6 vs. 74.7 μM ± 3.2, P = 0.335) in patients receiving a standard versus an enhanced antiemetic regimen. The addition of aprepitant reduces both CINV and the use of rescue antiemetics. Aprepitant does not appear to affect the pharmacokinetics of methotrexate. Granisetron was prescribed more frequently than ondansetron, but selection of secondary and tertiary agents, if any, was highly variable. © 2017 Wiley Periodicals, Inc.

Control of nausea with palonosetron versus granisetron, both combined with dexamethasone, in patients receiving cisplatin- or anthracycline plus cyclophosphamide-based regimens.

PubMed

Kubota, Kaoru; Saito, Mitsue; Aogi, Kenjiro; Sekine, Ikuo; Yoshizawa, Hirohisa; Yanagita, Yasuhiro; Sakai, Hiroshi; Inoue, Kenichi; Kitagawa, Chiyoe; Ogura, Takashi

2016-09-01

In a comparative phase 3 study involving 1114 Japanese patients receiving highly emetogenic chemotherapy (HEC), palonosetron (PALO) was found to be superior to granisetron (GRA) for the prophylaxis of chemotherapy-induced nausea and vomiting (CINV) in the delayed phase. This post hoc analysis of the phase 3 study evaluated the efficacy of PALO for the control of nausea. The proportion of patients without nausea was assessed at 24-h intervals during the acute phase (0-24 h), delayed phase (24-120 h), and overall (0-120 h). No nausea rates were also evaluated by sex, type of chemotherapy (cisplatin or doxorubicin/epirubicin plus cyclophosphamide [AC/EC]), and age (<55 vs. ≥55 years). Nausea severity was categorized using a 4-point Likert scale (0 = no nausea to 3 = severe nausea). The proportion of patients without nausea was significantly higher in the PALO arm than in the GRA arm in the delayed phase (37.8 % vs. 27.2 %; p = 0.002) and overall (31.9 % vs. 25.0 %; p = 0.0117). When analyzed by stratification factors, the proportion of patients without nausea was significantly higher in the PALO arm in the delayed phase and overall in patients who were female, younger, or treated with cisplatin and in the delayed phase in patients who were older or treated with doxorubicin or epirubicin plus cyclophosphamide (all p < 0.05). PALO was more effective than GRA in prophylaxis of HEC-induced nausea in the delayed phase and overall. In addition, PALO was more effective than GRA in young and female patients, who are at high risk of CINV, both in the delayed phase and overall.

Formulation and development of pH-independent/dependent sustained release matrix tablets of ondansetron HCl by a continuous twin-screw melt granulation process.

PubMed

Patil, Hemlata; Tiwari, Roshan V; Upadhye, Sampada B; Vladyka, Ronald S; Repka, Michael A

2015-12-30

The objective of the present study was to develop pH-independent/dependent sustained release (SR) tablets of ondansetron HCl dihydrate (OND), a selective 5-HT3 receptor antagonist that is used for prevention of nausea and vomiting caused by chemotherapy, radiotherapy and postoperative treatment. The challenge with the OND API is its pH-dependent solubility and relatively short elimination half-life. Therefore, investigations were made to solve these problems in the current study. Formulations were prepared using stearic acid as a binding agent via a melt granulation process in a twin-screw extruder. The micro-environmental pH of the tablet was manipulated by the addition of fumaric acid to enhance the solubility and release of OND from the tablet. The in vitro release study demonstrated sustained release for 24h with 90% of drug release in formulations using stearic acid in combination with ethyl cellulose, whereas 100% drug release in 8h for stearic acid-hydroxypropylcellulose matrices. The formulation release kinetics was correlated to the Higuchi diffusion model and a non-Fickian drug release mechanism. The results of the present study demonstrated for the first time the pH dependent release from hydrophilic-lipid matrices as well as pH independent release from hydrophobic-lipid matrices for OND SR tablets manufactured by means of a continuous melt granulation technique utilizing a twin-screw extruder. Copyright © 2015 Elsevier B.V. All rights reserved.

Effect of low doses of cannabidiolic acid and ondansetron on LiCl-induced conditioned gaping (a model of nausea-induced behaviour) in rats

PubMed Central

Rock, EM; Parker, LA

2013-01-01

Background and Purpose To determine the minimally effective dose of cannabidiolic acid (CBDA) that effectively reduces lithium chloride (LiCl)-induced conditioned gaping reactions (nausea-induced behaviour) in rats and to determine if these low systemic doses of CBDA (5–0.1 μg·kg−1) relative to those of CBD could potentiate the anti-nausea effects of the classic 5-hydroxytryptamine 3 (5-HT3) receptor antagonist, ondansetron (OND). Experimental Approach We investigated the efficacy of low doses of CBDA to suppress acute nausea, assessed by the establishment of conditioned gaping to a LiCl-paired flavour in rats. The potential of threshold and subthreshold doses of CBDA to enhance the reduction of nausea-induced conditioned gaping by OND were then determined. Key Results CBDA (at doses as low as 0.5 μg·kg−1) suppressed nausea-induced conditioned gaping to a flavour. A low dose of OND (1.0 μg·kg−1) alone reduced nausea-induced conditioned gaping, but when it was combined with a subthreshold dose of CBDA (0.1 μg·kg−1) there was an enhancement in the suppression of LiCl-induced conditioned gaping. Conclusions and Implications CBDA potently reduced conditioned gaping in rats, even at low doses and enhanced the anti-nausea effect of a low dose of OND. These findings suggest that combining low doses of CBDA and OND will more effectively treat acute nausea in chemotherapy patients. PMID:23488964

Effect of low doses of cannabidiolic acid and ondansetron on LiCl-induced conditioned gaping (a model of nausea-induced behaviour) in rats.

PubMed

Rock, E M; Parker, L A

2013-06-01

To determine the minimally effective dose of cannabidiolic acid (CBDA) that effectively reduces lithium chloride (LiCl)-induced conditioned gaping reactions (nausea-induced behaviour) in rats and to determine if these low systemic doses of CBDA (5-0.1 μg·kg⁻¹) relative to those of CBD could potentiate the anti-nausea effects of the classic 5-hydroxytryptamine 3 (5-HT₃) receptor antagonist, ondansetron (OND). We investigated the efficacy of low doses of CBDA to suppress acute nausea, assessed by the establishment of conditioned gaping to a LiCl-paired flavour in rats. The potential of threshold and subthreshold doses of CBDA to enhance the reduction of nausea-induced conditioned gaping by OND were then determined. CBDA (at doses as low as 0.5 μg·kg⁻¹) suppressed nausea-induced conditioned gaping to a flavour. A low dose of OND (1.0 μg·kg⁻¹) alone reduced nausea-induced conditioned gaping, but when it was combined with a subthreshold dose of CBDA (0.1 μg·kg⁻¹) there was an enhancement in the suppression of LiCl-induced conditioned gaping. CBDA potently reduced conditioned gaping in rats, even at low doses and enhanced the anti-nausea effect of a low dose of OND. These findings suggest that combining low doses of CBDA and OND will more effectively treat acute nausea in chemotherapy patients. © 2013 The Authors. British Journal of Pharmacology © 2013 The British Pharmacological Society.

Stability of Alprazolam, Atropine Sulfate, Glutamine, Levofloxacin, Metoprolol Tartrate, Nitrofurantoin, Ondansetron Hydrochloride, Oxandrolone, Pregabaline, and Riboflavin in SyrSpend SF pH4 Oral Suspensions.

PubMed

Ferreira, Anderson O; Polonini, Hudson C; Loures da Silva, Sharlene; Cerqueira de Melo, Victor Augusto; de Andrade, Laura; Brandão, Marcos Antônio Fernandes

2017-01-01

The objective of this study was to evaluate the stability of 10 commonly used active pharmaceutical ingredients compounded in oral suspensions using an internationally used suspending vehicle (SyrSpend SF PH4): alprazolam 1.0 mg/mL, atropine sulfate 0.1 mg/mL, glutamine 250.0 mg/mL, levofloxacin 50.0 mg/mL, metoprolol tartrate 10.0 mg/mL, nitrofurantoin 2.0 mg/mL, ondansetron hydrochloride 0.8 mg/mL, oxandrolone 3.0 mg/mL, pregabaline 20.0 mg/mL, riboflavin 10.0 mg/mL. All suspensions were stored at both controlled refrigeration (2°C to 8°C) and controlled room temperature (20°C to 25°C). Stability was assessed by measuring the percent recovery at varying time points throughout a 90-day period. Active pharmaceutical ingredients quantification was performed by high-performance liquid chromatography via a stability-indicating method. Given the percentage of recovery of the active pharmaceutical ingredients within the suspensions, the beyond-use date of the final products (active pharmaceutical ingredients + vehicle) was at least 90 days for all suspensions with regard to both temperatures. This suggests that the vehicle is stable for compounding active pharmaceutical ingredients from different pharmacological classes. Copyright© by International Journal of Pharmaceutical Compounding, Inc.

Emesis and Defecations Induced by the 5-Hydroxytryptamine (5-HT3) Receptor Anatagonist Zacopride in the Ferret

DTIC Science & Technology

1990-02-16

TERMS 8. NUMBER OF PAGES 8 16. PRICE CODE 17 SECURITY CLASSIFICATION is. SECURITY CLASSIFICATION 19. SECURITY CLASSIFICATION 20. LIMITATION OF OP...the Defense Nuclear erties, i.e., granisetron [BRL43694; Endo-N-[9-methyl-9-aza- Agency has been given or should be inferred. Research was conducted...BMY25801, batanopride; BRL43694, granisetron ; GI, gastrointestinal; ACh, acetylcholine. 1034 1990 Emetic Properties of Zacopnde 1035 benzamide HCI; Gylys et

Low doses of haloperidol combined with ondansetron are not effective for prophylaxis of postoperative nausea and vomiting in susceptible patients.

PubMed

Veiga-Gil, Leonor; López-Olaondo, Luis; Pueyo, Javier; Callejas, Raquel; Duque, Paula; Carrascosa, Francisco

2015-02-01

In this observational study we reviewed the efficacy and side effects of different antiemetic combinations used in our hospital for postoperative nausea and vomiting (PONV) prophylaxis in high-risk women undergoing highly emetogenic surgery. After reviewing retrospectively the medical records of patients undergoing highly emetogenic elective surgeries under general anaesthesia, we selected 368 women whose Apfel risk score was ≥ 3 and receiving a combination of 2 antiemetics for PONV prophylaxis. We analysed the incidence of PONV at 2, 6, 12 and 24h after surgery, antiemetic rescue requirements, pattern of occurrence of PONV, side effects and level of sedation were also assessed. The main goal was complete response defined as no PONV within 24h after surgery. Ondansetron 4mg i.v. plus dexamethasone 8mg i.v. (O&Dex), haloperidol 1mg i.v. (O&Hal1), haloperidol 2mg i.v. (O&Hal2) or droperidol 1.25mg i.v. (O&Dro) were the combinations most frequently used. The complete response was better in groups O&Dex: 68.5% (CI: 58-78), O&Hal2: 64.1% (CI: 53-74) and O&Dro 63% (CI: 52-73) than in group O&Hal1: 41.3% (CI: 31-52) (p<0,01). Peak incidence of PONV occurred within the 2-6h period. The incidence of side effects was higher in group O&Hal2. In high risk patients for PONV who underwent highly emetogenic surgeries, the efficacy of low-dose haloperidol (1mg) in combination is limited. Higher doses (2mg) are more effective but its use is associated with a high incidence of side effects. Copyright © 2013 AEC. Publicado por Elsevier España, S.L.U. All rights reserved.

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

PubMed

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

2015-12-01

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

Evaluation of nootropic and neuroprotective effects of low dose aspirin in rats.

PubMed

Ghosh, Arijit; Dhumal, V R; Tilak, A V; Das, Nina; Singh, Amarinder; Bondekar, Abhijit A

2011-01-01

To evaluate the nootropic and neuroprotective effects of aspirin in Sprague Dawley rats. Retention of conditioned avoidance response (CAR) and central 5-HT-mediated behavior (lithium-induced head twitches) were assessed using repeated electroconvulsive shock (ECS) in rats. Rats were divided into eight groups: control (pretreated with distilled water), scopolamine (0.5 mg/kg i.p.), ECS (150 V, 50 Hz sinusoidal with intensity of 210 mA for 0.5 s) pretreated, aspirin (6.75 mg/kg orally) pretreated, combined scopolamine and aspirin pretreated, ondansetron (0.36 mg/kg orally) pretreated, combined ECS and ondansetron pretreated and combined ECS and aspirin pretreated groups. Data was analyzed by the chi-square test and ANOVA. Findings show that administration of single ECS daily for consecutive 8 days results in enhancement of 5-HT-mediated behavior (lithium-induced head twitches) and in disruption of the retention of CAR. Aspirin and ondansetron administration significantly increased the retention of conditioned avoidance response compared to control. Ondansetron and aspirin significantly prevented ECS-induced attenuation of the retention of conditioned avoidance response also. On the other hand, ondansetron and aspirin significantly retarded the ECS-induced enhancement of 5-HT-mediated behavior. Inhibition of the serotonergic transmission by aspirin is responsible for its nootropic and neuroprotective actions.

Effects of cholera toxin on the potential difference and motor responses induced by distension in the rat proximal small intestine in vivo.

PubMed

Kordasti, Shirin; Sapnara, Maria; Thomas, Evan A; Lindstrom, Erik; Forsman, Mikael; Bornstein, Joel C; Sjövall, Henrik

2006-05-01

Cholera toxin (CT) may induce uncontrolled firing in recurrent networks of secretomotor neurons in the submucous plexus. This hypothesis was tested in chloralose-anesthetized rats in vivo. The secretory reflex response to graded intestinal distension was measured with or without prior exposure to luminal CT. The transmural potential difference (PD) was used as a marker for electrogenic chloride secretion. In controls, distension increased PD, and this response was reduced by the neural blocker tetrodotoxin given serosally and the vasoactive intestinal peptide (VIP) receptor antagonist [4Cl-d-Phe(6),Leu(17)]VIP (2 mug.min(-1).kg(-1) iv) but unaffected by the serotonin 5-HT(3) receptor antagonist granisetron, by the nicotinic receptor antagonist hexamethonium, by the muscarinic receptor antagonist atropine, or by the cyclooxygenase inhibitor indomethacin. Basal PD increased significantly with time in CT-exposed segments, an effect blocked by granisetron, by indomethacin, and by [4Cl-d-Phe(6),Leu(17)]VIP but not by hexamethonium or atropine. In contrast, once the increased basal PD produced by CT was established, [4Cl-d-Phe(6),Leu(17)]VIP and indomethacin had no significant effect, whereas granisetron and hexamethonium markedly depressed basal PD. CT significantly reduced the increase in PD produced by distension, an effect reversed by granisetron, indomethacin, and atropine. CT also activated a specific motility response to distension, repeated cluster contractions, but only in animals pretreated with granisetron, indomethacin, or atropine. These data are compatible with the hypothesis that CT induces uncontrolled activity in submucous secretory networks. Development of this state depends on 5-HT(3) receptors, VIP receptors, and prostaglandin synthesis, whereas its maintenance depends on 5-HT(3) and nicotinic receptors but not VIP receptors. The motility effects of CT (probably reflecting myenteric activity) are partially suppressed via a mechanism involving 5-HT(3

Evaluation of nootropic and neuroprotective effects of low dose aspirin in rats

PubMed Central

Ghosh, Arijit; Dhumal, V. R.; Tilak, A. V.; Das, Nina; Singh, Amarinder; Bondekar, Abhijit A.

2011-01-01

Objective: To evaluate the nootropic and neuroprotective effects of aspirin in Sprague Dawley rats. Materials and Methods: Retention of conditioned avoidance response (CAR) and central 5-HT-mediated behavior (lithium-induced head twitches) were assessed using repeated electroconvulsive shock (ECS) in rats. Rats were divided into eight groups: control (pretreated with distilled water), scopolamine (0.5 mg/kg i.p.), ECS (150 V, 50 Hz sinusoidal with intensity of 210 mA for 0.5 s) pretreated, aspirin (6.75 mg/kg orally) pretreated, combined scopolamine and aspirin pretreated, ondansetron (0.36 mg/kg orally) pretreated, combined ECS and ondansetron pretreated and combined ECS and aspirin pretreated groups. Data was analyzed by the chi-square test and ANOVA. Results: Findings show that administration of single ECS daily for consecutive 8 days results in enhancement of 5-HT-mediated behavior (lithium-induced head twitches) and in disruption of the retention of CAR. Aspirin and ondansetron administration significantly increased the retention of conditioned avoidance response compared to control. Ondansetron and aspirin significantly prevented ECS-induced attenuation of the retention of conditioned avoidance response also. On the other hand, ondansetron and aspirin significantly retarded the ECS-induced enhancement of 5-HT-mediated behavior. Conclusion: Inhibition of the serotonergic transmission by aspirin is responsible for its nootropic and neuroprotective actions. PMID:21701638

A Physiologically Based Pharmacokinetic Model for Pregnant Women to Predict the Pharmacokinetics of Drugs Metabolized Via Several Enzymatic Pathways.

PubMed

Dallmann, André; Ince, Ibrahim; Coboeken, Katrin; Eissing, Thomas; Hempel, Georg

2017-09-18

Physiologically based pharmacokinetic modeling is considered a valuable tool for predicting pharmacokinetic changes in pregnancy to subsequently guide in-vivo pharmacokinetic trials in pregnant women. The objective of this study was to extend and verify a previously developed physiologically based pharmacokinetic model for pregnant women for the prediction of pharmacokinetics of drugs metabolized via several cytochrome P450 enzymes. Quantitative information on gestation-specific changes in enzyme activity available in the literature was incorporated in a pregnancy physiologically based pharmacokinetic model and the pharmacokinetics of eight drugs metabolized via one or multiple cytochrome P450 enzymes was predicted. The tested drugs were caffeine, midazolam, nifedipine, metoprolol, ondansetron, granisetron, diazepam, and metronidazole. Pharmacokinetic predictions were evaluated by comparison with in-vivo pharmacokinetic data obtained from the literature. The pregnancy physiologically based pharmacokinetic model successfully predicted the pharmacokinetics of all tested drugs. The observed pregnancy-induced pharmacokinetic changes were qualitatively and quantitatively reasonably well predicted for all drugs. Ninety-seven percent of the mean plasma concentrations predicted in pregnant women fell within a twofold error range and 63% within a 1.25-fold error range. For all drugs, the predicted area under the concentration-time curve was within a 1.25-fold error range. The presented pregnancy physiologically based pharmacokinetic model can quantitatively predict the pharmacokinetics of drugs that are metabolized via one or multiple cytochrome P450 enzymes by integrating prior knowledge of the pregnancy-related effect on these enzymes. This pregnancy physiologically based pharmacokinetic model may thus be used to identify potential exposure changes in pregnant women a priori and to eventually support informed decision making when clinical trials are designed in this

Prevention of chemotherapy-induced nausea: the role of neurokinin-1 (NK1) receptor antagonists.

PubMed

Bošnjak, Snežana M; Gralla, Richard J; Schwartzberg, Lee

2017-05-01

Chemotherapy-induced nausea (CIN) has a significant negative impact on the quality of life of cancer patients. The use of 5-hydroxytryptamine-3 (5-HT 3 ) receptor antagonists (RAs) has reduced the risk of vomiting, but (except for palonosetron) their effect on nausea, especially delayed nausea, is limited. This article reviews the role of NK 1 RAs when combined with 5-HT 3 RA-dexamethasone in CIN prophylaxis. Aprepitant has not shown consistent superiority over a two-drug (ondansetron-dexamethasone) combination in nausea control after cisplatin- or anthracycline-cyclophosphamide (AC)-based highly emetogenic chemotherapy (HEC). Recently, dexamethasone and dexamethasone-metoclopramide were demonstrated to be non-inferior to aprepitant and aprepitant-dexamethasone, respectively, for the control of delayed nausea after HEC (AC/cisplatin), and are now recognized in the guidelines. The potential impact of the new NK 1 RAs rolapitant and netupitant (oral fixed combination with palonosetron, as NEPA) in CIN prophylaxis is discussed. While the clinical significance of the effect on nausea of the rolapitant-granisetron-dexamethasone combination after cisplatin is not conclusive, rolapitant addition showed no improvement in nausea prophylaxis after AC or moderately emetogenic chemotherapy (MEC). NEPA was superior to palonosetron in the control of nausea after HEC (AC/cisplatin). Moreover, the efficacy of NEPA in nausea control was maintained over multiple cycles of HEC/MEC. Recently, NK 1 RAs have been challenged by olanzapine, with olanzapine showing superior efficacy in nausea prevention after HEC. Fixed antiemetic combinations (such as NEPA) or new antiemetics with a long half-life that may be given once per chemotherapy cycle (rolapitant or NEPA) may improve patient compliance with antiemetic treatment.

A comparative analysis of the potential of cannabinoids and ondansetron to suppress cisplatin-induced emesis in the Suncus murinus (house musk shrew).

PubMed

Kwiatkowska, Magdalena; Parker, Linda A; Burton, Page; Mechoulam, Raphael

2004-07-01

The 5-HT3 antagonist, ondansetron (OND), and the cannabinoid, delta9-tetrahydrocannabinol (delta9-THC), have been shown to interfere with emesis; however, their relative and/or combined effectiveness in suppressing vomiting produced by the chemotherapeutic agent, cisplatin, is unknown. To evaluate the potential of: 1) a broad range of doses of delta9-THC and OND to prevent cisplatin-induced vomiting and retching in the Suncus murinus (house musk shrew), 2) combined treatment with ineffective individual doses of delta9-THC and OND to prevent cisplatin-induced vomiting and retching, 3) the CB1 receptor antagonist, SR141716, to reverse the antiemetic effects of OND, and 4) cannabidiol (CBD), the principal non-psychoactive component of marijuana, to reverse cisplatin-induced vomiting in the shrew. Shrews were injected with various doses of OND (0.02-6.0 mg/kg), delta9-THC (1.25-10 mg/kg) and a combination of ineffective doses of each (0.02 mg/kg OND+1.25 mg/kg delta9-THC) prior to being injected with cisplatin (20 mg/kg) which induces vomiting. Shrews were also injected with CBD (5 mg/kg and 40 mg/kg) prior to an injection of cisplatin. OND and delta9-THC both dose-dependently suppressed cisplatin-induced vomiting and retching. Furthermore, a combined pretreatment of doses of the two drugs that were ineffective alone completely suppressed vomiting and retching. CBD produced a biphasic effect, suppressing vomiting at 5 mg/kg and potentiating it at 40 mg/kg. A low dose of the non-intoxicating cannabinoid CBD may be an effective anti-emetic treatment and combined doses of OND and delta9-THC that are ineffective alone suppresses cisplatin-induced emetic reactions in shrews.

Transdermal skin patch based on reduced graphene oxide: A new approach for photothermal triggered permeation of ondansetron across porcine skin.

PubMed

Teodorescu, Florina; Quéniat, Gurvan; Foulon, Catherine; Lecoeur, Marie; Barras, Alexandre; Boulahneche, Samia; Medjram, Mohmaed Salah; Hubert, Thomas; Abderrahmani, Amar; Boukherroub, Rabah; Szunerits, Sabine

2017-01-10

The development of a skin-mounted patch capable of controlled transcutaneous delivery of therapeutics through thermal activation provides a unique solution for the controlled release of active principles over long-term periods. Here, we report on a flexible transdermal patch for photothermal triggered release of ondansetron (ODS), a commonly used drug for the treatment of chemotherapy-induced nausea and vomiting and used as model compound here. To achieve this, a dispersion of ODS-loaded reduced graphene oxide (rGO-ODS) nanosheets were deposited onto Kapton to produce a flexible polyimide-based patch. It is demonstrated that ODS loaded Kapton/rGO patches have a high drug delivery performance upon irradiation with a continuous laser beam at 980nm for 10min due to an induced photothermal heating effect. The ability of ODS impregnated Kapton/rGO patches as transdermal delivery scaffolds for ODS across the skin is in addition investigated using porcine ear skin as a model. We show that the cumulative quantity and flux of ODS passing the skin are highly depending on the laser power density used. At 5Wcm -2 irradiation, the ODS flux across pig skin was determined to be 1.6μgcm -2 h -1 comparable to other approaches. The use of tween 20 as skin enhancer could significantly increase the ODS flux to 13.2μgcm -2 h -1 . While the skin penetration enhancement is comparable to that obtained using other well-known permeation enhancers, the actual superiority and interest of the proposed approach is that the Kapton/rGO photoactivatable skin patch can be loaded with any drugs and therapeutics of interest, making the approach extremely versatile. The on demand delivery of drugs upon local laser irradiation and the possibility to reload the interface with the drug makes this new drug administration route very appealing. Copyright © 2016 Elsevier B.V. All rights reserved.

Ondansetron Injection

MedlinePlus

... serotonin 5-HT3 receptor antagonists. It works by blocking the action of serotonin, a natural substance that ... treatment: rash hives itching swelling of the eyes, face, lips, tongue, throat, hands, feet, ankles, or lower ...

The serotonin receptor mediates changes in autonomic neurotransmission and gastrointestinal transit induced by heat-killed Lactobacillus brevis SBC8803.

PubMed

Horii, Y; Nakakita, Y; Misonou, Y; Nakamura, T; Nagai, K

2015-01-01

Lactobacilli exhibit several health benefits in mammals, including humans. Our previous reports established that heat-killed Lactobacillus brevis SBC8803 (SBC8803) increased both efferent gastric vagal nerve activity and afferent intestinal vagal nerve activity in rats. We speculated that this strain could be useful for the treatment of gastrointestinal (GI) disorders. In this study, we examined the effects of SBC8803 on peristalsis and the activity of the efferent celiac vagal nerve innervating the intestine in rats. First, we examined the effects of intraduodenal (ID) administration of SBC8803 on efferent celiac vagal nerve activity (efferent CVNA) in urethane-anesthetised rats using electrophysiological studies. The effects of intravenous injection of the serotonin 5-HT3 receptor antagonist granisetron on changes in efferent CVNA due to ID administration of SBC8803 were also investigated. Finally, the effects of oral gavage of SBC8803 on GI transit were analysed using the charcoal propulsion method in conscious rats treated with or without granisetron. ID administration of SBC8803 increased efferent CVNA. Pretreatment with granisetron eliminated SBC8803-dependent changes in efferent CVNA. Furthermore, oral gavage of SBC8803 significantly accelerated GI transit, while pretreatment with granisetron inhibited GI transit. Our findings suggested that SBC8803 increased efferent CVNA and GI transit of charcoal meal via 5-HT3 receptors. Moreover, SBC8803 enhanced the activity of efferent vagal nerve innervating the intestine and promoted peristalsis via 5-HT3 receptors.

Comparative efficacy of maropitant and selected drugs in preventing emesis induced by centrally or peripherally acting emetogens in dogs.

PubMed

Sedlacek, H S; Ramsey, D S; Boucher, J F; Eagleson, J S; Conder, G A; Clemence, R G

2008-12-01

Maropitant (Cerenia; a novel, selective neurokinin(1) receptor antagonist), chlorpromazine, metoclopramide and ondansetron were compared in two randomized, placebo-controlled studies for efficacy in preventing emesis induced by emetogens acting centrally (apomorphine; Study 1) or peripherally (syrup of ipecac; Study 2) in dogs. In each study, ten male and ten female beagles were treated in a five-treatment, five-period crossover design. The five treatments were 0.9% saline (0.1 mL/kg), maropitant (1 mg/kg), metoclopramide (0.5 mg/kg), or chlorpromazine (0.5 mg/kg) all administered subcutaneously, or ondansetron (0.5 mg/kg) administered intravenously. One hour posttreatment dogs were challenged with apomorphine at 0.1 mg/kg intravenously (Study 1) or syrup of ipecac at 0.5 mL/kg orally (Study 2). Following emetogen challenge, dogs were observed for 30 min (Study 1) or 1 h (Study 2) for emesis. No clinical signs, other than those related to emesis, were observed. Efficacy of maropitant in preventing emesis induced centrally by apomorphine was not different (P > 0.05) from metoclopramide or chlorpromazine but was superior (P < 0.0001) to ondansetron. Efficacy of maropitant in preventing emesis induced by syrup of ipecac was not different (P > 0.05) from ondansetron but was superior (P ondansetron; P < 0.0001) stimulation but not both.

[The effects of selective 5HT3 receptor blockade on physiological markers of abdominal pain in awake dogs].

PubMed

Panteleev, S S; Busygina, I I; Liubashina, O A

2013-04-01

In awake dogs, the visceromotor and cardioautonomic responses to the rectal balloon distension were studied before and after intravenous administration of a selective 5HT3 receptor antagonist granisetron. It was shown that balloon distension level up to 60 mmHg caused neither noticeable muscle responses nor substantial changes in heart rate. In turn, distending pressures of 80 mmHg and higher induced vigorous abdominal muscle contractions and tachycardia that were graded with increasing intensities of stimulation. Thus, the rectal stimulation with pressures 80 mmHg and more produced the changes in visceromotor and cardiovascular indices which could be considered as suitable indicators of visceral nociception in conscious animals. Based on monitoring of these physiological markers in a model of abdominal pain the dose-dependent antinociceptive effect of granisetron in awake dogs has been demonstrated for the first time. It was determined that granisetron in doses of 0.25, 0.5 or 1.0 mg/kg induced correspondingly 33.6 +/- 9.2, 58.0+/- 8.6 [see text] 76.7 +/- 5.5 % decrease in visceromotor response of dogs to nociceptive visceral stimulation. The effect occurred immediately after the drug administration and was lasting more than 90 min. In turn, the dose-dependent suppression of the rectal distension-induced tachycardia was less prominent and only observed during the initial period of granisetron action. The described model of abdominal pain in awake dogs might be useful for preclinical screening of new pharmacological substances, whereas the obtained data could contribute to the development of more efficient analgesics aimed in patients with irritable bowel syndrome.

Pharmacological Approach for Managing Pain in Irritable Bowel Syndrome: A Review Article

PubMed Central

Chen, Longtu; Ilham, Sheikh J.; Feng, Bin

2017-01-01

Context Visceral pain is a leading symptom for patients with irritable bowel syndrome (IBS) that affects 10% - 20 % of the world population. Conventional pharmacological treatments to manage IBS-related visceral pain is unsatisfactory. Recently, medications have emerged to treat IBS patients by targeting the gastrointestinal (GI) tract and peripheral nerves to alleviate visceral pain while avoiding adverse effects on the central nervous system (CNS). Several investigational drugs for IBS also target the periphery with minimal CNS effects. Evidence of Acquisition In this paper, reputable internet databases from 1960 - 2016 were searched including Pubmed and ClinicalTrials.org, and 97 original articles analyzed. Search was performed based on the following keywords and combinations: irritable bowel syndrome, clinical trial, pain, visceral pain, narcotics, opioid, chloride channel, neuropathy, primary afferent, intestine, microbiota, gut barrier, inflammation, diarrhea, constipation, serotonin, visceral hypersensitivity, nociceptor, sensitization, hyperalgesia. Results Certain conventional pain managing drugs do not effectively improve IBS symptoms, including NSAIDs, acetaminophen, aspirin, and various narcotics. Anxiolytic and antidepressant drugs (Benzodiazepines, TCAs, SSRI and SNRI) can attenuate pain in IBS patients with relevant comorbidities. Clonidine, gabapentin and pregabalin can moderately improve IBS symptoms. Lubiprostone relieves constipation predominant IBS (IBS-C) while loperamide improves diarrhea predominant IBS (IBS-D). Alosetron, granisetron and ondansetron can generally treat pain in IBS-D patients, of which alosetron needs to be used with caution due to cardiovascular toxicity. The optimal drugs for managing pain in IBS-D and IBS-C appear to be eluxadoline and linaclotide, respectively, both of which target peripheral GI tract. Conclusions Conventional pain managing drugs are in general not suitable for treating IBS pain. Medications that target

Palonosetron with aprepitant plus dexamethasone to prevent chemotherapy-induced nausea and vomiting during gemcitabine/cisplatin in urothelial cancer patients.

PubMed

Kitamura, Hiroshi; Takahashi, Atsushi; Hotta, Hiroshi; Kato, Ryuichi; Kunishima, Yasuharu; Takei, Fumiyasu; Horita, Hiroki; Masumori, Naoya

2015-10-01

To evaluate the appearance of chemotherapy-induced nausea and vomiting, and to compare the antiemetic efficacy of the triple combination of palonosetron, aprepitant and dexamethasone with that of our old regimen using first-generation 5-hydroxytryptamine 3-receptor antagonists and dexamethasone during gemcitabine and cisplatin chemotherapy in patients with advanced urothelial cancer. We carried out a multi-institutional study including 122 patients who received gemcitabine and cisplatin for advanced urothelial cancer between February 2005 and January 2012. Uncontrolled chemotherapy-induced nausea and vomiting events were identified through records of nausea and vomiting, additional infusion, rescue medications, and/or records of food intake. First-generation 5-hydroxytryptamine 3-receptor antagonists (ondansetron or granisetron) plus dexamethasone were used for 75 patients (cohort 1), and palonosetron with dexamethasone plus aprepitant for 47 patients (cohort 2). Patients in cohort 2 had significantly higher complete response (defined as no emetic episodes and no rescue medication use) rates than those in cohort 1 during the overall phase in the first cycle (85.7% vs 65.3%, P = 0.012), and all cycles (78.7% vs 50.7%, P = 0.0019) of gemcitabine and cisplatin. Patients in cohort 2 were more likely to achieve more favorable chemotherapy-induced nausea and vomiting control; that is, a lower grade of nausea, vomiting or anorexia, lower incidence of rescue therapy required, and shorter time to become chemotherapy-induced nausea- and vomiting-free than patients in cohort 1. The present results show that palonosetron in combination with aprepitant and dexamethasone is more effective to prevent chemotherapy-induced nausea and vomiting in urothelial cancer patients treated with gemcitabine and cisplatin than first-generation 5-hydroxytryptamine 3-receptor antagonists plus dexamethasone. © 2015 The Japanese Urological Association.

Palonosetron versus older 5-HT3 receptor antagonists for nausea prevention in patients receiving chemotherapy: a multistudy analysis

PubMed Central

Morrow, Gary R; Schwartzberg, Lee; Barbour, Sally Y; Ballinari, Gianluca; Thorn, Michael D; Cox, David

2015-01-01

Background No clinical standard currently exists for the optimal management of nausea induced by emetogenic chemotherapy, particularly delayed nausea. Objective To compare the efficacy and safety of palonosetron with older 5-HT3 receptor antagonists (RAs) in preventing chemotherapy-induced nausea. Methods Data were pooled from 4 similarly designed multicenter, randomized, double-blind, clinical trials that compared single intravenous doses of palonosetron 0.25 mg or 0.75 mg with ondansetron 32 mg, dolasetron 100 mg, or granisetron 40 μg/kg, administered 30 minutes before moderately emetogenic chemotherapy (MEC) or highly emetogenic chemotherapy (HEC). Pooled data within each chemotherapy category (MEC: n = 1,132; HEC: n = 1,781) were analyzed by a logistic regression model. Nausea endpoints were complete control rates (ie, no more than mild nausea, no vomiting, and no rescue medication), nausea-free rates, nausea severity, and requirement for rescue antiemetic/antinausea medication over 5 days following chemotherapy. Pooled safety data were summarized descriptively. Results Numerically more palonosetron-treated patients were nausea-free on each day, and fewer had moderate-severe nausea. Similarly, usage of rescue medication was less frequent among palonosetron-treated patients. Complete control rates for palonosetron and older 5-HT3 RAs in the acute phase were 66% vs 63%, 52% vs 42% in the delayed phase (24-120 hours), and 46% vs 37% in the overall phase. The incidence of adverse events was similar for palonosetron and older 5-HT3 RAs. Limitations This post hoc analysis summarized data for palonosetron and several other 5-HT3 RAs but was not powered for statistical comparisons between individual agents. Because nausea is inherently subjective, the reliability of assessments of some aspects (eg, severity) may be influenced by interindividual variability. Conclusion Palonosetron may be more effective than older 5-HT3 RAs in preventing nausea, with comparable

Development and validation of a high performance liquid chromatographic method for the separation of exo and endo isomers of granatamine (9-methyl-9-azabicyclo[3.3.1]nonan-3-amine); a key intermediate of granisetron.

PubMed

Krishna, S Radha; Babu, P Suresh; Rao, B M; Rao, N Someswara

2009-12-01

A simple and accurate high-performance liquid chromatographic method was developed for the determination of exo-9-methyl-9-azabicyclo[3.3.1]nonan-3-amine in endo-9-methyl-9-azabicyclo[3.3.1]nonan-3-amine, commercially known as grantamine and used as a key intermediate in the preparation of granisetron bulk drug. Chromatographic separation of the exo and endo isomers of 9-methyl-9-azabicyclo[3.3.1]nonan-3-amine was achieved on an Inertsil C8 column using a mobile phase containing 0.3% trifluoroacetic acid. The resolution between the two isomers was found to be more than 4. The limit of detection (LOD) and limit of quantification (LOQ) of exo isomer were 0.8 and 2.5 microg x mL(-1) respectively, for a 10 microL injection volume. The percentage recovery of exo-isomer ranged from 99 to 102% w/w in the endo-9-methyl-9-azabicyclo[3.3.1]nonan-3-amine sample. The test solution and mobile phase were observed to be stable up to 48 h after preparation. The validated method yielded good results for precision, linearity, accuracy, robustness and ruggedness. The proposed method was found to be suitable and accurate for the quantitative determination of exo-isomer in bulk samples of endo-9-methyl-9-azabicyclo[3.3.1]nonan-3-amine.

Involvement of substance P in the development of cisplatin-induced acute and delayed pica in rats

PubMed Central

Yamamoto, Kouichi; Asano, Keiko; Tasaka, Ayana; Ogura, Yuko; Kim, Seikou; Ito, Yui; Yamatodani, Atsushi

2014-01-01

Background and Purpose Although substance P (SP) and neurokinin NK1 receptors have been reported to be involved in cisplatin-induced acute and delayed emesis, their precise roles remain unclear. Pica, the consumption of non-nutrient materials such as kaolin in rats, can be used as a model of nausea in humans. We investigated the time-dependent changes in cisplatin-induced pica and the involvement of SP and NK1 receptors in this behaviour. Experimental Approach Rats were administered cisplatin with or without a daily injection of a 5-HT3 receptor antagonist (granisetron) or an NK1 receptor antagonist (aprepitant), and kaolin intake was then monitored for 5 days. The effects of granisetron on the cisplatin-induced expression of preprotachykinin-A (PPT-A) mRNA, which encodes mainly for SP, and on SP release in the medulla, measured by in vivo brain microdialysis, were also investigated. Key Results Cisplatin induced pica within 8 h of its administration that continued for 5 days. Granisetron inhibited the acute phase (day 1), but not the delayed phase (days 2–5), of pica, whereas aprepitant abolished both phases. Within 24 h of the injection of cisplatin, PPT-A mRNA expression and SP release in the medulla were significantly increased; these findings lasted during the observation period and were inhibited by granisetron for up to 24 h. Conclusions and Implications The profiles of cisplatin-induced pica in rats are similar to clinical findings for cisplatin-induced emesis in humans, and we showed that SP production in the medulla and activation of NK1 receptors are involved in this cisplatin-induced pica. PMID:24641692

Involvement of substance P in the development of cisplatin-induced acute and delayed pica in rats.

PubMed

Yamamoto, Kouichi; Asano, Keiko; Tasaka, Ayana; Ogura, Yuko; Kim, Seikou; Ito, Yui; Yamatodani, Atsushi

2014-06-01

Although substance P (SP) and neurokinin NK1 receptors have been reported to be involved in cisplatin-induced acute and delayed emesis, their precise roles remain unclear. Pica, the consumption of non-nutrient materials such as kaolin in rats, can be used as a model of nausea in humans. We investigated the time-dependent changes in cisplatin-induced pica and the involvement of SP and NK1 receptors in this behaviour. Rats were administered cisplatin with or without a daily injection of a 5-HT3 receptor antagonist (granisetron) or an NK1 receptor antagonist (aprepitant), and kaolin intake was then monitored for 5 days. The effects of granisetron on the cisplatin-induced expression of preprotachykinin-A (PPT-A) mRNA, which encodes mainly for SP, and on SP release in the medulla, measured by in vivo brain microdialysis, were also investigated. Cisplatin induced pica within 8 h of its administration that continued for 5 days. Granisetron inhibited the acute phase (day 1), but not the delayed phase (days 2-5), of pica, whereas aprepitant abolished both phases. Within 24 h of the injection of cisplatin, PPT-A mRNA expression and SP release in the medulla were significantly increased; these findings lasted during the observation period and were inhibited by granisetron for up to 24 h. The profiles of cisplatin-induced pica in rats are similar to clinical findings for cisplatin-induced emesis in humans, and we showed that SP production in the medulla and activation of NK1 receptors are involved in this cisplatin-induced pica. © 2014 The British Pharmacological Society.

Antiemetic efficacy of smoked marijuana: subjective and behavioral effects on nausea induced by syrup of ipecac.

PubMed

Söderpalm, A H; Schuster, A; de Wit, H

2001-01-01

Although the public debate about the legalization of marijuana has continued for as long as 25 years, few controlled studies have been conducted to assess its potential medical benefits. The present study examined the antiemetic effect of smoked marijuana cigarettes (8.4 and 16.9 mg Delta(9)-tetrahydrocannabinol [THC]) compared to a highly potent antiemetic drug, ondansetron (8 mg) in 13 healthy volunteers. Nausea and emesis were induced by syrup of ipecac. Marijuana significantly reduced ratings of "queasiness" and slightly reduced the incidence of vomiting compared to placebo. Ondansetron completely eliminated the emetic effects of ipecac. These findings support and extend previous results, indicating that smoked marijuana reduces feelings of nausea and also reduces emesis in this model. However, its effects are very modest relative to ondansetron, and the psychoactive effects of marijuana are likely to limit its clinical usefulness in the general population.

Chewing gum for the treatment of postoperative nausea and vomiting: a pilot randomized controlled trial.

PubMed

Darvall, J N; Handscombe, M; Leslie, K

2017-01-01

A novel treatment, chewing gum, may be non-inferior to ondansetron in inhibiting postoperative nausea and vomiting (PONV) in female patients after laparoscopic or breast surgery. In this pilot study, we tested the feasibility of a large randomized controlled trial. We randomized 94 female patients undergoing laparoscopic or breast surgery to ondansetron 4 mg i.v. or chewing gum if PONV was experienced in the postanaesthesia care unit (PACU). The primary outcome was full resolution of PONV, with non-inferiority defined as a difference between groups of <15% in a per protocol analysis. Secondary outcomes were PACU stay duration, anti-emetic rescue use, and acceptability of anti-emetic treatment. The feasibility of implementing the protocol in a larger trial was assessed. Postoperative nausea and vomiting in the PACU occurred in 13 (28%) ondansetron patients and 15 (31%) chewing gum patients (P=0.75). Three chewing gum patients could not chew gum when they developed PONV. On a per protocol basis, full resolution of PONV occurred in five of 13 (39%) ondansetron vs nine of 12 (75%) chewing gum patients [risk difference 37% (6.3-67%), P=0.07]. There was no difference in secondary outcomes between groups. Recruitment was satisfactory, the protocol was acceptable to anaesthetists and nurses, and data collection was complete. In this pilot trial, chewing gum was not inferior to ondansetron for treatment of PONV after general anaesthesia for laparoscopic or breast surgery in female patients. Our findings demonstrate the feasibility of a larger, multicentred randomized controlled trial to investigate this novel therapy. Australian New Zealand Clinical Trials Registry: ACTRN12615001327572. © The Author 2016. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Involvement of 5-HT3 receptors in the action of vortioxetine in rat brain: Focus on glutamatergic and GABAergic neurotransmission.

PubMed

Riga, Maurizio S; Sánchez, Connie; Celada, Pau; Artigas, Francesc

2016-09-01

The antidepressant vortioxetine is a 5-HT3-R, 5-HT7-R and 5-HT1D-R antagonist, 5-HT1B-R partial agonist, 5-HT1A-R agonist, and serotonin (5-HT) transporter (SERT) inhibitor. Vortioxetine occupies all targets at high therapeutic doses and only SERT and 5-HT3-R at low doses. Vortioxetine increases extracellular monoamine concentrations in rat forebrain more than selective serotonin reuptake inhibitors (SSRI) and shows pro-cognitive activity in preclinical models. Given its high affinity for 5-HT3-R (Ki = 3.7 nM), selectively expressed in GABA interneurons, we hypothesized that vortioxetine may disinhibit glutamatergic and monoaminergic neurotransmission following 5-HT3-R blockade. Here we assessed vortioxetine effect on pyramidal neuron activity and extracellular 5-HT concentration using in vivo extracellular recordings of rat medial prefrontal cortex (mPFC) pyramidal neurons and microdialysis in mPFC and ventral hippocampus (vHPC). Vortioxetine, but not escitalopram, increased pyramidal neuron discharge in mPFC. This effect was prevented by SR57227A (5-HT3-R agonist) and was mimicked by ondansetron (5-HT3-R antagonist) and by escitalopram/ondansetron combinations. In microdialysis experiments, ondansetron augmented the 5-HT-enhancing effect of escitalopram in mPFC and vHPC. Local ondansetron in vHPC augmented escitalopram effect, indicating the participation of intrinsic mechanisms. Since 5-HT neurons express GABAB receptors, we examined their putative involvement in controlling 5-HT release after 5-HT3-R blockade. Co-perfusion of baclofen (but not muscimol) reversed the increased 5-HT levels produced by vortioxetine and escitalopram/ondansetron combinations in vHPC. The present results suggest that vortioxetine increases glutamatergic and serotonergic neurotransmission in rat forebrain by blocking 5-HT3 receptors in GABA interneurons. Copyright © 2016. Published by Elsevier Ltd.

Evaluation of Pentravan®, Pentravan® Plus, Phytobase®, Lipovan® and Pluronic Lecithin Organogel for the transdermal administration of antiemetic drugs to treat chemotherapy-induced nausea and vomiting at the hospital.

PubMed

Bourdon, F; Lecoeur, M; Leconte, L; Ultré, V; Kouach, M; Odou, P; Vaccher, C; Foulon, C

2016-12-30

The objective of this study was to evaluate five commercial ready-to-use transdermal vehicles (Phytobase ® , Lipovan ® , Pentravan ® , Pentravan ® Plus and Pluronic Lecithin Organogel (PLO)), for the compounding of three antiemetic drugs (ondansetron, dexamethasone and aprepitant) and their administration in combination to treat chemotherapy-induced nausea and vomiting (CINV) at the hospital. Drugs were individually formulated in these vehicles and in mixture in Pentravan ® Plus using different penetration enhancers. Quality control of the forms has demonstrated that formulation process was mastered and convenient for the hospital (time required: 20min). Diffusion experiments through synthetic membranes and pig ear epidermis performed using Franz-type diffusion cells, have shown that the release and permeation process were greater for ondansetron than for dexamethasone and aprepitant, with a release step not limiting. As permeation of aprepitant was too low, it was discarded of the study. When ondansetron and dexamethasone were compounded in combination in Pentravan ® Plus, the most efficient vehicle, a permeation decrease was observed. Finally, the use of tween 20 instead of EtOH as chemical enhancer has led to 2-fold factor increase in the flux of dexamethasone, resulting in fluxes convenient for transdermal administration of ondansetron to a child, but insufficient for an adult and for dexamethasone. Copyright © 2016 Elsevier B.V. All rights reserved.

Controlled transdermal iontophoresis for poly-pharmacotherapy: Simultaneous delivery of granisetron, metoclopramide and dexamethasone sodium phosphate in vitro and in vivo.

PubMed

Cázares-Delgadillo, Jennyfer; Ganem-Rondero, Adriana; Merino, Virginia; Kalia, Yogeshvar N

2016-03-31

Iontophoresis has been used to deliver small molecules, peptides and proteins into and across the skin. In principle, it provides a controlled, non-invasive method for poly-pharmacotherapy since it is possible to formulate and to deliver multiple therapeutic agents simultaneously from the anodal and cathodal compartments. The objective of this proof-of-principle study was to investigate the simultaneous anodal iontophoretic delivery of granisetron (GST) and metoclopramide (MCL) and cathodal iontophoresis of dexamethasone sodium phosphate (DEX-P). In addition to validating the hypothesis, these are medications that are routinely used in combination to treat chemotherapy-induced emesis. Two preliminary in vitro studies using porcine skin were performed: Study 1 - effect of formulation composition on anodal co-iontophoresis of GST and MCL and Study 2 - combined anodal iontophoresis of GST (10mM) and MCL (110 mM) and cathodal iontophoresis of DEX-P (40 mM). The results from Study 1 demonstrated the dependence of GST/MCL transport on the respective drug concentrations when co-iontophoresed at 0.3 mA·cm(-2). Although they possess similar physicochemical properties, MCL seemed to be a more efficient charge carrier (JMCL=0.0591∗CMCLvs JGST=0.0414∗CGST). In Study 2, MCL permeation was markedly superior to that of GST (2324.83 ± 307.85 and 209.83 ± 24.84 μg·cm(-2), respectively); this was consistent with the difference in their relative concentrations; DEX-P permeation was 336.94 ± 71.91 μg·cm(-2). The in vivo studies in Wistar rats (10mM GST, 110 mM MCL and 40 mM DEX-P (0.5 mA·cm(-2) for 5h with Ag/AgCl electrodes and salt bridges) demonstrated that significant drug levels were achieved rapidly for each drug. This was most noticeable for dexamethasone (DEX) where relatively constant plasma levels were obtained from the 1 to 5h time-points; DEX-P was not detected in the plasma since it was completely hydrolyzed to the active metabolite. The calculated input

Altered Gastrointestinal Function in the Neuroligin-3 Mouse Model of Autism

DTIC Science & Technology

2013-10-01

autism . Clearly, characterizing the dysfunction seen with the mixed 5 -HT3/ 5 -HT4 antagonist, tropisetron, when specific antagonists do not show such...gastrointestinal disorders. Current opinion in pharmacology 6, 547 (Dec, 2006). K. B. Neal, J. C. Bornstein, Mapping 5 - HT inputs to enteric neurons of...descending inhibition in guinea-pig ileum. PLoS ONE 10.1371/journal.pone.0040840 (2013) 3. ELLIS M, CHAMBERS JD, GWYNNE RM, BORNSTEIN JC Serotonin ( 5 - HT

Granisetron Transdermal Patch

MedlinePlus

... patch. Each patch is stuck onto a thin plastic liner and a separate rigid plastic film. Do not open the pouch in advance, ... cut the patch into pieces. Peel the thin plastic liner off of the printed side of the ...

Unbinding Pathways of an Agonist and an Antagonist from the 5-HT3 Receptor

PubMed Central

Thompson, A. J.; Chau, P.-L.; Chan, S. L.; Lummis, S. C. R.

2006-01-01

The binding sites of 5-HT3 and other Cys-loop receptors have been extensively studied, but there are no data on the entry and exit routes of ligands for these sites. Here we have used molecular dynamics simulations to predict the pathway for agonists and antagonists exiting from the 5-HT3 receptor binding site. The data suggest that the unbinding pathway follows a tunnel at the interface of two subunits, which is ∼8 Å long and terminates ∼20 Å above the membrane. The exit routes for an agonist (5-HT) and an antagonist (granisetron) were similar, with trajectories toward the membrane and outward from the ligand binding site. 5-HT appears to form many hydrogen bonds with residues in the unbinding pathway, and experiments show that mutating these residues significantly affects function. The location of the pathway is also supported by docking studies of granisetron, which show a potential binding site for granisetron on the unbinding route. We propose that leaving the binding pocket along this tunnel places the ligands close to the membrane and prevents their immediate reentry into the binding pocket. We anticipate similar exit pathways for other members of the Cys-loop receptor family. PMID:16387779

Rotavirus and Serotonin Cross-Talk in Diarrhoea

PubMed Central

Nordgren, Johan; Karlsson, Thommie; Sharma, Sumit; Magnusson, Karl-Eric; Svensson, Lennart

2016-01-01

Rotavirus (RV) has been shown to infect and stimulate secretion of serotonin from human enterochromaffin (EC) cells and to infect EC cells in the small intestine of mice. It remains to identify which intracellularly expressed viral protein(s) is responsible for this novel property and to further establish the clinical role of serotonin in RV infection. First, we found that siRNA specifically silencing NSP4 (siRNANSP4) significantly attenuated secretion of serotonin from Rhesus rotavirus (RRV) infected EC tumor cells compared to siRNAVP4, siRNAVP6 and siRNAVP7. Second, intracellular calcium mobilization and diarrhoeal capacity from virulent and avirulent porcine viruses correlated with the capacity to release serotonin from EC tumor cells. Third, following administration of serotonin, all (10/10) infants, but no (0/8) adult mice, responded with diarrhoea. Finally, blocking of serotonin receptors using Ondansetron significantly attenuated murine RV (strain EDIM) diarrhoea in infant mice (2.9 vs 4.5 days). Ondansetron-treated mice (n = 11) had significantly (p < 0.05) less diarrhoea, lower diarrhoea severity score and lower total diarrhoea output as compared to mock-treated mice (n = 9). Similarly, Ondansetron-treated mice had better weight gain than mock-treated animals (p < 0.05). A most surprising finding was that the serotonin receptor antagonist significantly (p < 0.05) also attenuated total viral shedding. In summary, we show that intracellularly expressed NSP4 stimulates release of serotonin from human EC tumor cells and that serotonin participates in RV diarrhoea, which can be attenuated by Ondansetron. PMID:27459372

Role of 5-HT3 Receptor on Food Intake in Fed and Fasted Mice

PubMed Central

Li, Bingjin; Shao, Dongyuan; Luo, Yungang; Wang, Pu; Liu, Changhong; Zhang, Xingyi; Cui, Ranji

2015-01-01

Background Many studies have shown that 5-hydroxytryptamine (5-HT) receptor subtypes are involved in the regulation of feeding behavior. However, the relative contribution of 5-HT3 receptor remains unclear. The present study was aimed to investigate the role of 5-HT3 receptor in control of feeding behavior in fed and fasted mice. Methodology/Principal Findings Food intake and expression of c-Fos, tyrosine hydroxylase (TH), proopiomelanocortin (POMC) and 5-HT in the brain were examined after acute treatment with 5-HT3 receptor agonist SR-57227 alone or in combination with 5-HT3 receptor antagonist ondansetron. Food intake was significantly inhibited within 3 h after acute treatment with SR 57227 in fasted mice but not fed mice, and this inhibition was blocked by ondansetron. Immunohistochemical study revealed that fasting-induced c-Fos expression was further enhanced by SR 57227 in the brainstem and the hypothalamus, and this enhancement was also blocked by ondansetron. Furthermore, the fasting-induced downregulation of POMC expression in the hypothalamus and the TH expression in the brain stem was blocked by SR 57227 in the fasted mice, and this effect of SR 57227 was also antagonized by ondansetron. Conclusion/Significance Taken together, our findings suggest that the effect of SR 57227 on the control of feeding behavior in fasted mice may be, at least partially, related to the c-Fos expression in hypothalamus and brain stem, as well as POMC system in the hypothalamus and the TH system in the brain stem. PMID:25789930

Acute opioid withdrawal is associated with increased neural activity in reward-processing centers in healthy men: A functional magnetic resonance imaging study.

PubMed

Chu, Larry F; Lin, Joanne C; Clemenson, Anna; Encisco, Ellen; Sun, John; Hoang, Dan; Alva, Heather; Erlendson, Matthew; Clark, J David; Younger, Jarred W

2015-08-01

Opioid analgesics are frequently prescribed for chronic pain. One expected consequence of long-term opioid use is the development of physical dependence. Although previous resting state functional magnetic resonance imaging (fMRI) studies have demonstrated signal changes in reward-associated areas following morphine administration, the effects of acute withdrawal on the human brain have been less well-investigated. In an earlier study by our laboratory, ondansetron was shown to be effective in preventing symptoms associated with opioid withdrawal. The purpose of this current study was to characterize neural activity associated with acute opioid withdrawal and examine whether these changes are modified by ondansetron. Ten participants were enrolled in this placebo-controlled, randomized, double-blind, crossover study and attended three acute opioid withdrawal sessions. Participants received either placebo or ondansetron (8Ymg IV) before morphine administration (10Ymg/70Ykg IV). Participants then underwent acute naloxone-precipitated withdrawal during a resting state fMRI scan. Objective and subjective opioid withdrawal symptoms were assessed. Imaging results showed that naloxone-precipitated opioid withdrawal was associated with increased neural activity in several reward processing regions, including the right pregenual cingulate, putamen, and bilateral caudate, and decreased neural activity in networks involved in sensorimotor integration. Ondansetron pretreatment did not have a significant effect on the imaging correlates of opioid withdrawal. This study presents a preliminary investigation of the regional changes in neural activity during acute opioid withdrawal. The fMRI acute opioid withdrawal model may serve as a tool for studying opioid dependence and withdrawal in human participants. Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

The lesser of two adverse reactions.

PubMed

Chakraborti, Chayan; Egan, John

2010-01-01

Fundamental to complex systems are interconnected processes involved in providing high-quality patient care. A case study and a root cause analysis (RCA) illustrate a patient safety effort with unintended consequences. A 38-year-old woman presented to the hospital for odynophagia and vomiting. The patient developed Mobitz type 2, second-degree heart block temporally associated with the administration of intravenous ondansetron. RESPONSE TO THE EVENT: An Ishikawa, or fishbone, diagram conducted to enumerate potential contributing factors indicated that a key factor appeared to be an institutional restriction against using intravenous (i.v.) promethazine, which resulted in ondansetron being the only readily available i.v. anti-emetic on formulary. The anesthesia department requested that i.v. promethazine be removed from all operating and recovery room automated medication dispensing machines. The pharmacy department, given the realization that individual departments were taking independent action regarding promethazine, discussed the matter with the medical director, who issued a memo banning the use of i.v. promethazine. An institutional ban on i.v. anti-emetics such as promethazine may have resulted in an increase in the use of ondansetron and contributed to this adverse reaction. The reason to restrict promethazine is not well reported in the literature. In limiting the use of promethazine for patient safety concerns, the inadvertent increase in adverse reactions of the alternative medication, ondansetron, may have been overlooked. The resultant RCA underscores the need for careful cataloguing of adverse medication effects. Stakeholders should anticipate as many "downstream effects" of quality and patient safety improvements as possible. Comprehensive reporting of adverse medication effects will augment the emerging science of patient safety.

A comparison of three antiemetic combinations for the prevention of postoperative nausea and vomiting.

PubMed

Sanchez-Ledesma, M J; López-Olaondo, L; Pueyo, F J; Carrascosa, F; Ortega, A

2002-12-01

In this study we compared the efficacy and safety of three antiemetic combinations in the prevention of postoperative nausea and vomiting (PONV). Ninety ASA status I-II women, aged 18-65 yr, undergoing general anesthesia for major gynecological surgery, were included in a prospective, randomized, double-blinded study. A standardized anesthetic technique and postoperative analgesia (intrathecal morphine plus IV patient-controlled analgesia (PCA) with morphine) were used in all patients. Patients were randomly assigned to receive ondansetron 4 mg plus droperidol 1.25 mg after the induction of anesthesia and droperidol 1.25 mg 12 h later (Group 1, n = 30), dexamethasone 8 mg plus droperidol 1.25 mg after the induction of anesthesia and droperidol 1.25 mg 12 h later (Group 2, n = 30), or ondansetron 4 mg plus dexamethasone 8 mg after the induction of anesthesia and placebo 12 h later (Group 3, n = 30). A complete response, defined as no PONV in 48 h, occurred in 80% of patients in Group 1, 70% in Group 3, and 40% in Group 2 (P = 0.004 versus Groups 1 and 3). The incidences of side effects and other variables that could modify the incidence of PONV were similar among groups. In conclusion, ondansetron, in combination with droperidol or dexamethasone, is more effective than dexamethasone in combination with droperidol in women undergoing general anesthesia for major gynecological surgery with intrathecal morphine plus IV PCA with morphine for postoperative analgesia. The combination of ondansetron plus dexamethasone or droperidol was significantly better than the combination of dexamethasone plus droperidol in the prophylaxis of postoperative nausea and vomiting in women undergoing general anesthesia for major gynecological surgery, with intrathecal and IV morphine (patient-controlled analgesia) for management of postoperative pain.

Sterile Basics of Compounding: Relationship Between Syringe Size and Dosing Accuracy.

PubMed

Kosinski, Tracy M; Brown, Michael C; Zavala, Pedro J

2018-01-01

The purpose of this study was to investigate the accuracy and reproducibility of a 2-mL volume injection using a 3-mL and 10-mL syringe with pharmacy student compounders. An exercise was designed to assess each student's accuracy in compounding a sterile preparation with the correct 4-mg strength using a 3-mL and 10-mL syringe. The average ondansetron dose when compounded with the 3-mL syringe was 4.03 mg (standard deviation ± 0.45 mg), which was not statistically significantly different than the intended 4-mg desired dose (P=0.497). The average ondansetron dose when compounded with the 10-mL syringe was 4.18 mg (standard deviation + 0.68 mg), which was statistically significantly different than the intended 4-mg desired dose (P=0.002). Additionally, there also was a statistically significant difference in the average ondansetron dose compounded using a 3-mL syringe (4.03 mg) and a 10-mL syringe (4.18 mg) (P=0.027). The accuracy and reproducibility of the 2-mL desired dose volume decreased as the compounding syringe size increased from 3 mL to 10 mL. Copyright© by International Journal of Pharmaceutical Compounding, Inc.

Effect of formulation pH on transdermal penetration of antiemetics formulated in poloxamer lecithin organogel.

PubMed

Woodall, Rachel; Arnold, John J; McKay, Doug; Asbill, C Scott

2013-01-01

The purpose of this study was to assess the impact of altering formulation pH on the transdermal penetration of several commonly used antiemetic, weakly basic drugs incorporated into poloxamer lecithin organogel vehicle. Poloxamer lecithin organogel formulations containing promethazine hydrochloride (25 mg/mL), metoclopramide hydrochloride (10 mg/mL), and ondansetron hydrochloride (8 mg/mL) were examined for both drug release and transdermal penetration across porcine skin in modified Franz diffusion cells for a period of 24 hours. For the transdermal studies, each antiemetic drug was formulated at a pH above and below their acid dissociation constant (pKa) in an attempt to assure that the drug would be primarily in their respective ionized or non-ionized states. In addition, drug content in skin was assessed at the end of the 24-hour experiment. Drug content analysis was determined via high-performance liquid chromatography. As a percent of total drug release from the poloxamer lecithin organogel vehicle, promethazine hydrochloride demonstrated the most transdermal drug penetration after 24 hours (30.2% +/- 20.2%), followed by ondansetron hydrochloride (2.7% +/- 1.1%) and metoclopramide hydrochloride (1.8% +/- 1.6%). Subsequently, the pH of the Pluronic F-127 gel was adjusted in order to ensure that each antiemetic drug would be primarily in its unionized state. The transdermal permeation of each antiemetic drug primarily in its unionized state increased over that observed with the drug primarily in its ionized state after 24 hours (promethazine: 1.6-fold increase; metoclopramide: 1.3-fold increase; ondansetron: 1.8-fold increase). A similar trend was noted in the amount of each drug found in the skin after 24 hours (promethazine: 1.2-fold increase; metoclopramide: 2.4-fold increase; ondansetron: 3.0-fold increase). These results suggest that proper optimization of drug ionization state may be a useful strategy for compounding pharmacists to increase the efficacy

Grape

MedlinePlus

... fruit, skin, leaves and seed of the grape plant are used as medicine. Grape seeds are by- ... haloperidol (Haldol), imipramine (Tofranil), mexiletine (Mexitil), mirtazapine (Remeron), naproxen (Naprosyn), nortriptyline (Pamelor), olanzapine (Zyprexa), ondansetron (Zofran), propafenone ( ...

Palonosetron versus older 5-HT3 receptor antagonists for nausea prevention in patients receiving chemotherapy: a multistudy analysis.

PubMed

Morrow, Gary R; Schwartzberg, Lee; Barbour, Sally Y; Ballinari, Gianluca; Thorn, Michael D; Cox, David

2014-07-01

No clinical standard currently exists for the optimal management of nausea induced by emetogenic chemotherapy, 7particularly delayed nausea. To compare the effcacy and safety of palonosetron with older 5-HT3 receptor antagonists (RAs) in preventing chemotherapy-induced nausea. Data were pooled from 4 similarly designed multicenter, randomized, double-blind, clinical trials that compared single intravenous doses of palonosetron 0.25 mg or 0.75 mg with ondansetron 32 mg, dolasetron 100 mg, or granisetron 40 μg/kg, administered 30 minutes before moderately emetogenic chemotherapy (MEC) or highly emetogenic chemotherapy (HEC). Pooled data within each chemotherapy category (MEC: n = 1,132; HEC: n = 1,781) were analyzed by a logistic regression model. Nausea endpoints were complete control rates (ie, no more than mild nausea, no vomiting, and no rescue medication), nausea-free rates, nausea severity, and requirement for rescue antiemetic/antinausea medication over 5 days following chemotherapy. Pooled safety data were summarized descriptively. Numerically more palonosetron-treated patients were nausea-free on each day, and fewer had moderate-severe nausea. Similarly, usage of rescue medication was less frequent among palonosetron-treated patients. Complete control rates for palonosetron and older 5-HT3 RAs in the acute phase were 66% vs 63%, 52% vs 42% in the delayed phase (24-120 hours), and 46% vs 37% in the overall phase. The incidence of adverse events was similar for palonosetron and older 5-HT3 RAs. This post hoc analysis summarized data for palonosetron and several other 5-HT3 RAs but was not powered for statistical comparisons between individual agents. Because nausea is inherently subjective, the reliability of assessments of some aspects (eg, severity) may be infuenced by interindividual variability. Palonosetron may be more effective than older 5-HT3 RAs in preventing nausea, with comparable tolerability. Dr Schwartzberg is a consultant to and Dr Cox an

Pharmacological action of DA-9701 on the motility of feline stomach circular smooth muscle.

PubMed

Nguyen, Thanh Thao; Song, Hyun Ju; Ko, Sung Kwon; Sohn, Uy Dong

2015-03-01

DA-9701, a new prokinetic agent for the treatment of functional dyspepsia, is formulated with Pharbitis semen and Corydalis tuber. This study wasconducted to determine the pharmacological action of DA-9701 and to identify the receptors involved in DA-9701 -induced contractile responsesin the feline gastric corporal, fundic and antral circular smooth muscle. Concentration-response curve to DA-9701 was established. The tissue trips were exposed to methylsergide, ketanserin, ondansetron, GR 113808, atropine and dopamine before administration of DA-9701. The contractile force was determined before and after administration of drugs by a polygraph.DA-9701 enhanced the spontaneous contractile amplitude of antrum, corpus and fundus. However, it did not change the spontaneous contractile frequency of antrum and corpus, but concentration-dependently reduced that of fundus. In the fundus, DA-9701 -induced tonic contractions were inhibited by dopamine, methylsergide, ketanserine, ondansetron or GR 113808 respectively, but not by atropine, indicating that the contractile responses are mediated by multiple receptors: 5-HT2, 5-HT3, 5-HT4, and dopamine receptors. In the corpus, DA-9701-induced contractions were blocked by atropine, dopamine or GR 113808, but not by methysergide, ketanserin or ondansetron, indicating that they are involved in receptors on both, smooth muscles and neurons: 5-HT4 and dopamine receptors. However, contractile responses to DA-9701 are mainly mediated by dopamine receptors in the antrum. These results suggest that DA-9701 has important roles in gastric accommodation by enhancing tonic activity of fundus, and in gastric emptying and gastrointestinal transit by phasic contractions of corpus and antrum mediated by multiple receptors.

Radiological Dispersal Devices: Select Issues in Consequence Management

DTIC Science & Technology

2004-12-07

STATEMENT Approved for public release, distribution unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT 15. SUBJECT TERMS 16. SECURITY CLASSIFICATION OF: 17...Surveying the Security Risks, Center for Nonproliferation Studies, Monterey Institute of International Studies, January 2003; Anthony H. Cordesman...the radiation-exposure-related damage itself. For example, the DOD uses granisetron , an anti-vomiting drug, to allow soldiers to complete mission

Proceedings: TRIAGE of Irradiated Personnel, 25-27 September 1996

DTIC Science & Technology

1998-03-01

thermoluminescent dosimeter project group (PG-29) has recommended grani- (TLD) systems accredited by the National Volun- setron as the deployable...individual phylactic antiemetic medications and regimens dosimeter system currently fielded is the high-range were evaluated prior to adoption of...granisetron. photoluminescent AN/PDR-75. This system con- sists of the ruggedized DT-236 wristband dosimeter Two drugs exceeded the criteria (shown below

Selectivity of antagonists for the Cys-loop native receptors for ACh, 5-HT and GABA in guinea-pig myenteric neurons.

PubMed

Juárez, E H; Ochoa-Cortés, F; Miranda-Morales, M; Espinosa-Luna, R; Montaño, L M; Barajas-López, C

2014-01-01

The three most common Cys-loop receptors expressed by myenteric neurons are nACh, 5-HT3 and GABAA . To investigate the function of these proteins researchers have used channel inhibitors such as hexamethonium (antagonist of nACh receptors), ondansetron (antagonist of 5-HT3 receptors), picrotoxin and bicuculline (both antagonists of GABAA receptors). The aim of this study was to investigate the specificity of these inhibitors on Cys-loop receptors of primary cultured neurons obtained from the guinea-pig small intestine. The whole-cell configuration of the patch clamp techniques was used to record membrane currents induced by ACh (IACh ), 5-HT (I5-HT ) and GABA (IGABA ) in the absence and the presence of various concentrations of hexamethonium, ondansetron, picrotoxin or bicuculline. The three Cys-loop receptors present in enteric neurons are expressed independently and they do not cross-desensitized. Hexamethonium inhibited IACh without affecting I5-HT and IGABA . Ondansetron inhibited I5-HT and also IACh but did not affect IGABA . Picrotoxin and bicuculline inhibited I5-HT , IACh and IGABA with different potency, being the lowest potency on 5-HT3 receptors. All these inhibitory effects were concentration dependent and reversible. Our observations showed that except for hexamethonium, all other inhibitors used here show different degrees of selectivity, which has to be considered when these antagonists are used in experimental studies aimed to investigate the functions of these receptors. In particular, in tissues expressing nACh receptors because these are the targets of all other inhibitors used here. The low potency of picrotoxin and bicuculline to inhibit 5-HT3 receptors suggests that these receptors are heteromeric proteins. © 2013 John Wiley & Sons Ltd.

Diffuse noxious inhibitory controls and nerve injury: restoring an imbalance between descending monoamine inhibitions and facilitations.

PubMed

Bannister, Kirsty; Patel, Ryan; Goncalves, Leonor; Townson, Louisa; Dickenson, Anthony H

2015-09-01

Diffuse noxious inhibitory controls (DNICs) utilize descending inhibitory controls through poorly understood brain stem pathways. The human counterpart, conditioned pain modulation, is reduced in patients with neuropathy aligned with animal data showing a loss of descending inhibitory noradrenaline controls together with a gain of 5-HT3 receptor-mediated facilitations after neuropathy. We investigated the pharmacological basis of DNIC and whether it can be restored after neuropathy. Deep dorsal horn neurons were activated by von Frey filaments applied to the hind paw, and DNIC was induced by a pinch applied to the ear in isoflurane-anaesthetized animals. Spinal nerve ligation was the model of neuropathy. Diffuse noxious inhibitory control was present in control rats but abolished after neuropathy. α2 adrenoceptor mechanisms underlie DNIC because the antagonists, yohimbine and atipamezole, markedly attenuated this descending inhibition. We restored DNIC in spinal nerve ligated animals by blocking 5-HT3 descending facilitations with the antagonist ondansetron or by enhancing norepinephrine modulation through the use of reboxetine (a norepinephrine reuptake inhibitor, NRI) or tapentadol (μ-opioid receptor agonist and NRI). Additionally, ondansetron enhanced DNIC in normal animals. Diffuse noxious inhibitory controls are reduced after peripheral nerve injury illustrating the central impact of neuropathy, leading to an imbalance in descending excitations and inhibitions. Underlying noradrenergic mechanisms explain the relationship between conditioned pain modulation and the use of tapentadol and duloxetine (a serotonin, NRI) in patients. We suggest that pharmacological strategies through manipulation of the monoamine system could be used to enhance DNIC in patients by blocking descending facilitations with ondansetron or enhancing norepinephrine inhibitions, so possibly reducing chronic pain.

Biochemical enhancement of transdermal delivery with magainin peptide: modification of electrostatic interactions by changing pH.

PubMed

Kim, Yeu-Chun; Late, Sameer; Banga, Ajay K; Ludovice, Peter J; Prausnitz, Mark R

2008-10-01

Magainin is a naturally occurring, pore-forming peptide that has recently been shown to increase skin permeability. This study tested the hypothesis that electrostatic forces between magainin peptides and drugs mediate drug transport across the skin. Electrostatic interaction between positively charged magainin and a negatively charged model drug, fluorescein, was attractive at pH 7.4 and resulted in a 35-fold increase in delivery across human epidermis in vitro when formulated with 2% N-lauroylsarcosine in 50% ethanol. Increasing to pH 10 or 11 largely neutralized magainin's charge, which eliminated enhancement due to magainin. Shielding electrostatic interactions with 1-2M NaCl solution similarly eliminated enhancement. Showing the opposite dependence on pH, electrostatic interaction between magainin and a positively charged anti-nausea drug, granisetron, was largely neutralized at pH 10 and resulted in a 92-fold increase in transdermal delivery. Decreasing to pH 5 increased magainin's positive charge, which repelled granisetron and progressively decreased transdermal flux. Circular dichroism analysis, multi-photon microscopy, and FTIR spectroscopy showed no significant pH effect on magainin secondary structure, magainin deposition in stratum corneum, or stratum corneum lipid order, respectively. We conclude that magainin increases transdermal delivery by a mechanism involving electrostatic interaction between magainin peptides and drugs.

Biochemical enhancement of transdermal delivery with magainin peptide: Modification of electrostatic interactions by changing pH

PubMed Central

Kim, Yeu-Chun; Late, Sameer; Banga, Ajay K.; Ludovice, Peter J.; Prausnitz, Mark R.

2008-01-01

Magainin is a naturally occurring, pore-forming peptide that has recently been shown to increase skin permeability. This study tested the hypothesis that electrostatic forces between magainin peptides and drugs mediate drug transport across the skin. Electrostatic interaction between positively charged magainin and a negatively charged model drug, fluorescein, was attractive at pH 7.4 and resulted in a 35 fold increase in delivery across human epidermis in vitro when formulated with 2% N-lauroylsarcosine in 50% ethanol. Increasing to pH 10 or 11 largely neutralized magainin’s charge, which eliminated enhancement due to magainin. Shielding electrostatic interactions with 1–2 M NaCl solution similarly eliminated enhancement. Showing the opposite dependence on pH, electrostatic interaction between magainin and a positively charged anti-nausea drug, granisetron, was largely neutralized at pH 10 and resulted in a 59 fold increase in transdermal delivery. Decreasing to pH 5 increased magainin’s positive charge, which repelled granisetron and progressively decreased transdermal flux. Circular dichroism analysis, multi-photon microscopy, and FTIR spectroscopy showed no significant pH effect on magainin secondary structure, magainin deposition in stratum corneum, or stratum corneum lipid order, respectively. We conclude that magainin increases transdermal delivery by a mechanism involving electrostatic interaction between magainin peptides and drugs. PMID:18601987

Pregabalin Suppresses Spinal Neuronal Hyperexcitability and Visceral Hypersensitivity in the Absence of Peripheral Pathophysiology

PubMed Central

Bannister, Kirsty; Sikandar, Shafaq; Bauer, Claudia S.; Dolphin, Annette C.; Porreca, Frank; Dickenson, Anthony H.

2011-01-01

Background Opioid induced hyperalgesia is recognised in the laboratory and the clinic, generating central hyperexcitability in the absence of peripheral pathology. We investigated pregabalin, indicated for neuropathic pain, and ondansetron, a drug that disrupts descending serotonergic processing in the central nervous system, on spinal neuronal hyperexcitability and visceral hypersensitivity in a rat model of opioid induced hyperalgesia. Methods Sprague-Dawley rats (180-200 g) were implanted with morphine (90μg · μl−1 · hr−1) or saline (0.9% w/v) filled osmotic mini-pumps. On days 7-10 in isoflurane anaesthetized animals we evaluated the effects of (a) systemic pregabalin on spinal neuronal and visceromotor responses and (b) spinal ondansetron on dorsal horn neuronal responses. The messenger RNA levels of α2δ-1, 5HT3A and mu-opioid receptor in the dorsal root ganglia of all animals were analysed. Results In morphine-treated animals the evoked spinal neuronal responses were enhanced to a sub-set of thermal and mechanical stimuli. This activity was attenuated by pregabalin (by at least 71%) and ondansetron (37%), and the visceromotor response to a sub-set of colorectal distension pressures was attenuated by pregabalin (52.8%) (n = 8 for all measures, P < 0.05). Messenger RNA levels were unchanged. Conclusions The inhibitory action of pregabalin in opioid induced hyperalgesia animals is not neuropathy-dependent nor reliant on up-regulation of the α2δ-1 subunit of voltage gated calcium channels, mechanisms proposed essential for pregabalin’s efficacy in neuropathy. In opioid induced hyperalgesia, which extends to colonic distension, a serotonergic facilitatory system may be upregulated creating an environment that’s permissive for pregabalin-mediated analgesia without peripheral pathology. PMID:21602662

Aprepitant as an add-on therapy in children receiving highly emetogenic chemotherapy: a randomized, double-blind, placebo-controlled trial.

PubMed

Bakhshi, Sameer; Batra, Atul; Biswas, Bivas; Dhawan, Deepa; Paul, Reeja; Sreenivas, Vishnubhatla

2015-11-01

Aprepitant, a neurokinin-1 receptor antagonist, in combination with 5 HT-3 antagonist and dexamethasone is recommended in adults receiving moderately and highly emetogenic chemotherapy to reduce chemotherapy-induced vomiting (CIV). Data for use of aprepitant in children is limited and hence aprepitant is not recommended by Pediatric Oncology Group of Ontario guidelines for prevention of CIV in children <12 years. A randomized, double-blind, placebo-controlled trial was conducted at a single center in chemotherapy naïve children (5-18 years) receiving highly emetogenic chemotherapy. All patients received intravenous ondansetron (0.15 mg/kg) and dexamethasone (0.15 mg/kg) prior to chemotherapy followed by oral ondansetron and dexamethasone. Patients randomly assigned to aprepitant arm received oral aprepitant (15-40 kg = days 1-3, 80 mg; 41-65 kg = day 1, 125 mg and days 2-3, 80 mg) 1 h before chemotherapy. Control group received placebo as add-on therapy. Primary outcome measure was the incidence of acute moderate to severe vomiting, which was defined as more than two vomiting episodes within 24 h after the administration of the first chemotherapy dose until 24 h after the last chemotherapy dose in the block. Complete response (CR) was defined as absence of vomiting and retching during the specified phase. Of the 96 randomized patients, three were excluded from analysis; 93 patients were analyzed (50 in aprepitant arm and 43 in placebo arm). Acute moderate and severe vomiting was reported in 72 % patients receiving placebo and 38 % patients receiving aprepitant (p = 0.001). Complete response rates during acute phase were significantly higher in aprepitant arm (48 vs. 12 %, p < 0.001). No major adverse effects were reported by patients/guardians. This double-blind, randomized, placebo-controlled trial shows that aprepitant significantly decreases the incidence of CIV during acute phase when used as an add-on drug with ondansetron and dexamethasone in children

Gastroenteritis Therapies in Developed Countries: Systematic Review and Meta-Analysis.

PubMed

Freedman, Stephen B; Pasichnyk, Dion; Black, Karen J L; Fitzpatrick, Eleanor; Gouin, Serge; Milne, Andrea; Hartling, Lisa

2015-01-01

Gastroenteritis remains a leading cause of childhood morbidity. Because prior reviews have focused on isolated symptoms and studies conducted in developing countries, this study focused on interventions commonly considered for use in developed countries. Intervention specific, patient-centered outcomes were selected. MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews, trial registries, grey literature, and scientific meetings. Randomized controlled trials, conducted in developed countries, of children aged <18 years, with gastroenteritis, performed in emergency department or outpatient settings which evaluated oral rehydration therapy (ORT), antiemetics, probiotics or intravenous fluid administration rate. The study was conducted in accordance with the Cochrane Handbook for Systematic Reviews of Interventions and the PRISMA guidelines. Data were independently extracted by multiple investigators. Analyses employed random effects models. 31 trials (4,444 patients) were included. ORT: Compared with intravenous rehydration, hospitalization (RR 0.80, 95%CI 0.24, 2.71) and emergency department return visits (RR 0.86, 95%CI 0.39, 1.89) were similar. Antiemetics: Fewer children administered an antiemetic required intravenous rehydration (RR 0.40, 95%CI 0.26, 0.60) While the data could not be meta-analyzed, three studies reported that ondansetron administration does increase the frequency of diarrhea. Probiotics: No studies reported on the primary outcome, three studies evaluated hospitalization within 7 days (RR 0.87, 95%CI 0.25, 2.98). Rehydration: No difference in length of stay was identified for rapid vs. standard intravenous or nasogastric rehydration. A single study found that 5% dextrose in normal saline reduced hospitalizations compared with normal saline alone (RR 0.70, 95% CI 0.53, 0.92). There is a paucity of patient-centered outcome evidence to support many interventions. Since ORT is a low-cost, non-invasive intervention, it should continue to be

Impact of 5-HT3 receptor antagonists on chemotherapy-induced nausea and vomiting: a retrospective cohort study

PubMed Central

2012-01-01

Background 1st generation 5-hydroxytryptamine receptor antagonists (5-HT3 RAs), and palonosetron, a 2nd generation 5-HT3 RA, are indicated for the prevention of chemotherapy (CT)-induced nausea and vomiting (CINV) associated with moderately (MEC) and highly emetogenic CT agents (HEC). This study explores the impact of step therapy policies requiring use of an older 5-HT3 RA before palonosetron on risk of CINV associated with hospital or emergency department (ED) admissions. Methods Patients who received cyclophosphamide post breast cancer (BC) surgery or who were diagnosed with lung cancer on carboplatin (LC-carboplatin) or cisplatin (LC-cisplatin) were selected from PharMetrics’ (IMS LifeLink) claims dataset (2005-2008). Patients were followed for 6 months from initial CT administration for CINV events identified through ICD-9-CM codes. Patients were grouped into those initiated with older, generic 5-HT3 RAs (ondansetron, granisetron, and dolasetron) and those initiated and maintained on palonosetron throughout study follow-up. CINV events and CINV days were analyzed using multivariate regressions controlling for demographic and clinical variables. Results Eligible patients numbered 3,606 in BC, 4,497 in LC-carboplatin and 1,154 in LC-cisplatin cohorts, with 52%, 40%, and 34% in the palonosetron group, respectively. There was no significant difference between the two 5-HT3 RA groups in age or Charlson Comorbidity Index among the two MEC cohorts (BC and LC-carboplatin). Among the LC-cisplatin cohort, palonosetron users were older with more males than the older 5-HT3 RA group (age: 60.1 vs. 61.3; males, 66.9% vs. 56.9%). Compared to the older 5-HT3 RAs, the palonosetron groups incurred 22%-51% fewer 5-HT3 RA pharmacy claims, had fewer patients with CINV events (3.5% vs. 5.5% in BC, 9.5% vs. 12.8% in LC-carboplatin, 16.4% vs. 21.7% in LC-cisplatin), and had lower risk for CINV events (odds ratios 0.62, 0.71, or 0.71, respectively; p < 0.05). The BC and LC

Impact of 5-HT3 receptor antagonists on chemotherapy-induced nausea and vomiting: a retrospective cohort study.

PubMed

Lin, Swu-Jane; Hatoum, Hind T; Buchner, Deborah; Cox, David; Balu, Sanjeev

2012-07-23

1st generation 5-hydroxytryptamine receptor antagonists (5-HT3 RAs), and palonosetron, a 2nd generation 5-HT3 RA, are indicated for the prevention of chemotherapy (CT)-induced nausea and vomiting (CINV) associated with moderately (MEC) and highly emetogenic CT agents (HEC). This study explores the impact of step therapy policies requiring use of an older 5-HT3 RA before palonosetron on risk of CINV associated with hospital or emergency department (ED) admissions. Patients who received cyclophosphamide post breast cancer (BC) surgery or who were diagnosed with lung cancer on carboplatin (LC-carboplatin) or cisplatin (LC-cisplatin) were selected from PharMetrics' (IMS LifeLink) claims dataset (2005-2008). Patients were followed for 6 months from initial CT administration for CINV events identified through ICD-9-CM codes. Patients were grouped into those initiated with older, generic 5-HT3 RAs (ondansetron, granisetron, and dolasetron) and those initiated and maintained on palonosetron throughout study follow-up. CINV events and CINV days were analyzed using multivariate regressions controlling for demographic and clinical variables. Eligible patients numbered 3,606 in BC, 4,497 in LC-carboplatin and 1,154 in LC-cisplatin cohorts, with 52%, 40%, and 34% in the palonosetron group, respectively. There was no significant difference between the two 5-HT3 RA groups in age or Charlson Comorbidity Index among the two MEC cohorts (BC and LC-carboplatin). Among the LC-cisplatin cohort, palonosetron users were older with more males than the older 5-HT3 RA group (age: 60.1 vs. 61.3; males, 66.9% vs. 56.9%). Compared to the older 5-HT3 RAs, the palonosetron groups incurred 22%-51% fewer 5-HT3 RA pharmacy claims, had fewer patients with CINV events (3.5% vs. 5.5% in BC, 9.5% vs. 12.8% in LC-carboplatin, 16.4% vs. 21.7% in LC-cisplatin), and had lower risk for CINV events (odds ratios 0.62, 0.71, or 0.71, respectively; p<0.05). The BC and LC-carboplatin palonosetron groups

Intracolonic capsaicin stimulates colonic motility and defecation in conscious dogs.

PubMed

Hayashi, Keiichi; Shibata, Chikashi; Nagao, Munenori; Sato, Manabu; Kakyo, Masayuki; Kinouchi, Makoto; Saijo, Fumito; Miura, Koh; Ogawa, Hitoshi; Sasaki, Iwao

2010-06-01

The aim of this study was to investigate the effects of intracolonic capsaicin on colonic motility and defecation. The effects of capsaicin (1, 2, 5, and 10 mg) administrated into the proximal colon on ileocolonic motility and defecation were studied in neurally intact dogs with or without various antagonists (atropine, hexamethonium, ondansetron, propranolol, and FK224), dogs with extrinsic denervation of an ileocolonic segment, and dogs with enterically isolated ileocolonic loops equipped with strain gauge force transducers. Capsaicin at 5 and 10 mg evoked giant migrating contractions in a dose-independent manner, and it induced defecations with more than 90% probability in neurally intact dogs. These effects of capsaicin were abolished by atropine and hexamethonium. Ondansetron inhibited the capsaicin-induced increase in colonic motility but did not affect the induction of defecation. The other antagonists had no effect. In dogs with extrinsic denervation, capsaicin did not evoke giant migrating contractions in the colon but still induced defecation in 30-40% of experiments. In dogs with ileocolonic loops, capsaicin did not stimulate colonic motility nor induce defecation. These results indicate that intracolonic capsaicin causes giant migrating contractions and defecation. Intact extrinsic innervation, continuity of the colon, and intraluminal contents were considered necessary for this effect. Copyright 2010 Mosby, Inc. All rights reserved.

Fabrication and optimization of fast disintegrating tablets employing interpolymeric chitosan-alginate complex and chitin as novel superdisintegrants.

PubMed

Goel, Honey; Tiwary, Ashok K; Rana, Vikas

2011-01-01

The objective of the present work was to optimize the formulation of fast disintegrating tablets (FDTs) of ondansetron HCl containing novel superdisintegrants, possessing sufficient mechanical strength and disintegration time comparable to those containing crospovidone or croscarmellose sodium. The FDTs were formulated using a novel superdisintegrant (chitosan-alginate (1:1) interpolymer complex and chitin) to achieve a sweet tasting disintegrating system. The results revealed that chitin (5-20%) increased the porosity and decreased the DT of tablets. At higher concentrations chitin maintained tablet porosity even at 5.5 kg crushing strength. Ondansetron HCl was found to antagonize the wicking action of glycine. Further, evaluation of the mechanism of disintegration revealed that glycine transported the aqueous medium to different parts of the tablets while the chitosan-alginate complex swelled up due to transfer of moisture from glycine. This phenomenon resulted in breakage of the tablet within seconds. For preparing optimized FDTs, the reduced model equations generated from Box-Behnken design (BBD) were solved after substituting the known disintegration time of FDTs containing superdisintegrants in the reduced model equations. The results suggested that excipient system under investigation not only improved the disintegration time but also made it possible to prepare FDTs with higher crushing strength as compared to tablets containing known superdisintegrants.

Gastroenteritis Therapies in Developed Countries: Systematic Review and Meta-Analysis

PubMed Central

Freedman, Stephen B.; Pasichnyk, Dion; Black, Karen J. L.; Fitzpatrick, Eleanor; Gouin, Serge; Milne, Andrea; Hartling, Lisa

2015-01-01

Context Gastroenteritis remains a leading cause of childhood morbidity. Objective Because prior reviews have focused on isolated symptoms and studies conducted in developing countries, this study focused on interventions commonly considered for use in developed countries. Intervention specific, patient-centered outcomes were selected. Data Sources MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews, trial registries, grey literature, and scientific meetings. Study Selection Randomized controlled trials, conducted in developed countries, of children aged <18 years, with gastroenteritis, performed in emergency department or outpatient settings which evaluated oral rehydration therapy (ORT), antiemetics, probiotics or intravenous fluid administration rate. Data Extraction The study was conducted in accordance with the Cochrane Handbook for Systematic Reviews of Interventions and the PRISMA guidelines. Data were independently extracted by multiple investigators. Analyses employed random effects models. Results 31 trials (4,444 patients) were included. ORT: Compared with intravenous rehydration, hospitalization (RR 0.80, 95%CI 0.24, 2.71) and emergency department return visits (RR 0.86, 95%CI 0.39, 1.89) were similar. Antiemetics: Fewer children administered an antiemetic required intravenous rehydration (RR 0.40, 95%CI 0.26, 0.60) While the data could not be meta-analyzed, three studies reported that ondansetron administration does increase the frequency of diarrhea. Probiotics: No studies reported on the primary outcome, three studies evaluated hospitalization within 7 days (RR 0.87, 95%CI 0.25, 2.98). Rehydration: No difference in length of stay was identified for rapid vs. standard intravenous or nasogastric rehydration. A single study found that 5% dextrose in normal saline reduced hospitalizations compared with normal saline alone (RR 0.70, 95% CI 0.53, 0.92). Conclusions There is a paucity of patient-centered outcome evidence to support many

Maerua angolensis stem bark extract reverses anxiety and related behaviours in zebrafish-Involvement of GABAergic and 5-HT systems.

PubMed

Benneh, Charles Kwaku; Biney, Robert Peter; Mante, Priscilla Kolibea; Tandoh, Augustine; Adongo, Donatus Wewura; Woode, Eric

2017-07-31

Maerua angolensis DC (Capparaceae) has been employed in the management of several central nervous system (CNS) disorders including anxiety. This study evaluated the anxiolytic effects of the petroleum ether/ethyl acetate fraction stem bark extract and its possible mechanism(s) using zebrafish anxiety models. Adult zebrafish, tested in the novel tank and light dark tests, have shown by previous authors to be sensitive to the anxiolytic effects of known anxiolytic drugs. Adult zebrafish were treated with M. angolensis extract, fluoxetine, desipramine, and diazepam followed by testing in the novel tank and light dark tests. We further assessed the effect of the extract on anxiety after inducing an anxiogenic phenotype using the ethanol-withdrawal and chronic unpredictable stress (CUS) tests. The anxiolytic effect was further investigated after pretreatment with flumazenil, granisetron, cyproheptadine, methysergide and pizotifen. M. angolensis extract, similar to fluoxetine and desipramine, demonstrated significant anxiolytic behaviour at doses that did not reduce locomotor activity significantly. Similar anxiolytic effects were recorded in the ethanol withdrawal-induced anxiety test. Furthermore, the anxiogenic effects induced by the CUS paradigm were significantly reversed by treatment M. angolensis extract and fluoxetine. The anxiolytic effects of M. angolensis extract were however reversed after pre-treatment with flumazenil, granisetron, cyproheptadine, methysergide and pizotifen. Taken together, this suggests that the petroleum ether/ ethyl acetate fraction of M. angolensis possesses significant anxiolytic activity, which could partly be accounted for by an interaction with the serotoninergic system and the GABA A receptor. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

The muscarinic antagonists scopolamine and atropine are competitive antagonists at 5-HT3 receptors.

PubMed

Lochner, Martin; Thompson, Andrew J

2016-09-01

Scopolamine is a high affinity muscarinic antagonist that is used for the prevention of post-operative nausea and vomiting. 5-HT3 receptor antagonists are used for the same purpose and are structurally related to scopolamine. To examine whether 5-HT3 receptors are affected by scopolamine we examined the effects of this drug on the electrophysiological and ligand binding properties of 5-HT3A receptors expressed in Xenopus oocytes and HEK293 cells, respectively. 5-HT3 receptor-responses were reversibly inhibited by scopolamine with an IC50 of 2.09 μM. Competitive antagonism was shown by Schild plot (pA2 = 5.02) and by competition with the 5-HT3 receptor antagonists [(3)H]granisetron (Ki = 6.76 μM) and G-FL (Ki = 4.90 μM). The related molecule, atropine, similarly inhibited 5-HT evoked responses in oocytes with an IC50 of 1.74 μM, and competed with G-FL with a Ki of 7.94 μM. The reverse experiment revealed that granisetron also competitively bound to muscarinic receptors (Ki = 6.5 μM). In behavioural studies scopolamine is used to block muscarinic receptors and induce a cognitive deficit, and centrally administered concentrations can exceed the IC50 values found here. It is therefore possible that 5-HT3 receptors are also inhibited. Studies that utilise higher concentrations of scopolamine should be mindful of these potential off-target effects. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

PI3 kinase is involved in cocaine behavioral sensitization and its reversal with brain area specificity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang Xiuwu; Mi Jing; Wetsel, William C.

Phosphatidylinositol 3-kinase (PI3K) is an important signaling molecule involved in cell differentiation, proliferation, survival, and phagocytosis, and may participate in various brain functions. To determine whether it is also involved in cocaine sensitization, we measured the p85{alpha}/p110 PI3K activity in the nuclear accumbens (NAc) shell, NAc core, and prefrontal cortex (PFC) following establishment of cocaine sensitization and its subsequent reversal. Naive rats were rank-ordered and split into either daily cocaine or saline pretreatment group based on their locomotor responses to an acute cocaine injection (7.5 mg/kg, i.p.). These two groups were then injected with cocaine (40 mg/kg, s.c.) or salinemore » for 4 consecutive days followed by 9-day withdrawal. Cocaine sensitization was subsequently reversed by 5 daily injections of the D{sub 1}/D{sub 2} agonist pergolide (0.1 mg/kg, s.c.) in combination with the 5-HT{sub 3} antagonist ondansetron (0.2 mg/kg, s.c., 3.5 h after pergolide injection). After another 9-day withdrawal, behavioral cocaine sensitization and its reversal were confirmed with an acute cocaine challenge (7.5 mg/kg, i.p.), and animals were sacrificed the next day for measurement of p85{alpha}/p110 PI3K activity. Cocaine-sensitized animals exhibited increased PI3K activity in the NAc shell, and this increase was reversed by combined pergolide/ondansetron treatment, which also reversed behavioral sensitization. In the NAc core and PFC, cocaine sensitization decreased and increased the PI3K activity, respectively. These changes, in contrast to that in the NAc shell, were not normalized following the reversal of cocaine-sensitization. Interestingly, daily injections of pergolide alone in saline-pretreated animals induced PI3K changes that were similar to the cocaine sensitization-associated changes in the NAc core and PFC but not the NAc shell; furthermore, these changes in saline-pretreated animals were prevented by ondansetron given 3.5 h

The analgesic agent tapentadol inhibits calcitonin gene-related peptide release from isolated rat brainstem via a serotonergic mechanism.

PubMed

Greco, Maria Cristina; Navarra, Pierluigi; Tringali, Giuseppe

2016-01-15

In this study we tested the hypothesis that tapentadol inhibits GGRP release from the rat brainstem through a mechanism mediated by the inhibition of NA reuptake; as a second alternative hypothesis, we investigated whether tapentadol inhibits GGRP release via the inhibition of 5-HT reuptake. Rat brainstems were explanted and incubated in short-term experiments. CGRP released in the incubation medium was taken as a marker of CGRP release from the central terminals of trigeminal neurons within the brainstem. CGRP levels were measured by radioimmunoassay under basal conditions or in the presence of tapentadol; NA, 5-HT, clonidine, yohimbine and ondansetron were used as pharmacological tools to investigate the action mechanism of tapentadol. The α2-antagonist yohimbine failed to counteract the effects of tapentadol. Moreover, neither NA nor the α2-agonist clonidine per se inhibited K(+)-stimulated CGRP release, thereby indicating that the effects of tapentadol are nor mediated through the block of NA reuptake. Further experiments showed that 5-HT and tramadol, which inhibits both NA and 5-HT reuptake, significantly reduced K(+)-stimulated CGRP release. Moreover, the 5-HT3 antagonist ondansetron was able to counteract the effects of tapentadol in this system. This study provided pharmacological evidence that tapentadol inhibits stimulated CGRP release from the rat brainstem in vitro through a mechanism involving an increase in 5-HT levels in the system and the subsequent activation of 5-HT3 receptors. Copyright © 2015 Elsevier Inc. All rights reserved.

Descending serotonergic facilitation mediated by spinal 5-HT3 receptors engages spinal rapamycin-sensitive pathways in the rat

PubMed Central

Asante, Curtis O.; Dickenson, Anthony H.

2010-01-01

We have recently reported the importance of spinal rapamycin-sensitive pathways in maintaining persistent pain-like states. A descending facilitatory drive mediated through spinal 5-HT3 receptors (5-HT3Rs) originating from superficial dorsal horn NK1-expressing neurons and that relays through the parabrachial nucleus and the rostroventral medial medulla to act on deep dorsal horn neurons is known be important in maintaining these pain-like states. To determine if spinal rapamycin-sensitive pathways are activated by a descending serotonergic drive, we investigated the effects of spinally administered rapamycin on responses of deep dorsal horn neurons that had been pre-treated with the selective 5-HT3R antagonist ondansetron. We also investigated the effects of spinally administered cell cycle inhibitor (CCI)-779 (a rapamycin ester analogue) on deep dorsal horn neurons from rats with carrageenan-induced inflammation of the hind paw. Unlike some other models of persistent pain, this model does not involve an altered 5-HT3R-mediated descending serotonergic drive. We found that the inhibitory effects of rapamycin were significantly reduced for neuronal responses to mechanical and thermal stimuli when the spinal cord was pre-treated with ondansetron. Furthermore, CCI-779 was found to be ineffective in attenuating spinal neuronal responses to peripheral stimuli in carrageenan-treated rats. Therefore, we conclude that 5-HT3R-mediated descending facilitation is one requirement for activation of rapamycin-sensitive pathways that contribute to persistent pain-like states. PMID:20709148

Peptide YY3–36 and 5-Hydroxytryptamine Mediate Emesis Induction by Trichothecene Deoxynivalenol (Vomitoxin)

PubMed Central

Pestka, James J.

2013-01-01

Deoxynivalenol (DON, vomitoxin), a trichothecene mycotoxin produced by Fusarium sp. that frequently occurs in cereal grains, has been associated with human and animal food poisoning. Although a common hallmark of DON-induced toxicity is the rapid onset of emesis, the mechanisms for this adverse effect are not fully understood. Recently, our laboratory has demonstrated that the mink (Neovison vison) is a suitable small animal model for investigating trichothecene-induced emesis. The goal of this study was to use this model to determine the roles of two gut satiety hormones, peptide YY3–36 (PYY3–36) and cholecystokinin (CCK), and the neurotransmitter 5-hydroxytryptamine (5-HT) in DON-induced emesis. Following ip exposure to DON at 0.1 and 0.25mg/kg bw, emesis induction ensued within 15–30min and then persisted up to 120min. Plasma DON measurement revealed that this emesis period correlated with the rapid distribution and clearance of the toxin. Significant elevations in both plasma PYY3–36 (30–60min) and 5-HT (60min) but not CCK were observed during emesis. Pretreatment with the neuropeptide Y2 receptor antagonist JNJ-31020028 attenuated DON- and PYY-induced emesis, whereas the CCK1 receptor antagonist devezapide did not alter DON’s emetic effects. The 5-HT3 receptor antagonist granisetron completely suppressed induction of vomiting by DON and the 5-HT inducer cisplatin. Granisetron pretreatment also partially blocked PYY3–36-induced emesis, suggesting a potential upstream role for this gut satiety hormone in 5-HT release. Taken together, the results suggest that both PYY3–36 and 5-HT play contributory roles in DON-induced emesis. PMID:23457120

Both exogenous 5-HT and endogenous 5-HT, released by fluoxetine, enhance distension evoked propulsion in guinea-pig ileum in vitro.

PubMed

Gwynne, Rachel M; Clarke, Amanda J; Furness, John B; Bornstein, Joel C

2014-01-01

The roles of 5-HT3 and 5-HT4 receptors in the modulation of intestinal propulsion by luminal application of 5-HT and augmentation of endogenous 5-HT effects were studied in segments of guinea-pig ileum in vitro. Persistent propulsive contractions evoked by saline distension were examined using a modified Trendelenburg method. When 5-HT (30 nM), fluoxetine (selective serotonin reuptake inhibitor; 1 nM), 2-methyl-5-HT (5-HT3 receptor agonist; 1 mM), or RS 67506 (5-HT4 receptor agonist, 1 μM) was infused into the lumen, the pressure needed to initiate persistent propulsive activity fell significantly. A specific 5-HT4 receptor antagonist, SB 207266 (10 nM in lumen), abolished the effects of 5-HT, fluoxetine, and RS 67506, but not those of 2-methyl-5-HT. Granisetron (5-HT3 receptor antagonist; 1 μM in lumen) abolished the effect of 5-HT, fluoxetine, RS 67506, and 2-methyl-5-HT. The NK3 receptor antagonist SR 142801 (100 nM in lumen) blocked the effects of 5-HT, fluoxetine, and 2-methyl-5-HT. SB 207266, granisetron, and SR 142801 had no effect by themselves. Higher concentrations of fluoxetine (100 and 300 nM) and RS 67506 (3 and 10 μM) had no effect on the distension threshold for propulsive contractions. These results indicate that luminal application of exogenous 5-HT, or increased release of endogenous mucosal 5-HT above basal levels, acts to lower the threshold for propulsive contractions in the guinea-pig ileum via activation of 5-HT3 and 5-HT4 receptors and the release of tachykinins. The results further indicate that basal release of 5-HT is insufficient to alter the threshold for propulsive motor activity.

Interventions for post-infectious irritable bowel syndrome: a systematic review of treatment efficacy.

PubMed

Torbicki, Emma; Oh, Justin; Mishra, Sharmistha; Page, Andrea V; Boggild, Andrea K

2015-01-01

Post-infectious irritable bowel syndrome (PI-IBS) due to traveler's diarrhea is the second most common illness seen in post-travel clinics, yet its optimal management remains unknown. We performed a systematic review to evaluate treatment efficacy in PI-IBS. We searched Medline, EMBASE, LILACS, CINAHL, CAB abstracts, and the Cochrane Library to February 3, 2014 for intervention studies of the pharmacologic and non-pharmacologic management of PI-IBS and examined the evidence according to a modified Grading of Recommendations Assessment, Development, and Evaluation (GRADE) scale. Of 336 records, 9 studies were included. Eight studies of pharmacologic interventions examined 5 agents (mesalazine or mesalamine, ondansetron, prednisolone, cholestyramine, and metronidazole). One study examined the non-pharmacologic intervention of different infant nutritional formulas following acute gastroenteritis. The quality of the evidence to date was low, with small sample size (fewer than 50 participants) and short duration of follow-up. Overall, the efficacy of pharmacological treatment ranged from no benefit (ondansetron and prednisolone) to moderately beneficial (cholestyramine and metronidazole). The evidence for mesalazine was equivocal: one study showed benefit, two others showed none. Heterogeneity in outcome measures and low strength of evidence preclude recommendations on the optimal management of PI-IBS by a specific agent. More comparative intervention research into PI-IBS treatment is needed for consistent best practice in PI-IBS management. Clinicians may elect to pursue therapeutic trials of mesalazine, cholestyramine, or metronidazole in individual patients, but should be aware that data supporting the efficacy of these agents is limited.

Beneficial Effects of Adding Ketamine to Intravenous Patient-Controlled Analgesia with Fentanyl after the Nuss Procedure in Pediatric Patients

PubMed Central

Cha, Moon Ho; Eom, Ji Hye; Lee, Yoon Sook; Kim, Woon Young; Park, Young Cheol; Min, Sam Hong

2012-01-01

Purpose The aim of this prospective, double-blind, randomized study was to investigate the analgesic effects of low-dose ketamine on intravenous patient-controlled analgesia (IV-PCA) with fentanyl for pain control in pediatric patients following the Nuss procedure for pectus excavatum. Materials and Methods Sixty pediatric patients undergoing the Nuss procedure were randomly assigned to receive fentanyl (Group F, n=30) or fentanyl plus ketamine (Group FK, n=30). Ten minutes before the end of surgery, following the loading dose of each solution, 0.5 µg/kg/hr of fentanyl or 0.5 µg/kg/hr of fentanyl plus 0.15 mg/kg/hr of ketamine was infused via an IV-PCA pump (basal rate, 1 mL/hr; bolus, 0.5 mL; lock out interval, 30 min). Fentanyl consumption, pain score, ketorolac use, nausea/vomiting, ondansetron use, pruritus, respiratory depression, hallucination, dreaming, and parent satisfaction with pain control were measured throughout the 48 hours following surgery. Results The pain scores, ketorolac use, and fentanyl consumption of Group FK were significantly lower than in Group F (p<0.05). The incidence of nausea/vomiting and ondansetron use in Group FK was significantly lower than in Group F (p<0.05). There were no reports of respiratory depression, hallucination or dreaming. Parent satisfaction with pain control was similar between the two groups. Conclusion We concluded that low-dose ketamine added to IV-PCA with fentanyl after the Nuss procedure in pediatric patients can reduce pain scores, consumption of fentanyl, and incidence of nausea/vomiting without increasing side effects. PMID:22318834

Intragastric Dai-Kenchu-To, a Japanese herbal medicine, stimulates colonic motility via transient receptor potential cation channel subfamily V member 1 in dogs.

PubMed

Kikuchi, Daisuke; Shibata, Chikashi; Imoto, Hirofumi; Naitoh, Takeshi; Miura, Koh; Unno, Michiaki

2013-08-01

Japanese herbal medicine, also known as Kampo, is used for various diseases in Japan. One of those medicines, Dai-Kenchu-To (DKT), is considered clinically effective for adhesive bowel obstruction and chronic constipation. Although scientific evidence of DKT to improve adhesive bowel obstruction was shown in several previous reports, mechanism of DKT to improve constipation remains unknown. Our aim was to study the effect of intragastric DKT on colonic motility and defecation, and the involvement of various receptors in DKT-induced colonic contractions. Five beagle dogs were instructed with serosal strain-gauge force transducers to measure circular muscle activity at the proximal, middle, and distal colon. Dogs are suitable for a present study to administer the drugs repeatedly to the same individual and look at its effect on colonic motility. We studied the effects of DKT (2.5 or 5 g) administered into the stomach on colonic motility. Muscarinic receptor antagonist atropine, nicotinic receptor antagonist hexamthonium, or 5-hydroxytryptamine-3 receptor antagonist ondansetron was injected intravenously 10 min before DKT administration. Capsazepine, an antagonist to transient receptor potential cation channel subfamily V member 1 (TRPV1), was administered into the stomach 5 min before DKT administration. Intragastric DKT (2.5 or 5 g) induced colonic contractions within 10 min after administration but did not induce defecation. Pretreatment with atropine, hexamthonium, ondansetron, or capsazepine inhibited DKT-induced colonic contractions. These results indicate that orally administered DKT stimulates colonic motility via TRPV1, muscarinic, nicotinic, and 5-hydroxytryptamine-3 receptors, thereby providing scientific support for the efficacy of oral DKT in chronic constipation.

A study of time- and sex-dependent effects of vortioxetine on rat sexual behavior: Possible roles of direct receptor modulation.

PubMed

Li, Yan; Pehrson, Alan L; Oosting, Ronald S; Gulinello, Maria; Olivier, Berend; Sanchez, Connie

2017-07-15

Treatment-related sexual dysfunction is a common side effect of antidepressants and contributes to patient non-compliance or treatment cessation. However, the multimodal antidepressant, vortioxetine, demonstrates low sexual side effects in depressed patients. To investigate the mechanisms involved, sexual behavior was assessed in male and female rats after acute, and repeated (7 and 14 days) treatment with vortioxetine, flesinoxan (a 5-HT 1A receptor agonist), CP-94253 (a 5-HT 1B receptor agonist), or ondansetron (a 5-HT 3 receptor antagonist). These selective ligands were chosen to simulate vortioxetine's direct modulation of these receptors. Paroxetine was also included in the male study. Acute and repeated treatment with vortioxetine at doses corresponding to clinical levels (based on serotonin transporter occupancy) had minimal effects on sexual behavior in male and female rats. High dose vortioxetine plus flesinoxan (to mimic predicted clinical levels of 5-HT 1A receptor occupancy by vortioxetine) facilitated male rat sexual behavior (acutely) while inhibiting female rat proceptive behavior (both acutely and after 14 days treatment). The selective serotonin reuptake inhibitor, paroxetine, inhibited male sexual behavior after repeated administration (7 and 14 days). Flesinoxan alone facilitated male sexual behavior acutely while inhibiting female rat proceptive behavior after repeated administration (7 and 14 days). CP-94253 inhibited sexual behavior in both male and female rats after repeated administration. Ondansetron had no effect on sexual behavior. These findings underline the complex serotonergic regulation of sexual behavior and indicate that the low sexual side effects of vortioxetine found in clinical studies are likely associated with its direct modulation of serotonin receptors. Copyright © 2017. Published by Elsevier Ltd.

Pharmacogenetically driven treatments for alcoholism: are we there yet?

PubMed

Arias, Albert J; Sewell, R Andrew

2012-06-01

Pharmacogenetic analyses of treatments for alcohol dependence attempt to predict treatment response and side-effect risk for specific medications. We review the literature on pharmacogenetics relevant to alcohol dependence treatment, and describe state-of-the-art methods of pharmacogenetic research in this area. Two main pharmacogenetic study designs predominate: challenge studies and treatment-trial analyses. Medications studied include US FDA-approved naltrexone and acamprosate, both indicated for treating alcohol dependence, as well as several investigational (and off-label) treatments such as sertraline, olanzapine and ondansetron. The best-studied functional genetic variant relevant to alcoholism treatment is rs1799971, a single-nucleotide polymorphism in exon 1 of the OPRM1 gene that encodes the μ-opioid receptor. Evidence from clinical trials suggests that the presence of the variant G allele of rs1799971 may predict better treatment response to opioid receptor antagonists such as naltrexone. Evidence from clinical trials also suggests that several medications interact pharmacogenetically with variation in genes that encode proteins involved in dopaminergic and serotonergic neurotransmission. Variation in the DRD4 gene, which encodes the dopamine D(4) receptor, may predict better response to naltrexone and olanzapine. A polymorphism in the serotonin transporter gene SLC6A4 promoter region appears related to differential treatment response to sertraline depending on the subject's age of onset of alcoholism. Genetic variation in SLC6A4 may also be associated with better treatment response to ondansetron. Initial pharmacogenetic efforts in alcohol research have identified functional variants with potential clinical utility, but more research is needed to further elucidate the mechanism of these pharmacogenetic interactions and their moderators in order to translate them into clinical practice.

Efficacy of ginger for prophylaxis of chemotherapy-induced nausea and vomiting in breast cancer patients receiving adriamycin-cyclophosphamide regimen: a randomized, double-blind, placebo-controlled, crossover study.

PubMed

Thamlikitkul, Lucksamon; Srimuninnimit, Vichien; Akewanlop, Charuwan; Ithimakin, Suthinee; Techawathanawanna, Sirisopa; Korphaisarn, Krittiya; Chantharasamee, Jomjit; Danchaivijitr, Pongwut; Soparattanapaisarn, Nopadol

2017-02-01

The purpose of this study is to determine the efficacy of ginger for reducing chemotherapy-induced nausea and vomiting (CINV) in breast cancer patients receiving adriamycin and cyclophosphamide (AC) regimens. We enrolled breast cancer patients receiving AC who experienced moderate to severe nausea or vomiting during the first chemotherapy cycle. Subjects were randomized to receive a 500-mg ginger capsule or placebo twice a day for 5 days starting on the first day of the second AC cycle and were switched to the other treatment in the third cycle. All participants also received ondansetron and dexamethasone for CINV prophylaxis. Nausea severity was recorded once a day during the first 5 days of each cycle. The primary outcome was reduction in nausea score. Thirty-four subjects (68 cycles of AC) were enrolled. Mean (range) maximum nausea score in the first AC cycle was 58 (40-90). Thirty-three subjects (97 %) received the same AC doses in the second as in the third cycle. Mean (±standard error) maximum nausea scores in patients receiving ginger and placebo were 35.36 (±4.43) and 32.17 (±3.71), respectively. The difference in mean maximum nausea scores was 3 (95 % confidence interval, -3 to 9; P = 0.3). There were no significant differences between ginger and placebo in terms of vomiting incidence and severity, rescue medication use, chemotherapy compliance, and adverse events. Ginger (500 mg) twice daily was safe, but conferred no additional benefit in terms of reducing nausea severity in breast cancer patients receiving AC and ondansetron and dexamethasone for CINV prophylaxis.

Anti-Hu antibodies activate enteric and sensory neurons

PubMed Central

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

2016-01-01

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

An update on pharmacotherapy for the treatment of fibromyalgia.

PubMed

Calandre, Elena P; Rico-Villademoros, Fernando; Slim, Mahmoud

2015-06-01

Fibromyalgia is a syndrome characterized by chronic generalized pain in addition to different symptoms such as fatigue, sleep disturbances, stiffness, cognitive impairment, and psychological distress. Multidisciplinary treatment combining pharmacological and nonpharmacological therapies is advised. Publications describing randomized controlled trials and long-term extension studies evaluating drug treatment for fibromyalgia were searched in PubMed and Scopus and included in this review. Different drugs are recommended for the treatment of fibromyalgia by different published guidelines, although only three of them have been approved for this indication by the US FDA, and none have been approved by the European Medicines Agency. According to the available evidence, pregabalin, duloxetine and milnacipran should be the drugs of choice for the treatment of this disease, followed by amitriptyline and cyclobenzaprine. Other drugs with at least one positive clinical trial include some selective serotonin reuptake inhibitors, moclobemide, pirlindole, gabapentin, tramadol, tropisetron, sodium oxybate and nabilone. None of the currently available drugs are fully effective against the whole spectrum of fibromyalgia symptoms, namely pain, fatigue, sleep disturbances and depression, among the most relevant symptoms. Combination therapy is an option that needs to be more thoroughly investigated in clinical trials.

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

PubMed Central

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

1995-01-01

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

Intravenous tacrolimus and cyclosporine induced anaphylaxis: what is next?

PubMed Central

Kang, Sung-Yoon; Sohn, Kyoung-Hee; Lee, Jeong-Ok; Kim, Sae-Hoon; Cho, Sang-Heon

2015-01-01

Tacrolimus and cyclosporine have been used in various formulations, but their hypersensitivity reactions are rare in practice. Castor oil derivatives are nonionic surfactants used in aqueous preparations of hydrophobic active pharmaceutical ingredients. Castor oil derivatives that can be used as additives to tacrolimus and cyclosporine may play a role in the development of hypersensitivity reactions, especially anaphylaxis. Various immunologic and nonimmunologic mechanisms have been implicated in hypersensitivity reactions induced by castor oil derivatives. Physicians should be aware that not only the drug itself, but also its additives or metabolites could induce hypersensitivity reactions. We report a case of anaphylaxis caused by vitamin K (phytonadine), serotonin antagonist (granisetron), intravenous tacrolimus, and cyclosporine. Interestingly, the patient tolerated oral cyclosporine, which did not contain Cremophor EL or polysorbate 80. PMID:26240796

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

PubMed

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

2010-10-01

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

Economic analysis of aprepitant-containing regimen to prevent chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy in Hong Kong.

PubMed

Chan, Stephen L; Jen, Jason; Burke, Thomas; Pellissier, James

2014-03-01

We aim to evaluate the cost effectiveness of aprepitant-containing regimens for the prevention of chemotherapy-induced nausea and vomiting (CINV) among patients receiving high emetogenic chemotherapy (HEC) in Hong Kong. Both cost-effectiveness and cost-utility analyses were conducted utilizing a decision-analytic model to measure the economic costs and clinical outcomes associated with the aprepitant-containing regimen versus a standard regimen in the prevention of CINV. Analyses were conducted on the basis of four published double-blind randomized clinical trials involving different usages of serotonin receptor antagonists. The use of aprepitant-containing regimens is associated with an improvement in quality-adjusted life years (QALYs) compared with non-aprepitant regimens. For cisplatin-based chemotherapy, the incremental cost per QALY gained is HKD 239,644 (1 USD approximates HKD 7.8) when ondansetron is administered on day 1 only. The incremental cost per QALY is HKD 440,950 when ondansetron is used on day 1 to 4. For anthracycline and cyclophosphamide chemotherapy, the aprepitant-containing regimen is associated with incremental cost of HKD 195,442 per QALY gained. Similar results were obtained when other 5HT3 receptor antagonists are used. The use of aprepitant was associated with higher cost of drug but lower costs of emesis-related management. With the cost-effectiveness threshold set at the World Health Organization endorsed criteria of three times gross domestic product (GDP) per capita (three times GDP per capita in Hong Kong in 2011 is HKD 798,078), the current analyses showed that the aprepitant-containing regimen was cost-effective. In patients undergoing HEC, the use of aprepitant as the anti-emetic is cost-effective in Hong Kong. © 2014 Wiley Publishing Asia Pty Ltd.

α-Terpineol, a monoterpene alcohol, complexed with β-cyclodextrin exerts antihyperalgesic effect in animal model for fibromyalgia aided with docking study.

PubMed

Oliveira, Makson G B; Brito, Renan G; Santos, Priscila L; Araújo-Filho, Heitor G; Quintans, Jullyana S S; Menezes, Paula P; Serafini, Mairim R; Carvalho, Yasmim M B G; Silva, Juliane C; Almeida, Jackson R G S; Scotti, Luciana; Scotti, Marcus T; Shanmugam, Saravanan; Thangaraj, Parimelazhagan; Araújo, Adriano A S; Quintans-Júnior, Lucindo J

2016-07-25

The anti-hyperalgesic effect of the complex containing α-terpineol (αTPN) and β-cyclodextrin (βCD) was analyzed in a non-inflammatory chronic muscle pain model, as well as its mechanism of action through docking study for a possible interaction with receptors. The αTPN-βCD complex was prepared and characterized through the thermogravimetry/derivate thermogravimetry (TG/DTG), Fourier transform infrared spectroscopy (FTIR) and scanning electron microscope (SEM). The model of chronic muscle pain was induced by two injections of pH 4.0 saline (20 μl) into the left gastrocnemius 5 days apart. After confirming hyperalgesia, male mice were treated with αTPN-βCD (25, 50 or 100 mg/kg; p.o.) or vehicle (saline 0.9%, p.o.) daily for 10 days. 1 h after the mechanical hyperalgesia, motor performance was evaluated. In addition, the systemic administration of naloxone and ondansetron tested the analgesic effect on the active opioid and serotonin receptors, respectively. The characterization tests indicated that αTPN was efficiently incorporated into βCD. The oral treatment with αTPN-βCD, at all doses tested, produced a significant (p < 0.001) decrease in the mechanical hyperalgesia, without causing any alteration in the force and in motor performance. This analgesic effect was reversed by the systemic administration of naloxone or ondansetron. These findings are corroborated by the docking study described in the present study, which verified a possible interaction of αTPN-βCD with opioid (MU, Kappa, Delta) and 5-HT receptors. Thus, it can be concluded that αTPN-βCD reduced the hyperalgesia followed by the chronic muscle pain model, probably evoked by the descending inhibitory pain system, specifically by opioid and serotoninergic receptors. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Hot and Cold Drugs: National Park Service Medication Stability at the Extremes of Temperature.

PubMed

Armenian, Patil; Campagne, Danielle; Stroh, Geoff; Ives Tallman, Crystal; Zeng, William Z D; Lin, Thomas; Gerona, Roy R

2017-01-01

National Park Service (NPS) Parkmedics provide medical care in austere environments. The objective of this study was to evaluate the stability of specific medications used by Parkmedics at extremes of temperatures likely to be faced in the field. This is a bench research study conducted in the laboratory setting over a 4-week period. Parenteral medications were separated into 4 temperature exposure groups: A) 45°C (hot); B) -20°C (cold); C) hot then cold temperatures alternating weekly; and D) cold then hot temperatures alternating weekly. At study start and the end of each week, three aliquots from each group were sampled to determine the remaining drug concentration through liquid chromatography-quadrupole time-of-flight mass spectrometry (Agilent LC 1260- QTOF/MS 6550). Quantitative analysis was done using Agilent MassHunter Quantitative Analysis software. The mean drug concentration from triplicate aliquots was expressed as percentage of its baseline concentration to monitor the drug's stability during storage. Eight medications were analyzed (atropine, diphenhydramine, fentanyl, hydromorphone, midazolam, morphine, naloxone, ondansetron). Hydromorphone, morphine, and ondansetron showed the greatest stability, at above 90% of original concentration in all study arms. Diphenhydramine, fentanyl and midazolam showed heat independent degradation, degrading the same way regardless of heat exposure. By the end of the study period, 51-56% midazolam remained in all groups. Atropine and naloxone showed heat dependent degradation, degrading more when exposed to heat. Atropine had the most degradation, being undetectable after 4 weeks of heat exposure. We recommend that EMS providers replace atropine, naloxone, diphenhydramine, fentanyl, and midazolam frequently if they are practicing in low call volume or high-temperature environments. Further studies will be needed to determine if re-dosing midazolam, naloxone, and atropine is the appropriate clinical strategy in this

Comparison of three preclinical models for nausea and vomiting assessment.

PubMed

Goineau, Sonia; Castagné, Vincent

Nausea is a subjective sensation often preceding emesis in humans. Drug-induced nausea remains difficult to predict in preclinical tests. The aim of this study was to compare the effects of emetic agents in rats (pica behavior), ferrets (acute and delayed phases of emesis) or dogs (emesis and cardiovascular endpoints). Rats and ferrets were administered cisplatin (±aprepitant/ondansetron or aprepitant) or apomorphine (±domperidone). Telemetered dogs were administered apomorphine (±domperidone). Food and kaolin intake was measured in rats whereas the number of emetic events was counted in ferrets and dogs. Cardiovascular changes were also monitored in dogs. In rats, cisplatin (6mg/kg, i.p.) increased kaolin intake (+2257%, p<0.001). The cisplatin effects were not reversed by the combination of aprepitant/ondansetron (2mg/kg, p.o./2mg/kg, i.p.) or by aprepitant (30mg/kg, p.o.). Apomorphine (10mg/kg, i.p.) did not induce pica behavior. In ferrets, cisplatin (8mg/kg, i.p.) induced acute and delayed emesis (371.8±47.8 emetic events over 72h) which was antagonized by aprepitant (1mg/kg, p.o.). Apomorphine (0.25mg/kg, s.c.) induced acute emesis (38.8±8.7 emetic events over 2h) which was abolished by domperidone (0.1mg/kg, s.c.). In dogs, apomorphine (100μg/kg, s.c.) induced emesis and tachycardia which were decreased by domperidone (0.2mg/kg, i.v.). The assessment of emesis in the ferret or in the dog displays a strong predictive value. In contrast, assessing nausea remains challenging in all animal species and the use of pica behavior remains questionable in the context of antiemetic drug development. Copyright © 2016 Elsevier Inc. All rights reserved.

Medications Used to Treat Nausea and Vomiting of Pregnancy and the Risk of Selected Birth Defects

PubMed Central

Anderka, Marlene; Mitchell, Allen A.; Louik, Carol; Werler, Martha M.; Hernández-Diaz, Sonia; Rasmussen, Sonja A.

2012-01-01

Background Nausea and vomiting of pregnancy (NVP) occurs in up to 80% of pregnant women, yet its association with birth outcomes is not clear. Several medications are used for the treatment of NVP; however, data are limited on their possible associations with birth defects. Methods Using data from the National Birth Defects Prevention Study (NBDPS), a multi-site population-based case-control study, we examined whether NVP or its treatment was associated with the most common non-cardiac defects in the NBDPS (non-syndromic cleft lip with or without cleft palate (CL/P), cleft palate alone (CP), neural tube defects (NTDs), and hypospadias) compared to randomly-selected non-malformed live births. Results Among the 4524 cases and 5859 controls included in this study, 67.1% reported first trimester NVP, and 15.4% of them reported using at least one agent for NVP. Nausea and vomiting of pregnancy was not associated with CP or NTDs, but modest risk reductions were observed for CL/P (aOR=0.87, 0.77–0.98), and hypospadias (OR=0.84, 0.72–0.98). In regards to treatments for NVP in the first trimester, the following adjusted associations were observed with an increased risk: proton pump inhibitors and hypospadias (aOR=4.36, 1.21–15.81), steroids and hypospadias (aOR=2.87, 1.03–7.97), and ondansetron and CP (aOR=2.37, 1.18–4.76), while antacids were associated with a reduced risk for CL/P (aOR=0.58, 0.38–0.89). Conclusions Nausea and vomiting of pregnancy was not observed to be associated with an increased risk of birth defects, but possible risks related to three treatments (i.e. proton pump inhibitors, steroids and ondansetron), which could be chance findings, warrant further investigation. PMID:22102545

Non-IgE-mediated gastrointestinal food allergies.

PubMed

Biermé, Priscille; Nowak-Wegrzyn, Anna; Caubet, Jean-Christoph

2017-12-01

We focus on recent advances regarding the epidemiology, physiopathology, diagnosis and managements of non-IgE-mediated gastrointestinal food allergies (non-IgE-GI-FAs), particularly food protein-induced enterocolitis syndrome (FPIES). The first international FPIES diagnostic and management guidelines have been recently published. Although FPIES largely remains a diagnosis of exclusion, it may be more prevalent than previously thought. Ondansetron has emerged as a major tool for the treatment of FPIES acute reactions. Recent data also suggest an important role for innate immune cells in FPIES pathogenesis. Despite major advances in the diagnosis and management of non-IgE-GI-FAs, particularly FPIES, the lack of specific diagnostic tests and biomarkers to guide clinical management remains challenging.

Ondansetron in Preventing Nausea and Vomiting in Patients Undergoing Stem Cell Transplant

ClinicalTrials.gov

2017-04-20

Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Atypical Chronic Myeloid Leukemia, BCR-ABL Negative; Blastic Phase Chronic Myelogenous Leukemia; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Chronic Neutrophilic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; de Novo Myelodysplastic Syndromes; Disseminated Neuroblastoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Poor Prognosis Metastatic Gestational Trophoblastic Tumor; Previously Treated Myelodysplastic Syndromes; Primary Myelofibrosis; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Malignant Testicular Germ Cell Tumor; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Neuroblastoma; Recurrent Ovarian Epithelial Cancer; Recurrent Ovarian Germ Cell Tumor; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Splenic Marginal Zone Lymphoma; Stage I Multiple Myeloma; Stage II Multiple Myeloma; Stage II Ovarian Epithelial Cancer; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Malignant Testicular Germ Cell Tumor; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Multiple Myeloma; Stage III Ovarian Epithelial Cancer; Stage III Small Lymphocytic Lymphoma; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Hodgkin Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Breast Cancer; Stage IV Chronic Lymphocytic Leukemia; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Ovarian Epithelial Cancer; Stage IV Small Lymphocytic Lymphoma

Reduction of adverse effects from intravenous acetylcysteine treatment for paracetamol poisoning: a randomised controlled trial.

PubMed

Bateman, D Nicholas; Dear, James W; Thanacoody, H K Ruben; Thomas, Simon H L; Eddleston, Michael; Sandilands, Euan A; Coyle, Judy; Cooper, Jamie G; Rodriguez, Aryelly; Butcher, Isabella; Lewis, Steff C; Vliegenthart, A D Bastiaan; Veiraiah, Aravindan; Webb, David J; Gray, Alasdair

2014-02-22

Paracetamol poisoning is common worldwide. It is treated with intravenous acetylcysteine, but the standard regimen is complex and associated with frequent adverse effects related to concentration, which can cause treatment interruption. We aimed to ascertain whether adverse effects could be reduced with either a shorter modified acetylcysteine schedule, antiemetic pretreatment, or both. We undertook a double-blind, randomised factorial study at three UK hospitals, between Sept 6, 2010, and Dec 31, 2012. We randomly allocated patients with acute paracetamol overdose to either the standard intravenous acetylcysteine regimen (duration 20·25 h) or a shorter (12 h) modified protocol, with or without intravenous ondansetron pretreatment (4 mg). Masking was achieved by infusion of 5% dextrose (during acetylcysteine delivery) or saline (for antiemetic pretreatment). Randomisation was done via the internet and included a minimisation procedure by prognostic factors. The primary outcome was absence of vomiting, retching, or need for rescue antiemetic treatment at 2 h. Prespecified secondary outcomes included a greater than 50% increase in alanine aminotransferase activity over the admission value. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov (identifier NCT01050270). Of 222 patients who underwent randomisation, 217 were assessable 2 h after the start of acetylcysteine treatment. Vomiting, retching, or need for rescue antiemetic treatment at 2 h was reported in 39 of 108 patients assigned to the shorter modified protocol compared with 71 of 109 allocated to the standard acetylcysteine regimen (adjusted odds ratio 0·26, 97·5% CI 0·13-0·52; p<0·0001), and in 45 of 109 patients who received ondansetron compared with 65 of 108 allocated placebo (0·41, 0·20-0·80; p=0·003). Severe anaphylactoid reactions were recorded in five patients assigned to the shorter modified acetylcysteine regimen versus 31 who were allocated to the

The pharmacologic management of nausea and vomiting of pregnancy.

PubMed

Niebyl, Jennifer R; Briggs, Gerald G

2014-02-01

Nausea and vomiting are common in early pregnancy. Forty percent or more of pregnant women may continue to suffer beyond the first trimester and 10% beyond the second trimester. A focus of the assessment is to confirm that the nausea and vomiting is due to the pregnancy and not some other cause. Nonpharmacologic options, particularly dietary modification, are a mainstay of treatment. For those who continue to experience symptoms, pharmacologic management can be employed. The combination of doxylamine succinate/pyridoxine hydrochloride was reintroduced in the United States following FDA approval in early 2013. The product was given a pregnancy safety rating of A and is recommended as first-line pharmacologic treatment for NVP. Other options include antihistamines, metoclopramide, ondansetron, phenothiazines, and after the first trimester, corticosteroids.

The herbal medicine, Dai-Kenchu-to, accelerates delayed gastrointestinal transit after the operation in rats.

PubMed

Fukuda, Hiroyuki; Chen, Cindy; Mantyh, Christopher; Ludwig, Kirk; Pappas, Theodore N; Takahashi, Toku

2006-04-01

Post-operative ileus (POI) is a transient bowel dysmotility after operation. We have previously shown that laparotomy alone significantly delayed gastrointestinal (GI) transit, compared to anesthesia alone. The GI transit was further delayed after laparotomy plus intestinal manipulation. Dai-Kenchu-to (DKT), an herbal medicine, has been used for treating adhesive bowel obstruction in Japan. We studied whether DKT improves delayed GI transit after the operation, with or without morphine administration in rats. Under isoflurane anesthesia, POI was induced by laparotomy with intestinal manipulation. Immediately after the operation, the rats received 51Cr by gavage. Three hours after the operation, the rats were sacrificed and GI transit was estimated by calculating the geometric center (GC). DKT (120, 360, and 1,200 mg/kg) were administered by gavage after the operation, with or without morphine administration (1 mg/kg s.c.). A muscarinic receptor antagonist (atropine; 50 mug/kg), a 5HT3 receptor antagonist (ondansetron; 1 mg/kg) and a 5HT4 receptor antagonist (GR113,808; 3 mg/kg) were administered before the operation. Truncal vagotomy was performed preceding the operation. Laparotomy with intestinal manipulation produced a significant delay in GI transit (GC = 2.93 +/- 0.16), compared to that of anesthesia alone (9.51 +/- 0.45). DKT at the dose of 360 mg/kg (GC = 3.77 +/- 0.10, P < 0.01) and 1,200 mg/kg (GC = 3.77 +/- 0.20, P < 0.01) significantly accelerated delayed GI transit induced by operation. Ondansetron, GR113,808, atropine, and truncal vagotomy abolished the stimulatory effect of DKT (360 mg/kg). When morphine was administered, GI transit was further reduced (GC = 1.97 +/- 0.10). DKT at the dose of 360 mg/kg (GC = 2.81 +/- 0.22, P < 0.05) and 1,200 mg/kg (GC = 2.87 +/- 0.23, P < 0.05) significantly improved delayed GI transit in morphine treated rats. DKT accelerates delayed GI transit induced by intestinal manipulation with and without concomitant morphine

Vortioxetine dose-dependently reverses 5-HT depletion-induced deficits in spatial working and object recognition memory: a potential role for 5-HT1A receptor agonism and 5-HT3 receptor antagonism.

PubMed

du Jardin, Kristian Gaarn; Jensen, Jesper Bornø; Sanchez, Connie; Pehrson, Alan L

2014-01-01

We previously reported that the investigational multimodal antidepressant, vortioxetine, reversed 5-HT depletion-induced memory deficits while escitalopram and duloxetine did not. The present report studied the effects of vortioxetine and the potential impact of its 5-HT1A receptor agonist and 5-HT3 receptor antagonist properties on 5-HT depletion-induced memory deficits. Recognition and spatial working memory were assessed in the object recognition (OR) and Y-maze spontaneous alternation (SA) tests, respectively. 5-HT depletion was induced in female Long-Evans rats using 4-cholro-DL-phenylalanine methyl ester HCl (PCPA) and receptor occupancies were determined by ex vivo autoradiography. Rats were acutely dosed with vortioxetine, ondansetron (5-HT3 receptor antagonist) or flesinoxan (5-HT1A receptor agonist). The effects of chronic vortioxetine administration on 5-HT depletion-induced memory deficits were also assessed. 5-HT depletion reliably impaired memory performance in both the tests. Vortioxetine reversed PCPA-induced memory deficits dose-dependently with a minimal effective dose (MED) ≤0.1mg/kg (∼80% 5-HT3 receptor occupancy; OR) and ≤3.0mg/kg (5-HT1A, 5-HT1B, 5-HT3 receptor occupancy: ∼15%, 60%, 95%) in SA. Ondansetron exhibited a MED ≤3.0μg/kg (∼25% 5-HT3 receptor occupancy; OR), but was inactive in the SA test. Flesinoxan had a MED ≤1.0mg/kg (∼25% 5-HT1A receptor occupancy; SA); only 1.0mg/kg ameliorated deficits in the NOR. Chronic p.o. vortioxetine administration significantly improved memory performance in OR and occupied 95%, 66%, and 9.5% of 5-HT3, 5-HT1B, and 5-HT1A receptors, respectively. Vortioxetine's effects on SA performance may involve 5-HT1A receptor agonism, but not 5-HT3 receptor antagonism, whereas the effects on OR performance may involve 5-HT3 receptor antagonism and 5-HT1A receptor agonism. Copyright © 2013 Elsevier B.V. and ECNP. All rights reserved.

Evaluation of an every-other-day palonosetron schedule to control emesis in multiple-day high-dose chemotherapy.

PubMed

Mirabile, Aurora; Celio, Luigi; Magni, Michele; Bonizzoni, Erminio; Gianni, Alessandro Massimo; Di Nicola, Massimo

2014-12-01

Efficacy of intermittent palonosetron dosing in patients undergoing multiple-day, high-dose chemotherapy (HDC) was investigated. Fifty-eight patients received palonosetron (0.25 mg intravenous [iv.]) every other day plus daily dexamethasone (8 mg iv. twice daily) dosing. The primary end point was complete control (CC; no emesis, no rescue anti-emetics, and no more than mild nausea) in the overall acute-period (until 24 h after chemotherapy completion). Acute-period CC occurred in 81% and 50% of patients receiving palonosetron and ondansetron (historical control cohort), respectively. Palonosetron (odds ratio [OR]: 4.37; p = 0.001) and a longer duration of HDC regimen (OR: 3.47; p = 0.011) independently predicted a better anti-emetic outcome. Palonosetron every other day plus daily dexamethasone is an effective anti-emetic coverage in patients undergoing HDC.

Pharmacological profile of dexketoprofen in orofacial pain.

PubMed

Miranda, Hugo F; Sierralta, Fernando; Aranda, Nicolás; Noriega, Viviana; Prieto, Juan Carlos

2016-12-01

Non-steroidal anti-inflammatory drugs (NSAIDs) may act through others mechanisms, in addition to inhibition of prostaglandin synthesis. These includes cholinergic, NO, serotonergic and opioids pathways. The aim of this work was to evaluate the effect of systemic action of (S)-+-ketoprofen (dexketoprofen, DEX) on pain behaviors using the orofacial formalin test in mice and the potential involvement of cholinergic, NO, serotonergic and opioids pathways. The pretreatment of the mice with 1mg/kg ip of atropine or opoid antagonists: 1mg/kg, ip of NTX or 1mg/kg ip of NTI or 1mg/kg of NOR-BNI ip, did not produce significant change in the ED 50 values of the antinociception to orofacial test induced by DEX. The pretreatment of the mice with 0.5mg/kg ip tropisetron, increased in a significant fashion the values of ED 50 of DEX. When the mice were treated with 5mg/kg ip of L-NAME or 25mg/kg ip of aminoguanidine or 50mg/kg ip of 7-nitroindazole reversed the antinociception of DEX. The findings of this study demonstrate activation of NO and 5-HTpathways play important roles in the systemic antinociceptive effect of DEX in a murine model of inflammatory pain. Copyright © 2016. Published by Elsevier Urban & Partner Sp. z o.o.

[Pharmacogenetics and the treatment of addiction].

PubMed

Schellekens, Arnt

2013-01-01

This article describes the current scientific knowledge regarding pharmacogenetic predictors of treatment outcome for substance-dependent patients. PubMed was searched for articles on pharmacogenetics and addiction. This search yielded 53 articles, of which 27 were selected. The most promising pharmacogenetic findings are related to the treatment of alcohol dependence. Genetic variation in the µ-opioid receptor (OPRM1) and the serotonin transporter (5-HTTLPR) appear to be associated with treatment outcomes for naltrexone and ondansetron, respectively. Genetic variation in CYP2D6 is related to efficacy of methadone treatment for opiate dependence. Pharmacogenetics may help explain the great inter-individual variation in treatment response. In the future, treatment matching, based on genetic characteristics of individual patients, could lead to a 'personalized medicine' approach. Pharmacogenetic matching of naltrexone in alcohol-dependent carriers of the OPRM1 G-allele currently seems most promising.

The usefulness of interpectoral block as an analgesic technique in breast cancer surgery.

PubMed

Ortiz de la Tabla González, R; Gómez Reja, P; Moreno Rey, D; Pérez Naranjo, C; Sánchez Martín, I; Echevarría Moreno, M

2018-04-01

To compare the analgesic efficacy of continuous interpectoral block (CIPB) compared to intravenous analgesia (IV) after breast surgery. A prospective, comparative and randomised study of women aged from 18-75years, ASAI-III, operated for breast cancer. In group1 (CIPB) after general anaesthetic, an ultrasound-guided interpectoral catheter was placed and 30mL of 0.5% ropivacaine was administered through it. In the event of an increase in heart rate and blood pressure >15% after the surgical incision, intravenous fentanyl 1μg·kg -1 was administered, repeating the dose as necessary. In the postoperative period, perfusion of ropivacaine 0.2% 5mL·h -1 ; with PCA bolus 5mL/30minutes was administered through the catheter for 24hours and rescue analgesia prescribed with 5mg subcutaneous morphine chloride. In group2 (IV), after induction of general anaesthesia, intravenous fentanyl was administered in the same way as in the other group. The patients received metamizole 2g with dexketoprofen 50mg and ondansetron 4mg postoperatively followed by perfusion of metamizole 4%, tramadol 0.2% and ondansetron 0.08% 2ml·h -1 ; with PCA bolus 2mL/20min for 24hours. The same rescue analgesia was prescribed. The principal variables recorded were pain at rest and during movement, according to a simple verbal scale (VAS 0-10) and the rescue analgesia required on discharge from recovery, at 12 and at 24hours. 137 patients were included: 81 in group1 (59.12%) and 56 in group2 (40.87%). No significant differences were observed in the analgesia between either group, but differences were observed in the dose of intraoperative fentanyl (P<.05). Differences that were not significant were observed in the rescue analgesia required on recovery (10% fewer on group1). Both techniques provided effective postoperative analgesia, but the CIPB group required significantly less intraoperative fentanyl. Copyright © 2017 Sociedad Española de Anestesiología, Reanimación y Terapéutica del Dolor

Human-derived gut microbiota modulates colonic secretion in mice by regulating 5-HT3 receptor expression via acetate production.

PubMed

Bhattarai, Yogesh; Schmidt, Bradley A; Linden, David R; Larson, Eric D; Grover, Madhusudan; Beyder, Arthur; Farrugia, Gianrico; Kashyap, Purna C

2017-07-01

Serotonin [5-hydroxytryptamine (5-HT)], an important neurotransmitter and a paracrine messenger in the gastrointestinal tract, regulates intestinal secretion by its action primarily on 5-HT 3 and 5-HT 4 receptors. Recent studies highlight the role of gut microbiota in 5-HT biosynthesis. In this study, we determine whether human-derived gut microbiota affects host secretory response to 5-HT and 5-HT receptor expression. We used proximal colonic mucosa-submucosa preparation from age-matched Swiss Webster germ-free (GF) and humanized (HM; ex-GF colonized with human gut microbiota) mice. 5-HT evoked a significantly greater increase in short-circuit current (Δ I sc ) in GF compared with HM mice. Additionally, 5-HT 3 receptor mRNA and protein expression was significantly higher in GF compared with HM mice. Ondansetron, a 5-HT 3 receptor antagonist, inhibited 5-HT-evoked Δ I sc in GF mice but not in HM mice. Furthermore, a 5-HT 3 receptor-selective agonist, 2-methyl-5-hydroxytryptamine hydrochloride, evoked a significantly higher Δ I sc in GF compared with HM mice. Immunohistochemistry in 5-HT 3A -green fluorescent protein mice localized 5-HT 3 receptor expression to enterochromaffin cells in addition to nerve fibers. The significant difference in 5-HT-evoked Δ I sc between GF and HM mice persisted in the presence of tetrodotoxin (TTX) but was lost after ondansetron application in the presence of TTX. Application of acetate (10 mM) significantly lowered 5-HT 3 receptor mRNA in GF mouse colonoids. We conclude that host secretory response to 5-HT may be modulated by gut microbiota regulation of 5-HT 3 receptor expression via acetate production. Epithelial 5-HT 3 receptor may function as a mediator of gut microbiota-driven change in intestinal secretion. NEW & NOTEWORTHY We found that gut microbiota alters serotonin (5-HT)-evoked intestinal secretion in a 5-HT 3 receptor-dependent mechanism and gut microbiota metabolite acetate alters 5-HT 3 receptor expression in

Thiolated xyloglucan: Synthesis, characterization and evaluation as mucoadhesive in situ gelling agent.

PubMed

Mahajan, Hitendra S; Tyagi, Vinod Kumar; Patil, Ravindra R; Dusunge, Sanket B

2013-01-16

The objective of present study was to enhance bioadhesive potential of xyloglucan by thiolation. Thiolation of xyloglucan was achieved with esterification with thioglycolic acid. Thiolated xyloglucan was characterized by NMR, DSC, and XRD analysis. Thiolated xyloglucan was determined to possess 4mmol of thiol groups/g of polymer by Ellman's method. Comparative evaluation of mucoadhesive property of ondansetron containing in situ gel system of xyloglucan and thiolated xyloglucan using sheep nasal mucosa revealed higher ex vivo bioadhesion time of thiolated xyloglucan as compared to xyloglucan. Improved mucoadhesive property of thiolated xyloglucan over the xyloglucan can be attributed to the formation of disulfide bond between mucus and thiolated xyloglucan. Ex vivo permeation study conducted using sheep nasal showed improved drug permeation in formulation based on thiolated xyloglucan. In conclusion, thiolation of xyloglucan improves its bioadhesion and drug permeation without affecting the resultant gel properties. Copyright © 2012 Elsevier Ltd. All rights reserved.

New therapeutic options for IBS: the role of the first in class mixed µ- opioid receptor agonist and δ-opioid receptor antagonist (mudelta) eluxadoline.

PubMed

Corsetti, Maura; Whorwell, Peter

2017-04-01

Irritable bowel syndrome (IBS) is a prevalent functional gastrointestinal disorder which represents a major cost to healthcare services. IBS-D patients represent about one-third of the IBS population and are currently treated with antispasmodics, loperamide, bile acid sequestrants and antidepressants. Alosetron and rifaximin are also available in USA, ramosetron in Japan, Korea and Thailand and ondansetron as an off-label treatment. Areas covered: This article focuses on eluxadoline, a novel pharmacological agent that has recently been approved by both the FDA and EMA for treatment of patients with IBS-D. Expert commentary: The efficacy and safety of eluxadoline in treating bowel habit alterations and pain, both in the short and long-term, make the drug a welcome addition to our therapeutic alternatives in IBS-D. Its positioning in any IBS algorithm will depend on the 'real world' prevalence of the small risk of sphincter of Oddi spasm and mild pancreatitis.

Cannabinoid Regulation of Acute and Anticipatory Nausea

PubMed Central

Rock, Erin M.; Sticht, Martin A.; Limebeer, Cheryl L.; Parker, Linda A.

2016-01-01

Abstract Chemotherapy-induced nausea is one of the most distressing symptoms reported by patients undergoing treatment, and even with the introduction of newer antiemetics such as ondansetron and aprepitant, nausea remains problematic in the clinic. Indeed, when acute nausea is not properly managed, the cues of the clinic can become associated with this distressing symptom resulting in anticipatory nausea for which no effective treatments are available. Clinical trials exploring the potential of exogenous or endogenous cannabinoids to reduce chemotherapy-induced nausea are sparse; therefore, we must rely on the data from pre-clinical rat models of nausea. In this review, we explore the human and pre-clinical animal literature examining the potential for exogenous and endogenous cannabinoid treatments to regulate chemotherapy-induced nausea. The pre-clinical evidence points to a compelling need to evaluate the antinausea potential of cannabidiol, cannabidiolic acid, and treatments that boost the functioning of the endocannabinoid system in human clinical trials. PMID:28861486

The analgesic effect of clonixine is not mediated by 5-HT3 subtype receptors.

PubMed

Paeile, C; Bustamante, S E; Sierralta, F; Bustamante, D; Miranda, H F

1995-10-01

1. The analgesic effect of clonixinate of L-lysine (Clx) in the nociceptive C-fiber reflex in rat and in the writhing test in mice is reported. 2. Clx was administered by three routes, i.v., i.t. and i.c.v., inducing a dose-dependent antinociception. 3. The antinociceptive effect of Clx was 40-45% with respect to the control integration values in the nociceptive C-fiber reflex method. 4. The writhing test yielded ED50 values (mg/kg) of 12.0 +/- 1.3 (i.p.), 1.8 +/- 0.2 (i.t.) and 0.9 +/- 0.1 (i.c.v.) for Clx administration. 5. Ondansetron was not able to antagonize the antinociception response of Clx in the algesiometric tests used. 6. Chlorophenilbiguanide did not produce any significative change in the analgesic effect of Clx in the nociceptive C-fiber reflex method. 7. It is suggested that the mechanism of action of the central analgesia of Clx is not mediated by 5-HT3 subtype receptors.

Treating morning sickness in the United States--changes in prescribing are needed.

PubMed

Koren, Gideon

2014-12-01

Presently, 97.7% of prescriptions for the treatment of nausea and vomiting in pregnancy in the United States are with medications not labeled for use in pregnancy, not indicated for nausea and vomiting in pregnancy, and not classified as safe in pregnancy by the Food and Drug Administration. The use of ondansetron for nausea and vomiting in pregnancy has increased from 50,000 monthly prescriptions in 2008 to 110,000 at the end of 2013, despite unresolved issues regarding fetal safety and Food and Drug Administration warnings about serious dysrhythmias. In April 2013, the Food and Drug Administration approved the combination of doxylamine and pyridoxine, specifically for nausea and vomiting in pregnancy symptoms. Now that a safe and effective drug is available in the United States, there is no reason for women to be exposed to a drug of unproven maternal and fetal safety. Copyright © 2014 Elsevier Inc. All rights reserved.

Interventions for preventing or treating alcohol hangover: systematic review of randomised controlled trials

PubMed Central

Pittler, Max H; Verster, Joris C; Ernst, Edzard

2005-01-01

Objective To assess the clinical evidence on the effectiveness of any medical intervention for preventing or treating alcohol hangover. Data sources Systematic searches on Medline, Embase, Amed, Cochrane Central, the National Research Register (UK), and ClincalTrials.gov (USA); hand searches of conference proceedings and bibliographies; contact with experts and manufacturers of commercial preparations. Language of publication was not restricted. Study selection and data extraction All randomised controlled trials of any medical intervention for preventing or treating alcohol hangover were included. Trials were considered if they were placebo controlled or controlled against a comparator intervention. Titles and abstracts of identified articles were read and hard copies were obtained. The selection of studies, data extraction, and validation were done independently by two reviewers. The Jadad score was used to evaluate methodological quality. Results Fifteen potentially relevant trials were identified. Seven publications failed to meet all inclusion criteria. Eight randomised controlled trials assessing eight different interventions were reviewed. The agents tested were propranolol, tropisetron, tolfenamic acid, fructose or glucose, and the dietary supplements Borago officinalis (borage), Cynara scolymus (artichoke), Opuntia ficus-indica (prickly pear), and a yeast based preparation. All studies were double blind. Significant intergroup differences for overall symptom scores and individual symptoms were reported only for tolfenamic acid, γ linolenic acid from B officinalis, and a yeast based preparation. Conclusion No compelling evidence exists to suggest that any conventional or complementary intervention is effective for preventing or treating alcohol hangover. The most effective way to avoid the symptoms of alcohol induced hangover is to practise abstinence or moderation. PMID:16373736

A critical overview of the current myofascial pain literature - March 2016.

PubMed

Dommerholt, Jan; Hooks, Todd; Finnegan, Michelle; Grieve, Rob

2016-04-01

The worldwide interest in myofascial pain syndrome (MPS) and trigger points (TrPs) is reflected in the increasing number of publications. In this overview of the literature, we included 26 studies, case reports and review articles by authors from 18 different countries. Several research groups are exploring the characteristic of TrPs such as Chen and colleagues, who continued their work on the quantification of the taut bands. Meng and colleagues studied the relationships between TrPs and central sensitization, while Yu and colleagues examined the electrophysiological characteristics that occur as a result of active TrPs. Several researchers used objective measurements to determine clinical outcomes, such as Koppenhaver and colleagues who measured objective changes in the function and nociceptive sensitivity of lumbar multifidus muscle subjects with low back pain. Turo and colleagues quantified muscle tissue changes after dry needling in chronic myofascial pain using elastography. Multiple studies explored various treatment options for TrPs, such as dry needling, injections with lidocaine or granisetron, traditional Thai massage, self-myofascial release, kinesiotaping, and monochromatic infrared photo energy, among others. Copyright © 2016 Elsevier Ltd. All rights reserved.

Emergent management of primary headache: a review of current literature.

PubMed

Naeem, Farnia; Schramm, Chris; Friedman, Benjamin W

2018-06-01

The current article reviews recent data on treatment of acute headache patients in the acute care setting. Intravenous fluid hydration, a common component of emergency department (ED) migraine therapy, does not improve pain outcomes and leads to longer ED lengths of stay. Therefore, intravenous fluids should be administered only to migraine patients with clinical evidence of dehydration. Similarly, intravenous ketamine has garnered interest as a treatment for acute pain but does not provide substantial relief to migraine patients. New studies on the serotonin (5-HT3; 5-hydroxytryptamine-3) antagonist granisetron, intranasal lidocaine, and high-flow oxygen have reported conflicting results for migraine patients. Finally, although experts recommend avoiding opioids in migraine treatment, opioid administration remains prevalent in the ED. A new study has demonstrated that patients who receive intravenous hydromorphone in the ED are much less likely to attain acute headache relief. Standardized headache protocols may decrease opioid use and provide significant pain relief for patients. Recent data have clarified the role of opioids and ketamine in the ED (do not use!). The role of treatment protocols and intravenous fluids is still ill-defined. Subpopulations of migraine patients may benefit from high-flow oxygen and intranasal lidocaine.

Aprepitant, Granisetron, & Dexamethasone in Preventing Nausea & Vomiting in Pts. Receiving Cyclophosphamide Before a Stem Cell Transplant

ClinicalTrials.gov

2016-02-12

Breast Cancer; Chronic Myeloproliferative Disorders; Gestational Trophoblastic Tumor; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasms; Nausea and Vomiting; Neuroblastoma; Ovarian Cancer; Testicular Germ Cell Tumor

Acute radiation sickness amelioration analysis. Technical report, 20 July 1990-19 July 1993

DOE Office of Scientific and Technical Information (OSTI.GOV)

Robinson, S.I.; Feister, A.J.; Bareis, D.L.

1994-05-01

Three tasks were conducted under the Acute Radiation Sickness Amelioration Analysis in support of the Defense Nuclear Agency (DNA) and NATO Army Armaments Group (NAAG) Project Group 29 (PG-29) on drugs for the prevention of radiation-induced nausea and vomiting: (1) documents were collected and entered into a data base, (2) data reviews and analyses were performed, and (3) PG-29 and Triservice meetings involving anti-emetic drug development were supported and documented. Approximately 2000 documents were collected, with 1424 complete bibliographic citations entered into a WordPerfect 5.1 data base. Eight reviews and analyses addressing different aspects of the safety and efficacy ofmore » the candidate anti-emetic drugs ondansetron and granistron were prepared. Support was provided for seven international PG-29 meetings and two U.S. Triservice meetings in which the efforts of PG-29 were discussed. These tasks have enabled the DNA and PG-29 to make good progress toward the goal of recommending a serotonin type-3 (5-HT3) receptor antagonist anti-emetic drug for use in military personnel.« less

A Phase II/III Randomized, Placebo-Controlled, Double-Blind Clinical Trial of Ginger (Zingiber officinale) for Nausea Caused by Chemotherapy for Cancer: A Currently Accruing URCC CCOP Cancer Control Study.

PubMed

Hickok, Jane T; Roscoe, Joseph A; Morrow, Gary R; Ryan, Julie L

2007-09-01

Despite the widespread use of 5-HT3 receptor antagonist antiemetics such as ondansetron and granistron, up to 70% of patients with cancer receiving highly emetogenic chemotherapy agents experience postchemotherapy nausea and vomiting. Delayed postchemotherapy nausea (nausea that occurs >/= 24 hours after chemotherapy administration) and anticipatory nausea (nausea that develops before chemotherapy administration, in anticipation of it) are poorly controlled by currently available antiemetic agents. Scientific studies suggest that ginger (Zingiber officinale) might have beneficial effects on nausea and vomiting associated with motion sickness, surgery, and pregnancy. In 2 small studies of patients with cancer receiving chemotherapy, addition of ginger to standard antiemetic medication further reduced the severity of postchemotherapy nausea. This article describes a phase II/III randomized, dose-finding, placebo-controlled, double-blind clinical trial to assess the efficacy of ginger for nausea associated with chemotherapy for cancer. The study is currently being conducted by private practice oncology groups that are funded by the National Cancer Institute's Community Clinical Oncology Program and affiliated with the University of Rochester Cancer Center Community Clinical Oncology Program Research Base.

Calcium modified edible Canna (Canna edulis L) starch for controlled released matrix

NASA Astrophysics Data System (ADS)

Putri, A. P.; Ridwan, M.; Darmawan, T. A.; Darusman, F.; Gadri, A.

2017-07-01

Canna edulis L starch was modified with calcium chloride in order to form controlled released matrix. Present study aim to analyze modified starch characteristic. Four different formulation of ondansetron granules was used to provide dissolution profile of controlled released, two formula consisted of 15% and 30% modified starch, one formula utilized matrix reference standards and the last granules was negative control. Methocel-hydroxypropyl methyl cellulose was used as controlled released matrix reference standards in the third formula. Calcium starch was synthesized in the presence of sodium hydroxide to form gelatinized mass and calcium chloride as the cross linking agent. Physicochemical and dissolution properties of modified starch for controlled released application were investigated. Modified starch has higher swelling index, water solubility and compressibility index. Three of four different formulation of granules provide dissolution profile of controlled released. The profiles indicate granules which employed calcium Canna edulis L starch as matrix are able to resemble controlled drug released profile of matrix reference, however their bigger detain ability lead to lower bioavailability.

Intraduodenal and intrajejunal administration of the herbal medicine, dai-kenchu-tou, stimulates small intestinal motility via cholinergic receptors in conscious dogs.

PubMed

Jin, X L; Shibata, C; Naito, H; Ueno, T; Funayama, Y; Fukushima, K; Matsuno, S; Sasaki, I

2001-06-01

The aim of the present study was to study the effect and mechanism of action of intraduodenal and intrajejunal dai-kenchu-to, an herbal medicine clinically effective for uncomplicated postoperative adhesive intestinal obstruction, on upper gastrointestinal motility. Five mongrel dogs were equipped with four strain-gauge force transducers on the antrum, duodenum, and proximal and distal jejunum to measure contractile activity. Dai-kenchu-to (0.5, 1.5, and 3.0 g) was administered into the duodenal or proximal jejunal lumen. The effect of atropine, hexamethonium, phentolamine, propranolol, and ondansetron on intraduodenal and intrajejunal dai-kenchu-to-induced contractions was studied. Plasma motilin was measured by specific radioimmunoassay. Intraduodenal and intrajejunal dai-kenchu-to induced phasic contractions in the duodenum and proximal jejunum, respectively, and those contractions migrated distally. Phasic contractions induced by intraduodenal and intrajejunal dai-kenchu-to were inhibited by atropine and hexamethonium at all sites. Plasma motilin was not affected by dai-kenchu-to. Intraduodenal and intrajejunal dai-kenchu-to stimulates upper gastrointestinal motility at and distal to the administration sites through cholinergic receptors.

An alternative for rapid administration of medication and fluids in the emergency setting using a novel device.

PubMed

Lyons, Neal; Nejak, Daniel; Lomotan, Nadine; Mokszycki, Robert; Jamieson, Stephen; McDowell, Marc; Kulstad, Erik

2015-08-01

Routes of administration for medications and fluids in the acute care setting have primarily focused on oral, intravenous, or intraosseous routes, but, in many patients, none of these routes is optimal. A novel device (Macy Catheter; Hospi Corp) that offers an easy route for administration of medications or fluids via rectal mucosal absorption (proctoclysis) has recently become available in the palliative care market; we describe here the first known uses of this device in the emergency setting. Three patients presenting to the hospital with conditions limiting more typical routes of medication or fluid administration were treated with this new device; patients were administered water for hydration, lorazepam for treatment of alcohol withdrawal, ondansetron for nausea, acetaminophen for fever, aspirin for antiplatelet effect, and methimazole for hyperthyroidism. Placement of the device was straightforward, absorption of administered medications (judged by immediacy of effects, where observable) was rapid, and use of the device was well tolerated by patients, suggesting that this device may be an appealing alternative route to medication and fluid administration for a variety of indications in acute and critical care settings.

Evidence based knee injections for the management of arthritis

PubMed Central

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

2012-01-01

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

Ondansetron in Treating Patients With Advanced Cancer and Chronic Nausea and Vomiting Not Caused by Cancer Treatment

ClinicalTrials.gov

2016-07-01

Chronic Myeloproliferative Disorders; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Nausea and Vomiting; Precancerous Condition; Small Intestine Cancer; Unspecified Adult Solid Tumor, Protocol Specific; Unspecified Childhood Solid Tumor, Protocol Specific

An inherent acceleratory effect of insulin on small intestinal transit and its pharmacological characterization in normal mice

PubMed Central

Peddyreddy, Murali Krishna Reddy; Dkhar, Steven Aibor; Ramaswamy, Subramanian; Naveen, Amrithraj Theophilus; Shewade, Deepak Gopal

2006-01-01

AIM: To study an inherent effect of insulin on small intestinal transit and to explore involvement of various systems/mechanisms in normal mice. METHODS: Insulin at the doses of 2 μU/kg, 2 mU/kg, 2 U/kg or vehicle was subcutaneously administered to four groups of overnight fasted normal male mice. Blood glucose (BG) levels were measured 2 min before insulin administration and 2 min before sacrificing the animals for the measurement of small intestinal transit (SIT). Charcoal meal was administered (0.3 mL) intragastrically 20 min after insulin administration and animals were sacrificed after 20 min and SIT was determined. For exploration of the various mechanisms involved in insulin-induced effect on SIT, the dose of insulin which can produce a significant acceleration of SIT without altering BG levels was determined. The following drugs, atropine (1 mg/kg), clonidine (0.1 mg/kg), ondansetron (1 mg/kg), naloxone (5 mg/kg), verapamil (8 mg/kg) and glibenclamide (10 mg/kg), were administered intravenously 10 min prior to the administration of insulin (2 μU/kg). RESULTS: The lower doses of insulin (2 μU/kg and 2 mU/kg) produced a significant acceleration of SIT from 52.0% to 70.7% and 73.5% without lowering blood glucose levels (P < 0.01), while the highest dose of insulin (2 U/kg) produced a fall in blood glucose levels which was also associated with significant acceleration of SIT (P < 0.01). After pretreatment of insulin (2 μU/kg) group with atropine, insulin could reverse 50% of the inhibition produced by atropine. In clonidine-pretreated group, insulin administration could reverse only 37% of the inhibition produced by clonidine and inhibition of SIT was significant compared with vehicle + insulin-treated group, i.e. from 74.7% to 27.7% (P < 0.01). In ondansetron-pretreated group, insulin administration could produce only mild acceleration of SIT (23.5%). In naloxone-pretreated group, insulin administration could significantly reverse the

Mangiferin, a natural xanthone, accelerates gastrointestinal transit in mice involving cholinergic mechanism

PubMed Central

Morais, Talita Cavalcante; Lopes, Synara Cavalcante; Carvalho, Karine Maria Martins Bezerra; Arruda, Bruno Rodrigues; de Souza, Francisco Thiago Correia; Trevisan, Maria Teresa Salles; Rao, Vietla Satyanarayana; Santos, Flávia Almeida

2012-01-01

AIM: To investigate the effects of mangiferin on gastrointestinal transit (GIT) in normal and constipated mice, together with the possible mechanism. METHODS: Intragastrically-administered charcoal meal was used to measure GIT in overnight starved Swiss mice. In the first experiments, mangiferin (3 mg/kg, 10 mg/kg, 30 mg/kg, and 100 mg/kg, po) or tegaserod (1 mg/kg, ip) were administered 30 min before the charcoal meal to study their effects on normal transit. In the second series, mangiferin (30 mg/kg) was tested on delayed GIT induced by several different pharmacological agonists (morphine, clonidine, capsaicin) or antagonists (ondansetron, verapamil, and atropine) whereas in the third series, mangiferin (30 mg/kg, 100 mg/kg and 300 mg/kg) or tegaserod (1 mg/kg) were tested on 6 h fecal pellets outputted by freely fed mice. The ratio of wet to dry weight was calculated and used as a marker of fecal water content. RESULTS: Mangiferin administered orally significantly (P < 0.05) accelerated GIT at 30 mg/kg and 100 mg/kg (89% and 93%, respectively), similarly to 5-hydroxytryptamine4 (5-HT4) agonist tegaserod (81%) when compared to vehicle-treated control (63%). Co-administered mangiferin (30 mg/kg) totally reversed the inhibitory effect of opioid agonist morphine, 5-HT3-receptor antagonist ondansetron and transient receptor potential vanilloid-1 receptor agonist capsaicin on GIT, but only to a partial extent with the GIT-delay induced by α2-adrenoceptor agonist clonidine, and calcium antagonist verapamil. However, co-administered atropine completely blocked the stimulant effect of mangiferin on GIT, suggesting the involvement of muscarinic acetylcholine receptor activation. Although mangiferin significantly enhanced the 6 h fecal output at higher doses (245.5 ± 10.43 mg vs 161.9 ± 10.82 mg and 227.1 ± 20.11 mg vs 161.9 ± 10.82 mg of vehicle-treated control, at 30 and 100 mg/kg, P < 0.05, respectively), the effect of tegaserod was more potent (297.4 ± 7.42 mg

The Combination of Scopolamine and Psychostimulants for the Prevention of Severe Motion Sickness.

PubMed

Zhang, Li-Li; Liu, Hong-Qi; Yu, Xu-Hong; Zhang, Ying; Tian, Jia-Sheng; Song, Xu-Rui; Han, Bing; Liu, Ai-Jun

2016-08-01

Severe motion sickness is a huge obstacle for people conducting precise aviation, marine or emergency service tasks. The combination of scopolamine and d-amphetamine is most effective in preventing severe motion sickness. However, this combination is not included in any present pharmacopoeia due to the abuse liability of d-amphetamine. We wanted to find a combination to replace it for the treatment of severe motion sickness. We compared the efficacy of scopolamine, diphenhydramine, and granisetron (representing three classes of drugs) with different doses, and found that scopolamine was the most effective one. We also found scopolamine inhibited central nervous system at therapeutic doses and caused anxiety. Then, we combined it with different doses of psychostimulants (d-amphetamine, modafinil, caffeine) to find the best combination for motion sickness. The efficacy of scopolamine with modafinil (1 + 10 mg/kg) was equivalent to that of scopolamine with d-amphetamine (1 + 1 mg/kg); This combination also excited central nervous system and abolished the anxiety caused by scopolamine. The optimal dose ratio of scopolamine and modafinil is 1:10. This combination is beneficial for motion sickness and can abolish the side effects of scopolamine. So, it might be a good replacement of scopolamine and d-amphetamine for severe motion sickness. © 2016 John Wiley & Sons Ltd.

5-Fluorotryptamine is a partial agonist at 5-HT3 receptors, and reveals that size and electronegativity at the 5 position of tryptamine are critical for efficient receptor function.

PubMed

Bower, Kiowa S; Price, Kerry L; Sturdee, Laura E C; Dayrell, Mariza; Dougherty, Dennis A; Lummis, Sarah C R

2008-02-12

Antagonists, but not agonists, of the 5-HT3 receptor are useful therapeutic agents, and it is possible that partial agonists may also be potentially useful in the clinic. Here we show that 5-fluorotryptamine (5-FT) is a partial agonist at both 5-HT3A and 5-HT3AB receptors with an Rmax (Imax/Imax 5-HT) of 0.64 and 0.45 respectively. It is about 10 fold less potent than 5-HT: EC50=16 and 27 microM, and Ki for displacement of [3H]granisetron binding=0.8 and 1.8 microM for 5-HT3A and 5-HT3AB receptors respectively. We have also explored the potencies and efficacies of tryptamine and a range of 5-substituted tryptamine derivatives. At 5-HT3A receptors tryptamine is a weak (Rmax=0.15), low affinity (EC50=113 microM; Ki=4.8 microM) partial agonist, while 5-chlorotryptamine has a similar affinity to 5-FT (EC50=8.1 microM; Ki=2.7 microM) but is a very weak partial agonist (Rmax=0. 0037). These, and data from 5-methyltryptamine and 5-methoxytryptamine, reveal the importance of size and electronegativity at this location for efficient channel opening.

Evidence for a central mechanism of action of S-(+)-ketoprofen.

PubMed

Díaz-Reval, María Irene; Ventura-Martínez, Rosa; Déciga-Campos, Myrna; Terrón, José A; Cabré, Francesc; López-Muñoz, Francisco Javier

2004-01-12

It has been observed that some non-steroidal anti-inflammatory drugs (NSAIDs) may act through several mechanisms, in addition to central inhibition of prostaglandin synthesis. These other mechanisms include the L-arginine-nitric oxide (L-arginine-NO) pathway, as well as endogenous opiate and serotonergic mechanisms. Some of these mechanisms can explain the efficacy of NSAIDs in chronic pain conditions such as rheumatoid arthritis. The present study was designed to elucidate the involvement of the above pathways/mechanisms in the antinociceptive effect of S-(+)-ketoprofen at supraspinal and spinal levels. S-(+)-ketoprofen induced dose-dependent antinociception in the pain-induced functional impairment model in the rat. The antinociceptive effect of S-(+)-ketoprofen was not altered by i.t. or intracerebroventricula (i.c.v.) pre-treatment with L-arginine (29.6 microg/site) and L-nitro-arginine-monomethylester (L-NAME) (21.1 microg/site) and neither was the effect of S-(+)-ketoprofen modified by the opiate antagonist, naloxone (1 mg/kg, s.c.). In marked contrast, both i.c.v. administration of the 5-hydroxytryptamine (5-HT)(1)/5-HT(2)/5-HT(7) receptor antagonist, methiothepin (1.5 microg/site), and i.t. administration of the 5-HT(3)/5-HT(4) receptor antagonist, tropisetron (0.9 microg/site), significantly inhibited the S-(+)-ketoprofen-induced antinociceptive effect. These data suggest that the antinociceptive response to S-(+)-ketoprofen involves serotoninergic mechanisms via both supraspinal 5-HT(1)/5-HT(2)/5-HT(7) receptors and 5-HT(3) receptors located at spinal level. A role of the L-arginine-NO and opiate systems in S-(+)-ketoprofen-induced antinociception in the pain-induced functional impairment model in the rat model seems unlikely.

Pharmacological approaches to methamphetamine dependence: a focused review.

PubMed

Karila, Laurent; Weinstein, Aviv; Aubin, Henri-Jean; Benyamina, Amine; Reynaud, Michel; Batki, Steven L

2010-06-01

Methamphetamine dependence is a serious worldwide public health problem with major medical, psychiatric, socioeconomic and legal consequences. Various neuronal mechanisms implicated in methamphetamine dependence have suggested several pharmacological approaches. A literature search from a range of electronic databases (PubMed, EMBASE, PsycInfo, the NIDA research monograph index and the reference list of clinicaltrials.gov) was conducted for the period from January 1985 to October 2009. There were no restrictions on the identification or inclusion of studies in terms of publication status, language and design type. A variety of medications have failed to show efficacy in clinical trials, including a dopamine partial agonist (aripiprazole), GABAergic agents (gabapentin) and serotonergic agents (SSRI, ondansetron, mirtazapine). Three double-blind placebo-controlled trials using modafinil, bupropion and naltrexone have shown positive results in reducing amphetamine or methamphetamine use. Two studies employing agonist replacement medications, one with d-amphetamine and the other with methylphenidate, have also shown promise. Despite the lack of success in most studies to date, increasing efforts are being made to develop medications for the treatment of methamphetamine dependence and several promising agents are targets of further research.

Pharmacotherapy of alcoholism - an update on approved and off-label medications.

PubMed

Soyka, Michael; Müller, Christian A

2017-08-01

Only a few medications are available for the treatment of alcohol use disorders (AUDs). Areas covered: This paper discusses approved AUD medications, including the opioid antagonists naltrexone and nalmefene (the latter is licensed for reduction of alcohol consumption only), the putative glutamate receptor antagonist acamprosate and the aldehyde dehydrogenase inhibitor disulfiram. It also covers off-label medications of interest, including topiramate, gabapentin, ondansetron, varenicline, baclofen, sodium oxybate and antidepressants. Clinical implications, benefits and risks of treatment are discussed. Expert opinion: Acamprosate, naltrexone, nalmefene and disulfiram are the only approved 'alcohol-specific' drugs. Acamprosate and naltrexone have been evaluated in numerous clinical trials and represent evidence-based treatments in AUDs. Nalmefene use, however, is controversial. Supervised disulfiram is a second-line treatment approach. Compounds developed and licensed for different neuropsychiatric disorders are potential alternatives. Encouraging results have been reported for topiramate, gabapentin and also varenicline, which might be useful in patients with comorbid nicotine dependence. The GABA (γ-aminobutyric acid)-B receptor agonist baclofen has shown mixed results; it is currently licensed for the treatment of AUDs in France only. Gabapentin may be close to approval in the USA. Further studies of these novel treatment approaches in AUDs are needed.

Involvement of the dorsomedial hypothalamus and the nucleus tractus solitarii in chronic cardiovascular changes associated with anxiety in rats.

PubMed

Sévoz-Couche, Caroline; Brouillard, Charly; Camus, Françoise; Laude, Dominique; De Boer, Sietse F; Becker, Chrystel; Benoliel, Jean-Jacques

2013-04-01

Anxiety disorders in humans reduce both the heart rate variability (HRV) and the sensitivity of the cardiac baroreflex (BRS). Both may contribute to sudden death. To elucidate the mechanisms underlying these alterations, male rats were subjected to social defeat sessions on four consecutive days. Five days later, the rats were found to be in an anxiety-like state. At this time point, we analysed HRV and BRS in the defeated rats, with or without treatment with the anxiolytic chlordiazepoxide (CDZ). HRV was reduced after social defeat, due to changes in the autonomic balance favouring the sympathetic over the parasympathetic component. Spontaneous and pharmacological baroreflex gains were also reduced. CDZ abolished anxiety-like symptoms as well as HRV and BRS alterations. Inhibition of the dorsomedial hypothalamus (DMH) with muscimol reversed all cardiovascular alterations, whereas blockade of the nucleus tractus solitarii (NTS) 5-HT3 receptor by the local or systemic administration of granisetron restored only baroreflex gains and the parasympathetic component of HRV. In conclusion, repeated social defeat in the rat lead to an anxiety-like state that was associated with lasting reduction in HRV and baroreflex gains. The DMH and the NTS were responsible for these chronic cardiovascular alterations. These regions may therefore constitute new therapeutic targets for reducing cardiac dysfunction and fibrillation in anxiety disorders.

Dietary glutamate signal evokes gastric juice excretion in dogs.

PubMed

Khropycheva, Raisa; Andreeva, Julia; Uneyama, Hisayuki; Torii, Kunio; Zolotarev, Vasiliy

2011-01-01

Dietary-free L-glutamate (Glu) in the stomach interacts with specific Glu receptors (T1R1/T1R3 and mGluR1-8) expressed on surface epithelial and gastric gland cells. Furthermore, luminal Glu activates the vagal afferents in the stomach through the paracrine cascade including nitric oxide and serotonin (5-HT). To elucidate the role of dietary Glu in neuroendocrine control of the gastrointestinal phase of gastric secretion. In Pavlov or Heidenhain gastric pouch dogs, secretion was measured in the pouch while monosodium glutamate (MSG) was intubated into the main stomach alone or in combination with liquid diets. In both experimental models, supplementation of the amino acid-rich diet with MSG (100 mmol/l) enhanced secretions of acid, pepsinogen and fluid, and elevated plasma gastrin-17. However, MSG did not affect secretion stimulated by the carbohydrate-rich diet and had no effect on basal secretion when applied in aqueous solution. Effects of MSG were abolished by denervation of the stomach and proximal small intestine with intragastrically applied lidocaine and partially suppressed with the 5-HT(3) receptor blocker granisetron. Supplementation of amino acid-rich liquid diets with MSG enhances gastrointestinal phase secretion through neuroendocrine pathways which are partially mediated by 5-HT. Possible mechanisms are discussed. Copyright © 2011 S. Karger AG, Basel.

Involvement of the dorsomedial hypothalamus and the nucleus tractus solitarii in chronic cardiovascular changes associated with anxiety in rats

PubMed Central

Sévoz-Couche, Caroline; Brouillard, Charly; Camus, Françoise; Laude, Dominique; De Boer, Sietse F; Becker, Chrystel; Benoliel, Jean-Jacques

2013-01-01

Anxiety disorders in humans reduce both the heart rate variability (HRV) and the sensitivity of the cardiac baroreflex (BRS). Both may contribute to sudden death. To elucidate the mechanisms underlying these alterations, male rats were subjected to social defeat sessions on four consecutive days. Five days later, the rats were found to be in an anxiety-like state. At this time point, we analysed HRV and BRS in the defeated rats, with or without treatment with the anxiolytic chlordiazepoxide (CDZ). HRV was reduced after social defeat, due to changes in the autonomic balance favouring the sympathetic over the parasympathetic component. Spontaneous and pharmacological baroreflex gains were also reduced. CDZ abolished anxiety-like symptoms as well as HRV and BRS alterations. Inhibition of the dorsomedial hypothalamus (DMH) with muscimol reversed all cardiovascular alterations, whereas blockade of the nucleus tractus solitarii (NTS) 5-HT3 receptor by the local or systemic administration of granisetron restored only baroreflex gains and the parasympathetic component of HRV. In conclusion, repeated social defeat in the rat lead to an anxiety-like state that was associated with lasting reduction in HRV and baroreflex gains. The DMH and the NTS were responsible for these chronic cardiovascular alterations. These regions may therefore constitute new therapeutic targets for reducing cardiac dysfunction and fibrillation in anxiety disorders. PMID:23297312

Treating OCD: what to do when first-line therapies fail.

PubMed

Castle, David; Bosanac, Peter; Rossell, Susan

2015-08-01

To provide a clinically-focused review of the biological treatment of treatment-resistant obsessive compulsive disorder (OCD). There is a paucity of research on how to manage OCD patients who fail to respond adequately to first line therapies. High-dose selective serotonin reuptake inhibitors (SSRIs) and clomipramine have good evidence-based data. Combinations of SSRIs have little support in clinical trials, but the combination of SSRIs and clomipramine can be helpful: careful clinical and cardiac monitoring is required. Certain adjunctive antipsychotics have a reasonable evidence base in OCD, but their use also needs to be weighed against the potential side effect burden. In patients with substantial generalised anxiety symptoms, clonazepam is worth considering. Of the other augmenting strategies, memantine and ondansetron appear useful in some cases, and are well tolerated. Topiramate might ameliorate compulsions to some degree, but it is less well tolerated. If all these strategies, along with expert psychological therapy, fail, careful consideration should be given to deep brain stimulation (DBS), which has an emerging evidence base and which can result in dramatic benefits for some individuals. For some patients, gamma radiosurgery might also still have a place. © The Royal Australian and New Zealand College of Psychiatrists 2015.

Case 252: Acute Hyperammonemic Encephalopathy Resulting from Late-Onset Ornithine Transcarbamylase Deficiency.

PubMed

Hershman, Michelle; Carmody, Raymond; Udayasankar, Unni K

2018-04-01

History A 19-year-old woman with no pertinent medical history was brought to the emergency department after being found unconscious on her bathroom floor by her roommate. In the preceding weeks, she had reported intractable nausea and vomiting, for which she had been taking ondansetron. No other medications had been prescribed. The day prior to presentation, she had contacted her mother and described increasing confusion. Glasgow coma scale score on arrival in the emergency department was 4. Intravenous naloxone was administered, without immediate response. Initial blood glucose level was 232 mg/dL (12.8 mmol/L) (normal range, 79-140 mg/dL [4.4- 7.7 mmol/L]), and other routine laboratory test results were normal. Urine toxicology results were negative. Cerebrospinal fluid evaluation revealed levels were within normal limits. Neurologic examination revealed dilated pupils, which showed a sluggish response to light, and left lower extremity rigidity with intermittent tremors. Initial unenhanced cranial computed tomographic (CT) findings were negative. Magnetic resonance (MR) imaging of the brain was performed. The patient's condition deteriorated, with increasing cerebral edema over the next week, and she was declared brain dead. Her liver was transplanted into an adult recipient, who subsequently developed cerebral edema and elevated plasma ammonia levels, resulting in death in the immediate postoperative period.

The effects of varenicline on sensory gating and exploratory behavior with pretreatment with nicotinic or 5-HT3A receptor antagonists.

PubMed

Kucinski, Aaron; Wersinger, Scott; Stachowiak, Ewa K; Becker, Chani; Lippiello, Pat; Bencherif, Merouane; Stachowiak, Michal K

2015-02-01

Individuals with schizophrenia smoke at high frequency relative to the general population. Despite the harmful effects of cigarette smoking, smoking among schizophrenic patients improves cognitive impairments not addressed or worsened by common neuroleptics. Varenicline, a nonselective neuronal nicotinic receptor (NNR) agonist and full agonist of 5-HT3A receptors, helps reduce smoking among schizophrenic patients. To determine whether varenicline also improves a cognitive symptom of schizophrenia, namely, impaired sensory gating, a transgenic mouse with schizophrenia, th-fgfr1(tk-), was used. Varenicline dose-dependently increased prepulse inhibition (PPI) of the startle response, a measure of sensory gating, in th-fgfr1(tk-) mice and normalized PPI deficits relative to nontransgenic controls. With the highest dose (10 mg/kg), however, there was a robust elevation of PPI and startle response, as well as reduced exploratory behavior in the open field and elevated plus maze. Pretreatment with the nonspecific NNR antagonist mecamylamine attenuated the exaggerated PPI response and, similar to the 5-HT3A receptor antagonist ondansetron, it prevented the reduction in exploratory behavior. Collectively, these results indicate that varenicline at low-to-moderate doses may be beneficial against impaired sensory gating in schizophrenia; however, higher doses may induce anxiogenic effects, which can be prevented with antagonists of NNRs or 5-HT3A receptors.

Intracolonic Administration of the TRPA1 Agonist Allyl Isothiocyanate Stimulates Colonic Motility and Defecation in Conscious Dogs.

PubMed

Someya, Soutoku; Nagao, Munenori; Shibata, Chikashi; Tanaka, Naoki; Sasaki, Hiroyuki; Kikuchi, Daisuke; Miyachi, Tomohiro; Naitoh, Takeshi; Unno, Michiaki

2015-07-01

The aim of the present study was to investigate the effects of the intracolonic transient receptor potential (TRP) A1 agonist allyl isothiocyanate (AITC) on colonic motility and defecation. The effects of AITC administered into the proximal colonic lumen on colonic motility and defecation were studied in neurally intact dogs equipped with strain-gauge force transducers on the colon, with or without various antagonists. Effects of intracolonic AITC were also studied in dogs with either transection/re-anastomosis (T/R) between the proximal and middle colon and complete extrinsic denervation of an ileocolonic segment. AITC increased colonic motility and induced giant migrating contractions (GMCs) with defecations in 75% of experiments in neurally intact dogs. These effects were inhibited by atropine, hexamethonium, ondansetron, and HC-030031 but unaltered by capsazepine. In dogs with T/R, the increase in colonic motility was inhibited in the middle-distal colon. In dogs with extrinsic denervation, the increase in colonic motility in the distal colon was decreased. Intracolonic AITC stimulates colonic motility and defecation via cholinergic, serotonergic, and TRPA1 pathways. Continuity of colonic enteric neurons plays an essential role in the intracolonic AITC-induced colonic motor response, while extrinsic nerves are important in occurrence and propagation of GMCs.

Tramadol and Tramadol+Caffeine Synergism in the Rat Formalin Test Are Mediated by Central Opioid and Serotonergic Mechanisms

PubMed Central

Carrillo-Munguía, Norma; González-Trujano, Ma. Eva; Huerta, Miguel; Trujillo, Xochitl; Díaz-Reval, M. Irene

2015-01-01

Different analgesic combinations with caffeine have shown this drug to be capable of increasing the analgesic effect. Many combinations with nonsteroidal anti-inflammatory drugs (NSAIDs) have been carried out, but, in regard to opioids, only combinations with morphine and tramadol have been reported. The antinociceptive synergism mechanism of these combinations is not well understood. The purpose of the present study was to determine the participation of spinal and supraspinal opioidergic and serotonergic systems in the synergic effect of the tramadol+caffeine combination in the rat formalin test. At the supraspinal level, the opioid antagonist, naloxone, completely reversed the effect of the drug combination, whereas ketanserin, a 5-HT2 receptor antagonist, inhibited the effect by 60%; however, ondansetron, a 5-HT3 receptor antagonist, did not alter the combination effect. When the antagonists were intrathecally administered, there was a significant reduction in all tramadol-caffeine combination effects. With respect to tramadol alone, there was significant participation of the opioid system at the supraspinal level, whereas it was the serotonergic system that participated at the spinal level by means of the two receptors studied. In conclusion, the tramadol+caffeine combination synergically activated the opioid and serotonergic systems at the supraspinal level, as well as at the spinal level, to produce the antinociception. PMID:26146627

Examination of the effectiveness of peppermint aromatherapy on nausea in women post C-section.

PubMed

Lane, Betty; Cannella, Kathi; Bowen, Cathy; Copelan, David; Nteff, Grace; Barnes, Katrina; Poudevigne, Melanie; Lawson, Jacqueline

2012-06-01

This study examined the effect of peppermint spirits on postoperative nausea in women following a scheduled C-section. A pretest-posttest research design with three groups was used. The peppermint group inhaled peppermint spirits, the placebo aromatherapy control group inhaled an inert placebo, green-colored sterile water, and the standard antiemetic therapy control group received standard antiemetics, usually intravenous ondansetron or promethazine suppositories. Women were randomly assigned to a group on admission to the hospital. If they became nauseated, nurses on the mother-baby unit assessed their nausea (baseline), administered the assigned intervention, and then reassessed participants' nausea 2 and 5 minutes after the initial intervention. Participants rated their nausea using a 6-point nausea scale. Thirty-five participants became nauseated post-operatively. Participants in all three intervention groups had similar levels of nausea at baseline. The nausea levels of participants in the peppermint spirits group were significantly lower than those of participants in the other two groups 2 and 5 minutes after the initial intervention. Peppermint spirits may be a useful adjunct in the treatment of postoperative nausea. This study should be replicated with more participants, using a variety of aromatherapies to treat nausea in participants with different preoperative diagnoses.

5-Fluorotryptamine is a partial agonist at 5-HT3 receptors, and reveals that size and electronegativity at the 5 position of tryptamine are critical for efficient receptor function

PubMed Central

Bower, Kiowa S.; Price, Kerry L.; Sturdee, Laura E.C.; Dayrell, Mariza; Dougherty, Dennis A.; Lummis, Sarah C.R.

2008-01-01

Antagonists, but not agonists, of the 5-HT3 receptor are useful therapeutic agents, and it is possible that partial agonists may also be potentially useful in the clinic. Here we show that 5-fluorotryptamine (5-FT) is a partial agonist at both 5-HT3A and 5-HT3AB receptors with an Rmax (Imax / Imax5-HT) of 0.64 and 0.45 respectively. It is about 10 fold less potent than 5-HT: EC50 = 16 and 27 μM, and Ki for displacement of [3H]granisetron binding = 0.8 and 1.8 μM for 5-HT3A and 5-HT3AB receptors respectively. We have also explored the potencies and efficacies of tryptamine and a range of 5-substituted tryptamine derivatives. At 5-HT3A receptors tryptamine is a weak (Rmax = 0.15), low affinity (EC50 = 113 μM; Ki = 4.8 μM) partial agonist, while 5-chlorotryptamine has a similar affinity to 5-FT (EC50 = 8.1 μM; Ki = 2.7 μM) but is a very weak partial agonist (Rmax = 0. 0037). These, and data from 5-methyltryptamine and 5-methoxytryptamine, reveal the importance of size and electronegativity at this location for efficient channel opening. PMID:18082160

Acute and anticipatory emesis in breast cancer patients.

PubMed

Fernández-Marcos, A; Martín, M; Sanchez, J J; Rodriguez-Lescure, A; Casado, A; López Martin, J A; Diaz-Rubio, E

1996-09-01

A group of 90 breast cancer patients undergoing chemotherapy were assessed prospectively to estimate the prevalence of acute (post-treatment) and anticipatory emesis in the 1990s. For this purpose, two protocols of chemotherapy were analysed separately: cyclophosphamide/methotrexate/5-fluorouracil (CMF) and 5-fluorouracil/doxorubicin/cyclophosphamide (FAC). All patients were treated with antiemetic therapy, which included one corticoid plus ondansetron (in the FAC regimen), or one corticoid plus thiethylperazine (in the CMF regimen). For at least one cycle of chemotherapy 86.1% and 91.7% patients in the FAC protocol presented vomiting and nausea respectively: 11.1% had anticipatory vomiting and 30.6% had anticipatory nausea. In the CMF protocol, 79.6% had post-chemotherapy vomiting and 71.7% had post-chemotherapy nausea associated with at least one cycle. In this group, 7.4% had anticipatory vomiting and 16.6% had anticipatory nausea. A high proportion of patients suffered anticipatory anxiety in both groups (75% in FAC, 74.1% in CMF). The stimuli most frequently associated with the appearance of anticipatory emesis were olfactory stimuli and cognitive stimuli. In summary, as a result of the advances made in antiemetic control during the last decade, the severity of chemotherapy-induced emesis seems to have significantly decreased, but the prevalence of these symptoms along the course of the treatment still remains high.

Antinociceptive effect and mechanism of action of isatin, N-methyl isatin and oxopropyl isatin in mice.

PubMed

Giorno, Thais Biondino Sardella; Silva, Bárbara Vasconcellos da; Pinto, Angelo da Cunha; Fernandes, Patricia Dias

2016-04-15

There has been growing interest in the synthesis of new derivatives from isatin, found in Isatis genus. Our objectives were to characterize the antinociceptive mechanism of action of isatin, N-methyl-isatin (MI) and N-methyl-3-(2-oxopropyl)-3-hydroxy-2-oxindole (MOI). Substances (0.1-10mg/kg, p.o.) were studied in chemical (paw licking induced by formalin, capsaicin or glutamate) or thermal (hot plate) models of nociception. The involvement of several systems was evaluated using different receptor antagonists. All three substances inhibit both phases of formalin-induced licking, increase the area under the curve and MI and MOI have a higher effect than that of morphine (in hot plate). Capsaicin and glutamate-induced licking were also reduced by all three substances. In the hot plate model, the antinociceptive effect of isatin was reduced by naloxone and atropine; naloxone, atropine and L-NAME reduced MI effect while naloxone, atropine, L-NAME, mecamylamine and ondansetron reduced MOI effect. Our results suggest that isatin, MI and MOI: 1) present activity in models of nociception; 2) capsaicin and glutamate receptors seems to participate in the mechanism of action; 3) opioid, cholinergic, serotoninergic, nitrergic and adrenergic systems may be involved, at least in part, in the mechanism of action of some of these substances. Copyright © 2016 Elsevier Inc. All rights reserved.

Peripheral 5-HT3 Receptors Are Involved in the Antinociceptive Effect of Bunodosine 391.

PubMed

Ferreira Junior, Wilson Alves; Zaharenko, Andre Junqueira; Kazuma, Kohei; Picolo, Gisele; Gutierrez, Vanessa Pacciari; de Freitas, Jose Carlos; Konno, Katsuhiro; Cury, Yara

2017-12-27

Bunodosine 391 (BDS 391), a low molecular weight compound isolated from the sea anemone Bunodosoma cangicum , increases the nociceptive threshold and inhibits inflammatory hyperalgesia. Serotonin receptors are involved in those effects. In this study, we have expanded the characterization of the antinociceptive effect of BDS 391 demonstrating that, in rats: (a) the compound inhibits (1.2-12 ng/paw) overt pain, in the formalin test, and mechanical hyperalgesia (0.6-6.0 ng/paw) detected in a model of neuropathic pain; (b) intraplantar administration of ondansetron, a selective 5-HT3 receptor antagonist, blocks the effect of BDS 391, whereas ketanserin, a 5-HT2 receptor antagonist, partially reversed this effect, indicating the involvement of peripheral 5-HT2 and 5-HT3 receptors in BDS 391 antinociception; and (c) in binding assay studies, BDS 391 was not able to displace the selective 5-HT receptor antagonists, suggesting that this compound does not directly bind to these receptors. The effect of biguanide, a selective 5-HT3 receptor agonist, was also evaluated. The agonist inhibited the formalin's nociceptive response, supporting an antinociceptive role for 5-HT3 receptors. Our study is the first one to show that a non-peptidic low molecular weight compound obtained from a sea anemone is able to induce antinociception and that activation of peripheral 5-HT3 receptors contributes to this effect.

Granisetron, Aprepitant, and Dexamethasone in Preventing Nausea and Vomiting in Patients Receiving Chemotherapy for Stage II, III, or IV Ovarian Cancer

ClinicalTrials.gov

2018-04-24

Nausea and Vomiting; Ovarian Brenner Tumor; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Seromucinous Carcinoma; Ovarian Serous Cystadenocarcinoma; Stage II Ovarian Cancer; Stage IIA Fallopian Tube Cancer; Stage IIA Ovarian Cancer; Stage IIB Fallopian Tube Cancer; Stage IIB Ovarian Cancer; Stage IIC Fallopian Tube Cancer; Stage IIC Ovarian Cancer; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Primary Peritoneal Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Primary Peritoneal Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Primary Peritoneal Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Primary Peritoneal Cancer; Undifferentiated Ovarian Carcinoma

Noncompetitive Inhibition of 5-HT3 Receptors by Citral, Linalool, and Eucalyptol Revealed by Nonlinear Mixed-Effects Modeling

PubMed Central

Jarvis, Gavin E.; Barbosa, Roseli

2016-01-01

Citral, eucalyptol, and linalool are widely used as flavorings, fragrances, and cosmetics. Here, we examined their effects on electrophysiological and binding properties of human 5-HT3 receptors expressed in Xenopus oocytes and human embryonic kidney 293 cells, respectively. Data were analyzed using nonlinear mixed-effects modeling to account for random variance in the peak current response between oocytes. The oils caused an insurmountable inhibition of 5‐HT–evoked currents (citral IC50 = 120 µM; eucalyptol = 258 µM; linalool = 141 µM) and did not compete with fluorescently labeled granisetron, suggesting a noncompetitive mechanism of action. Inhibition was not use‐dependent but required a 30-second preapplication. Compound washout caused a slow (∼180 seconds) but complete recovery. Coapplication of the oils with bilobalide or diltiazem indicated they did not bind at the same locations as these channel blockers. Homology modeling and ligand docking predicted binding to a transmembrane cavity at the interface of adjacent subunits. Liquid chromatography coupled to mass spectrometry showed that an essential oil extracted from Lippia alba contained 75.9% citral. This inhibited expressed 5‐HT3 receptors (IC50 = 45 µg ml−1) and smooth muscle contractions in rat trachea (IC50 = 200 µg ml−1) and guinea pig ileum (IC50 = 20 µg ml−1), providing a possible mechanistic explanation for why this oil has been used to treat gastrointestinal and respiratory ailments. These results demonstrate that citral, eucalyptol, and linalool inhibit 5-HT3 receptors, and their binding to a conserved cavity suggests a valuable target for novel allosteric modulators. PMID:26669427

The effect of requesting a reason for non-adherence to a guideline in a long running automated reminder system for PONV prophylaxis.

PubMed

Kooij, Fabian O; Klok, Toni; Preckel, Benedikt; Hollmann, Markus W; Kal, Jasper E

2017-03-29

Automated reminders are employed frequently to improve guideline adherence, but limitations of automated reminders are becoming more apparent. We studied the reasons for non-adherence in the setting of automated reminders to test the hypothesis that a separate request for a reason in itself may further improve guideline adherence. In a previously implemented automated reminder system on prophylaxis for postoperative nausea and vomiting (PONV), we included additional automated reminders requesting a reason for non-adherence. We recorded these reasons in the pre-operative screening clinic, the OR and the PACU. We compared adherence to our PONV guideline in two study groups with a historical control group. Guideline adherence on prescribing and administering PONV prophylaxis (dexamethasone and granisetron) all improved compared to the historical control group (89 vs. 82% (p< 0.0001), 96 vs 95% (not significant) and 90 vs 82% (p<0.0001)) while decreasing unwarranted prescription for PONV prophylaxis (10 vs. 13 %). In the pre-operative screening clinic, the main reason for not prescribing PONV prophylaxis was disagreement with the risk estimate by the decision support system. In the OR/PACU, the main reasons for not administering PONV prophylaxis were: 'unintended non-adherence' and 'failure to document'. In this study requesting a reason for non-adherence is associated with improved guideline adherence. The effect seems to depend on the underlying reason for non-adherence. It also illustrates the importance of human factors principles in the design of decision support. Some reasons for non-adherence may not be influenced by automated reminders.

Gastric relaxation induced by hyperglycemia is mediated by vagal afferent pathways in the rat

PubMed Central

Zhou, Shi-Yi; Lu, Yuan-Xu; Owyang, Chung

2011-01-01

Hyperglycemia has a profound effect on gastric motility. However, little is known about site and mechanism that sense alteration in blood glucose level. The identification of glucose-sensing neurons in the nodose ganglia led us to hypothesize that hyperglycemia acts through vagal afferent pathways to inhibit gastric motility. With the use of a glucose clamp rat model, we showed that glucose decreased intragastric pressure in a dose-dependent manner. In contrast to intravenous infusion of glucose, intracisternal injection of glucose at 250 and 500 mg dL−1 had little effect on intragastric pressure. Pretreatment with hexamethonium, as well as truncal vagotomy, abolished the gastric motor responses to hyperglycemia (250 mg dL−1), and perivagal and gastroduodenal applications of capsaicin significantly reduced the gastric responses to hyperglycemia. In contrast, hyperglycemia had no effect on the gastric contraction induced by electrical field stimulation or carbachol (10−5 M). To rule out involvement of serotonergic pathways, we showed that neither granisetron (5-HT3 antagonist, 0.5 g kg−1) nor pharmacological depletion of 5-HT using p-chlorophenylalanine (5-HT synthesis inhibitor) affected gastric relaxation induced by hyperglycemia. Lastly, NG-nitro-L-arginine methyl ester (l-NAME) and a VIP antagonist each partially reduced gastric relaxation induced by hyperglycemia, and in combination, completely abolished gastric responses. In conclusion, hyperglycemia inhibits gastric motility through a capsaicin-sensitive vagal afferent pathway originating from the gastroduodenal mucosa. Hyperglycemia stimulates vagal afferents, which, in turn, activate vagal efferent cholinergic pathways synapsing with intragastric nitric oxide- and VIP-containing neurons to mediate gastric relaxation. PMID:18356537

Evidence for a vagal pathophysiology for bulimia nervosa and the accompanying depressive symptoms.

PubMed

Faris, Patricia L; Eckert, Elke D; Kim, Suck-Won; Meller, William H; Pardo, Jose V; Goodale, Robert L; Hartman, Boyd K

2006-05-01

The bilateral vagus nerves (Cranial X) provide both afferent and efferent connections between the viscera and the caudal medulla. The afferent branches increasingly are being recognized as providing significant input to the central nervous system for modulation of complex behaviors. In this paper, we review evidence from our laboratory that increases in vagal afferent activity are involved in perpetuating binge-eating and vomiting in bulimia nervosa. Preliminary findings are also presented which suggest that a subgroup of depressions may have a similar pathophysiology. Two main approaches were used to study the role of vagal afferents. Ondansetron (ONDAN), a 5-HT3 antagonist, was used as a pharmacological tool for inhibiting or reducing vagal afferent neurotransmission. Second, somatic pain detection thresholds were assessed for monitoring a physiological process known to be modulated by vagal afferents, including the gastric branches involved in meal termination and satiety. High levels of vagal activity result in an increase in pain detection thresholds. Depressive symptoms were assessed using the Beck Depression Inventory (BDI). Positron Emission Tomography (PET) was used to identify higher cortical brain areas activated by vagal stimulation produced by proximal gastric distention in normal eating subjects. Double-blind treatment of severe bulimia nervosa subjects with ONDAN resulted in a rapid and significant decrease in binge-eating and vomiting compared to placebo controls. The decrease in abnormal eating episodes was accompanied by a return of normal satiety. Pain detection thresholds measured weekly over the course of the treatment protocol were found to dynamically fluctuate in association with bulimic episodes. Thresholds were the most elevated during periods of short-term abstinence from the behaviors, suggesting that not engaging in a binge/vomit episode is accompanied by an increase in vagal activity. ONDAN also resulted in abolition of the

Implementation of institutional antiemetic guidelines for low emetic risk chemotherapy with docetaxel: a clinical and cost evaluation.

PubMed

Hayashi, Toshinobu; Ikesue, Hiroaki; Esaki, Taito; Fukazawa, Mami; Abe, Motoaki; Ohno, Shinji; Tomizawa, Tatsuru; Oishi, Ryozo

2012-08-01

The purposes of this study were to evaluate the effect of implementation of institutional guidelines for low emetic risk chemotherapy with docetaxel and estimate the cost saving for all low emetic risk chemotherapies. We examined the clinical effect of preparing and implementing institutional antiemetic guidelines for the breast cancer patients receiving adjuvant docetaxel therapy. Although the antiemetic medication for such patients used to be ondansetron 4 mg plus dexamethasone 8 mg (OND + DEX), it was changed to dexamethasone (DEX) 12 mg alone after implementation of the institutional guidelines. The effectiveness and adverse effects of DEX alone (56 patients, 205 courses) were compared with those of OND + DEX (41 patients, 151 courses). The cost saving was calculated from the antiemetic costs in both groups. The annual cost saving was estimated from the number of all low emetic risk chemotherapies in a year. The incidences of nausea (19.5% versus 16.1%), vomiting (2.4% versus 0%), constipation (34.1% versus 30.4%), and insomnia (17.1% versus 17.9%) were not significantly different between the OND + DEX group and DEX alone group. In all low emetic risk chemotherapies, US $78,883 of potential cost saving was estimated in the first year after changing the antiemetic treatment. The present results suggest that DEX alone is equally effective for preventing nausea and vomiting and less expensive compared with a 5-HT(3) receptor antagonist plus DEX in low emetic risk chemotherapy with docetaxel.

The Role of Serotonin in Ventricular Repolarization in Pregnant Mice

PubMed Central

Park, Hyelim; Mun, Dasom; Lee, Seung-Hyun; Kim, Hyoeun; Yun, Nuri; Kim, Hail; Kim, Michael; Pak, Hui-Nam; Lee, Moon-Hyoung

2018-01-01

Purpose The mechanisms underlying repolarization abnormalities during pregnancy are not fully understood. Although maternal serotonin (5-hydroxytryptamine, 5-HT) production is an important determinant for normal fetal development in mice, its role in mothers remains unclear. We evaluated the role of serotonin in ventricular repolarization in mice hearts via 5Htr3 receptor (Htr3a) and investigated the mechanism of QT-prolongation during pregnancy. Materials and Methods We measured current amplitudes and the expression levels of voltage-gated K+ (Kv) channels in freshly-isolated left ventricular myocytes from wild-type non-pregnant (WT-NP), late-pregnant (WT-LP), and non-pregnant Htr3a homozygous knockout mice (Htr3a−/−-NP). Results During pregnancy, serotonin and tryptophan hydroxylase 1, a rate-limiting enzyme for the synthesis of serotonin, were markedly increased in hearts and serum. Serotonin increased Kv current densities concomitant with the shortening of the QT interval in WT-NP mice, but not in WT-LP and Htr3a−/−-NP mice. Ondansetron, an Htr3 antagonist, decreased Kv currents in WT-LP mice, but not in WT-NP mice. Kv4.3 directly interacted with Htr3a, and this binding was facilitated by serotonin. Serotonin increased the trafficking of Kv4.3 channels to the cellular membrane in WT-NP. Conclusion Serotonin increases repolarizing currents by augmenting Kv currents. Elevated serotonin levels during pregnancy counterbalance pregnancy-related QT prolongation by facilitating Htr3-mediated Kv currents. PMID:29436197

The Role of Serotonin in Ventricular Repolarization in Pregnant Mice.

PubMed

Cui, Shanyu; Park, Hyewon; Park, Hyelim; Mun, Dasom; Lee, Seung Hyun; Kim, Hyoeun; Yun, Nuri; Kim, Hail; Kim, Michael; Pak, Hui Nam; Lee, Moon Hyoung; Joung, Boyoung

2018-03-01

The mechanisms underlying repolarization abnormalities during pregnancy are not fully understood. Although maternal serotonin (5-hydroxytryptamine, 5-HT) production is an important determinant for normal fetal development in mice, its role in mothers remains unclear. We evaluated the role of serotonin in ventricular repolarization in mice hearts via 5Htr3 receptor (Htr3a) and investigated the mechanism of QT-prolongation during pregnancy. We measured current amplitudes and the expression levels of voltage-gated K⁺ (Kv) channels in freshly-isolated left ventricular myocytes from wild-type non-pregnant (WT-NP), late-pregnant (WT-LP), and non-pregnant Htr3a homozygous knockout mice (Htr3a(-/-)-NP). During pregnancy, serotonin and tryptophan hydroxylase 1, a rate-limiting enzyme for the synthesis of serotonin, were markedly increased in hearts and serum. Serotonin increased Kv current densities concomitant with the shortening of the QT interval in WT-NP mice, but not in WT-LP and Htr3a(-/-)-NP mice. Ondansetron, an Htr3 antagonist, decreased Kv currents in WT-LP mice, but not in WT-NP mice. Kv4.3 directly interacted with Htr3a, and this binding was facilitated by serotonin. Serotonin increased the trafficking of Kv4.3 channels to the cellular membrane in WT-NP. Serotonin increases repolarizing currents by augmenting Kv currents. Elevated serotonin levels during pregnancy counterbalance pregnancy-related QT prolongation by facilitating Htr3-mediated Kv currents. © Copyright: Yonsei University College of Medicine 2018

Antidepressant-like effect of m-trifluoromethyl-diphenyl diselenide in the mouse forced swimming test involves opioid and serotonergic systems.

PubMed

Brüning, César Augusto; Souza, Ana Cristina Guerra; Gai, Bibiana Mozzaquatro; Zeni, Gilson; Nogueira, Cristina Wayne

2011-05-11

Serotonergic and opioid systems have been implicated in major depression and in the action mechanism of antidepressants. The organoselenium compound m-trifluoromethyl-diphenyl diselenide (m-CF(3)-PhSe)(2) shows antioxidant and anxiolytic activities and is a selective inhibitor of monoamine oxidase A activity. The present study was designed to investigate the antidepressant-like effect of (m-CF(3)-PhSe)(2) in female mice, employing the forced swimming test. The involvement of the serotonergic and opioid systems in the antidepressant-like effect of (m-CF(3)-PhSe)(2) was appraised. (m-CF(3)-PhSe)(2) at doses of 50 and 100mg/kg (p.o.) exhibited antidepressant-like action in the forced swimming test. The effect of (m-CF(3)-PhSe)(2) (50mg/kg p.o.) was prevented by pretreatment of mice with WAY100635 (0.1mg/kg, s.c. a selective 5-HT(1A) receptor antagonist), ritanserin (4 mg/kg, i.p., a non-selective 5HT(2A/2C) receptor antagonist), ondansetron (1mg/kg, i.p., a selective 5-HT(3) receptor antagonist) and naloxone (1mg/kg, i.p., a non-selective antagonist of opioid receptors). These results suggest that (m-CF(3)-PhSe)(2) produced an antidepressant-like effect in the mouse forced swimming test and this effect seems most likely to be mediated through an interaction with serotonergic and opioid systems. Copyright © 2011 Elsevier B.V. All rights reserved.

Comparison of the effects of sugammadex and neostigmine on postoperative nausea and vomiting.

PubMed

Yağan, Özgür; Taş, Nilay; Mutlu, Tuğçe; Hancı, Volkan

The aim of our study is to compare the effects of sugammadex and neostigmine, used for neuromuscular blockage antagonism, on postoperative nausea and vomiting (PONV). Our study was completed with 98 ASA I-II risk patients undergoing endotracheal intubation under general anesthesia. At the end of the surgery patients were randomly divided into two groups given 2mgkg -1 sugammadex (Group S) or 50μgkg -1 neostigmine plus 0.2mgkg -1 atropine (Group N). Monitoring and recording times were set as 1 hour postoperative and from 1-6, 6-12, and 12-24hours. The anti-emetic amounts administered were recorded. In the first hour postoperative 13 patients in Group N (27%) and 4 in Group S (8%) were observed to have nausea and/or vomiting and the difference was statistically significant (p=0.0016). During the 24 hours of monitoring there was no significant difference in the incidence and severity of PONV (p>0.05), however the number of patients given ondansetron for PONV treatment in Group N was statistically significantly higher than the number in Group S (16 in Group N, 6 in Group S, p<0.011). At the end of our study comparing neostigmine with sugammadex for neuromuscular blockage antagonism, we found use of sugammadex had lower incidence of PONV in the postoperative 1st hour and less anti-emetic use in 24 hours of monitoring. Copyright © 2016 Sociedade Brasileira de Anestesiologia. Published by Elsevier Editora Ltda. All rights reserved.

Nociceptive vascular reflexes evoked by scorpion venom modulate cardiorespiratory parameters involving vanilloid receptor 1 in anaesthetised rats.

PubMed

Singh, Sanjeev K; Deshpande, Shripad B

2009-02-27

Involvement of vanilloid and 5-HT(3) receptors in the cardiorespiratory reflexes evoked by intra-arterial (i.a.) injection of Mesobuthus tamulus (BT) venom was examined. In anaesthetised rats, blood pressure, respiratory excursions and ECG were recorded for 60min after the injection of venom in the absence or presence of antagonists. Injection of BT venom (1mg/kg, i.a.) produced alterations in respiratory frequency (RF), blood pressure (BP) and heart rate (HR). The changes in RF were manifested as immediate increase (40%) followed by a decrease (40%) and subsequent sustained increase (60%). In case of BP, the increase began around 40s, peaked at 5min (50%) and remained above the initial level subsequently. The bradycardiac response began around 5min which peaked (50% of the initial) around 25min and remained at that level. Thus, exhibiting immediate-tachypnoeic, intermediate-hypertensive and delayed-bradycardiac responses. Pretreatment with lignocaine, blocked the respiratory responses and attenuated the pressor responses evoked by venom. Pretreatment with capsazepine, vanilloid receptor 1 (VR1) antagonist, antagonized all the three parameters of cardiorespiratory responses evoked by venom. Whereas, ondansetron (5-HT(3) antagonist) attenuated the pressor and bradycardiac responses significantly but not the respiratory responses. These observations indicate that the cardiorespiratory changes induced by intra-arterial injection of venom are carried by afferents in addition to somatic nerves, involving mainly VR1 receptors and partially by 5-HT(3) receptors.

Atrial stretch delays gastric emptying of liquids in awake rats.

PubMed

Palheta, R C; Silva, M T B; Barbosa, H L G; Pinheiro, A D N; Cardoso, K V V; Graça, J R V; Magalhães, P J C; Oliveira, R B; Santos, A A

2013-03-21

We previously reported that mechanical atrial stretch (AS) by balloon distention increased gastric tonus in anesthetized rats. The present study evaluated the effect of AS on the gastric emptying of a liquid test meal in awake rats and its underlying neural mechanisms. Anesthetized male rats received a balloon catheter into the right atrium and a gastrostomy cannula. The next day, mean arterial pressure (MAP), heart rate (HR), central venous pressure (CVP), and cardiac output (CO) were continuously monitored. After the first 20min of monitoring (basal interval), the balloon was either distended or not (control) with 30, 50, or 70μl saline for 5min. Fifteen minutes later, the rats received the test meal (glucose solution with phenol red), and fractional gastric dye retention was determined 10, 20, or 30min later. Heart rate and CVP values were transiently increased by 50 or 70μl AS but not 30μl AS, whereas gastric emptying was slower after 30, 50, or 70μl AS than after sham distention. Subdiaphragmatic vagotomy or splanchnicotomy+celiac ganglionectomy and capsaicin, ondansetron, hexamethonium, L-NAME, and glibenclamide treatment prevented the AS-induced delay in gastric emptying, whereas atropine and guanethidine treatment failed to prevent it. Atrial stretch inhibited the gastric emptying of liquid via non-adrenergic and non-cholinergic pathways that activate nitric oxide-K(+)ATP channels. Copyright © 2013 Elsevier Inc. All rights reserved.

Effect of Pregabalin and Dexamethasone on Postoperative Analgesia after Septoplasty

PubMed Central

Demirhan, Abdullah; Akkaya, Akcan; Tekelioglu, Umit Yasar; Apuhan, Tayfun; Bilgi, Murat; Yurttas, Veysel; Bayir, Hakan; Yildiz, Isa; Gok, Uzeyir; Kocoglu, Hasan

2014-01-01

Objectives. The aim of this study was to explore effect of a combination of pregabalin and dexamethasone on pain control after septoplasty operations. Methods. In this study, 90 patients who were scheduled for septoplasty under general anesthesia were randomly assigned into groups that received either placebo (Group C), pregabalin (Group P), or pregabalin and dexamethasone (Group PD). Preoperatively, patients received either pregabalin 300 mg one hour before surgery, dexamethasone 8 mg intravenously during induction, or placebo according to their allocation. Postoperative pain treatment included tramadol and diclofenac sodium 30 minutes before the end of the operation. Numeric rating scale (NRS) for pain assessment, side effects, and consumption of tramadol, pethidine, and ondansetron were recorded. Results. The median NRS score at the postoperative 0 and the 2nd h was significantly higher in Group C than in Group P and Group PD (P ≤ 0.004 for both). The 24 h tramadol and pethidine, consumptions were significantly reduced in Groups P and PD compared to Group C (P < 0.001 and P < 0.001). The incidence of blurred vision was significantly higher in Group PD compared to Group C within both 0–2 h and 0–24 h periods (P = 0.002 and P < 0.001, resp.). Conclusions. We conclude that administration of 300 mg pregabalin preoperatively may be an adequate choice for pain control after septoplasty. Addition of dexamethasone does not significantly reduce pain in these patients. PMID:24876957

Severe forms of food allergy.

PubMed

Sarinho, Emanuel; Lins, Maria das Graças Moura

To guide the diagnostic and therapeutic management of severe forms of food allergy. Search in the Medline database using the terms "severe food allergy," "anaphylaxis and food allergy," "generalized urticaria and food allergy," and "food protein-induced enterocolitis syndrome" in the last ten years, searching in the title, abstract, or keyword fields. Food allergy can be serious and life-threatening. Milk, eggs, peanuts, nuts, walnuts, wheat, sesame seeds, shrimp, fish, and fruit can precipitate allergic emergencies. The severity of reactions will depend on associated cofactors such as age, drug use at the onset of the reaction, history and persistence of asthma and/or severe allergic rhinitis, history of previous anaphylaxis, exercise, and associated diseases. For generalized urticaria and anaphylaxis, intramuscular epinephrine is the first and fundamental treatment line. For the treatment in acute phase of food-induced enterocolitis syndrome in the emergency setting, prompt hydroelectrolytic replacement, administration of methylprednisolone and ondansetron IV are necessary. It is important to recommend to the patient with food allergy to maintain the exclusion diet, seek specialized follow-up and, in those who have anaphylaxis, to emphasize the need to carry epinephrine. Severe food allergy may occur in the form of anaphylaxis and food-protein-induced enterocolitis syndrome, which are increasingly observed in the pediatric emergency room; hence, pediatricians must be alert so they can provide the immediate diagnosis and treatment. Copyright © 2017 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

Peripheral 5-HT3 Receptors Are Involved in the Antinociceptive Effect of Bunodosine 391

PubMed Central

Ferreira Junior, Wilson Alves; Zaharenko, Andre Junqueira; Kazuma, Kohei; Picolo, Gisele; Gutierrez, Vanessa Pacciari; de Freitas, Jose Carlos; Konno, Katsuhiro

2017-01-01

Bunodosine 391 (BDS 391), a low molecular weight compound isolated from the sea anemone Bunodosoma cangicum, increases the nociceptive threshold and inhibits inflammatory hyperalgesia. Serotonin receptors are involved in those effects. In this study, we have expanded the characterization of the antinociceptive effect of BDS 391 demonstrating that, in rats: (a) the compound inhibits (1.2–12 ng/paw) overt pain, in the formalin test, and mechanical hyperalgesia (0.6–6.0 ng/paw) detected in a model of neuropathic pain; (b) intraplantar administration of ondansetron, a selective 5-HT3 receptor antagonist, blocks the effect of BDS 391, whereas ketanserin, a 5-HT2 receptor antagonist, partially reversed this effect, indicating the involvement of peripheral 5-HT2 and 5-HT3 receptors in BDS 391 antinociception; and (c) in binding assay studies, BDS 391 was not able to displace the selective 5-HT receptor antagonists, suggesting that this compound does not directly bind to these receptors. The effect of biguanide, a selective 5-HT3 receptor agonist, was also evaluated. The agonist inhibited the formalin’s nociceptive response, supporting an antinociceptive role for 5-HT3 receptors. Our study is the first one to show that a non-peptidic low molecular weight compound obtained from a sea anemone is able to induce antinociception and that activation of peripheral 5-HT3 receptors contributes to this effect. PMID:29280949

Actions of 5-hydroxytryptamine and 5-HT1A receptor ligands on rat dorso-lateral septal neurones in vitro.

PubMed

Van den Hooff, P; Galvan, M

1992-08-01

1. The actions of 5-hydroxytryptamine (5-HT) and some 5-HT1A receptor ligands on neurones in the rat dorso-lateral septal nucleus were recorded in vitro by intracellular recording techniques. 2. In the presence of tetrodotoxin (1 microM) to block any indirect effects, bath application of 5-HT (0.3-30 microM) hyperpolarized the neurones in a concentration-dependent manner and reduced membrane resistance. The hyperpolarization did not exhibit desensitization and was sometimes followed by a small depolarization. 3. The 5-HT1A receptor ligands, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), N,N-dipropyl-5-carboxamidotryptamine (DP-5-CT) and buspirone but not the non-selective 5-HT1 receptor agonist, 1-m-trifluoromethylphenylpiperazine (TFMPP), also hyperpolarized the neurones. 4. 5-HT, 8-OH-DPAT and DP-5-CT appeared to act as full agonists whereas buspirone behaved as a partial agonist. The estimated EC50S were: DP-5-CT 15 nM, 8-OH-DPAT 110 nM, 5-HT 3 microM and buspirone 110 nM. 5. At a concentration of 3 microM, the putative 5-HT1A receptor antagonists, spiperone, methiothepin, NAN-190 (1-(2-methoxyphenyl)-4-[4-(2-pthalimido)butyl]piperazine) and MDL 73005EF (8-[2-(2,3-dihydro-1,4-benzodioxin-2-yl-methylamino)ethyl]-8- azaspiro[4,5]decane-7,9-dione methyl sulphonate), produced a parallel rightward shift in the concentration-response curve to 5-HT with no significant reduction in the maximum response. The estimated pA2 values were: NAN-190 6.79, MDL 73005EF 6.59, spiperone 6.54 and methiothepin 6.17.6. The 5-HT2/5-HTlc receptor antagonist, ketanserin (3 microM) and the 5HT3 receptor antagonist, tropisetron (3 microM) did not antagonize the 5-HT-induced hyperpolarizations; however, ketanserin blocked the depolarization which sometimes followed the hyperpolarization.7. It is concluded that the 5-HT-induced membrane hyperpolarization of rat dorso-lateral septal neurones is mediated by 5-HTA receptors.

High-Throughput Screening for Identification of Blood-Brain Barrier Integrity Enhancers: A Drug Repurposing Opportunity to Rectify Vascular Amyloid Toxicity.

PubMed

Qosa, Hisham; Mohamed, Loqman A; Al Rihani, Sweilem B; Batarseh, Yazan S; Duong, Quoc-Viet; Keller, Jeffrey N; Kaddoumi, Amal

2016-07-06

The blood-brain barrier (BBB) is a dynamic interface that maintains brain homeostasis and protects it from free entry of chemicals, toxins, and drugs. The barrier function of the BBB is maintained mainly by capillary endothelial cells that physically separate brain from blood. Several neurological diseases, such as Alzheimer's disease (AD), are known to disrupt BBB integrity. In this study, a high-throughput screening (HTS) was developed to identify drugs that rectify/protect BBB integrity from vascular amyloid toxicity associated with AD progression. Assessing Lucifer Yellow permeation across in-vitro BBB model composed from mouse brain endothelial cells (bEnd3) grown on 96-well plate inserts was used to screen 1280 compounds of Sigma LOPAC®1280 library for modulators of bEnd3 monolayer integrity. HTS identified 62 compounds as disruptors, and 50 compounds as enhancers of the endothelial barrier integrity. From these 50 enhancers, 7 FDA approved drugs were identified with EC50 values ranging from 0.76-4.56 μM. Of these 7 drugs, 5 were able to protect bEnd3-based BBB model integrity against amyloid toxicity. Furthermore, to test the translational potential to humans, the 7 drugs were tested for their ability to rectify the disruptive effect of Aβ in the human endothelial cell line hCMEC/D3. Only 3 (etodolac, granisetron, and beclomethasone) out of the 5 effective drugs in the bEnd3-based BBB model demonstrated a promising effect to protect the hCMEC/D3-based BBB model integrity. These drugs are compelling candidates for repurposing as therapeutic agents that could rectify dysfunctional BBB associated with AD.

High-throughput screening for identification of blood-brain barrier integrity enhancers: a drug repurposing opportunity to rectify vascular amyloid toxicity

PubMed Central

Qosa, Hisham; Mohamed, Loqman A.; Al Rihani, Sweilem B.; Batarseh, Yazan S.; Duong, Quoc-Viet; Keller, Jeffrey N.; Kaddoumi, Amal

2016-01-01

The blood-brain barrier (BBB) is a dynamic interface that maintains brain homeostasis and protects it from free entry of chemicals, toxins and drugs. The barrier function of the BBB is maintained mainly by capillary endothelial cells that physically separate brain from blood. Several neurological diseases, such as Alzheimer’s disease (AD), are known to disrupt BBB integrity. In this study, a high-throughput screening (HTS) was developed to identify drugs that rectify/protect BBB integrity from vascular amyloid toxicity associated with AD progression. Assessing Lucifer Yellow permeation across in-vitro BBB model composed from mouse brain endothelial cells (bEnd3) grown on 96-well plate inserts was used to screen 1280 compounds of Sigma LOPAC®1280 library for modulators of bEnd3 monolayer integrity. HTS identified 62 compounds as disruptors, and 50 compounds as enhancers of the endothelial barrier integrity. From these 50 enhancers, 7 FDA approved drugs were identified with EC50 values ranging from 0.76–4.56 μM. Of these 7 drugs, five were able to protect bEnd3-based BBB model integrity against amyloid toxicity. Furthermore, to test the translational potential to humans, the 7 drugs were tested for their ability to rectify the disruptive effect of Aβ in the human endothelial cell line hCMEC/D3. Only 3 (etodolac, granisetron and beclomethasone) out of the 5 effective drugs in the bEnd3-based BBB model demonstrated a promising effect to protect the hCMEC/D3-based BBB model integrity. These drugs are compelling candidates for repurposing as therapeutic agents that could rectify dysfunctional BBB associated with AD. PMID:27392852

Noncompetitive Inhibition of 5-HT3 Receptors by Citral, Linalool, and Eucalyptol Revealed by Nonlinear Mixed-Effects Modeling.

PubMed

Jarvis, Gavin E; Barbosa, Roseli; Thompson, Andrew J

2016-03-01

Citral, eucalyptol, and linalool are widely used as flavorings, fragrances, and cosmetics. Here, we examined their effects on electrophysiological and binding properties of human 5-HT3 receptors expressed in Xenopus oocytes and human embryonic kidney 293 cells, respectively. Data were analyzed using nonlinear mixed-effects modeling to account for random variance in the peak current response between oocytes. The oils caused an insurmountable inhibition of 5-HT-evoked currents (citral IC50 = 120 µM; eucalyptol = 258 µM; linalool = 141 µM) and did not compete with fluorescently labeled granisetron, suggesting a noncompetitive mechanism of action. Inhibition was not use-dependent but required a 30-second preapplication. Compound washout caused a slow (∼180 seconds) but complete recovery. Coapplication of the oils with bilobalide or diltiazem indicated they did not bind at the same locations as these channel blockers. Homology modeling and ligand docking predicted binding to a transmembrane cavity at the interface of adjacent subunits. Liquid chromatography coupled to mass spectrometry showed that an essential oil extracted from Lippia alba contained 75.9% citral. This inhibited expressed 5-HT3 receptors (IC50 = 45 µg ml(-1)) and smooth muscle contractions in rat trachea (IC50 = 200 µg ml(-1)) and guinea pig ileum (IC50 = 20 µg ml(-1)), providing a possible mechanistic explanation for why this oil has been used to treat gastrointestinal and respiratory ailments. These results demonstrate that citral, eucalyptol, and linalool inhibit 5-HT3 receptors, and their binding to a conserved cavity suggests a valuable target for novel allosteric modulators. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Canadian Headache Society systematic review and recommendations on the treatment of migraine pain in emergency settings.

PubMed

Orr, Serena L; Aubé, Michel; Becker, Werner J; Davenport, W Jeptha; Dilli, Esma; Dodick, David; Giammarco, Rose; Gladstone, Jonathan; Leroux, Elizabeth; Pim, Heather; Dickinson, Garth; Christie, Suzanne N

2015-03-01

There is a considerable amount of practice variation in managing migraines in emergency settings, and evidence-based therapies are often not used first line. A peer-reviewed search of databases (MEDLINE, Embase, CENTRAL) was carried out to identify randomized and quasi-randomized controlled trials of interventions for acute pain relief in adults presenting with migraine to emergency settings. Where possible, data were pooled into meta-analyses. Two independent reviewers screened 831 titles and abstracts for eligibility. Three independent reviewers subsequently evaluated 120 full text articles for inclusion, of which 44 were included. Individual studies were then assigned a US Preventive Services Task Force quality rating. The GRADE scheme was used to assign a level of evidence and recommendation strength for each intervention. We strongly recommend the use of prochlorperazine based on a high level of evidence, lysine acetylsalicylic acid, metoclopramide and sumatriptan, based on a moderate level of evidence, and ketorolac, based on a low level of evidence. We weakly recommend the use of chlorpromazine based on a moderate level of evidence, and ergotamine, dihydroergotamine, lidocaine intranasal and meperidine, based on a low level of evidence. We found evidence to recommend strongly against the use of dexamethasone, based on a moderate level of evidence, and granisetron, haloperidol and trimethobenzamide based on a low level of evidence. Based on moderate-quality evidence, we recommend weakly against the use of acetaminophen and magnesium sulfate. Based on low-quality evidence, we recommend weakly against the use of diclofenac, droperidol, lidocaine intravenous, lysine clonixinate, morphine, propofol, sodium valproate and tramadol. © International Headache Society 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Transmission to interneurons is via slow excitatory synaptic potentials mediated by P2Y(1) receptors during descending inhibition in guinea-pig ileum.

PubMed

Thornton, Peter D J; Gwynne, Rachel M; McMillan, Darren J; Bornstein, Joel C

2013-01-01

The nature of synaptic transmission at functionally distinct synapses in intestinal reflex pathways has not been fully identified. In this study, we investigated whether transmission between interneurons in the descending inhibitory pathway is mediated by a purine acting at P2Y receptors to produce slow excitatory synaptic potentials (EPSPs). Myenteric neurons from guinea-pig ileum in vitro were impaled with intracellular microelectrodes. Responses to distension 15 mm oral to the recording site, in a separately perfused stimulation chamber and to electrical stimulation of local nerve trunks were recorded. A subset of neurons, previously identified as nitric oxide synthase immunoreactive descending interneurons, responded to both stimuli with slow EPSPs that were reversibly abolished by a high concentration of PPADS (30 μM, P2 receptor antagonist). When added to the central chamber of a three chambered organ bath, PPADS concentration-dependently depressed transmission through that chamber of descending inhibitory reflexes, measured as inhibitory junction potentials in the circular muscle of the anal chamber. Reflexes evoked by distension in the central chamber were unaffected. A similar depression of transmission was seen when the specific P2Y(1) receptor antagonist MRS 2179 (10 μM) was in the central chamber. Blocking either nicotinic receptors (hexamethonium 200 μM) or 5-HT(3) receptors (granisetron 1 μM) together with P2 receptors had no greater effect than blocking P2 receptors alone. Slow EPSPs mediated by P2Y(1) receptors, play a primary role in transmission between descending interneurons of the inhibitory reflexes in the guinea-pig ileum. This is the first demonstration for a primary role of excitatory metabotropic receptors in physiological transmission at a functionally identified synapse.

UPDATE ON NEUROPHARMACOLOGICAL TREATMENTS FOR ALCOHOLISM: SCIENTIFIC BASIS AND CLINICAL FINDINGS

PubMed Central

JOHNSON, BANKOLE A.

2008-01-01

The past decade has seen an expansion of research and knowledge on pharmacotherapy for the treatment of alcohol dependence. The Food and Drug Administration (FDA)–approved medications naltrexone and acamprosate have shown mixed results in clinical trials. Oral naltrexone and naltrexone depot formulations have generally demonstrated efficacy at treating alcohol dependence, but their treatment effect size is small, and more research is needed to compare the effects of different doses on drinking outcome. Acamprosate has demonstrated efficacy for treating alcohol dependence in European trials, but with a small effect size. In U.S. trials, acamprosate has not proved to be efficacious. Research continues to explore which types of alcohol-dependent individual would benefit the most from treatment with naltrexone or acamprosate. The combination of the two medications demonstrated efficacy for treating alcohol dependence in one European study but not in a multi-site U.S. study. Another FDA-approved medication, disulfiram, is an aversive agent that does not diminish craving for alcohol. Disulfiram is most effective when given to those who are highly compliant or who are receiving their medication under supervision. Of the non-approved medications, topiramate is among the most promising, with a medium effect size in clinical trials. Another promising medication, baclofen, has shown efficacy in small trials. Serotonergic agents such as selective serotonin reuptake inhibitors and the serotonin-3 receptor antagonist, ondansetron, appear to be efficacious only among certain genetic subtypes of alcoholic. As neuroscientific research progresses, other promising medications, as well as medication combinations, for treating alcohol dependence continue to be explored. PMID:17880925

Accidental intoxication with Veratrum album.

PubMed

Grobosch, T; Binscheck, T; Martens, F; Lampe, D

2008-01-01

A 49-year-old man consumed two glasses (approximately 2 x 20 mL) of a beverage containing yellow gentian (Gentiana lutea). Shortly after ingestion, he developed nausea, vomiting, and oral paraesthesia. On admission to the hospital he suffered from severe bradycardia (35 beats/min) and hypotension (50/30 mm Hg), and he was treated with activated charcoal, antiemetics (metoclopramide, ondansetron), atropine, and intravenous electrolytic solution. The initial suspicion of Veratrum poisoning could be confirmed by identifying protoveratrines A (ProA) and protoveratrine B (ProB) in a sample from the beverage as well as in the patients serum by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS-MS). The yellow-colored beverage contained 25% ethanol (by headspace gas chromatography), 20.4 mg/L ProA, and 13.7 mg/L ProB. The serum concentration of ProA was 1162 ng/L and ProB was 402 ng/L. Veratridine, cevadine, and jervine were not detected, neither in the beverage nor in the serum sample. The lower limits of quantitation for all compounds is 10 microg/L (S/N > 10, beverage) and 100 ng/L (S/N > 10, serum). After treatment, the patient completely recovered from the symptoms within 24 h and was discharged from the hospital. The analytical method described was developed for the simultaneous identification and quantitation of five Veratrum alkaloids. The method is based on a liquid-liquid extraction followed by LC-MS-MS analysis. The time needed for analysis was 6 min.

[Doses of anti-infectives for systemic use are scarcely notified in clinical cases reported to the Revista Española de Anestesiología y Reanimación].

PubMed

Gerónimo-Pardo, M

2014-01-01

To describe the frequency of dose notification of antiinfectives for systemic use in clinical cases published in Revista Española de Anestesiología y Reanimación. Review of individualized clinical cases published in the sections «Clinical case» or «Letter to the Editor» of the above mentioned journal from year 2010 to 2012, and identification of the drugs and their therapeutic regimens cited in such publications, being dose notification the main variable. Drugs have been classified according to the Anatomical Therapeutic Chemical Classification System. One thousand one hundred and thirty-five drugs cited 1,317 times were identified in 167 articles describing the clinical pictures of 182 patients, 73 of the citations (5.6%) regarding to drugs belonging to group J (Antiinfectives for systemic use) which were divided into perioperative prophylaxis (n=15) and active treatment (n=58). Doses were scarcely notified for group J drugs as a whole (27.4%), but especially for active treatment (17.2%) compared to perioperative prophylaxis (66.7%), percentage which was similar to those more classical anesthetic drugs (fentanyl: 86.6%; remifentanil: 70.5%; sevoflurane: 78%; propofol: 79%; rocuronium:79.6%; cisatracurium: 68.4%) or even for antiemetics (ondansetron: 92.3%; dexamethasone: 84.6%). Quality of case reports could be improved by including dose notification for antiinfective agents. Copyright © 2013 Sociedad Española de Anestesiología, Reanimación y Terapéutica del Dolor. Published by Elsevier España. All rights reserved.

Serotonergic modulation of nicotine-induced kinetic tremor in mice.

PubMed

Kunisawa, Naofumi; Iha, Higor A; Nomura, Yuji; Onishi, Misaki; Matsubara, Nami; Shimizu, Saki; Ohno, Yukihiro

2017-06-01

We previously demonstrated that nicotine elicited kinetic tremor by elevating the neural activity of the inferior olive via α7 nicotinic acetylcholine (nACh) receptors. Since α7 nACh receptors reportedly facilitate synaptic monoamine release, we explored the role of 5-HT receptors in induction and/or modulation of nicotine tremor. Treatment of mice with nicotine induced kinetic tremor that normally appeared during movement. The 5-HT 1A agonist, 8-hydroxydipropylaminotetraline (8-OH-DPAT), significantly enhanced nicotine-induced tremor and the action of 8-OH-DPAT was antagonized by WAY-100135 (5-HT 1A antagonist). In addition, the cerebral 5-HT depletion by repeated treatment with p-chlorophenylalanine did not reduce, but rather potentiated the facilitatory effects of 8-OH-DPAT. In contrast, the 5-HT 2 agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI), significantly attenuated nicotine tremor, which was antagonized by ritanserin (5-HT 2 antagonist). The 5-HT 3 agonist SR-57227 did not affect nicotine-induced tremor. Furthermore, when testing the direct actions of 5-HT antagonists, nicotine tremor was inhibited by WAY-100135, but was unaffected by ritanserin, ondansetron (5-HT 3 antagonist) or SB-258585 (5-HT 6 antagonist). These results suggest that postsynaptic 5-HT 1A receptors are involved in induction of nicotine tremor mediated by α7 nACh receptors. In addition, 5-HT 2 receptors have an inhibitory modulatory role in induction of nicotine tremor. Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

Efficacy and safety of aprepitant for the prevention of chemotherapy-induced nausea and vomiting during the first cycle of moderately emetogenic chemotherapy in Korean patients with a broad range of tumor types.

PubMed

Kim, Jeong Eun; Jang, Joung-Soon; Kim, Jae-Weon; Sung, Yong Lee; Cho, Chi-Heum; Lee, Myung-Ah; Kim, Do-Jin; Ahn, Myung-Ju; Lee, Kil Yeon; Sym, Sun Jin; Lim, Myong Choel; Jung, Hun; Cho, Eun Kim; Min, Kyung Wan

2017-03-01

This study evaluated the efficacy and safety of a 3-day aprepitant regimen for the prevention of chemotherapy-induced nausea and vomiting (CINV) during the first cycle of non-anthracycline plus cyclophosphamide (AC)-based moderately emetogenic chemotherapy (MEC) based on government guidelines in Korean patients. This multicenter, randomized, double-blind, phase IV trial (NCT01636947) enrolled adult South Korean patients with a broad range of tumor types who were scheduled to receive a single dose of ≥1 MEC agent. Patients were randomized to a 3-day regimen of aprepitant (aprepitant regimen) or placebo (control regimen) on top of ondansetron plus dexamethasone. The primary and key secondary efficacy endpoints were the proportions of subjects who achieved no vomiting and complete response (CR) during the overall phase. Of the 494 randomized subjects, 480 were included in the modified intent-to-treat population. Response rates for no vomiting and CR in the overall phase were numerically higher for the aprepitant regimen compared with the control regimen groups, but failed to reach statistical significance (no vomiting 77.2 vs 72.0%; p = 0.191; CR 73.4 vs 70.4%; p = 0.458). Both the aprepitant and control regimens were generally well tolerated. A 3-day aprepitant regimen was numerically better but not statistically superior to a control regimen with respect to the achievement of no vomiting or CR during the overall phase in a non-AC MEC Korean population based on government reimbursement guidelines. ClinicalTrials.gov NCT01636947 ( https://clinicaltrials.Gov/ct2/show/NCT01636947 ).

Diabetic and Nondiabetic Gastroparesis.

PubMed

McCallum; Brown

1998-12-01

Nutritional support is essential in treating patients with gastroparesis. Initially, dietary changes should be instituted to reduce extra fat and bulk, and patients should be encouraged to eat frequent small meals with liquid supplementation. Enteral feeding should be introduced in the event of weight loss or persistent vomiting. Medical therapy is usually necessary early in treatment. Cisapride is the initial agent of choice and may be combined with an antiemetic agent, such as promethazine or chlorpromazine or, if side effects occur, ondansetron and granesitron. If cisapride is ineffective or contraindicated, metoclopramide is a reasonable option, though limited by side effects. Erythromycin is useful in the acute treatment of postoperative ileus and hospitalized gastroparetic patients, but its role is limited based on concerns about poor long-term effectiveness and antimicrobial resistance. Once domperidone becomes available in the United States, it will be useful for its promotility and antiemetic qualities. Combination therapy should be considered if monotherapy with cisapride or metoclopramide alone is ineffective. While not yet well studied, combination therapy has the potential to offer dramatic benefit for patients with refractory gastroparesis. Metoclopramide may be added to cisapride for patients with breakthrough symptoms or refractory chronic symptoms. Other combinations include metoclopramide with erythromycin, domperidone with cisapride, and domperidone with erythromycin. In the future, gastric pacing may become an effective option for patients not responding to medical therapy. Total gastrectomy should be performed only for end-stage gastroparesis when all other therapy has failed. Both procedures should be reserved for centers that specialize in severe gastric motility disorders.

Genetic Influences on Response to Alcohol and Response to Pharmacotherapies for Alcoholism

PubMed Central

Enoch, Mary-Anne

2014-01-01

Although very many individuals drink alcohol at safe levels, a significant proportion escalates their consumption with addiction as the end result. Alcoholism is a common, moderately heritable, psychiatric disorder that is accompanied by considerable morbidity and mortality. Variation in clinical presentation suggests inter-individual variation in mechanisms of vulnerability including genetic risk factors. The development of addiction is likely to involve numerous functional genetic variants of small effects. The first part of this review will focus on genetic factors underlying inter-individual variability in response to alcohol consumption, including variants in alcohol metabolizing genes that produce an aversive response (the flushing syndrome) and variants that predict the level of subjective and physiological response to alcohol. The second part of this review will report on genetic variants that identify subgroups of alcoholics who are more likely to respond to pharmacotherapy to reduce levels of drinking or maintain abstinence. Genetic analyses of the level of response to alcohol, particularly of the functional OPRM1 A118G polymorphism and 5′ and 3′ functional polymorphisms in SLC6A4, are beginning to provide insights into the etiology of alcoholism and also genotype-stratified subgroup responses to naltrexone and SSRIs / ondansetron respectively. Because of large inter-ethnic variation in allele frequencies, the relevance of these functional polymorphisms will vary between ethnic groups. However there are relatively few published studies in this field, particularly with large sample sizes in pharmacogenetic studies, therefore it is premature to draw any conclusions at this stage. PMID:24220019

Management strategies in the treatment of neonatal and pediatric gastroenteritis

PubMed Central

Ciccarelli, Simona; Stolfi, Ilaria; Caramia, Giuseppe

2013-01-01

Acute gastroenteritis, characterized by the onset of diarrhea with or without vomiting, continues to be a major cause of morbidity and mortality in children in mostly resource-constrained nations. Although generally a mild and self-limiting disease, gastroenteritis is one of the most common causes of hospitalization and is associated with a substantial disease burden. Worldwide, up to 40% of children aged less than 5 years with diarrhea are hospitalized with rotavirus. Also, some microorganisms have been found predominantly in resource-constrained nations, including Shigella spp, Vibrio cholerae, and the protozoan infections. Prevention remains essential, and the rotavirus vaccines have demonstrated good safety and efficacy profiles in large clinical trials. Because dehydration is the major complication associated with gastroenteritis, appropriate fluid management (oral or intravenous) is an effective and safe strategy for rehydration. Continuation of breastfeeding is strongly recommended. New treatments such as antiemetics (ondansetron), some antidiarrheal agents (racecadotril), and chemotherapeutic agents are often proposed, but not yet universally recommended. Probiotics, also known as “food supplement,” seem to improve intestinal microbial balance, reducing the duration and the severity of acute infectious diarrhea. The European Society for Paediatric Gastroenterology, Hepatology and Nutrition and the European Society of Paediatric Infectious Diseases guidelines make a stronger recommendation for the use of probiotics for the management of acute gastroenteritis, particularly those with documented efficacy such as Lactobacillus rhamnosus GG, Lactobacillus reuteri, and Saccharomyces boulardii. To date, the management of acute gastroenteritis has been based on the option of “doing the least”: oral rehydration-solution administration, early refeeding, no testing, no unnecessary drugs. PMID:24194646

Emergency department management of gastro-enteritis in Australia and New Zealand.

PubMed

Schutz, Jacquie; Babl, Franz E; Sheriff, Nisa; Borland, Meredith

2008-10-01

Comparison of clinical practice guideline (CPG) recommendations and reported physician management of gastro-enteritis at Paediatric Research in Emergency Departments International Collaborative (PREDICT) network sites as a baseline for further randomised controlled trials. Two part survey comprising: (i) review of CPGs from PREDICT sites for gastro-enteritis; and (ii) survey of senior emergency department physicians regarding the management of gastro-enteritis. All 11 PREDICT sites participated. Nine CPGs were available with three sites using a common CPG. For moderate dehydration, eight CPGs advocated nasogastric (NG) rehydration in preference to intravenous (IV) rehydration. The IV route was reserved for severe dehydration or failed NG rehydration. In the second component of the survey, 78 of 83 (94%) physicians responded. In moderate dehydration, 82% of respondents used NG rehydration. In severe dehydration, 86% used IV fluids; 12% used NG and 3% an initial IV bolus followed by NG fluid. Serum electrolytes were measured universally with IV fluid use and by 22% using NG rehydration. The IV fluid bolus was with normal saline (86%). Fifty-four per cent used anti-emetics 'rarely' or 'sometimes'. The commonest agents were ondansetron (60%) and metoclopramide (29%). CPG recommendations and physician practice for the management of gastro-enteritis were similar across PREDICT sites with a focus on NG for moderate dehydration and IV for severe dehydration. A variety of fluids and administration rates were used. Anti-emetics were used infrequently. The efficacy and safety of newer anti-emetics should be explored in collaborative studies. Collaborative development of new CPGs should be considered to simplify fluid regimens.

Ultrasound-guided transversus abdominal plane block with multimodal analgesia for pain management after total abdominal hysterectomy.

PubMed

Gasanova, Irina; Grant, Erica; Way, Megan; Rosero, Eric B; Joshi, Girish P

2013-07-01

Transversus abdominis plane (TAP) block has been shown to provide pain relief after abdominal procedures. However, TAP block combined with multimodal analgesia technique have not been assessed in a randomized controlled trial. This randomized, controlled, observer-blinded study was designed to evaluate the analgesic efficacy of bilateral ultrasound-guided TAP blocks with or without acetaminophen and non-steroidal anti-inflammatory drug (NSAID) combination. Patients undergoing total abdominal hysterectomy were randomized to one of three groups. Group 1 (n = 25) received a TAP block and ketorolac 30 mg, IV at the end of surgery and then ketorolac plus paracetamol 650 mg, orally, every 6 h for 24 h. Group 2 (n = 24) received only TAP block at the end of surgery. Group 3 (n = 25) received ketorolac 30 mg, IV at the end of surgery and then ketorolac plus paracetamol 650 mg, orally, every 6 h for 24 h. All patients received IV-PCA morphine for 24-h, postoperatively. All patients received a standardized general anaesthetic technique and dexamethasone 4 mg and ondansetron 4 mg, IV for antiemetic prophylaxis. There were no statistically significant differences in pain at rest between the groups. However, the pain on coughing (dynamic pain) in Group 1 was significantly less variable, compared with the other two groups (P = 0.012). Opioid consumption and occurrences of nausea, vomiting, and rescue antiemetic were similar in three the groups. The combination of TAP block and acetaminophen and NSAID provided less variability in dynamic pain compared with either treatment alone.

Case report: intraoperative anaphylactoid reaction and hydroxyethyl starch in balanced electrolyte solution (Hextend).

PubMed

Hall, Brian A; Frigas, Evangelo; Matesic, Damir; Gillett, Michael D; Sprung, Juraj

2006-10-01

To report a first case of probable anaphylactoid reaction to 6% hydroxyethyl starch reconstituted in balanced electrolyte and glucose solution (Hextend). A 22-yr-old man was admitted for a partial nephrectomy. Near the end of the four-hour operation, an infusion of Hextend was initiated. Shortly thereafter, mechanical ventilation became difficult, peak inspiratory pressure increased to 55 cm H2O with audible wheezing over the patient's lungs. Blood pressure suddenly decreased to 68/46 mmHg. Multiple doses of phenylephrine, ephedrine and epinephrine were required to restore the patient's blood pressure. Postoperatively, a diffuse urticarial rash was apparent on his upper torso. The patient recovered uneventfully. His postoperative serum tryptase was 26.3 ng x mL(-1) (reference range, < 11.5 ng x mL(-1)) and the urine N-methyl-histamine was 2448 microg x g(-1) creatinine (reference range, 30-200 microg x g(-1) creatinine). Two months after the event, skin testing was conducted to test for possible allergy to latex, lidocaine, propofol, cisatracurium, succinylcholine, vecuronium, midazolam, fentanyl, ondansetron, neostigmine, and cephazolin, and all were negative. Hextend was also tested, starting with a 1:100,000 dilution and the results were negative. The temporal relationship of severe hypotension, bronchospasm and skin rash within ten minutes from administration of Hextend in this patient suggests an immediate hypersensitivity reaction to hetastarch. The elevated levels of serum tryptase and urinary N-methyl-histamine suggest that this hypersensitivity was mediated from mast cell degranulation. Negative skin testing suggests that the reaction was anaphylactoid.

Use of uridine triacetate for the management of fluorouracil overdose.

PubMed

McEvilly, Margaret; Popelas, Carl; Tremmel, Bob

2011-10-01

The use of uridine triacetate for the management of fluorouracil toxicity is reported. A 55-year-old man with malignant neoplasm of the sigmoid colon (stage IIIC) was seen in an outpatient chemotherapy center for his first six-month regimen of leucovorin calcium, fluorouracil, and oxaliplatin. Fluorouracil 2400 mg/m(2) i.v. was prescribed to be given over the next 46 hours at a home infusion center. Due to a medication error, a home infusion pharmacist incorrectly programmed the 46-hour infusion of fluorouracil to be administered over 4 hours. To manage the fluorouracil overdose, the physician decided to start the patient on uridine triacetate. The patient received his first dose of uridine triacetate 18 hours after the fluorouracil overdose. He was admitted to the hospital for observation and daily laboratory tests during treatment with uridine triacetate. He received ondansetron (as the hydrochloride salt) 8 mg orally 20 minutes before each dose of uridine triacetate to prevent nausea and vomiting. Uridine triacetate 11 g every 6 hours was administered orally for a total of 20 doses. It was mixed with applesauce at the time of administration and followed with 8 oz of water. The patient's laboratory values remained stable. The patient did not experience any nausea or vomiting during treatment. He was discharged from the hospital on day 5, with no clinical complications and an Eastern Cooperative Oncology Group Performance score of 0. A patient with colon cancer who had received an overdose of fluorouracil was successfully treated with a five-day course of oral uridine triacetate.

Off-label prescribing patterns of antiemetics in children: a multicenter study in Italy.

PubMed

Zanon, Davide; Gallelli, Luca; Rovere, Francesca; Paparazzo, Rossella; Maximova, Natalia; Lazzerini, Marzia; Reale, Antonio; Corsetti, Tiziana; Renna, Salvatore; Emanueli, Tullia; Mannelli, Francesco; Manteghetti, Francesco; Da Dalt, Liviana; Palleria, Caterina; Banchieri, Nicola; Urbino, Antonio; Miglietta, Mario; Cardoni, Giovanni; Pompilio, Adriana; Arrighini, Alberto; Lazzari, Clara; Messi, Gianni

2013-03-01

Acute gastroenteritis (AG) represents both the main cause of acute vomiting in children under 3 years old and a major cause of access to the emergency department. Even if several drugs may be able to reduce the emesis, the pharmacological treatment of vomiting in children remains a controversial issue, and several drugs are prescribed outside their authorized drug label with respect dosage, age, indication, or route of administration and are named as off-label. The aim of present study was to assess the off-label use of antiemetic drugs in patients less than 18 years with vomiting related to AG. This study was carried out in eight pediatric emergency departments in Italy. The following data were obtained crossing the pharmacy distribution records with emergency departments' patient data: sex and age of the patients and detailed information for each drug used (indication, dose, frequency, and route of administration). We recorded that antiemetic drugs were prescribed in every year, particularly in children up to 2 years old, and compared with both literature data and data sheet; 30 % of the administered antiemetics were used off-label. In particular, domperidone was the only antiemetic used labeled for AG treatment in pediatric patients, while metoclopramide and ondansetron have been off-label for both age and indications (i.e., AG treatment). In conclusion, we documented an off-label use of antiemetics in children, and this could represents a problem of safety for the patient and a legal risk for the prescribing physician if patients have an unwanted or bad outcome from treatment.

Localized Release of Serotonin (5-Hydroxytryptamine) by a Fecal Pellet Regulates Migrating Motor Complexes in Murine Colon

PubMed Central

HEREDIA, DANTE J.; DICKSON, EAMONN J.; BAYGUINOV, PETER O.; HENNIG, GRANT W.; SMITH, TERENCE K.

2009-01-01

Background & Aims The colonic migrating motor complex (CMMC) is a motor pattern that regulates the movement of fecal matter, through a rhythmic sequence of electrical activity and/or contractions, along the large bowel. CMMCs have largely been studied in empty preparations; we investigated whether local reflexes generated by a fecal pellet modify the CMMC to initiate propulsive activity. Methods Recordings of CMMCs were made from the isolated murine large bowel, with or without a fecal pellet. Transducers were placed along the colon to record muscle tension and propulsive force on the pellet and microelectrodes were used to record electrical activity from circular muscle cells anal and oral of a pellet and in colons without the mucosa. Results Spontaneous CMMCs propagated in both an oral or anal direction. When a pellet was inserted, CMMCs increased in frequency and propagated anally, exerting propulsive force on the pellet. The amplitude of slow waves increased during the CMMC. Localized mucosal stimulation/circumferential stretch evoked a CMMC, regardless of stimulus strength. The serotonin (5-hydroxytryptamine-3) antagonist ondansetron reduced the amplitude of the CMMC, the propulsive force on the pellet, and the response to mucosal stroking, but increased the apparent conduction velocity of the CMMC. Removing the mucosa abolished spontaneous CMMCs, which still could be evoked by electrical stimulation. Conclusions The fecal pellet activates local mucosal reflexes, which release serotonin (5-hydroxytryptamine) from enterochromaffin cells, and stretch reflexes that determine the site of origin and propagation of the CMMC, facilitating propulsion. PMID:19138686

Aggravation by paroxetine, a selective serotonin reuptake inhibitor, of antral lesions generated by nonsteroidal anti-inflammatory drugs in rats.

PubMed

Takeuchi, Koji; Tanaka, Akiko; Nukui, Kazuo; Kojo, Azusa; Gyenge, Melinda; Amagase, Kikuko

2011-09-01

Recent clinical studies have suggested a risk of adverse gastric reactions from the concomitant use of selective serotonin (5-HT) reuptake inhibitors (SSRIs) with nonsteroidal anti-inflammatory drugs (NSAIDs). We examined the adverse effects of SSRIs on antral lesions produced by indomethacin in rats. Rats fasted for 24 h were refed for 1 h, then administered indomethacin (30 mg/kg s.c.) 1 h after the refeeding and killed 6 h later. Paroxetine (1-10 mg/kg) was given orally 30 min before indomethacin. Indomethacin caused antral lesions in refed rats. Paroxetine dose-dependently aggravated these lesions, despite provoking no damage by itself. Similar results were obtained when other NSAIDs such as diclofenac, flurbiprofen, and loxoprofen were coadministered with paroxetine or when indomethacin was coadministered with other antidepressants such as fluvoxamine and milnacipran, but not imipramine or maprotiline. Exogenous 5-HT also worsened the indomethacin-induced antral damage, whereas the aggravating effect of paroxetine was attenuated by ondansetron, a selective 5-HT(3) antagonist, but not antagonists for other 5-HT receptor subtypes. Indomethacin plus paroxetine had no effect on gastric secretion but significantly decreased mucosal superoxide dismutase (SOD) activity as well as GSH content. The antral damage induced by indomethacin plus paroxetine was significantly prevented by antisecretory (acid or pepsin) agents and mucosal protective agents as well as SOD and allopurinol. These results suggest that SSRIs aggravate NSAID-induced antral lesions, probably via the activation of 5HT(3) receptors, and the mechanism of aggravation may involve the corrosive action of acid/pepsin as well as an impaired antioxidative system.

Fast track endoscopic thoracic sympathicotomy.

PubMed

Duarte, João Bosco Vieira; Kux, Peter; Castro, Carlos H V; Cruvinel, Marcos G C; Costa, José R R

2003-12-01

The length of hospital stay is an important factor of cost and psychological discomfort in the treatment of hyperhidrosis by endoscopic thoracic sympathicotomy (ETS). Our experience enrolls 1587 patients operated on an outpatient basis in the last 10 years and seven months. This study aimed to confirm that ETS can be performed on an outpatient basis. Fifty-two consecutive patients (30 males and 22 females) were submitted to ETS under general anesthesia using a single lumen endotracheal tube, with lung collapse by intrapleural injection of CO(2). The sympathetic chain and the communicating rami were severed at different levels according to hyperhidrosis location. Patients were physical state American Society of Anesthesiologists 1 and 2. Age varied between 13 and 55 years (27.3 +/- 10.2 years). They were monitored with ECG, SPO2, NIBP, expired CO(2), sevoflurane analyzer, and airway pressure. Normal saline (40.0 +/- 2.7 ml/kg) was infused intravenously. The drugs used were propofol, alfentanil, rocuronium, ondansetron, dexamethasone, dipyrone, cetoprofene and sevoflurane. Anesthesia and post-operative data were analyzed. Post-operative thoracic X-rays were taken in 20 patients before discharge. Anesthesia lasted 67.2 +/- 20.8 minutes, and the surgical procedure took 46.3 +/- 20.9 minutes. The patients stayed 18.0 +/- 11.0 minutes in the post-anaesthetic care unit and were discharged from hospital after 150.3 +/- 43.1 minutes. The only abnormal post-operative event observed was insignificant residual carbothorax, found in 2 (10%) of the thoracic X-rays taken. In conclusion, this study confirmed that ETS can be performed safely on an outpatient basis.

Pharmacogenomics and pharmacogenetics for the intensive care unit: a narrative review.

PubMed

MacKenzie, Meghan; Hall, Richard

2017-01-01

Knowledge of how alterations in pharmacogenomics and pharmacogenetics may affect drug therapy in the intensive care unit (ICU) has received little study. We review the clinically relevant application of pharmacogenetics and pharmacogenomics to drugs and conditions encountered in the ICU. We selected relevant literature to illustrate the important concepts contained within. Two main approaches have been used to identify genetic abnormalities - the candidate gene approach and the genome-wide approach. Genetic variability in response to drugs may occur as a result of alterations of drug-metabolizing (cytochrome P [CYP]) enzymes, receptors, and transport proteins leading to enhancement or delay in the therapeutic response. Of relevance to the ICU, genetic variation in CYP-450 isoenzymes results in altered effects of midazolam, fentanyl, morphine, codeine, phenytoin, clopidogrel, warfarin, carvedilol, metoprolol, HMG-CoA reductase inhibitors, calcineurin inhibitors, non-steroidal anti-inflammatory agents, proton pump inhibitors, and ondansetron. Changes in cholinesterase enzyme function may affect the disposition of succinylcholine, benzylisoquinoline muscle relaxants, remifentanil, and hydralazine. Genetic variation in transport proteins leads to differences in the response to opioids and clopidogrel. Polymorphisms in drug receptors result in altered effects of β-blockers, catecholamines, antipsychotic agents, and opioids. Genetic variation also contributes to the diversity and incidence of diseases and conditions such as sepsis, malignant hyperthermia, drug-induced hypersensitivity reactions, cardiac channelopathies, thromboembolic disease, and congestive heart failure. Application of pharmacogenetics and pharmacogenomics has seen improvements in drug therapy. Ongoing study and incorporation of these concepts into clinical decision making in the ICU has the potential to affect patient outcomes.

An Investigation of Drug-Drug Interaction Alert Overrides at a Pediatric Hospital.

PubMed

Humphrey, Kate; Jorina, Maria; Harper, Marvin; Dodson, Brenda; Kim, Seung-Yeon; Ozonoff, Al

2018-05-01

Drug-drug interactions (DDIs) can result in patient harm. DDI alerts are intended to help prevent harm; when the majority of alerts presented to providers are being overridden, their value is diminished. Our objective was to evaluate the overall rates of DDI alert overrides and how rates varied by specialty, clinician type, and patient complexity. A retrospective study of DDI alert overrides that occurred during 2012 and 2013 within the inpatient setting described at the medication-, hospital-, provider-, and patient encounter-specific levels was performed at an urban, quaternary-care, pediatric hospital. There were >41 000 DDI alerts presented to clinicians; ∼90% were overridden. The 5 DDI pairs that were most frequently presented and overridden included the following: potassium chloride-spironolactone, methadone-ondansetron, ketorolac-ibuprofen, cyclosporine-fluconazole, and potassium chloride-enalapril, each with an alert override rate of ≥0.89. Override rates across provider groups ranged between 0.84 and 0.97. In general, patients with high complexity had a higher frequency of alert overrides, but the rates of alert overrides for each DDI pairing did not differ significantly. High rates of DDI alert overrides occur across medications, provider groups, and patient encounters. Methods to decrease DDI alerts which are likely to be overridden exist, but it is also clear that more robust and intelligent tools are needed. Characteristics exist at the medication, hospital, provider, and patient levels that can be used to help specialize and enhance information transmission. Copyright © 2018 by the American Academy of Pediatrics.

Genetic influences on response to alcohol and response to pharmacotherapies for alcoholism.

PubMed

Enoch, Mary-Anne

2014-08-01

Although very many individuals drink alcohol at safe levels, a significant proportion escalates their consumption with addiction as the end result. Alcoholism is a common, moderately heritable, psychiatric disorder that is accompanied by considerable morbidity and mortality. Variation in clinical presentation suggests inter-individual variation in mechanisms of vulnerability including genetic risk factors. The development of addiction is likely to involve numerous functional genetic variants of small effects. The first part of this review will focus on genetic factors underlying inter-individual variability in response to alcohol consumption, including variants in alcohol metabolizing genes that produce an aversive response (the flushing syndrome) and variants that predict the level of subjective and physiological response to alcohol. The second part of this review will report on genetic variants that identify subgroups of alcoholics who are more likely to respond to pharmacotherapy to reduce levels of drinking or maintain abstinence. Genetic analyses of the level of response to alcohol, particularly of the functional OPRM1 A118G polymorphism and 5' and 3' functional polymorphisms in SLC6A4, are beginning to provide insights into the etiology of alcoholism and also genotype-stratified subgroup responses to naltrexone and SSRIs/ondansetron respectively. Because of large inter-ethnic variation in allele frequencies, the relevance of these functional polymorphisms will vary between ethnic groups. However there are relatively few published studies in this field, particularly with large sample sizes in pharmacogenetic studies, therefore it is premature to draw any conclusions at this stage. Published by Elsevier Inc.

The antimalarial drugs quinine, chloroquine and mefloquine are antagonists at 5-HT3 receptors

PubMed Central

Thompson, A J; Lochner, M; Lummis, S C R

2007-01-01

Background and Purpose: The antimalarial compounds quinine, chloroquine and mefloquine affect the electrophysiological properties of Cys-loop receptors and have structural similarities to 5-HT3 receptor antagonists. They may therefore act at 5-HT3 receptors. Experimental Approach: The effects of quinine, chloroquine and mefloquine on electrophysiological and ligand binding properties of 5-HT3A receptors expressed in HEK 293 cells and Xenopus oocytes were examined. The compounds were also docked into models of the binding site. Key Results: 5-HT3 responses were blocked with IC 50 values of 13.4 μM, 11.8 μM and 9.36 μM for quinine, chloroquine and mefloquine. Schild plots indicated quinine and chloroquine behaved competitively with pA 2 values of 4.92 (K B=12.0 μM) and 4.97 (K B=16.4 μM). Mefloquine displayed weakly voltage-dependent, non-competitive inhibition consistent with channel block. On and off rates for quinine and chloroquine indicated a simple bimolecular reaction scheme. Quinine, chloroquine and mefloquine displaced [3H]granisetron with K i values of 15.0, 24.2 and 35.7 μ M. Docking of quinine into a homology model of the 5-HT3 receptor binding site located the tertiary ammonium between W183 and Y234, and the quinoline ring towards the membrane, stabilised by a hydrogen bond with E129. For chloroquine, the quinoline ring was positioned between W183 and Y234 and the tertiary ammonium stabilised by interactions with F226. Conclusions and Implications: This study shows that quinine and chloroquine competitively inhibit 5-HT3 receptors, while mefloquine inhibits predominantly non-competitively. Both quinine and chloroquine can be docked into a receptor binding site model, consistent with their structural homology to 5-HT3 receptor antagonists. PMID:17502851

Effect of lipophilicity on the bioavailability of drugs after percutaneous administration by dissolving microneedles.

PubMed

Ito, Yukako; Yoshimura, Masahiro; Tanaka, Tsutomu; Takada, Kanji

2012-03-01

To elucidate drug lipophilicity effects on the bioavailability (BA) of drugs from skin after administration by dissolving microneedles, nine compounds with different lipophilicity indexes (log p value) were formulated into two-layered dissolving microneedles and administered percutaneously to rat skin: desmopressin (DDAVP), sumatriptan (ST), fluorescein (FL), granisetron (GRN), pindolol (PDL), pravastatin (PRV), rhodamine 123 (Rho), rifampicin (RFP), and salmeterol (SLM). Plasma drug concentrations were measured using liquid chromatography-tandem mass spectrometry and spectrofluorometry. In vivo dissolution and diffusion in both horizontal and vertical directions of FL and RH in the skin were studied using fluorescence microscopy. Respective BAs were 95.1 ± 7.9% (DDAVP), 84.2 ± 2.7% (ST), 82.3 ± 7.2% (FL), 82.7 ± 6.7% (GRN), 71.6 ± 3.8% (PDL), 63.6 ± 7.5% (PRV), 53.7 ± 8.3% (Rho), 46.2 ± 6.1% (RFP), and 38.4 ± 2.7% (SM). BA decreased as the lipophilicity index, log p value, of the drug increased from-1.95 to 1.73. The respective remaining percentages in skin tissue were 1.4 ± 0.7% (DDAVP), 0.9 ± 0.1% (ST), 1.0 ± 0.2% (FL), 3.4 ± 1.2% (GRN), 14.5 ± 3.7% (PDL), 23.4 ± 5.2% (PRV), 32.2 ± 6.0% (Rho), 40.7 ± 4.9% (RFP), and 40.6 ± 5.1% (SLM), dependent on log p. Fluorescence microscopy showed no FL or Rho in skin tissue within 4 and 24 h after administration, respectively. The BA of drugs delivered by dissolving microneedles depends on the drug solubility in the skin epidermis and dermis. Copyright © 2011 Wiley Periodicals, Inc.

Management of cholestatic pruritus in paediatric patients with alagille syndrome: the King's College Hospital experience.

PubMed

Kronsten, Victoria; Fitzpatrick, Emer; Baker, Alastair

2013-08-01

The aims of the study were to perform a retrospective observational review of the present management and outcome of cholestatic pruritus in children with Alagille syndrome (AGS) at King's College Hospital and to use results to inform appropriate guidelines. A retrospective review of 62 patients diagnosed as having AGS from January 1995 to November 2010 treated at King's College Hospital was performed. The departmental database of the Paediatric Liver Centre was searched to identify all patients and the clinical records were then analysed. Fifty-one (82.3%) patients experienced pruritus and 50 (80.6%) received antipruritic medication. Ursodeoxycholic acid was the most prescribed drug (n = 40). Other drugs prescribed were rifampicin (n = 39), cholestyramine (n = 18), naltrexone (n = 14), alimemazine (n = 13), nonsedating antihistamine agents (n = 7), ondansetron (n = 5), and phenobarbitone (n = 1). Albumin dialysis using the molecular adsorbent recirculation system was used in 1 patient. Sixteen patients (25.8%) were listed for liver transplantation, and 11 had undergone transplantation by November 2010. Patient survival was high at 95.2%. Pruritus resolved permanently in 39.2% (n = 20) of patients. Fifty-five percent (n = 11) of such patients had undergone liver transplantation. Pruritus was controlled by medication in 41.2% (n = 21). Itching remained a significant problem, affecting quality of life in 19.6% of patients (n = 10). The management of cholestatic pruritus in AGS is difficult and often suboptimal. Pruritus may remain intractable even with combination medical treatment, and at this stage, surgery or liver transplantation is indicated. At our centre, pruritus was successfully treated in 80.4% of patients with medical and surgical management.

Do serotonin(1-7) receptors modulate short and long-term memory?

PubMed

Meneses, A

2007-05-01

Evidence from invertebrates to human studies indicates that serotonin (5-hydroxytryptamine; 5-HT) system modulates short- (STM) and long-term memory (LTM). This work is primarily focused on analyzing the contribution of 5-HT, cholinergic and glutamatergic receptors as well as protein synthesis to STM and LTM of an autoshaping learning task. It was observed that the inhibition of hippocampal protein synthesis or new mRNA did not produce a significant effect on autoshaping STM performance but it did impair LTM. Both non-contingent protein inhibition and 5-HT depletion showed no effects. It was basically the non-selective 5-HT receptor antagonist cyproheptadine, which facilitated STM. However, the blockade of glutamatergic and cholinergic transmission impaired STM. In contrast, the selective 5-HT(1B) receptor antagonist SB-224289 facilitated both STM and LTM. Selective receptor antagonists for the 5-HT(1A) (WAY100635), 5-HT(1D) (GR127935), 5-HT(2A) (MDL100907), 5-HT(2C/2B) (SB-200646), 5-HT(3) (ondansetron) or 5-HT(4) (GR125487), 5-HT(6) (Ro 04-6790, SB-399885 and SB-35713) or 5-HT(7) (SB-269970) did not impact STM. Nevertheless, WAY100635, MDL100907, SB-200646, GR125487, Ro 04-6790, SB-399885 or SB-357134 facilitated LTM. Notably, some of these changes shown to be independent of food-intake. Concomitantly, these data indicate that '5-HT tone via 5-HT(1B) receptors' might function in a serial manner from STM to LTM, whereas working in parallel using 5-HT(1A), 5-HT(2A), 5-HT(2B/2C), 5-HT(4), or 5-HT(6) receptors.

Vortioxetine Treatment Reverses Subchronic PCP Treatment-Induced Cognitive Impairments: A Potential Role for Serotonin Receptor-Mediated Regulation of GABA Neurotransmission

PubMed Central

Pehrson, Alan L.; Pedersen, Christian S.; Tølbøl, Kirstine Sloth; Sanchez, Connie

2018-01-01

Major depressive disorder (MDD) is associated with cognitive impairments that may contribute to poor functional outcomes. Clinical data suggests that the multimodal antidepressant vortioxetine attenuates some cognitive impairments in MDD patients, but the mechanistic basis for these improvements is unclear. One theory suggests that vortioxetine improves cognition by suppressing γ-amino butyric acid (GABA)ergic neurotransmission, thereby increasing glutamatergic activation. Vortioxetine’s effects on cognition, GABA and glutamate neurotransmission have been supported in separate experiments, but no empirical work has directly connected vortioxetine’s cognitive effects to those on GABA and glutamate neurotransmission. In this paper, we attempt to bridge this gap by evaluating vortioxetine’s effects in the subchronic PCP (subPCP) model, which induces impaired cognitive function and altered GABA and glutamate neurotransmission. We demonstrate that acute or subchronic vortioxetine treatment attenuated subPCP-induced deficits in attentional set shifting (AST) performance, and that the selective 5-HT3 receptor antagonist ondansetron or the 5-HT reuptake inhibitor escitalopram could mimic this effect. Furthermore, acute vortioxetine treatment reversed subPCP-induced object recognition (OR) deficits in rats, while subchronic vortioxetine reversed subPCP-induced Object Recognition and object placement impairments in mice. Finally, subPCP treatment reduced GABAB receptor expression in a manner that was insensitive to vortioxetine treatment, and subchronic vortioxetine treatment alone, but not in combination with subPCP, significantly increased GABA’s affinity for the GABAA receptor. These data suggest that vortioxetine reverses cognitive impairments in a model associated with altered GABA and glutamate neurotransmission, further supporting the hypothesis that vortioxetine’s GABAergic and glutamatergic effects are relevant for cognitive function. PMID:29559911

Combined antiallodynic effect of Neurotropin® and pregabalin in rats with L5-spinal nerve ligation.

PubMed

Okazaki, Ryohei; Namba, Hiroyoshi; Yoshida, Hiroyuki; Okai, Hisashi; Taguchi, Kazuki; Kawamura, Minoru

2013-03-12

In this study, we investigated the combined effect of Neurotropin® and pregabalin for L5-spinal nerve ligation (L5-SNL) model in rats and thiopental-induced sleep in mice. The left fifth lumbar nerve of rats was tightly ligated with silk sutures under pentobarbital anesthesia. The hindpaw withdrawal threshold was measured by application of von Frey filaments. Thiopental sodium was intravenously administered in mice and sleeping time was measured. In L5-SNL rats, an isobolographic analysis was performed to clarify the combined antiallodynic effect of Neurotropin and pregabalin 14 days after ligation in rats. In isobolographic analysis and thiopental-induced sleep test, Neurotropin and pregabalin were orally administered to coincide with the timing of the peak effect of each drug. Neurotropin (50-200 NU/kg) and pregabalin (2.5-10mg/kg) showed a dose-dependent antiallodynic action in L5-SNL rats. The antiallodynic effect of pregabalin was reversed by intrathecal injection of yohimbine or ondansetron. Isobolographic analysis suggested that the combined antiallodynic effect of Neurotropin and pregabalin in L5-SNL rats may have been more than a mere additive effect. Neurotropin (50-400 NU/kg) had no effect on thiopental-induced sleeping time whereas pregabalin (30-100mg/kg) significantly prolonged it. When the dose of pregabalin was 30 mg/kg, Neurotropin (50-400 NU/kg) did not further exacerbate the prolongation effect of pregabalin on thiopental-induced sleep. It was suggested that when Neurotropin was administered in combination with pregabalin, it might provide more effective pain relief than that obtained with each agent alone in neuropathic pain without aggravating adverse effects of pregabalin. Copyright © 2013 Elsevier Inc. All rights reserved.

Autoradiographic distribution of 5-HT7 receptors in the human brain using [3H]mesulergine: comparison to other mammalian species

PubMed Central

Martín-Cora, Francisco J; Pazos, Angel

2003-01-01

The main aim of this investigation was to delineate the distribution of the 5-HT7 receptor in human brain. Autoradiographic studies in guinea-pig and rat brain were also carried out in order to revisit and compare the anatomical distribution of 5-HT7 receptors in different mammalian species.Binding studies were performed in rat frontal cortex membranes using 10 nM [3H]mesulergine in the presence of raclopride (10 μM) and DOI (0.8 μM). Under these conditions, a binding site with pharmacological characteristics consistent with those of the 5-HT7 receptors was identified (rank order of binding affinity values: 5-CT>5-HT>5-MeOT>mesulergine ≈methiothepin>8-OH-DPAT=spiperone ≈(+)-butaclamol≫imipramine ≈(±)-pindolol≫ondansetron ≈clonidine ≈prazosin).The autoradiographic studies revealed that the anatomical distribution of 5-HT7 receptors throughout the human brain was heterogenous. High densities were found over the caudate and putamen nuclei, the pyramidal layer of the CA2 field of the hippocampus, the centromedial thalamic nucleus, and the dorsal raphe nucleus. The inner layer of the frontal cortex, the dentate gyrus of the hippocampus, the subthalamic nucleus and superior colliculus, among others, presented intermediate concentrations of 5-HT7 receptors. A similar brain anatomical distribution of 5-HT7 receptors was observed in all three mammalian species studied.By using [3H]mesulergine, we have mapped for the first time the anatomical distribution of 5-HT7 receptors in the human brain, overcoming the limitations previously found in radiometric studies with other radioligands, and also revisiting the distribution in guinea-pig and rat brain. PMID:14656806

Fast-track surgery for uncomplicated appendicitis in children: a matched case-control study.

PubMed

Cundy, Thomas P; Sierakowski, Kyra; Manna, Alexandra; Cooper, Celia M; Burgoyne, Laura L; Khurana, Sanjeev

2017-04-01

Standardized post-operative protocols reduce variation and enhance efficiency in patient care. Patients may benefit from these initiatives by improved quality of care. This matched case-control study investigates the effect of a multidisciplinary criteria-led discharge protocol for uncomplicated appendicitis in children. Key protocol components included limiting post-operative antibiotics to two intravenous doses, avoidance of intravenous opioid analgesia, prompt resumption of diet, active encouragement of early ambulation and nursing staff autonomy to discharge patients that met assigned criteria. The study period was from August 2015 to February 2016. Outcomes were compared with a historical control group matched for operative approach. Outcomes for 83 patients enrolled to our protocol were compared with those of 83 controls. There was a 29.2% reduction in median post-operative length of stay in our protocol-based care group (19.6 versus 27.7 h; P < 0.001). The rate of discharges within 24 h improved from 12 to 42%. There was no significant difference in complication rate (4.8 versus 7.2%; P = 0.51). Mean oral morphine dose equivalent per kilogram requirement was less than half (46%) that of control group patients (P < 0.001). Mean number of ondansetron doses was also significantly lower. Projected annual direct cost savings following protocol implementation was AUD$77 057. Implementation of a criteria-led discharge protocol at our hospital decreased length of stay, reduced variation in care, preserved existing low morbidity, incurred substantial cost savings, and safely rationalized opioid and antiemetic medication. These protocols are inexpensive and offer tangible benefits that are accessible to all health care settings. © 2016 Royal Australasian College of Surgeons.

Molecular cloning of motilin and mechanism of motilin-induced gastrointestinal motility in Japanese quail.

PubMed

Apu, Auvijit Saha; Mondal, Anupom; Kitazawa, Takio; Takemi, Shota; Sakai, Takafumi; Sakata, Ichiro

2016-07-01

Motilin, a peptide hormone produced in the upper intestinal mucosa, plays an important role in the regulation of gastrointestinal (GI) motility. In the present study, we first determined the cDNA and amino acid sequences of motilin in the Japanese quail and studied the distribution of motilin-producing cells in the gastrointestinal tract. We also examined the motilin-induced contractile properties of quail GI tracts using an in vitro organ bath, and then elucidated the mechanisms of motilin-induced contraction in the proventriculus and duodenum of the quail. Mature quail motilin was composed of 22 amino acid residues, which showed high homology with chicken (95.4%), human (72.7%), and dog (72.7%) motilin. Immunohistochemical analysis showed that motilin-immunopositive cells were present in the mucosal layer of the duodenum (23.4±4.6cells/mm(2)), jejunum (15.2±0.8cells/mm(2)), and ileum (2.5±0.7cells/mm(2)), but were not observed in the crop, proventriculus, and colon. In the organ bath study, chicken motilin induced dose-dependent contraction in the proventriculus and small intestine. On the other hand, chicken ghrelin had no effect on contraction in the GI tract. Motilin-induced contraction in the duodenum was not inhibited by atropine, hexamethonium, ritanserin, ondansetron, or tetrodotoxin. However, motilin-induced contractions in the proventriculus were significantly inhibited by atropine and tetrodotoxin. These results suggest that motilin is the major stimulant of GI contraction in quail, as it is in mammals and the site of action of motilin is different between small intestine and proventriculus. Copyright © 2016 Elsevier Inc. All rights reserved.

Pregnancy, prescription medicines and the potential risk of herb-drug interactions: a cross-sectional survey.

PubMed

McLay, James S; Izzati, Naila; Pallivalapila, Abdul R; Shetty, Ashalatha; Pande, Binita; Rore, Craig; Al Hail, Moza; Stewart, Derek

2017-12-19

Pregnant women are routinely prescribed medicines while self-medicating with herbal natural products to treat predominantly pregnancy related conditions. The aim of this study was to assess the potential for herb-drug interactions (HDIs) in pregnant women and to explore possible herb-drug interactions and their potential clinical significance. A cross-sectional survey of women during early pregnancy or immediately postpartum in North-East Scotland. Outcome measures included; Prescription medicines use excluding vitamins and potential HDIs assessed using Natural Medicines Comprehensive Database. The survey was completed by 889 respondents (73% response rate). 45.3% (403) reported the use of at least one prescription medicine, excluding vitamins. Of those taking prescription medicines, 44.9% (181) also reported concurrent use of at least one HNP (Range 1-12). A total of 91 different prescription medicines were reported by respondents using HNPs. Of those taking prescription medicines, 44.9% (181) also reported concurrent use of at least one HNP (Range 1-12). Thirty-four herb-drug interactions were identified in 23 (12.7%) women with the potential to increase the risk of postpartum haemorrhage, alter maternal haemodynamics, and enhance maternal/fetal CNS depression. Almost all were rated as moderate (93.9%), one as a potentially major (ginger and nifedipine) and only one minor (ondansetron and chamomile). Almost half of pregnant women in this study were prescribed medicines excluding vitamins and minerals and almost half of these used HNPs. Potential moderate to severe HDIs were identified in an eighth of the study cohort. Healthcare professionals should be aware that the concurrent use of HNPs and prescription medicines during pregnancy is common and carries potential risks.

Dexamethasone Does Not Inhibit Sugammadex Reversal After Rocuronium-Induced Neuromuscular Block.

PubMed

Buonanno, Pasquale; Laiola, Anna; Palumbo, Chiara; Spinelli, Gianmario; Servillo, Giuseppe; Di Minno, Raffaele Maria; Cafiero, Tullio; Di Iorio, Carlo

2016-06-01

Sugammadex is a relatively new molecule that reverses neuromuscular block induced by rocuronium. The particular structure of sugammadex traps the cyclopentanoperhydrophenanthrene ring of rocuronium in its hydrophobic cavity. Dexamethasone shares the same steroidal structure with rocuronium. Studies in vitro have demonstrated that dexamethasone interacts with sugammadex, reducing its efficacy. In this study, we investigated the clinical relevance of this interaction and its influence on neuromuscular reversal. In this retrospective case-control study, we analyzed data from 45 patients divided into 3 groups: dexamethasone after induction group (15 patients) treated with 8 mg dexamethasone as an antiemetic drug shortly after induction of anesthesia; dexamethasone before reversal group (15 patients) treated with dexamethasone just before sugammadex injection; and control group (15 patients) treated with 8 mg ondansetron. All groups received 0.6 mg/kg rocuronium at induction, 0.15 mg/kg rocuronium at train-of-four ratio (TOF) 2 for neuromuscular relaxation, and 2 mg/kg sugammadex for reversal at the end of the procedure at TOF2. Neuromuscular relaxation was monitored with a TOF-Watch® system. The control group had a recovery time of 154 ± 54 seconds (mean ± SD), the dexamethasone after induction group 134 ± 55 seconds, and the dexamethasone before reversal group 131 ± 68 seconds. The differences among groups were not statistically significant (P = 0.5141). Our results show that the use of dexamethasone as an antiemetic drug for the prevention of postoperative nausea and vomiting does not interfere with reversal of neuromuscular blockade with sugammadex in patients undergoing elective surgery with general anesthesia in contrast to in vitro studies that support this hypothesis.

A randomized study to compare the efficacy of two intravenous fluid regimens of normal saline on the incidence of postoperative nausea and vomiting

PubMed Central

Bhukal, Ishwar; Srinivas, N.; Solanki, Sohan Lal; Yaddanapudi, L. N.; Jain, Amit

2012-01-01

Background: The purpose of this study was to evaluate the effect of two different volume of crystalloid given intraoperatively on postoperative nausea and vomiting (PONV). Materials and Methods: Eighty adult patients of either sex belonging to ASA I and II class undergoing elective surgeries under general anesthesia for 1–2 h were studied in this prospective, randomized double blinded study. First group (group L) (n=40) received normal saline 4 mL/kg and second group (group H) (n=40) received 10 mL/kg of normal saline. This was in excess of the fasting requirement of the patients. No propofol or antiemetic drugs were given. PONV was evaluated by verbal descriptive score (VDS) [0 = none, 1 = mild, 2 = moderate, 3 = severe, and 4 = unbearable]. Ondansetron (4 mg i.v.) was given if VDS score was 3 or more. Results: The median immediate PONV score was 2 and 1 in group L and H, respectively. The median 2 h PONV score in group L was 3 and in group H was 1. The median 6 h PONV score in group L was 3 and in group H was 1. The 24 h median postoperative PONV score was 1 and 0 in group L and H, respectively. In all these period of time the differences were statistically significant. The incidence of vomiting was more in group L [72.5% (29/40)] than in group H [30% (12/40)]. This was statistically significant (P=0.0003). Conclusion: From the current study it was concluded that patients who received larger volume of crystalloid intraoperatively have lesser incidence of PONV. PMID:25885496

Peristalsis and fecal pellet propulsion do not require nicotinic, purinergic, 5-HT3, or NK3 receptors in isolated guinea pig distal colon.

PubMed

Nicholas, Sarah; Spencer, Nick J

2010-06-01

The neuronal mechanism by which distension of the colon triggers peristalsis and the propulsion of colonic contents is incompletely understood. In this study, we used video imaging and spatiotemporal mapping techniques to investigate the neuroneuronal mechanisms underlying peristalsis in isolated guinea pig distal colon. In direct contrast to previous studies, we found that hexamethonium (100 muM-1 mM) or mecamylamine (20 muM) never abolished peristalsis or fecal pellet propulsion, although a temporary blockade of peristalsis was common, giving the impression perhaps that peristalsis was blocked permanently. During the initiation of peristalsis, the intraluminal propulsive force applied to an inserted fecal pellet was significantly reduced by hexamethonium 100 muM, even though, once initiated, the propagation velocity of fecal pellets was never reduced by nicotinic antagonists. In the presence of hexamethonium or mecamylamine, further addition of PPADS (10 muM), ondansetron (1 muM), and SR 142801 (300 nM) had no inhibitory effect on the propagation velocity of fecal pellets. In these preparations, antagonists for nicotinic, purinergic (P2), serotonergic (5-HT3), or tachykinergic (NK3) receptors always abolished responses to the agonists for these receptors, confirming that when peristalsis occurred, nicotinic, P2, 5-HT3, and NK3 receptors were blocked. Tetrodotoxin abolished nonnicotinic peristalsis. In summary, nicotinic transmission contributes to excitatory neuroneuronal transmission underlying peristalsis and fecal pellet propulsion but is not required for peristalsis, nor fecal pellet propulsion, as once thought. These observations could be explained by an excitatory nonnicotinic neuroneuronal pathway that can generate peristalsis and induce normal fecal pellet propagation velocities but does not require nicotinic, P2, 5-HT3, or NK3 receptors.

Leaves of Hippophae rhamnoides prevent taste aversion in gamma-irradiated rats.

PubMed

Gupta, Vanita; Bala, Madhu; Prasad, Jagdish; Singh, Surinder; Gupta, Manish

2011-12-01

Hippophae rhamnoides (Sea buckthorn), a traditionally known plant for nutritional and therapeutic values, is under active investigation for radioprotective properties. This study investigated effects of aqueous leaf extract from H. rhamnoides on (60)Co-γ-radiation induced changes in behavior, oxidative stress and serotonin levels in jejunum and plasma of rats. Conditioned taste aversion (CTA) was chosen as the assay to record behavioral changes and was assessed in terms of saccharine preference ratio (SPR). Whole body (60)Co-γ-irradiation (2 Gy) induced significant nonrecoverable CTA (25.6 ± 3.6% SPR, t(6) = 3.499, p < .05) and loss in body weight (b.w.). One time treatment with leaf extract before irradiation, countered radiation induced CTA and loss in body weight. The 12 mg/kg b.w. concentration of leaf extract caused complete extinction of CTA [100.3 ± 6.4% SPR, t(6) = 5.879, p < .01] after day 3 and the effect was significantly higher than positive control, Ondansetrone (70.0 ± 8.9% SPR). Treatment with leaf extract before irradiation significantly countered radiation induced (1) decrease in antioxidant protection, (2) increase in levels of corticosterone (CS) in plasma, (3) increase in levels of serotonin in jejunum and plasma. Present investigation demonstrated that H. rhamnoides leaf extract prevented behavioral changes induced at clinical radiation doses. Hippophae leaves are nontoxic and are being consumed as tea and other beverages. CTA in rats is a considered parallel process to nausea and vomiting in human beings. These findings, put together, suggest that dietary supplements from Hippophae leaves could be developed for preventing behavioral changes in subjects exposed to radiation.

The nucleus raphe magnus suppresses vomiting, and the solitary nucleus and 5-HT are not involved in this suppression.

PubMed

Hattori, Yuka; Hamaguchi, Chie; Yamada, Yuko; Urayama, Yukiko; Nakamura, Emi; Koga, Tomoshige; Fukuda, Hiroyuki

2010-01-15

In previous paper, we reported that stimulation of the nucleus raphe magnus (stim-NRM) inhibits the induction of retching by afferent vagal fibers (VAs). We performed the present study to identity the transmitter of inhibition and then the site. The following results were obtained in decerebrated and paralyzed dogs. 1) The induction of fictive retching was suppressed by i.v. injection of 5-HT, and by 4th ventricular administration of 5-HT or a 5-HT3-receptor (R) agonist, 1-(m-chlorophenyl)-biguanade hydrochloride (m-CPBG). 2) Both forms of suppression were antagonized by i.v. injection of ondansetron, a 5-HT3-R antagonist. 3) Administration of the antagonist into the 4th ventricle did not affect the induction or its suppression by stim-NRM. These results suggest that the transmission from VAs to neurons in the nucleus solitarius (NTS) is suppressed by 5-HT via 5-HT3-R. However, these results also suggest that both the transmitter and receptor are not involved in the induction of retching by VAs or in its suppression by the NRM. Next, we examined the site of suppression. Unitary firings of NTS neurons in response to pulse-train stimulation of VAs were not inhibited by NRM stimulation. Moreover, the firing of NTS neurons during the induction of retching by vagal stimulation did not significantly decrease with the superimposition of stim-NRM, although the induction of retching was completely suppressed. These results suggest that suppression of the induction of retching by the descending inhibitory system of pain did not occur in the synapse between afferent vagal fibers and NTS neurons. The site of suppression is discussed.

Tryptophan depletion in chronic fatigue syndrome, a pilot cross-over study.

PubMed

The, Gerard K H; Verkes, Robbert J; Fekkes, Durk; Bleijenberg, Gijs; van der Meer, Jos W M; Buitelaar, Jan K

2014-09-16

Chronic fatigue syndrome (CFS) is still an enigmatic disorder. CFS can be regarded as a complex disorder with tremendous impact on lives of CFS-patients. Full recovery without treatment is rare. A somatic explanation for the fatigue is lacking. There is clinical and experimental evidence implicating enhanced serotonergic neurotransmission in CFS. Genetic studies and imaging studies support the hypothesis of upregulated serotonin system in CFS. In line with the hypothesis of an increased serotonergic state in CFS, we performed a randomised clinical trial investigated the effect of 5-HT3 receptor antagonism in CFS. No benefit was found of the 5-HT3 receptor antagonist ondansetron compared to placebo.To further investigate the involvement of serotonin in CFS we performed a placebo controlled cross over pilot study investigating the effect of Acute Tryptophan Depletion. Five female CFS-patients who met the US Center for Disease Control and Prevention criteria for CFS were recruited. There were two test days, one week apart. Each participant received placebo and ATD. To evaluate the efficacy of the ATD procedure tryptophan and the large neutral amino acids were measured. The outcome measures were fatigue severity, concentration and mood states. ATD resulted in a significant plasma tryptophan to large neutral amino acid ratio reduction of 96%. There were no significant differences in fatigue-, depression and concentration between the placebo- and ATD condition. These first five CFS-patients did not respond to the ATD procedure. However, a much larger sample size is needed to draw final conclusions on the hypothesis of an increased serotonergic state in the pathophysiology of CFS. ISRCTN07518149.

A rapid recovery program: early home and pain free.

PubMed

Lombardi, Adolph V; Berend, Keith R; Adams, Joanne B

2010-09-07

Enhancement of our perioperative pain management protocols has resulted in accelerated rehabilitation. At our facility, the majority of patients undergoing total and partial knee arthroplasty are treated with a single-shot spinal anesthetic consisting of a combination of bupivacaine and duramorph. The bupivacaine affords the immediate perioperative anesthetic while the duramorph results in sustained analgesia for a period of 12 to 24 hours. We use intra-articular injections delivered directly into the soft tissue of the knee. Our current intra-articular injection is 60 mL of 0.5% ropivacaine with 0.5 mg of epinephrine. In patients with a normal renal function, 30 mg of ketorolac is added. The injection is administered throughout all of the soft tissues in and around the knee. Prophylactic antiemetics are administered in the form of dexamethasone, ondansetron, and a scopolamine patch. The use of this perioperative anesthesia provides effective pain relief with no motor blockade. Patients are able to participate in physiotherapy within several hours of the operative procedure, performing active range of motion and ambulating with assistive devices. Patients with no significant cardiovascular history are given celecoxib preoperatively, which is continued for approximately 2 weeks postoperatively. Additionally, all patients are treated with oxycodone, either preoperatively or within 2 hours of arrival to the floor postoperatively. Patients younger than 70 years are given 20 mg of oxycodone while those older than 70 years are given 10 mg of oxycodone. The oxycodone is continued for the first 24 hours of the hospital stay. Patients are then managed with oxycodone and hydrocodone. Length of stay has decreased and currently averages <2 days. Copyright 2010, SLACK Incorporated.

A phase II randomized double-blind placebo-controlled study of 6-gingerol as an anti-emetic in solid tumor patients receiving moderately to highly emetogenic chemotherapy.

PubMed

Konmun, J; Danwilai, K; Ngamphaiboon, N; Sripanidkulchai, B; Sookprasert, A; Subongkot, S

2017-04-01

6-Gingerol is a natural compound extracted from ginger. Preclinical studies demonstrated that 6-gingerol has an anti-emetic activity by inhibiting neurokinin-1, serotonin, and dopamine receptors. Several clinical trials examined crude ginger powder for preventing chemotherapy-induced nausea and vomiting (CINV), but none of them was conducted with a standardized bioactive compound. Patients who received moderately to highly emetogenic adjuvant chemotherapy were randomized to receive 6-gingerol 10 mg or placebo orally twice daily for 12 weeks. Ondansetron, metoclopramide, and dexamethasone were given to all patients. The primary endpoint was complete response (CR) rate defined as no emesis or rescue treatment at any time. Eighty-eight patients were randomized to receive 6-gingerol (N = 42) or placebo (N = 46). Most patients received highly emetogenic chemotherapy (93%). Overall CR rate was significantly higher in 6-gingerol group as compared with that of the placebo (77 vs. 32%; P < 0.001). The difference in means of appetite score was significant (P = 0.001) and more noticeable over time. Mean FACT-G score indicating quality of life was significantly higher (86.21) in 6-gingerol group at 64 days as compared with that of placebo group (72.36) (P < 0.001). No toxicity related to 6-gingerol was observed. Patients treated with 6-gingerol reported significantly less grade 3 fatigue (2 vs. 20%; P = 0.020). 6-Gingerol significantly improved overall CR rate in CINV, appetite and quality of life in cancer patients receiving adjuvant chemotherapy. A phase III randomized study of 6-gingerol is warranted to confirm these results.

Treatments for hyperemesis gravidarum and nausea and vomiting in pregnancy: a systematic review and economic assessment.

PubMed

O'Donnell, Amy; McParlin, Catherine; Robson, Stephen C; Beyer, Fiona; Moloney, Eoin; Bryant, Andrew; Bradley, Jennifer; Muirhead, Colin; Nelson-Piercy, Catherine; Newbury-Birch, Dorothy; Norman, Justine; Simpson, Emma; Swallow, Brian; Yates, Laura; Vale, Luke

2016-10-01

-three studies (75 reports) met the inclusion criteria. For RCTs, 33 and 11 studies had a low and high risk of bias respectively. For the remainder ( n  = 20) it was unclear. The non-randomised studies ( n  = 9) were low quality. There were 33 separate comparators. The most common were acupressure versus placebo ( n  = 12); steroid versus usual treatment ( n  = 7); ginger versus placebo ( n  = 6); ginger versus vitamin B6 ( n  = 6); and vitamin B6 versus placebo ( n  = 4). There was evidence that ginger, antihistamines, metoclopramide (mild disease) and vitamin B6 (mild to severe disease) are better than placebo. Diclectin ® [Duchesnay Inc.; doxylamine succinate (10 mg) plus pyridoxine hydrochloride (10 mg) slow release tablet] is more effective than placebo and ondansetron is more effective at reducing nausea than pyridoxine plus doxylamine. Diclectin before symptoms of NVP begin for women at high risk of severe NVP recurrence reduces risk of moderate/severe NVP compared with taking Diclectin once symptoms begin. Promethazine is as, and ondansetron is more, effective than metoclopramide for severe NVP/HG. I.v. fluids help correct dehydration and improve symptoms. Dextrose saline may be more effective at reducing nausea than normal saline. Transdermal clonidine patches may be effective for severe HG. Enteral feeding is effective but extreme method treatment for very severe symptoms. Day case management for moderate/severe symptoms is feasible, acceptable and as effective as inpatient care. For all other interventions and comparisons, evidence is unclear. The economic analysis was limited by lack of effectiveness data, but comparison of costs between treatments highlights the implications of different choices. The main limitations were the quantity and quality of the data available. There was evidence of some improvement in symptoms for some treatments, but these data may not be transferable across disease severities. Methodologically sound and

Important role of mucosal serotonin in colonic propulsion and peristaltic reflexes: in vitro analyses in mice lacking tryptophan hydroxylase 1

PubMed Central

Heredia, Dante J; Gershon, Michael D; Koh, Sang Don; Corrigan, Robert D; Okamoto, Takanubu; Smith, Terence K

2013-01-01

Although there is general agreement that mucosal 5-hydroxytryptamine (5-HT) can initiate peristaltic reflexes in the colon, recent studies have differed as to whether or not the role of mucosal 5-HT is critical. We therefore tested the hypothesis that the secretion of 5-HT from mucosal enterochromaffin (EC) cells is essential for the manifestation of murine colonic peristaltic reflexes. To do so, we analysed the mechanisms underlying faecal pellet propulsion in isolated colons of mice lacking tryptophan hydroxylase 1 (Tph1−/− mice), which is the rate-limiting enzyme in the biosynthesis of mucosal but not neuronal 5-HT. We used video analysis of faecal pellet propulsion, tension transducers to record colonic migrating motor complexes (CMMCs) and intracellular microelectrodes to record circular muscle activity occurring spontaneously or following intraluminal distension. When compared with control (Tph1+/+) mice, Tph1−/− animals exhibited: (1) an elongated colon; (2) larger faecal pellets; (3) orthograde propulsion followed by retropulsion (not observed in Tph1+/+ colon); (4) slower in vitro propulsion of larger faecal pellets (28% of Tph1+/+); (5) CMMCs that infrequently propagated in an oral to anal direction because of impaired descending inhibition; (6) reduced CMMCs and inhibitory responses to intraluminal balloon distension; (7) an absence of reflex activity in response to mucosal stimulation. In addition, (8) thin pellets that propagated along the control colon failed to do so in Tph1−/− colon; and (9) the 5-HT3 receptor antagonist ondansetron, which reduced CMMCs and blocked their propagation in Tph1+/+ mice, failed to alter CMMCs in Tph1−/− animals. Our observations suggest that mucosal 5-HT is essential for reflexes driven by mucosal stimulation and is also important for normal propagation of CMMCs and propulsion of pellets in the isolated colon. PMID:24127620

Important role of mucosal serotonin in colonic propulsion and peristaltic reflexes: in vitro analyses in mice lacking tryptophan hydroxylase 1.

PubMed

Heredia, Dante J; Gershon, Michael D; Koh, Sang Don; Corrigan, Robert D; Okamoto, Takanubu; Smith, Terence K

2013-12-01

Although there is general agreement that mucosal 5-hydroxytryptamine (5-HT) can initiate peristaltic reflexes in the colon, recent studies have differed as to whether or not the role of mucosal 5-HT is critical. We therefore tested the hypothesis that the secretion of 5-HT from mucosal enterochromaffin (EC) cells is essential for the manifestation of murine colonic peristaltic reflexes. To do so, we analysed the mechanisms underlying faecal pellet propulsion in isolated colons of mice lacking tryptophan hydroxylase 1 (Tph1(-/-) mice), which is the rate-limiting enzyme in the biosynthesis of mucosal but not neuronal 5-HT. We used video analysis of faecal pellet propulsion, tension transducers to record colonic migrating motor complexes (CMMCs) and intracellular microelectrodes to record circular muscle activity occurring spontaneously or following intraluminal distension. When compared with control (Tph1(+/+)) mice, Tph1(-/-) animals exhibited: (1) an elongated colon; (2) larger faecal pellets; (3) orthograde propulsion followed by retropulsion (not observed in Tph1(+/+) colon); (4) slower in vitro propulsion of larger faecal pellets (28% of Tph1(+/+)); (5) CMMCs that infrequently propagated in an oral to anal direction because of impaired descending inhibition; (6) reduced CMMCs and inhibitory responses to intraluminal balloon distension; (7) an absence of reflex activity in response to mucosal stimulation. In addition, (8) thin pellets that propagated along the control colon failed to do so in Tph1(-/-) colon; and (9) the 5-HT3 receptor antagonist ondansetron, which reduced CMMCs and blocked their propagation in Tph1(+/+) mice, failed to alter CMMCs in Tph1(-/-) animals. Our observations suggest that mucosal 5-HT is essential for reflexes driven by mucosal stimulation and is also important for normal propagation of CMMCs and propulsion of pellets in the isolated colon.

Aprepitant in adolescent patients for prevention of chemotherapy-induced nausea and vomiting: a randomized, double-blind, placebo-controlled study of efficacy and tolerability.

PubMed

Gore, Lia; Chawla, Sant; Petrilli, Antonio; Hemenway, Molly; Schissel, Debra; Chua, Vickey; Carides, Alexandra D; Taylor, Arlene; Devandry, Suzanne; Valentine, Jack; Evans, Judith K; Oxenius, Bettina

2009-02-01

The neurokinin-1 receptor antagonist aprepitant, plus a 5HT3 antagonist and corticosteroid is well-tolerated and effective in preventing chemotherapy-induced nausea and vomiting in adults but has not been formally assessed in adolescents. Patients age 11-19 years old receiving emetogenic chemotherapy were randomized 2:1 to aprepitant triple therapy (aprepitant [A] 125 mg p.o., dexamethasone [D] 8 mg p.o., and ondansetron [O] 0.15 mg/kg i.v. t.i.d. day 1; A 80 mg, D 4 mg, and O 0.15 mg/kg t.i.d. day 2; A 80 mg and D 4 mg day 3; and D 4 mg day 4) or a control regimen (D 16 mg and O 0.15 mg/kg t.i.d. day 1; D 8 mg and O 0.15 mg/kg t.i.d. day 2; and D 8 mg days 3 and 4). The primary endpoint was the difference in drug-related adverse events during and for 14 days following treatment. Efficacy and aprepitant pharmacokinetics were assessed. Baseline characteristics were similar between aprepitant (N = 28) and control (N = 18) groups. Febrile neutropenia was more frequent in the aprepitant group (25% vs. 11.1%). Complete response (CR) rates were 35.7% for aprepitant triple therapy versus 5.6% for the control group. Mean plasma aprepitant AUC(0-24 hr) and C(max) on day 1 and mean trough concentrations on days 2 and 3 were consistently lower compared to historical data obtained from healthy adults; however, the differences were not clinically significant. Aprepitant triple therapy was generally well tolerated; CR were greater with aprepitant, although not statistically significant. Pharmacokinetics suggest that the adult dosing regimen is appropriate for adolescents. (c) 2008 Wiley-Liss, Inc.

Characterisation of faecal protease activity in irritable bowel syndrome with diarrhoea: origin and effect of gut transit.

PubMed

Tooth, David; Garsed, Klara; Singh, Gulzar; Marciani, Luca; Lam, Ching; Fordham, Imogen; Fields, Annie; Banwait, Rawinder; Lingaya, Melanie; Layfield, Robert; Hastings, Maggie; Whorwell, Peter; Spiller, Robin

2014-05-01

Faecal serine proteases (FSPs) may play a role in irritable bowel syndrome with diarrhoea (IBS-D), but their origin is unclear. We aimed to structurally characterise them and define the impact of colonic cleansing and transit time. Faecal samples were obtained from 30 healthy volunteers (HV) and 79 patients with IBS-D participating in a trial of ondansetron versus placebo. Colonic transit was measured using radio-opaque markers. Samples were also obtained from 24 HV before and after colonic cleansing with the osmotic laxative MoviPrep. FSPs were purified from faecal extracts using benzamidine-Sepharose affinity chromatography. SDS-PAGE profiled components were identified using trypsinolysis and tandem mass spectrometry. Functional protease activity in faecal extracts was measured using a colorimetric assay based on the proteolysis of azo-casein. Protein analysis identified the most abundant FSPs as being of human origin and probably derived from pancreatic juice. Functional assays showed increased faecal protease (FP) and amylase in patients with IBS-D compared with HV. Those with higher amylase had significantly higher FP and greater anxiety. FP activity correlated negatively with whole gut transit in patients with IBS-D (Spearman r=-0.32, p=0.005) and HV (r=-0.55, p=0.014). Colon cleansing caused a significant rise in FP activity in HV from a baseline of median (IQR) 253 (140-426) to 1031 (435-2296), levels similar to those seen in patients with IBS-D. FSP activity correlated positively with days/week with urgency. The most abundant FSPs are of human origin. Rapid transit through the colon and/or decreased (possibly bacterial) proteolytic degradation increases their faecal concentration and could contribute to visceral hypersensitivity in patients with IBS-D. NCT00745004.

Aprepitant in pediatric patients using moderate and highly emetogenic protocols: a systematic review and meta‐analyses of randomized controlled trials

PubMed Central

D'Athayde Rodrigues, Fernanda; Ferreira, Maria Angelica Pires; Moreira, Leila Beltrami

2017-01-01

Aims To review the efficacy and safety of aprepitant in combination with ondansetron and dexamethasone (triple therapy) in children and adolescents on moderate to highly emetogenic chemotherapy. Methods Medline, Embase, Scielo, Lilacs, Cochrane and congress abstracts published until September 2016 were used as data sources. Two reviewers independently selected manuscripts and extracted data. A third reviewer solved discrepancies in study selection and data extraction. The primary outcome was overall complete response (no vomiting from 0 to 120 h). Secondary outcomes were: response in acute phase, delayed phase and reported toxicities. Each study was considered a unit of analysis. Summarized relative risks were recalculated based on reported data. All meta‐analyses used a random‐effects model and heterogeneity was reported using the I2 method. Results From 1004 studies, we screened 288 titles and abstracts and included three trials for data extraction. The population comprised 451 patients. Most patients were males, ranging from 6 months to 19 years of age, and weighing from 6 to 134 kg. Bone cancer was the most incident (≥50%) neoplasm, followed by rhabdomyosarcoma and Hodgkin's lymphoma. Triple therapy was associated with a reduced risk of developing chemotherapy‐induced vomiting (CIV) (RR = 0.48; 95% CI 0.34–0.67). There were no differences in incidence of febrile neutropenia between groups (RR = 1.02; 95% CI 0.66–1.58). Conclusions Triple therapy decreased CIV risk, without increasing the occurrence of febrile neutropenia. However, this review could not address which subpopulations would most benefit from using this strategy. Future studies should focus on assessing risk factors for nausea and vomiting, as many patients did not achieve a complete antiemetic response. PMID:27868231

The Role of 5-HT3 Receptors in Signaling from Taste Buds to Nerves.

PubMed

Larson, Eric D; Vandenbeuch, Aurelie; Voigt, Anja; Meyerhof, Wolfgang; Kinnamon, Sue C; Finger, Thomas E

2015-12-02

Activation of taste buds triggers the release of several neurotransmitters, including ATP and serotonin (5-hydroxytryptamine; 5-HT). Type III taste cells release 5-HT directly in response to acidic (sour) stimuli and indirectly in response to bitter and sweet tasting stimuli. Although ATP is necessary for activation of nerve fibers for all taste stimuli, the role of 5-HT is unclear. We investigated whether gustatory afferents express functional 5-HT3 receptors and, if so, whether these receptors play a role in transmission of taste information from taste buds to nerves. In mice expressing GFP under the control of the 5-HT(3A) promoter, a subset of cells in the geniculate ganglion and nerve fibers in taste buds are GFP-positive. RT-PCR and in situ hybridization confirmed the presence of 5-HT(3A) mRNA in the geniculate ganglion. Functional studies show that only those geniculate ganglion cells expressing 5-HT3A-driven GFP respond to 10 μM 5-HT and this response is blocked by 1 μM ondansetron, a 5-HT3 antagonist, and mimicked by application of 10 μM m-chlorophenylbiguanide, a 5-HT3 agonist. Pharmacological blockade of 5-HT3 receptors in vivo or genetic deletion of the 5-HT3 receptors reduces taste nerve responses to acids and other taste stimuli compared with controls, but only when urethane was used as the anesthetic. We find that anesthetic levels of pentobarbital reduce taste nerve responses apparently by blocking the 5-HT3 receptors. Our results suggest that 5-HT released from type III cells activates gustatory nerve fibers via 5-HT3 receptors, accounting for a significant proportion of the neural taste response. Copyright © 2015 the authors 0270-6474/15/3515984-12$15.00/0.

5-HT receptors as novel targets for optimizing pigmentary responses in dorsal skin melanophores of frog, Hoplobatrachus tigerinus

PubMed Central

Ali, Sharique A; Salim, Saima; Sahni, Tarandeep; Peter, Jaya; Ali, Ayesha S

2012-01-01

BACKGROUND AND PURPOSE Biochemical identification of 5-HT has revealed similar projection patterns across vertebrates. In CNS, 5-HT regulates major physiological functions but its peripheral functions are still emerging. The pharmacology of 5-HT is mediated by a diverse range of receptors that trigger different responses. Interestingly, 5-HT receptors have been detected in pigment cells indicating their role in skin pigmentation. Hence, we investigated the role of this monoaminergic system in amphibian pigment cells, melanophores, to further our understanding of its role in pigmentation biology together with its evolutionary significance. EXPERIMENTAL APPROACH Pharmacological profiling of 5-HT receptors was achieved using potent/selective agonists and antagonists. In vitro responses of melanophores were examined by Mean Melanophores Size Index assay. The melanophores of lower vertebrates are highly sensitive to external stimuli. The immediate cellular responses to drugs were defined in terms of pigment translocation within the cells. KEY RESULTS 5-HT exerted strong concentration-dependent pigment dispersion at threshold dose of 1 × 10−6 g·mL−1. Specific 5-HT1 and 5-HT2 receptor agonists, sumatriptan and myristicin. also induced dose-dependent dispersion. Yohimbine and metergoline synergistically antagonized sumatriptan-mediated dispersion, whereas trazodone partially blocked myristicin-induced dispersion. Conversely, 5-HT3 and 5-HT4 receptor agonists, 1 (3 chlorophenyl) biguanide (1,3 CPB) and 5-methoxytryptamine (5-MT), caused a dose-dependent pigment aggregation. The aggregatory effect of 1,3 CPB was completely blocked by ondansetron, whereas L-lysine partially blocked the effect of 5-MT. CONCLUSIONS AND IMPLICATIONS The results suggest that 5-HT-induced physiological effects are mediated via distinct classes of receptors, which possibly participate in the modulation of pigmentary responses in amphibian. PMID:21880033

A Pilot Project Demonstrating that Combat Medics Can Safely Administer Parenteral Medications in the Emergency Department.

PubMed

Schauer, Steven G; Cunningham, Cord W; Fisher, Andrew D; DeLorenzo, Robert A

2017-12-01

Introduction Select units in the military have improved combat medic training by integrating their functions into routine clinical care activities with measurable improvements in battlefield care. This level of integration is currently limited to special operations units. It is unknown if regular Army units and combat medics can emulate these successes. The goal of this project was to determine whether US Army combat medics can be integrated into routine emergency department (ED) clinical care, specifically medication administration. Project Design This was a quality assurance project that monitored training of combat medics to administer parenteral medications and to ensure patient safety. Combat medics were provided training that included direct supervision during medication administration. Once proficiency was demonstrated, combat medics would prepare the medications under direct supervision, followed by indirect supervision during administration. As part of the quality assurance and safety processes, combat medics were required to document all medication administrations, supervising provider, and unexpected adverse events. Additional quality assurance follow-up occurred via complete chart review by the project lead. Data During the project period, the combat medics administered the following medications: ketamine (n=13), morphine (n=8), ketorolac (n=7), fentanyl (n=5), ondansetron (n=4), and other (n=6). No adverse events or patient safety events were reported by the combat medics or discovered during the quality assurance process. In this limited case series, combat medics safely administered parenteral medications under indirect provider supervision. Future research is needed to further develop this training model for both the military and civilian setting. Schauer SG , Cunningham C W, Fisher AD , DeLorenzo RA . A pilot project demonstrating that combat medics can safely administer parenteral medications in the emergency department. Prehosp Disaster Med. 2017;32(6):679-681.

Management of a child with vomiting.

PubMed

Singhi, Sunit C; Shah, Ravi; Bansal, Arun; Jayashree, M

2013-04-01

Vomiting is a protective reflex that results in forceful ejection of stomach contents up to and out of the mouth. It is a common complaint and may be the presenting symptom of several life-threatening conditions. It can be caused by a variety of organic and nonorganic disorders; gastrointestinal (GI) or outside of GI. Acute gastritis and gastroenteritis (AGE) are the leading cause of acute vomiting in children. Important life threatening causes in infancy include congenital intestinal obstruction, atresia, malrotation with volvulus, necrotizing enterocolitis, pyloric stenosis, intussusception, shaken baby syndrome, hydrocephalus, inborn errors of metabolism, congenital adrenal hypoplasia, obstructive uropathy, sepsis, meningitis and encephalitis, and severe gastroenteritis, and in older children appendicitis, intracranial mass lesion, diabetic ketoacidosis, Reye's syndrome, toxic ingestions, uremia, and meningitis. Initial evaluation is directed at assessment of airway, breathing and circulation, assessment of hydration status and red flag signs (bilious or bloody vomiting, altered sensorium, toxic/septic/apprehensive look, inconsolable cry or excessive irritability, severe dehydration, concern for symptomatic hypoglycemia, severe wasting, Bent-over posture). The history and physical examination guides the approach in an individual patient. The diverse nature of causes of vomiting makes a "routine" laboratory or radiologic screen impossible. Investigations (Serum electrolytes and blood gases,renal and liver functions and radiological studies) are required in any child with dehydration or red flag signs, to diagnose surgical causes. Management priorities include treatment of dehydration, stoppage of oral fluids/feeds and decompression of the stomach with nasogastric tube in patients with bilious vomiting. Antiemetic ondansetron(0.2 mg/kg oral; parenteral 0.15 mg/kg; maximum 4 mg) is indicated in children unable to take orally due to persistent vomiting, post

Preventable drug waste among anesthesia providers: opportunities for efficiency.

PubMed

Atcheson, Carrie Leigh Hamby; Spivack, John; Williams, Robert; Bryson, Ethan O

2016-05-01

Health care service bundling experiments at the state and regional levels have showed reduced costs by providing a single lump-sum reimbursement for anesthesia services, surgery, and postoperative care. Potential for cost savings related to the provision of anesthesia care has the potential to significantly impact sustainability. This study defines and quantifies routine and preventable anesthetic drug waste and the patient, procedure, and anesthesia provider characteristics associated with increased waste. Over a 12-month period, the type and quantity of clean drugs prepared by the anesthesia team for the first case of the day were recorded. The amount of each drug administered was obtained from the computerized anesthesia record, and data were analyzed to determine the incidence and cost of routine and preventable drug waste. The monthly and yearly cost of preventable waste, including the cost of pharmacy tech labor and materials where applicable, was estimated based on surgical case volume at the study institution. All analyses were performed using SAS software v9.2. Anesthetic drugs prepared for 543 separate surgical cases were observed. Less than 20% of cases generated routine waste. Preventable waste was generated most frequently for ephedrine (59.5% of cases), succinylcholine (33.7%), and lidocaine (25.1%), and least frequently for ondansetron (1.3%), phenylephrine (2.6%), and dexamethasone (2.8%). The estimated yearly cost of preventable anesthetic drug waste was $185,250. Significant potential savings with little impact on clinically significant availability may be achieved through the use of prefilled syringes for some commonly used anesthetic drugs. An intelligently implemented switch to prefilled syringes for select drugs is a potential cost saving measure, but savings might be diminished by disposal of prefilled syringes when they expire, hidden costs in the hospital pharmacy, and inability to supply some medications in prefilled syringes due to

Action of (R)-sila-venlafaxine and reboxetine to antagonize cisplatin-induced acute and delayed emesis in the ferret

DOE Office of Scientific and Technical Information (OSTI.GOV)

Warneck, Julie B.; Cheng, Frankie H.M.; Barnes, Matthew J.

2008-11-01

The chemotherapeutic drug cisplatin is associated with severe gastrointestinal toxicity that can last for several days. A recent strategy to treat the nausea and emesis includes the combination of a 5-HT{sub 3} receptor antagonist, a glucocorticoid, and an NK{sub 1} receptor antagonist. The present studies explore the use of the selective noradrenaline reuptake inhibitors, (R)-sila-venlafaxine, (R,R)-reboxetine and (S,S)-reboxetine to prevent cisplatin (5 mg/kg, i.p.)-induced acute (0-24 h) and delayed (24-72 h) emesis in ferrets. The positive control regimen of ondansetron and dexamethasone, both at 1 mg/kg/8 h, reduced acute and delayed emesis by 100 (P < 0.001) and 61% (Pmore » < 0.05). (R)-sila-venlafaxine at 5 and 15 mg/kg/4 h reduced acute emesis by 86 (P < 0.01) and 66% (P < 0.05), respectively and both enantiomers of reboxetine at 1 mg/kg/12 h also reduced the response by {approx} 70-90% (P < 0.05). Out of the reuptake inhibitors, only (R)-sila-venlafaxine at 15 mg/kg/4 h was active to reduce delayed emesis (a 57% reduction was observed (P < 0.05)); its terminal plasma levels were positively correlated with an inhibition of emesis during the delayed phase (P < 0.05). (R)-sila-venlafaxine was also examined against a higher dose of cisplatin 10 mg/kg, i.p. (3 h test) and it dose-dependently antagonized the response (maximum reduction was 94% at 10 mg/kg, p.o.; P < 0.01) but it was ineffective against apomorphine (0.125 mg/kg, s.c.) and ipecacuanha (2 mg/kg, p.o.)-induced emesis (P > 0.05). In conclusion, the studies provide the first evidence for an anti-emetic potential of noradrenaline reuptake inhibitors to reduce chemotherapy-induced acute and delayed emesis.« less

The management of children with gastroenteritis and dehydration in the emergency department.

PubMed

Colletti, James E; Brown, Kathleen M; Sharieff, Ghazala Q; Barata, Isabel A; Ishimine, Paul

2010-06-01

Acute gastroenteritis is characterized by diarrhea, which may be accompanied by nausea, vomiting, fever, and abdominal pain. To review the evidence on the assessment of dehydration, methods of rehydration, and the utility of antiemetics in the child presenting with acute gastroenteritis. The evidence suggests that the three most useful predictors of 5% or more dehydration are abnormal capillary refill, abnormal skin turgor, and abnormal respiratory pattern. Studies are conflicting on whether blood urea nitrogen (BUN) or BUN/creatinine ratio correlates with dehydration, but several studies found that low serum bicarbonate combined with certain clinical parameters predicts dehydration. In most studies, oral or nasogastric rehydration with an oral rehydration solution was equally efficacious as intravenous (i.v.) rehydration. Many experts discourage the routine use of antiemetics in young children. However, children receiving ondensetron are less likely to vomit, have greater oral intake, and are less likely to be treated by intravenous rehydration. Mean length of Emergency Department (ED) stay is also less, and very few serious side effects have been reported. In the ED, dehydration is evaluated by synthesizing the historical and physical examination, and obtaining laboratory data points in select patients. No single laboratory value has been found to be accurate in predicting the degree of dehydration and this is not routinely recommended. The evidence suggests that the majority of children with mild to moderate dehydration can be treated successfully with oral rehydration therapy. Ondansetron (orally or intravenously) may be effective in decreasing the rate of vomiting, improving the success rate of oral hydration, preventing the need for i.v. hydration, and preventing the need for hospital admission in those receiving i.v. hydration. Copyright 2010. Published by Elsevier Inc.

5-HT3 and 5-HT4 antagonists inhibit peristaltic contractions in guinea-pig distal colon by mechanisms independent of endogenous 5-HT.

PubMed

Sia, Tiong C; Whiting, Malcolm; Kyloh, Melinda; Nicholas, Sarah J; Oliver, John; Brookes, Simon J; Dinning, Phil G; Wattchow, David A; Spencer, Nick J

2013-01-01

Recent studies have shown that endogenous serotonin is not required for colonic peristalsis in vitro, nor gastrointestinal (GI) transit in vivo. However, antagonists of 5-Hydroxytryptamine (5-HT) receptors can inhibit peristalsis and GI-transit in mammals, including humans. This raises the question of how these antagonists inhibit GI-motility and transit, if depletion of endogenous 5-HT does not cause any significant inhibitory changes to either GI-motility or transit? We investigated the mechanism by which 5-HT3 and 5-HT4 antagonists inhibit distension-evoked peristaltic contractions in guinea-pig distal colon. In control animals, repetitive peristaltic contractions of the circular muscle were evoked in response to fixed fecal pellet distension. Distension-evoked peristaltic contractions were unaffected in animals with mucosa and submucosal plexus removed, that were also treated with reserpine (to deplete neuronal 5-HT). In control animals, peristaltic contractions were blocked temporarily by ondansetron (1-10 μM) and SDZ-205-557 (1-10 μM) in many animals. Interestingly, after this temporary blockade, and whilst in the continued presence of these antagonists, peristaltic contractions recovered, with characteristics no different from controls. Surprisingly, similar effects were seen in mucosa-free preparations, which had no detectable 5-HT, as detected by mass spectrometry. In summary, distension-evoked peristaltic reflex contractions of the circular muscle layer of the guinea-pig colon can be inhibited temporarily, or permanently, in the same preparation by selective 5-HT3 and 5-HT4 antagonists, depending on the concentration of the antagonists applied. These effects also occur in preparations that lack any detectable 5-HT. We suggest caution should be exercised when interpreting the effects of 5-HT3 and 5-HT4 antagonists; and the role of endogenous 5-HT, in the generation of distension-evoked colonic peristalsis.

Strain-specific genetics, anatomy and function of enteric neural serotonergic pathways in inbred mice

PubMed Central

Neal, Kathleen B; Parry, Laura J; Bornstein, Joel C

2009-01-01

Serotonin (5-HT) powerfully affects small intestinal motility and 5-HT-immunoreactive (IR) neurones are highly conserved between species. 5-HT synthesis in central neurones and gastrointestinal mucosa depends on tissue-specific isoforms of the enzyme tryptophan hydroxylase (TPH). RT-PCR identified strain-specific expression of a polymorphism (1473C/G) of the tph2 gene in longitudinal muscle–myenteric plexus preparations of C57Bl/6 and Balb/c mice. The former expressed the high-activity C allele, the latter the low-activity G allele. Confocal microscopy was used to examine close contacts between 5-HT-IR varicosities and myenteric neurones immunoreactive for neuronal nitric oxide synthase (NOS) or calretinin in these two strains. Significantly more close contacts were identified to NOS- (P < 0.05) and calretinin-IR (P < 0.01) neurones in C57Bl/6 jejunum (NOS 1.6 ± 0.3, n= 52; calretinin 5.2 ± 0.4, n= 54), than Balb/c jejunum (NOS 0.9 ± 0.2, n= 78; calretinin 3.5 ± 0.3, n= 98). Propagating contractile complexes (PCCs) were identified in the isolated jejunum by constructing spatiotemporal maps from video recordings of cannulated segments in vitro. These clusters of contractions usually arose towards the anal end and propagated orally. Regular PCCs were initiated at intraluminal pressures of 6 cmH2O, and abolished by tetrodotoxin (1 μm). Jejunal PCCs from C57Bl/6 mice were suppressed by a combination of granisetron (1 μm, 5-HT3 antagonist) and SB207266 (10 nm, 5-HT4 antagonist), but PCCs from Balb/c mice were unaffected. There were, however, no strain-specific differences in sensitivity of longitudinal muscle contractions to exogenous 5-HT or blockade of 5-HT3 and 5-HT4 receptors. These data associate a genetic difference with significant structural and functional consequences for enteric neural serotonergic pathways in the jejunum. PMID:19064621

Mediation by 5-hydroxytryptamine of the femoral vasoconstriction induced by acid challenge of the rat gastric mucosa

PubMed Central

Wachter, Christof H; Heinemann, Ákos; Donnerer, Josef; Pabst, Maria A; Holzer, Peter

1998-01-01

Gastric mucosal barrier disruption in the presence of luminal acid causes femoral vasoconstriction via a pathway that appears to be stimulated by messengers generated in the injured gastric mucosa. This study was undertaken to analyse the gastric factors that are responsible for the femoral vasoconstrictor response. Gastric mucosal barrier disruption in the presence of luminal acid was induced by perfusing the stomach of urethane-anaesthetized rats with ethanol (15 %) in 0.01-0.15 M HCl. Blood flow in the left gastric and right femoral artery was estimated by the ultrasonic transit time shift technique. Gastric perfusion of ethanol in HCl caused loss of H+ ions from the gastric lumen, decreased the HCO3− concentration in hepatic portal vein blood, induced macroscopic histological damage to the gastric mucosa, dilated the left gastric artery and constricted the femoral artery. These responses were related to the HCl concentration in the ethanol-containing perfusion medium. The femoral vasoconstriction was also seen when, instead of ethanol, taurocholate (20 mM) was used to disrupt the gastric mucosal barrier in the presence of 0.15 M HCl. The femoral vasoconstriction evoked by gastric perfusion of ethanol in HCl was left unaltered by pharmacological blockade of gastrin and histamine receptors. In contrast, the 5-hydroxytryptamine 5-HT1/2 receptor antagonist methiothepin, but not the 5-HT2A receptor antagonist ketanserin or the 5-HT3 receptor antagonist granisetron, inhibited the ability of both 5-hydroxytryptamine and gastric acid back-diffusion to constrict the femoral artery. Gastric acid back-diffusion caused release of 5-hydroxytryptamine into the gastric lumen, which was related to the HCl concentration in the ethanol-containing perfusion medium. These data show that femoral vasoconstriction evoked by gastric mucosal barrier disruption depends on back-diffusion of acid into the mucosa. The acid-induced damage results in release of 5-hydroxytryptamine from the

Gateways to clinical trials.

PubMed

Bayes, M; Rabasseda, X; Prous, J R

2005-10-01

Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: (-)-Epigallocatechin gallate, (Z)-4-hydroxytamoxifen; Ad.muIFN-beta AD-237, adalimumab, adefovir dipivoxil, agalsidase alfa, alemtuzumab, almotriptan, ALVAC vCP1452, alvimopan hydrate, ambrisentan, anakinra, anti-IFN-gamma MAb; Bimatoprost, BMS-188797, BMS-214662, bortezomib, bosentan, bovine lactoferrin; Caffeine, canertinib dihydrochloride, canfosfamide hydrochloride, cannabidiol, caspofungin acetate, cetuximab, cH36, ChimeriVax-JE, ciclesonide, cilansetron, cinacalcet hydrochloride, clopidogrel, CpG-7909, Cypher; Daptomycin, darbepoetin alfa, darifenacin hydrobromide, decitabine, denufosol tetrasodium, Dexamet, diindolemethane, drotrecogin alfa (activated), duloxetine hydrochloride, DX-9065a; E-7010, edaravone, efalizumab, eicosapentaenoic acid/docosahexaenoic acid, elacridar, eletriptan, emtricitabine, epratuzumab, erlotinib hydrochloride, ertapenem sodium, eszopiclone, everolimus, ezetimibe; Fludarabine, fondaparinux sodium; gamma-Hydroxybutyrate sodium, gavestinel sodium, gefitinib, granisetron-Biochronomer; Human Albumin, human insulin; Imatinib mesylate, indiplon, interleukin-2 XL, isatoribine, ISS-1018, i.v. gamma-globulin, ivabradine hydrochloride, ixabepilone; Lanthanum carbonate, L-arginine hydrochloride, liposomal doxorubicin, LY-450139; Magnesium sulfate, melatonin, motexafin gadolinium, mycophenolic acid sodium salt; Natalizumab, nesiritide, niacin/lovastatin; OGX-011, olmesartan medoxomil, omalizumab, ospemifene; PACAP38, panitumumab, parathyroid hormone (human recombinant), parecoxib sodium, patupilone, pegfilgrastim, peginterferon alfa-2a, peginterferon alfa-2b, peginterferon alfa-2b

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

PubMed Central

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

1995-01-01

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

The antidepressant-like effect of 7-fluoro-1,3-diphenylisoquinoline-1-amine in the mouse forced swimming test is mediated by serotonergic and dopaminergic systems.

PubMed

Pesarico, Ana Paula; Sampaio, Tuane Bazanella; Stangherlin, Eluza Curte; Mantovani, Anderson C; Zeni, Gilson; Nogueira, Cristina Wayne

2014-10-03

The aim of the present study was to investigate the role of monoaminergic system in the antidepressant-like action of 7-fluoro-1,3-diphenylisoquinoline-1-amine (FDPI), a derivative of isoquinoline class, in Swiss mice. The antidepressant-like effect of FDPI was characterized in the modified forced swimming test (FST) and the possible mechanism of action was investigated by using serotonergic, dopaminergic and noradrenergic antagonists. Monoamine oxidase (MAO) activity and [(3)H]serotonin (5-HT) uptake were determined in prefrontal cortices of mice. The results showed that FDPI (1, 10 and 20mg/kg, i.g.) reduced the immobility time and increased the swimming time but did not alter climbing time in the modified FST. These effects were similar to those of paroxetine (8mg/kg, i.p.), a positive control. Pretreatments with p-chlorophenylalanine (100mg/kg, i.p., an inhibitor of 5-HT synthesis), WAY100635 (0.1mg/kg, s.c., 5-HT1A antagonist), ondansetron (1mg/kg, i.p., a 5-HT3 receptor antagonist), haloperidol (0.2mg/kg, i.p., a non-selective D2 receptor antagonist) and SCH23390 (0.05mg/kg, s.c., a D1 receptor antagonist) were effective to block the antidepressant-like effect of FDPI at a dose of 1mg/kg in the FST. Ritanserin (1mg/kg, i.p., a 5-HT2A/2C receptor antagonist), sulpiride (50mg/kg, i.p., a D2 and D3 receptor antagonist), prazosin (1mg/kg, i.p., an α1 receptor antagonist), yohimbine (1mg/kg, i.p., an α2 receptor antagonist) and propranolol (2mg/kg, i.p., a β receptor antagonist) did not modify the effect of FDPI in the FST. FDPI did not change synaptosomal [(3)H]5-HT uptake. At doses of 10 and 20mg/kg FDPI inhibited MAO-A and MAO-B activities. These results suggest that antidepressant-like effect of FDPI is mediated mostly by serotonergic and dopaminergic systems. Copyright © 2014 Elsevier Inc. All rights reserved.

Prostaglandin potentiates 5-HT responses in stomach and ileum innervating visceral afferent sensory neurons

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Sojin; Jin, Zhenhua; Lee, Goeun

2015-01-02

Highlights: • Prostaglandin E2 (PGE{sub 2}) effect was tested on visceral afferent neurons. • PGE{sub 2} did not evoke response but potentiated serotonin (5-HT) currents up to 167%. • PGE{sub 2}-induced potentiation was blocked by E-prostanoid type 4 receptors antagonist. • PGE{sub 2} effect on 5-HT response was also blocked by protein kinase A inhibitor KT5720. • Thus, PGE{sub 2} modulate visceral afferent neurons via synergistic signaling with 5-HT. - Abstract: Gastrointestinal disorder is a common symptom induced by diverse pathophysiological conditions that include food tolerance, chemotherapy, and irradiation for therapy. Prostaglandin E{sub 2} (PGE{sub 2}) level increase was oftenmore » reported during gastrointestinal disorder and prostaglandin synthetase inhibitors has been used for ameliorate the symptoms. Exogenous administration of PGE{sub 2} induces gastrointestinal disorder, however, the mechanism of action is not known. Therefore, we tested PGE{sub 2} effect on visceral afferent sensory neurons of the rat. Interestingly, PGE{sub 2} itself did not evoked any response but enhanced serotonin (5-HT)-evoked currents up to 167% of the control level. The augmented 5-HT responses were completely inhibited by a 5-HT type 3 receptor antagonist, ondansetron. The PGE{sub 2}-induced potentiation were blocked by a selective E-prostanoid type4 (EP{sub 4}) receptors antagonist, L-161,982, but type1 and 2 receptor antagonist AH6809 has no effect. A membrane permeable protein kinase A (PKA) inhibitor, KT5720 also inhibited PGE{sub 2} effects. PGE{sub 2} induced 5-HT current augmentation was observed on 15% and 21% of the stomach and ileum projecting neurons, respectively. Current results suggest a synergistic signaling in visceral afferent neurons underlying gastrointestinal disorder involving PGE{sub 2} potentiation of 5-HT currents. Our findings may open a possibility for screen a new type drugs with lower side effects than currently using steroidal

Chronic hypoxic incubation blunts a cardiovascular reflex loop in embryonic American alligator (Alligator mississippiensis).

PubMed

Eme, John; Hicks, James W; Crossley, Dane A

2011-10-01

Hypoxia is a naturally occurring environmental challenge for embryonic non-avian reptiles, and this study is the first to investigate the impact of chronic hypoxia on a possible chemoreflex loop in a developing non-avian reptile. We measured heart rate and blood pressure in normoxic and hypoxic-incubated (10% O(2)) American alligator embryos (Alligator mississippiensis) at 70 and 90/95% of development. We hypothesized that hypoxic incubation would blunt embryonic alligators' response to a reflex loop stimulated by phenylbiguanide (PBG), a 5-HT(3) receptor agonist that stimulates vagal pulmonary C-fiber afferents. PBG injection caused a hypotensive bradycardia in 70 and 95% of development embryos (paired t tests, P < 0.05), a response similar to mammals breathing inspired air (all injections made through occlusive catheter in tertiary chorioallantoic membrane artery). Hypoxic incubation blunted the bradycardic response to PBG in embryos at 95% of development (two-way ANOVA, P < 0.01). We also demonstrated that the vagally mediated afferent limb of this reflex can be partially or completely blocked in ovo with a 5-HT(3) receptor blockade using ondansetron hydrochloride dihydrate (OHD), with a ganglionic blockade using hexamethonium, or with a cholinergic blockade using atropine. Atropine eliminated the hypotensive and bradycardic responses to PBG, and OHD and hexamethonium significantly blunted these responses. This cardiovascular reflex mediated by the vagus was affected by hypoxic incubation, suggesting that reptilian sympathetic and parasympathetic reflex loops have the potential for developmental plasticity in response to hypoxia. We suggest that the American alligator, with an extended length of time between each developmental stage relative to avian species, may provide an excellent model to test the cardiorespiratory effects of prolonged exposure to changes in atmospheric gases. This extended period allows for lengthy studies at each stage without the

Cost-utility and budget impact analyses of the use of NEPA for chemotherapy-induced nausea and vomiting prophylaxis in Italy

PubMed Central

Restelli, Umberto; Saibene, Gabriella; Nardulli, Patrizia; Di Turi, Roberta; Bonizzoni, Erminio; Scolari, Francesca; Perrone, Tania; Croce, Davide; Celio, Luigi

2017-01-01

Objective To evaluate the efficiency of resources allocation and sustainability of the use of netupitant+palonosetron (NEPA) for chemotherapy-induced nausea and vomiting (CINV) prophylaxis assuming the Italian National Health Service (NHS) perspective. A published Markov model was adapted to assess the incremental cost-utility ratio of NEPA compared with aprepitant (APR) + palonosetron (PALO), fosaprepitant (fAPR) + PALO, APR + ondansetron (ONDA), fAPR + ONDA in patients receiving a highly emetogenic chemotherapy (HEC) and with APR + PALO and fAPR + PALO in patients receiving a moderately emetogenic chemotherapy (MEC). Setting Oncology hospital department in Italy. Methods A Markov model was used to determine the impact of NEPA on the budget of the Italian NHS on a 5-day time horizon, corresponding to the acute and delayed CINV prophylaxis phases. Direct medical costs considered were related to antiemetic drugs, adverse events management, CINV episodes management. Clinical and quality of life data referred to previously published works. The budget impact analysis considered the aforementioned therapies plus PALO alone (for HEC and MEC) on a 5-year time horizon, comparing two scenarios: one considering the use of NEPA and one not considering its use. Primary and secondary outcome measures Incremental cost per quality adjusted life year (QALY) and differential economic impact for the Italian NHS between the two scenarios considered. Results NEPA is more effective and less expensive (dominant) compared with APR + PALO (for HEC and MEC), fAPR + PALO (for HEC and MEC), APR + ONDA (for HEC), fAPR + ONDA (for HEC). The use of NEPA would lead to a 5-year cost decrease of €63.7 million (€42.7 million for HEC and €20.9 million for MEC). Conclusions NEPA allows an efficient allocation of resources for the Italian NHS and it is sustainable, leading to a cost decrease compared with a scenario which does not consider its use. PMID:28765126

Synthetic cannabinoid “Black Mamba” infidelity in patients presenting for emergency stabilization in Colorado: a P SCAN Cohort

PubMed Central

Brandehoff, Nicklaus; Adams, Axel; McDaniel, Kyle; Banister, Samuel D.; Gerona, Roy; Monte, Andrew A.

2017-01-01

Background Use of new psychoactive substances (NPS) has increased over the last decade. During this period, variability of both clinical presentations and chemical compositions of these compounds has increased. Synthetic cannabinoids (SCs) are the most commonly used NPS and there are more than 100 documented unique molecules in this class. “Black Mamba”, often associated to ADB-FUBINACA, is the most commonly used SC in Colorado. It has been linked to kidney injury, myocardial toxicity, seizures, and death. Objectives We aim to identify the chemical constituents and quantification of eight cases of reported “Black Mamba” use in order to further understand the clinical variability in patients presenting for emergency stabilization. Methods We report data from eight cases of reported “Black Mamba” use prospectively captured through the Colorado site of the Psychoactive Surveilance Consortium and Analysis Network (P SCAN). P SCAN is a geographically representative group of academic hospitals that capture clinical presentation, outcome, and biologic samples from patients that present for emergency stabilization following NPS use. Serum and urine samples were analyzed and quantified by liquid chromatography-quadrupole time-of-flight mass spectrometry after a qualitative screen for over 600 unique NPS compounds. Results In the reported eight cases, the median age was 28 years old. There were four male and four females. Four patients had agitation/delirium and four patients had chest pain. Normal saline, benzodiazepines and ondansetron were the common treatment provided in the emergency department (ED). Two patients were discharged from the ED and six patients being admitted for emergency observation with a median length of stay (LOS) of six hours. No deaths were reported. Confirmatory testing revealed that only five patients (62.5%) had SCs found in blood or urine samples. Cocaine, NRG-3, 3-methoxyphencyclidine hydrochloride (MeO-PCP), and methamfetamine were

Antidepressant-like effect of gallic acid in mice: Dual involvement of serotonergic and catecholaminergic systems.

PubMed

Can, Özgür Devrim; Turan, Nazlı; Demir Özkay, Ümide; Öztürk, Yusuf

2017-12-01

This study was planned to examine the antidepressant potency of gallic acid (30 and 60mg/kg), a phenolic acid widely distributed in nature, together with its possible underlying monoaminergic mechanisms. Antidepressant-like activity was assessed using the tail suspension (TST) and the modified forced swimming tests (MFST). Locomotor activity was evaluated in an activity cage. Administration of gallic acid at 60mg/kg reduced the immobility duration of mice in both the TST and MFST without any changes in the locomotor activity. The anti-immobility effect observed in the TST was abolished with pre-treatment of p-chlorophenylalanine methyl ester (an inhibitor of serotonin synthesis; 100mg/kg i.p. administered for 4-consecutive days), ketanserin (a 5-HT2A/2C antagonist; 1mg/kg i.p.), ondansetron (a 5-HT3 antagonist; 0.3mg/kg i.p.), α-methyl-para-tyrosine methyl ester (an inhibitor of catecholamine synthesis; 100mg/kg i.p.), phentolamine (non-selective alpha-adrenoceptor antagonist; 5mg/kg i.p.), SCH 23390 (a dopamine D1 antagonist; 0.05mg/kg s.c.), and sulpiride (a dopamine D2/D3 antagonist; 50mg/kg i.p.). However, NAN 190 (a 5-HT1A antagonist; 0.5mg/kg i.p.) and propranolol (a non-selective β-adrenoceptor antagonist; 5mg/kg i.p.) pre-treatments were ineffective at reversing the antidepressant-like effects of gallic acid. The results of the present study indicate that gallic acid seems to have a dual mechanism of action by increasing not only serotonin but also catecholamine levels in synaptic clefts of the central nervous system. Further alpha adrenergic, 5-HT2A/2C and 5-HT3 serotonergic, and D1, D2, and D3 dopaminergic receptors also seem to be involved in this antidepressant-like activity. Copyright © 2017 Elsevier Inc. All rights reserved.

A Physiologic Role for Serotonergic Transmission in Adult Rat Taste Buds

PubMed Central

Jaber, Luc; Zhao, Fang-li; Kolli, Tamara; Herness, Scott

2014-01-01

Of the multiple neurotransmitters and neuropeptides expressed in the mammalian taste bud, serotonin remains both the most studied and least understood. Serotonin is expressed in a subset of taste receptor cells that form synapses with afferent nerve fibers (type III cells) and was once thought to be essential to neurotransmission (now understood as purinergic). However, the discovery of the 5-HT1A serotonin receptor in a subset of taste receptor cells paracrine to type III cell suggested a role in cell-to-cell communication during the processing of taste information. Functional data describing this role are lacking. Using anatomical and neurophysiological techniques, this study proposes a modulatory role for serotonin during the processing of taste information. Double labeling immunocytochemical and single cell RT-PCR technique experiments documented that 5-HT1A-expressing cells co-expressed markers for type II cells, cells which express T1R or T2R receptors and release ATP. These cells did not co-express type III cells markers. Neurophysiological recordings from the chorda tympani nerve, which innervates anterior taste buds, were performed prior to and during intravenous injection of a 5-HT1A receptor antagonist. These experiments revealed that serotonin facilitates processing of taste information for tastants representing sweet, sour, salty, and bitter taste qualities. On the other hand, injection of ondansetron, a 5-HT3 receptor antagonist, was without effect. Collectively, these data support the hypothesis that serotonin is a crucial element in a finely-tuned feedback loop involving the 5-HT1A receptor, ATP, and purinoceptors. It is hypothesized that serotonin facilitates gustatory signals by regulating the release of ATP through ATP-release channels possibly through phosphatidylinositol 4,5-bisphosphate resynthesis. By doing so, 5-HT1A activation prevents desensitization of post-synaptic purinergic receptors expressed on afferent nerve fibers and enhances the

A Prospective Analysis of Patients Presenting for Medical Attention at a Large Electronic Dance Music Festival.

PubMed

Friedman, Matt S; Plocki, Alex; Likourezos, Antonios; Pushkar, Illya; Bazos, Andrew N; Fromm, Christian; Friedman, Benjamin W

2017-02-01

Mass-Gathering Medicine studies have identified variables that predict greater patient presentation rates (PPRs) and transport to hospital rates (TTHRs). This is a descriptive report of patients who presented for medical attention at an annual electronic dance music festival (EDMF). At this large, single EDMF in New York City (NYC; New York, USA), the frequency of patient presentation, the range of presentations, and interventions performed were identified. This descriptive report examined consecutive patients who presented to the medical tent of a summertime EDMF held at an outdoor venue with an active, mobile, bounded crowd. Alcohol was available for sale. Entry was restricted to persons 18 years and older. The festival occurred on three consecutive days with a total cumulative attendance of 58,000. Medical staffing included two Emergency Medicine physicians, four registered nurses, and 86 Emergency Medical Services (EMS) providers. Data collected included demographics, past medical history, vital signs, physical exam, drug and alcohol use, interventions performed, and transport decisions. Eighty-four patients were enrolled over 2.5 days. Six were transported and zero died. The ages of the subjects ranged from 17 to 61 years. Forty-three (51%) were male. Thirty-eight (45%) initially presented with abnormal vital signs; four (5%) were hyperthermic. Of these latter patients, 34 (90%) reported ingestions with 3,4-methylenedioxymethamphetamine (MDMA) or other drugs. Eleven (65%) patients were diaphoretic or mydriatic. The most common prehospital interventions were intravenous normal saline (8/84; 10%), ondansetron (6/84; 7%), and midazolam (3/84; 4%). Electronic dance music festivals are a growing trend and a new challenge for Mass-Gathering Medicine as new strategies must be employed to decrease TTHR and mortality. Addressing common and expected medical emergencies at mass-gathering events through awareness, preparation, and early, focused medical interventions may

Cost-utility and budget impact analyses of the use of NEPA for chemotherapy-induced nausea and vomiting prophylaxis in Italy.

PubMed

Restelli, Umberto; Saibene, Gabriella; Nardulli, Patrizia; Di Turi, Roberta; Bonizzoni, Erminio; Scolari, Francesca; Perrone, Tania; Croce, Davide; Celio, Luigi

2017-08-01

To evaluate the efficiency of resources allocation and sustainability of the use of netupitant+palonosetron (NEPA) for chemotherapy-induced nausea and vomiting (CINV) prophylaxis assuming the Italian National Health Service (NHS) perspective. A published Markov model was adapted to assess the incremental cost-utility ratio of NEPA compared with aprepitant (APR) + palonosetron (PALO), fosaprepitant (fAPR) + PALO, APR + ondansetron (ONDA), fAPR + ONDA in patients receiving a highly emetogenic chemotherapy (HEC) and with APR + PALO and fAPR + PALO in patients receiving a moderately emetogenic chemotherapy (MEC). Oncology hospital department in Italy. A Markov model was used to determine the impact of NEPA on the budget of the Italian NHS on a 5-day time horizon, corresponding to the acute and delayed CINV prophylaxis phases. Direct medical costs considered were related to antiemetic drugs, adverse events management, CINV episodes management. Clinical and quality of life data referred to previously published works. The budget impact analysis considered the aforementioned therapies plus PALO alone (for HEC and MEC) on a 5-year time horizon, comparing two scenarios: one considering the use of NEPA and one not considering its use. Incremental cost per quality adjusted life year (QALY) and differential economic impact for the Italian NHS between the two scenarios considered. NEPA is more effective and less expensive (dominant) compared with APR + PALO (for HEC and MEC), fAPR + PALO (for HEC and MEC), APR + ONDA (for HEC), fAPR + ONDA (for HEC). The use of NEPA would lead to a 5-year cost decrease of €63.7 million (€42.7 million for HEC and €20.9 million for MEC). NEPA allows an efficient allocation of resources for the Italian NHS and it is sustainable, leading to a cost decrease compared with a scenario which does not consider its use. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No

A physiologic role for serotonergic transmission in adult rat taste buds.

PubMed

Jaber, Luc; Zhao, Fang-li; Kolli, Tamara; Herness, Scott

2014-01-01

Of the multiple neurotransmitters and neuropeptides expressed in the mammalian taste bud, serotonin remains both the most studied and least understood. Serotonin is expressed in a subset of taste receptor cells that form synapses with afferent nerve fibers (type III cells) and was once thought to be essential to neurotransmission (now understood as purinergic). However, the discovery of the 5-HT1A serotonin receptor in a subset of taste receptor cells paracrine to type III cell suggested a role in cell-to-cell communication during the processing of taste information. Functional data describing this role are lacking. Using anatomical and neurophysiological techniques, this study proposes a modulatory role for serotonin during the processing of taste information. Double labeling immunocytochemical and single cell RT-PCR technique experiments documented that 5-HT1A-expressing cells co-expressed markers for type II cells, cells which express T1R or T2R receptors and release ATP. These cells did not co-express type III cells markers. Neurophysiological recordings from the chorda tympani nerve, which innervates anterior taste buds, were performed prior to and during intravenous injection of a 5-HT1A receptor antagonist. These experiments revealed that serotonin facilitates processing of taste information for tastants representing sweet, sour, salty, and bitter taste qualities. On the other hand, injection of ondansetron, a 5-HT3 receptor antagonist, was without effect. Collectively, these data support the hypothesis that serotonin is a crucial element in a finely-tuned feedback loop involving the 5-HT1A receptor, ATP, and purinoceptors. It is hypothesized that serotonin facilitates gustatory signals by regulating the release of ATP through ATP-release channels possibly through phosphatidylinositol 4,5-bisphosphate resynthesis. By doing so, 5-HT1A activation prevents desensitization of post-synaptic purinergic receptors expressed on afferent nerve fibers and enhances the

Amisulpride Prevents Postoperative Nausea and Vomiting in Patients at High Risk: A Randomized, Double-blind, Placebo-controlled Trial.

PubMed

Kranke, Peter; Bergese, Sergio D; Minkowitz, Harold S; Melson, Timothy I; Leiman, David G; Candiotti, Keith A; Liu, Ngai; Eberhart, Leopold; Habib, Ashraf S; Wallenborn, Jan; Kovac, Anthony L; Diemunsch, Pierre; Fox, Gabriel; Gan, Tong J

2018-06-01

Postoperative nausea and vomiting causes distress for patients and can prolong care requirements. Consensus guidelines recommend use of multiple antiemetics from different mechanistic classes as prophylaxis in patients at high risk of postoperative nausea and vomiting. The prophylactic efficacy of the dopamine D2/D3 antagonist amisulpride in combination with other antiemetics was investigated. This double-blind, randomized, placebo-controlled, international, multicenter trial was conducted in 1,147 adult surgical patients having three or four postoperative nausea and vomiting risk factors. Patients were randomized to receive either intravenous amisulpride (5 mg) or matching placebo at induction of general anesthesia, in addition to one standard, nondopaminergic antiemetic, most commonly ondansetron or dexamethasone. Vomiting/retching, nausea, and use of rescue medication were recorded for 24 h after wound closure. The primary endpoint was complete response, defined as no emesis or rescue medication use in the 24-h postoperative period. Complete response occurred in 330 of 572 (57.7%) of the amisulpride group and 268 of 575 (46.6%) of the control group (difference 11.1 percentage points; 95% CI, 5.3 to 16.8; P < 0.001). The incidences of emesis (13.8% vs. 20.0%, P = 0.003), any nausea (50.0% vs. 58.3%, P = 0.002), significant nausea (37.1% vs. 47.7%, P < 0.001), and rescue medication use (40.9% vs. 49.4%, P = 0.002) were significantly lower in the amisulpride group. Adverse events and laboratory and electrocardiogram abnormalities occurred no more frequently with amisulpride than with placebo. Intravenous amisulpride was safe and effective as prophylaxis of postoperative nausea and vomiting when given in combination with an antiemetic from another class to adult patients at high risk for suffering postoperative nausea and vomiting undergoing elective surgery under inhalational general anesthesia. An online visual overview is available for this article at http

The antinociceptive effect of intravenous imipramine in colorectal distension-induced visceral pain in rats: the role of serotonergic and noradrenergic receptors.

PubMed

İlkaya, Fatih; Bilge, S Sırrı; Bozkurt, Ayhan; Baş, Duygu B; Erdal, Arzu; Çiftçioğlu, Engin; Kesim, Yüksel

2014-07-01

It has been shown that imipramine, a tricyclic antidepressant (TCA), is a potent analgesic agent. However, the effect of imipramine on visceral pain has not been extensively investigated. In the current study, our aim was to characterise the putative analgesic effect of intravenous imipramine on visceral pain in rats. Our second aim was to assess the involvement of serotonergic (5-HT₂,₃,₄) and noradrenergic (α(2A, 2B, 2C)) receptor subtypes in this putative antinociceptive effect of imipramine. Male Sprague Dawley rats (250-300 g) were implanted with venous catheters for drug administration and implanted with enamelled nichrome electrodes for electromyography of the external oblique muscles. Noxious visceral stimulation was applied via by colorectal distension (CRD). The visceromotor responses (VMRs) to CRD were quantified electromyographically before and after imipramine administration at 5, 15, 30, 60, 90 and 120 min. In the antagonist groups, the agents were administered 10 min before imipramine. The administration of imipramine (5-40 mg/kg) produced a dose-dependent reduction in VMR. The administration of yohimbine (a nonselective α₂-adrenoceptor antagonist, 1 mg/kg), BRL-44408 (an α(2A)-adrenoceptor antagonist, 1 mg/kg) or MK-912 (an α2C-adrenoceptor antagonist, 300 μg/kg) but not imiloxan (an α(2B)-adrenoceptor antagonist, 1 mg/kg) inhibited the antinociceptive effect of imipramine (20 mg/kg). Additionally, ketanserin (a 5-HT₂ receptor antagonist, 0.5, 1, and 2 mg/kg) and GR113808 (a 5-HT₄ receptor antagonist, 1 mg/kg) enhanced, and ondansetron (a 5-HT₃ receptor antagonist, 0.5, 1, and 2 mg/kg) failed to alter the imipramine-induced antinociceptive effect. Our data demonstrated that, in the CDR-induced rat visceral pain model, intravenous imipramine appeared to have antinociceptive potential and that α(2A)-/α(2C)-adrenoceptors and 5-HT₂/5-HT₄ receptors may be responsible for the antinociceptive effect of imipramine on visceral pain

Successful management of minoxidil toxicosis in a dog.

PubMed

Jordan, Tyler J M; Yaxley, Page E; Culler, Christine A; Balakrishnan, Anusha

2018-01-15

CASE DESCRIPTION A 2-year-old sexually intact female mixed-breed dog was evaluated at an emergency hospital approximately 5 hours after ingestion of an unknown amount of over-the-counter topical hair growth promoter containing 5% minoxidil foam. Vomiting and signs of lethargy were reported by the owner, and physical examination revealed tachycardia and hypotension. No treatments were performed, and the dog was transferred to a veterinary referral hospital for management of suspected minoxidil toxicosis. CLINICAL FINDINGS On arrival at the referral hospital, the dog was tachycardic (heart rate, 200 to 220 beats/min) and hypotensive (systolic arterial blood pressure, 70 mm Hg). Electrocardiography revealed a regular, narrow-complex tachycardia with no evidence of ventricular ectopy. TREATMENT AND OUTCOME Hypotension was effectively managed with a constant rate infusion of dopamine hydrochloride (12.5 μg/kg/min [5.7 μg/lb/min], IV). Once normotensive, the dog remained tachycardic and a constant rate infusion of esmolol hydrochloride (40 μg/kg/min [18.2 μg/lb/min], IV) was initiated for heart rate control. A lipid emulsion was administered IV as a potential antidote for the toxic effects of the lipophilic minoxidil, with an initial bolus of 1.5 mL/kg (0.7 mL/lb) given over 15 minutes followed by a continuous rate infusion at 0.25 mL/kg/min (0.11 mL/lb/min) for 60 minutes. While hospitalized, the dog also received maropitant citrate and ondansetron. Resolution of clinical signs was achieved with treatment, and the dog was discharged from the hospital 36 hours after admission. Four days later, the owner reported that the dog had made a full recovery and had returned to its typical behavior and activity level at home. CLINICAL RELEVANCE To the authors' knowledge, this is the first report of successful clinical management of accidental minoxidil toxicosis in a dog.

Comparison of pain-relieving effects of fentanyl versus ketorolac after eye amputation surgery.

PubMed

Kim, Jin Hyung; Jang, Sun Young; Kim, Myung Jin; Lee, Sang Yeul; Yoon, Jin Sook

2013-08-01

To investigate the analgesic effect and incidence of postoperative nausea and vomiting (PONV) between the opioid fentanyl and the non-steroidal anti-inflammatory drug ketorolac in patients who underwent eye amputation surgery. Retrospective observational case series. Eighty-two patients underwent evisceration or enucleation surgery by one surgeon over a 2-year period. Fentanyl by intravenous patient-controlled analgesia (IV-PCA) at 20 µg/kg with 12 mg/kg ondansetron or intravenous ketorolac at 2 mg/kg/day was administered to patients at postoperative days 0, 1, and 2. The pain score was measured using an 11-point visual analog scale (VAS). The incidence of severe nausea requiring anti-emetics and the incidence of vomiting were reviewed. The mean postoperative VAS in the fentanyl group was significantly lower than that in the ketorolac group on the day of operation for both types of surgery (p = 0.001 and p = 0.004, respectively). At postoperative days 1 and 2, the mean VAS was not different between the two groups for either surgical type (p > 0.05 for both days). The mean VAS was significantly higher in eviscerated patients than in enucleated patients at postoperative days 0 and 1 in the fentanyl group (p = 0.023 and p = 0.016, respectively). However, this was not observed in the ketorolac group. The incidence of PONV was higher in the fentanyl group than in the ketorolac group, although this was not statistically significant for either surgical type (p > 0.05 for both groups). Fentanyl was more effective as an analgesic than was ketorolac on the day of operation for both surgical types. There was no difference between the two analgesics on postoperative day 1. The analgesic effect of fentanyl in enucleated patients was significantly higher than in eviscerated patients at postoperative days 0 and 1. The use of fentanyl by IV-PCA was associated with greater PONV despite co-administration with anti-emetics, although this finding was not significant.

Comparison of Pain-relieving Effects of Fentanyl versus Ketorolac after Eye Amputation Surgery

PubMed Central

Kim, Jin Hyung; Jang, Sun Young; Kim, Myung Jin; Lee, Sang Yeul

2013-01-01

Purpose To investigate the analgesic effect and incidence of postoperative nausea and vomiting (PONV) between the opioid fentanyl and the non-steroidal anti-inflammatory drug ketorolac in patients who underwent eye amputation surgery. Methods Retrospective observational case series. Eighty-two patients underwent evisceration or enucleation surgery by one surgeon over a 2-year period. Fentanyl by intravenous patient-controlled analgesia (IV-PCA) at 20 µg/kg with 12 mg/kg ondansetron or intravenous ketorolac at 2 mg/kg/day was administered to patients at postoperative days 0, 1, and 2. The pain score was measured using an 11-point visual analog scale (VAS). The incidence of severe nausea requiring anti-emetics and the incidence of vomiting were reviewed. Results The mean postoperative VAS in the fentanyl group was significantly lower than that in the ketorolac group on the day of operation for both types of surgery (p = 0.001 and p = 0.004, respectively). At postoperative days 1 and 2, the mean VAS was not different between the two groups for either surgical type (p > 0.05 for both days). The mean VAS was significantly higher in eviscerated patients than in enucleated patients at postoperative days 0 and 1 in the fentanyl group (p = 0.023 and p = 0.016, respectively). However, this was not observed in the ketorolac group. The incidence of PONV was higher in the fentanyl group than in the ketorolac group, although this was not statistically significant for either surgical type (p > 0.05 for both groups). Conclusions Fentanyl was more effective as an analgesic than was ketorolac on the day of operation for both surgical types. There was no difference between the two analgesics on postoperative day 1. The analgesic effect of fentanyl in enucleated patients was significantly higher than in eviscerated patients at postoperative days 0 and 1. The use of fentanyl by IV-PCA was associated with greater PONV despite co-administration with anti-emetics, although this finding

Comparison of Intraabdominal and Trocar Site Local Anaesthetic Infiltration on Postoperative Analgesia After Laparoscopic Cholecystectomy.

PubMed

Altuntaş, Gülsüm; Akkaya, Ömer Taylan; Özkan, Derya; Sayın, Mehmet Murat; Balas, Şener; Özlü, Elif

2016-12-01

This study aimed to compare the efficacy of local anaesthetic infiltration to trocar wounds and intraperitoneally on postoperative pain as a part of a multimodal analgesia method after laparoscopic cholecystectomies. The study was performed on 90 ASA I-III patients aged between 20 and 70 years who underwent elective laparoscopic cholecystectomy. All patients had the same general anaesthesia drug regimen. Patients were randomized into three groups by a closed envelope method: group I (n=30), trocar site local anaesthetic infiltration (20 mL of 0.5% bupivacaine); group II (n=30), intraperitoneal local anaesthetic instillation (20 mL of 0.5%) and group III (n=30), saline infiltration both trocar sites and intraperitoneally. Postoperative i.v. patient controlled analgesia was initiated for 24 h. In total, 4 mg of i.v. ondansetron was administered to all patients. Visual analogue scale (VAS), nausea and vomiting and shoulder pain were evaluated at 1., 2., 4., 8., 12., 24. hours. An i.v. nonsteroidal anti-inflammatory drug (NSAID) (50 mg of dexketoprofen) as a rescue analgesic was given if the VAS was ≥5. There were no statistical significant differences between the clinical and demographic properties among the three groups (p≥0.005). During all periods, VAS in group I was significantly lower than that in groups II and III (p<0.001). Among the groups, although there was no significant difference in nausea and vomiting (p=0.058), there was a significant difference in shoulder pain. Group III (p<0.05) had more frequent shoulder pain than groups I and II. The total morphine consumption was higher in groups II and III (p<0.001 vs p<0.001) than in group I. The requirement for a rescue analgesic was significantly higher in group III (p<0.05). Trocar site local anaesthetic infiltration is more effective for postoperative analgesia, easier to apply and safer than other analgesia methods. Morphine consumption is lesser and side effects are fewer; therefore, this method can be

Tianeptine: 5-HT uptake sites and 5-HT(1-7) receptors modulate memory formation in an autoshaping Pavlovian/instrumental task.

PubMed

Meneses, Alfredo

2002-05-01

Recent studies using invertebrate and mammal species have revealed that, endogenous serotonin (5-hydroxytryptamine, 5-HT) modulates cognitive processes, particularly learning and memory, though, at present, it is unclear the manner, where, and how long 5-HT systems are involved. Hence in this work, an attempt was made to study the effects of 5-HT endogenous on memory formation, using a 5-HT uptake facilitator (tianeptine) and, selective 5-HT(1-7) receptor antagonists to determine whether 5-HT uptake sites and which 5-HT receptors are involved, respectively. Results showed that post-training tianeptine injection enhanced memory consolidation in an autoshaping Pavlovian/instrumental learning task, which has been useful to detect changes on memory formation elicited by drugs or aging. On interaction experiments, ketanserin (5-HT(1D/2A/2C) antagonist) slightly enhanced tianeptine effects, while WAY 100635 (5-HT(1A) antagonist), SB-224289 (5-HT(1B) inverse agonist), SB-200646 (5-HT(2B/2C) antagonist), ondansetron (5-HT(3) antagonist), GR 127487 (5-HT(4) antagonist), Ro 04-6790 (5-HT(6) antagonist), DR 4004 (5-HT(7) antagonist), or fluoxetine (an inhibitor of 5-HT reuptake) blocked the facilitatory tianeptine effect. Notably, together tianeptine and Ro 04-6790 impaired learning consolidation. Moreover, 5-HT depletion completely reversed the tianeptine effect. Tianeptine also normalized an impaired memory elicited by scopolamine (an antimuscarinic) or dizocilpine (non-competitive glutamatergic antagonist), while partially reversed that induced by TFMPP (5-HT(1B/1D/2A-2C/7) agonist/antagonist). Finally, tianeptine-fluoxetine coadministration had no effect on learning consolidation; nevertheless, administration of an acetylcholinesterase inhibitor, phenserine, potentiated subeffective tianeptine or fluoxetine doses. Collectively, these data confirmed that endogenously 5-HT modulates, via uptake sites and 5-HT(1-7) receptors, memory consolidation, and are consistent with the

Dexamethasone does not diminish sugammadex reversal of neuromuscular block - clinical study in surgical patients undergoing general anesthesia.

PubMed

Rezonja, Katja; Mars, Tomaz; Jerin, Ales; Kozelj, Gordana; Pozar-Lukanovic, Neva; Sostaric, Maja

2016-10-21

Sugammadex reverses neuromuscular block (NMB) through binding aminosteroid neuromuscular blocking agents. Although sugammadex appears to be highly selective, it can interact with other drugs, like corticosteroids. A prospective single-blinded randomized clinical trial was designed to explore the significance of interactions between dexamethasone and sugammadex. Sixty-five patients who were anesthetized for elective abdominal or urological surgery were included. NMB was assessed using train-of-four stimulation (TOF), with rocuronium used to maintain the desired NMB depth. NMB reversal at the end of anaesthesia was achieved using sugammadex. According to their received antiemetics, the patients were randomized to either the granisetron or dexamethasone group. Blood samples were taken before and after NMB reversal, for plasma dexamethasone and rocuronium determination. Primary endpoint was time from sugammadex administration to NMB reversal. Secondary endpoints included the ratios of the dexamethasone and rocuronium concentrations after NMB reversal versus before sugammadex administration. There were no differences for time to NMB reversal between the control (mean 121 ± 61 s) and the dexamethasone group (mean 125 ± 57 s; P = 0.760). Time to NMB reversal to a TOF ratio ≥0.9 was significantly longer in patients with lower TOF prior to sugammadex administration (Beta = -0.268; P = 0.038). The ratio between the rocuronium concentrations after NMB reversal versus before sugammadex administration was significantly affected by sugammadex dose (Beta = -0.375; P = 0.004), as was rocuronium dose per hour of operation (Beta = -0.366; p = 0.007), while it was not affected by NMB depth before administration of sugammadex (Beta = -0.089; p = 0.483) and dexamethasone (Beta = -0.186; p = 0.131). There was significant drop in plasma dexamethasone after sugammadex administration and NMB reversal (p < 0.001). Administration

Using decision modeling to determine pricing of new pharmaceuticals: the case of neurokinin-1 receptor antagonist antiemetics for cancer chemotherapy.

PubMed

Dranitsaris, George; Leung, Pauline

2004-01-01

Decision analysis is commonly used to perform economic evaluations of new pharmaceuticals. The outcomes of such studies are often reported as an incremental cost per quality-adjusted life year (QALY) gained with the new agent. Decision analysis can also be used in the context of estimating drug cost before market entry. The current study used neurokinin-1 (NK-1) receptor antagonists, a new class of antiemetics for cancer patients, as an example to illustrate the process using an incremental cost of dollars Can20,000 per QALY gained as the target threshold. A decision model was developed to simulate the control of acute and delayed emesis after cisplatin-based chemotherapy. The model compared standard therapy with granisetron and dexamethasone to the same protocol with the addition of an NK-1 before chemotherapy and continued twice daily for five days. The rates of complete emesis control were abstracted from a double-blind randomized trial. Costs of standard antiemetics and therapy for breakthrough vomiting were obtained from hospital sources. Utility estimates characterized as quality-adjusted emesis-free days were determined by interviewing twenty-five oncology nurses and pharmacists by using the Time Trade-Off technique. These data were then used to estimate the unit cost of the new antiemetic using a target threshold of dollars Can20,000 per QALY gained. A cost of dollars Can6.60 per NK-1 dose would generate an incremental cost of dollars Can20,000 per QALY. The sensitivity analysis on the unit cost identified a range from dollars Can4.80 to dollars Can10.00 per dose. For the recommended five days of therapy, the total cost should be dollars Can66.00 (dollars Can48.00-dollars Can100.00) for optimal economic efficiency relative to Canada's publicly funded health-care system. The use of decision modeling for estimating drug cost before product launch is a powerful technique to ensure value for money. Such information can be of value to both drug manufacturers and

Changing the Management of Paracetamol Poisoning.

PubMed

Bateman, D Nicholas

2015-09-01

The management of paracetamol poisoning was revolutionized after use of acetylcysteine in the 1970s. The protocol used, 3 weight-related infusions, requires almost 24 hours in hospital. It is associated with adverse events in treated patients, particularly anaphylactoid reactions and vomiting. Present treatment nomograms were based on a small series of untreated patients: only 5 of 22 (23%) and 6 of 25 (24%) between the 100 to 200 mg/L and 200 to 300 mg/L nomogram lines, respectively, developed liver injury (alanine transaminase >1000 IU/L). Many patients treated today are unlikely to be at actual risk for major hepatotoxicity. This article discusses the background to future prospects in this area. The history behind approaches to the use of acetylcysteine is presented briefly. The rationale for, and key findings of, a new 12-hour antidote regimen for paracetamol poisoning are detailed. Newer markers of hepatotoxicity, such as miR-122, HMGB1, and necrosis K18, which predict patients at risk more reliably and earlier than existing tests, are discussed. A 2-phase 12-hour acetylcysteine infusion protocol (100 mg/kg over 2 hours: 200 mg/kg over 10 hours) was studied in a formal factorial design against the traditional 3-phase 20.25-hour infusion protocol, with and without pretreatment with ondansetron or placebo. The 12-hour regimen was associated with very significant reductions in anaphylactoid reactions (odds ratio = 0.23; 95% CI, 0.12-0.43; P < 0.0001) and vomiting (odds ratio = 0.37; 95% CI, 0.18-0.79; P = .003) compared with the 20.25-hour infusion protocol. There were few withdrawals from the clinical trial, indicating the feasibility of conducting such studies in Europe. Novel proteomic markers are better than existing standard tests (alanine transaminase and international normalized ratio) early in the course of paracetamol poisoning. Together with these new biomarkers of hepatotoxicity, a 12-hour acetylcysteine protocol offers clinicians and patients the

Simultaneous determination of erlotinib and tamoxifen in rat plasma using UPLC-MS/MS: Application to pharmacokinetic interaction studies.

PubMed

Maher, Hadir M; Alzoman, Nourah Z; Shehata, Shereen M

2016-08-15

Tamoxifen (TAM) is a non-steroidal estrogen receptor antagonist that enhances erlotinib (ERL)-induced cytotoxicity in the treatment of NSCLC. ERL and TAM are metabolized by CYP3A4 enzymes. In addition, both drugs have the potential of altering the enzymatic activity through either inhibition (ERL) or induction (TAM). Thus it was expected that pharmacokinetics (PK) drug-drug interactions (DDIs) could be encountered following their co-administration. In this respect, a bioanalytical UPLC-MS/MS method has been developed and validated for the simultaneous determination of ERL and TAM in rat plasma samples, using ondansetron (OND) as an internal standard (IS). Plasma samples were prepared using mixed mode cationic solid phase extraction (SPE) STRATA™ -X-C 33μm cartridges with good extraction recovery of both drugs from rat plasma (Er% from -13.92 to -3.32). The drugs were separated on a Waters BEH™ C18 column with an isocratic elution using a mobile phase composed of a mixture of acetonitrile and water, each with 0.15% formic acid, in the ratio of 80: 20, v/v. Quantitation was carried out using the positive ionization mode with multiple reaction monitoring (MRM) at m/z 394.20>278.04 (ERL), m/z 372.25>72.01 (TAM), and m/z 294.18>170.16 (OND). The method was fully validated as per the FDA guidelines over the concentration range of 0.2-50ng/mL with very low lower limit of quantification (LLOQ) of 0.2ng/mL for both ERL and TAM. The intra- and inter-day assay precision (in terms of relative standard deviation, RSD) and accuracy (in terms of percentage relative error, % Er) were evaluated for both drugs and the calculated values evaluated at four different concentration levels were within the acceptable limits (<15%) for concentrations other than LLOQ and 20% for LLOQ. The method was successfully applied to the study of possible PK-DDI following the oral administration of ERL and TAM in a combination, compared to their single administration. Copyright © 2016 Elsevier B

Application of miniaturized near-infrared spectroscopy for quality control of extemporaneous orodispersible films.

PubMed

Foo, Wen Chin; Widjaja, Effendi; Khong, Yuet Mei; Gokhale, Rajeev; Chan, Sui Yung

2018-02-20

Extemporaneous oral preparations are routinely compounded in the pharmacy due to a lack of suitable formulations for special populations. Such small-scale pharmacy preparations also present an avenue for individualized pharmacotherapy. Orodispersible films (ODF) have increasingly been evaluated as a suitable dosage form for extemporaneous oral preparations. Nevertheless, as with all other extemporaneous preparations, safety and quality remain a concern. Although the United States Pharmacopeia (USP) recommends analytical testing of compounded preparations for quality assurance, pharmaceutical assays are typically not routinely performed for such non-sterile pharmacy preparations, due to the complexity and high cost of conventional assay methods such as high performance liquid chromatography (HPLC). Spectroscopic methods including Raman, infrared and near-infrared spectroscopy have been successfully applied as quality control tools in the industry. The state-of-art benchtop spectrometers used in those studies have the advantage of superior resolution and performance, but are not suitable for use in a small-scale pharmacy setting. In this study, we investigated the application of a miniaturized near infrared (NIR) spectrometer as a quality control tool for identification and quantification of drug content in extemporaneous ODFs. Miniaturized near infrared (NIR) spectroscopy is suitable for small-scale pharmacy applications in view of its small size, portability, simple user interface, rapid measurement and real-time prediction results. Nevertheless, the challenge with miniaturized NIR spectroscopy is its lower resolution compared to state-of-art benchtop equipment. We have successfully developed NIR spectroscopy calibration models for identification of ODFs containing five different drugs, and quantification of drug content in ODFs containing 2-10mg ondansetron (OND). The qualitative model for drug identification produced 100% prediction accuracy. The quantitative

Further investigation into the signal transduction mechanism of the 5-HT4-like receptor in the circular smooth muscle of human colon.

PubMed Central

McLean, P. G.; Coupar, I. M.

1996-01-01

1. The nature of the receptor coupling mechanism of the 5-hydroxytryptamine4 (5-HT4) receptor in the circular smooth muscle of the human colon has been further investigated. 2. 5-HT stimulated cyclic AMP generation and caused a relaxation in a concentration-dependent fashion, with EC50 values of 175.5 and 274.9 nM respectively. DAU 6236 increased cyclic AMP formation and caused a relaxant effect but was a partial agonist relative to 5-HT. 3. The 5-HT4 receptor antagonist, GR 113808, inhibited cyclic AMP formation and relaxation induced by 5-HT with -log Ki values of 9.1 (cyclic AMP) and 8.9 (relaxation) and apparent pA2 values of 9.2 (cyclic AMP) and 9.5 (relaxation). 4. Ondansetron and methysergide failed to inhibit cyclic AMP formation or the relaxation induced by 5-HT. 5. The phosphodiesterase inhibitor, IBMX, produced a concentration-dependent relaxation (EC50 = 30 microM) and at 1 microM it enhanced the 5-HT-induced relaxation producing a leftward shift of the 5-HT concentration-effect curve with a concentration-ratio of 4.1. Rolipram caused a concentration-dependent relaxation (EC50 = 564.8 nM) and at 200 nm caused a leftward shift of the concentration-effect curve to 5-HT with a concentration-ratio of 5.5. 6. Application of the adenylyl cyclase inhibitor, SQ 22536 (0.1 mM), and the protein kinase inhibitors, H7 (100 nM) and H89 (200 nM), inhibited the relaxant effect of 5-HT inducing a rightward shift of the concentration-effect curve with concentration-ratios of 10.1, 2.7 and 4.2 respectively. 7. Forskolin stimulated cyclic AMP production and caused a relaxation. The maximum relaxant effect of forskolin (6 microM, 13.8 +/- 1.9 cm.s) was not significantly different from the maximum relaxant effect of 5-HT (10 microM, 12.7 +/- 4.9 cm.s). However, the cyclic AMP levels stimulated by forskolin (6 microM, 49.3 +/- 6.6 pmol mg-1) were markedly greater than those stimulated by 5-HT (10 microM, 7.6 +/- 2.0 pmol mg-1). 8. In conclusion, these results indicate that

Further investigation into the signal transduction mechanism of the 5-HT4-like receptor in the circular smooth muscle of human colon.

PubMed

McLean, P G; Coupar, I M

1996-06-01

1. The nature of the receptor coupling mechanism of the 5-hydroxytryptamine4 (5-HT4) receptor in the circular smooth muscle of the human colon has been further investigated. 2. 5-HT stimulated cyclic AMP generation and caused a relaxation in a concentration-dependent fashion, with EC50 values of 175.5 and 274.9 nM respectively. DAU 6236 increased cyclic AMP formation and caused a relaxant effect but was a partial agonist relative to 5-HT. 3. The 5-HT4 receptor antagonist, GR 113808, inhibited cyclic AMP formation and relaxation induced by 5-HT with -log Ki values of 9.1 (cyclic AMP) and 8.9 (relaxation) and apparent pA2 values of 9.2 (cyclic AMP) and 9.5 (relaxation). 4. Ondansetron and methysergide failed to inhibit cyclic AMP formation or the relaxation induced by 5-HT. 5. The phosphodiesterase inhibitor, IBMX, produced a concentration-dependent relaxation (EC50 = 30 microM) and at 1 microM it enhanced the 5-HT-induced relaxation producing a leftward shift of the 5-HT concentration-effect curve with a concentration-ratio of 4.1. Rolipram caused a concentration-dependent relaxation (EC50 = 564.8 nM) and at 200 nm caused a leftward shift of the concentration-effect curve to 5-HT with a concentration-ratio of 5.5. 6. Application of the adenylyl cyclase inhibitor, SQ 22536 (0.1 mM), and the protein kinase inhibitors, H7 (100 nM) and H89 (200 nM), inhibited the relaxant effect of 5-HT inducing a rightward shift of the concentration-effect curve with concentration-ratios of 10.1, 2.7 and 4.2 respectively. 7. Forskolin stimulated cyclic AMP production and caused a relaxation. The maximum relaxant effect of forskolin (6 microM, 13.8 +/- 1.9 cm.s) was not significantly different from the maximum relaxant effect of 5-HT (10 microM, 12.7 +/- 4.9 cm.s). However, the cyclic AMP levels stimulated by forskolin (6 microM, 49.3 +/- 6.6 pmol mg-1) were markedly greater than those stimulated by 5-HT (10 microM, 7.6 +/- 2.0 pmol mg-1). 8. In conclusion, these results indicate that

The Effect of a Combination Treatment Using Palonosetron, Promethazine, and Dexamethasone on the Prophylaxis of Postoperative Nausea and Vomiting and QTc Interval Duration in Patients Undergoing Craniotomy under General Anesthesia: A Pilot Study.

PubMed

Bergese, Sergio D; Puente, Erika G; Antor, Maria A; Capo, Gerardo; Yildiz, Vedat O; Uribe, Alberto A

2016-01-01

Postoperative nausea and vomiting (PONV) is a displeasing experience that distresses surgical patients during the first 24 h after a surgical procedure. The incidence of postoperative nausea occurs in about 50%, the incidence of postoperative vomiting is about 30%, and in high-risk patients, the PONV rate could be as high as 80%. Therefore, the study design of this single arm, non-randomized, pilot study assessed the efficacy and safety profile of a triple therapy combination with palonosetron, dexamethasone, and promethazine to prevent PONV in patients undergoing craniotomies under general anesthesia. The research protocol was approved by the institutional review board and 40 subjects were provided written informed consent. At induction of anesthesia, a triple therapy of palonosetron 0.075 mg IV, dexamethasone 10 mg IV, and promethazine 25 mg IV was given as PONV prophylaxis. After surgery, subjects were transferred to the surgical intensive care unit or post anesthesia care unit as clinically indicated. Ondansetron 4 mg IV was administered as primary rescue medication to subjects with PONV symptoms. PONV was assessed and collected every 24 h for 5 days via direct interview and/or medical charts review. The overall incidence of PONV during the first 24 h after surgery was 30% (n = 12). The incidence of nausea and emesis 24 h after surgery was 30% (n = 12) and 7.5% (n = 3), respectively. The mean time to first emetic episode, first rescue, and first significant nausea was 31.3 (±33.6), 15.1 (±25.8), and 21.1 (±25.4) hours, respectively. The overall incidence of nausea and vomiting after 24-120 h period after surgery was 30% (n = 12). The percentage of subjects without emesis episodes over 24-120 h postoperatively was 70% (n = 28). No subjects presented a prolonged QTc interval ≥500 ms before and/or after surgery. Our data demonstrated that this triple therapy regimen may be an adequate alternative regimen for the

The Role of 5-HT3 Receptors in Signaling from Taste Buds to Nerves

PubMed Central

Vandenbeuch, Aurelie; Voigt, Anja; Meyerhof, Wolfgang; Kinnamon, Sue C.; Finger, Thomas E.

2015-01-01

Activation of taste buds triggers the release of several neurotransmitters, including ATP and serotonin (5-hydroxytryptamine; 5-HT). Type III taste cells release 5-HT directly in response to acidic (sour) stimuli and indirectly in response to bitter and sweet tasting stimuli. Although ATP is necessary for activation of nerve fibers for all taste stimuli, the role of 5-HT is unclear. We investigated whether gustatory afferents express functional 5-HT3 receptors and, if so, whether these receptors play a role in transmission of taste information from taste buds to nerves. In mice expressing GFP under the control of the 5-HT3A promoter, a subset of cells in the geniculate ganglion and nerve fibers in taste buds are GFP-positive. RT-PCR and in situ hybridization confirmed the presence of 5-HT3A mRNA in the geniculate ganglion. Functional studies show that only those geniculate ganglion cells expressing 5-HT3A-driven GFP respond to 10 μm 5-HT and this response is blocked by 1 μm ondansetron, a 5-HT3 antagonist, and mimicked by application of 10 μm m-chlorophenylbiguanide, a 5-HT3 agonist. Pharmacological blockade of 5-HT3 receptors in vivo or genetic deletion of the 5-HT3 receptors reduces taste nerve responses to acids and other taste stimuli compared with controls, but only when urethane was used as the anesthetic. We find that anesthetic levels of pentobarbital reduce taste nerve responses apparently by blocking the 5-HT3 receptors. Our results suggest that 5-HT released from type III cells activates gustatory nerve fibers via 5-HT3 receptors, accounting for a significant proportion of the neural taste response. SIGNIFICANCE STATEMENT Historically, serotonin (5-hydroxytryptamine; 5-HT) has been described as a candidate neurotransmitter in the gustatory system and recent studies show that type III taste receptor cells release 5-HT in response to various taste stimuli. In the present study, we demonstrate that a subset of gustatory sensory neurons express functional

Management of pediatric patients with concussion by emergency medicine physicians.

PubMed

Kinnaman, Karen A; Mannix, Rebekah C; Comstock, R Dawn; Meehan, William P

2014-07-01

Despite an increase in concussion diagnoses among pediatric patients, little is known about the management of pediatric patients with concussion in emergency departments (EDs). The objective of this study was to assess strategies used by emergency medicine physicians when treating pediatric patients with concussions. A 17-item questionnaire was e-mailed to members of the American Academy of Pediatrics Section on Emergency Medicine. Two serial e-mails were distributed at 2-week intervals to nonresponders. The survey included multiple-choice and free-text questions that were created by the team of investigators on the basis of prior surveys of family practitioners and physical trainers. We collected demographic information and specific information regarding the use of medications, neuropsychological testing, neuroimaging, return-to-play decision making, and use of published guidelines. Simple descriptive statistics were used. Two hundred sixty-five (29%) physicians completed the questionnaire, of which 52% had been an attending physician for more than 10 years. Ninety-nine percent of the respondents reported managing concussions, with the majority (76%) seeing more than 24 patients with concussion per year. Most clinicians (81%) reported using a published guideline in their management of concussions. The symptoms most likely to prompt head imaging in the ED included a focal neurological deficit (92%), altered mental status (82%), and intractable vomiting (80%). Most (91%) respondents reported using medications to manage the symptoms of patients with concussion, mainly acetaminophen (78%) and nonsteroidal anti-inflammatory medications (77%), whereas 54% of the respondents used ondansetron and 7% of the respondents used narcotics. More than half (56%) of the respondents referred patients with concussion for neuropsychological testing from the ED. Of those, nearly half (49%) of the respondents refer their patients to a sports concussion clinic, whereas 5% of the

Antidepressant potential of novel flavonoids derivatives from sweet violet (Viola odorata L): Pharmacological, biochemical and computational evidences for possible involvement of serotonergic mechanism.

PubMed

Karim, Nasiara; Khan, Imran; Abdelhalim, Abeer; Khan, Ajmal; Halim, Sobia Ahsan

2018-05-22

Plant-derived natural constituents are of great interest in modern drug discovery due to their natural diversity. Viola odorata L has been traditionally used for the treatment of neuropsychiatric disorders. The present study was undertaken to isolate phytoconstituents including three flavonoids 5,7-Dihydroxy-3,6-dimethoxyflavone[1] 5,7,4'-trihydroxy-3',5'dimethoxyflavone [2] and 5,7,4'-trihydroxy-3'-methoxyflavone [3] from the whole plant of Viola odorata L and to investigate the antidepressant-like effects of these compounds and their possible mechanism of action using antagonists of the serotonergic, dopaminergic and adrenergic system. Classical animal models of depression including tail suspension test (TST) and forced swimming test (FST) using mice were used to evaluate the antidepressant-like effects. Mice were divided into various groups and were administered with either vehicle control, fluoxetine (FLX), or test compounds 1-3 intraperitoneally (i.p.). For experiments involving mechanism determination, mice were pretreated with 5-HT, dopamine and adrenergic antagonists. The brain 5-HT levels were determined following FST. Molecular docking studies were carried out to determine the binding affinity of compounds 1-3 to serotonergic receptors. The results indicated that compounds 1-3 at the dose of 1-30 mg/kg, i.p significantly decreased the immobility time in the FST and TST in mice. The reduction in immobility time was reversed by pre-treating the mice with pCPA (5-HT synthesis inhibitor) 100 mg/kg, i.p. and 5-HT receptor antagonists including WAY100635 (5-HT1a antagonist), ketanserin (a 5-HT2a antagonist) and ondansetron (5-HT3 antagonist) but not with prazosin (α1-adrenergic antagonist) and SCH23390 (D1 dopaminergic antagonist) or haloperidol (D2 dopaminergic antagonist). Moreover, in neurochemical assays, compounds 1-3 caused a significant increase in the 5-HT level in the brain tissue as compared to vehicle. These increases were reversed in the mice

Efficacy and safety of 5-hydroxytryptamine 3 receptor antagonists in irritable bowel syndrome: A systematic review and meta-analysis of randomized controlled trials

PubMed Central

Tang, Yurong; Xiong, Wenjie; Shen, Xiaoxue; Jiang, Ling; Lin, Lin

2017-01-01

(non-constipated IBS and IBS-D: RR = 5.28 [95% CI: 3.93, 7.08] vs. IBS-D only 3.24 [2.54, 4.12]). Conclusions Ramosetron, cilansetron, ondansetron, and alosetron are effective for treating non-constipated IBS and IBS-D. Our systematic review found rare serious adverse events. PMID:28291778

A comparative study of functional 5-HT4 receptors in human colon, rat oesophagus and rat ileum.

PubMed Central

McLean, P. G.; Coupar, I. M.; Molenaar, P.

1995-01-01

1. The pharmacological properties of 5-hydroxytryptamine (5-HT), the 5-HT4 receptor agonists, DAU 6236 and SC 53116 and the 5-HT4 receptor antagonist, GR 1130808, were studied in the rat oesophagus, rat ileum and human colon. 2. 5-HT relaxed the longitudinal muscle of the rat oesophagus and rat ileum and the circular muscle of the human colon. Absolute values of relaxation were measured and showed the order of the maximum responses, rat oesophagus >> human colon > rat ileum with EC50 values of 189 +/- 15 nM, 157 +/- 4 nM, 306 +/- 72 nM, respectively. 5-HT also inhibited the spontaneous contractions of the human colon with an EC50 value of 119 +/- 1 nM. The effect of 5-HT on the human colon was not affected by methysergide (10 microM) or ondansetron (1 microM). 3. The use of the uptake and metabolism inhibitors, cocaine (30 microM) and pargyline (100 microM), did not increase the potency of 5-HT in the rat oesophagus or human colon. In the rat oesophagus, cocaine (30 microM) produced a reduction in carbachol-induced tone of 22.2 +/- 0.6% and reduced the 5-HT maximum effect by 52.0 +/- 0.4%. 4. The compounds, DAU 6236 and SC 53116, showed a different pattern of potencies and efficacies in the rat oesophagus, rat ileum and human colon compared to 5-HT. DAU 6236 relaxed the human colonic circular muscle with an EC50 value of 129 +/- 16 nM but its efficacy was less than that of 5-HT. DAU 6236 (1 microM) also antagonized the 5-HT-induced relaxation of the human colon with a dose-ratio of 9.9. In the rat oesophagus and rat ileum, DAU 6236 was inactive in the majority of tissues. In the minority of oesophagus tissues that did respond the EC50 value was 1.2 +/- 0.7 microM. DAU 6236 also antagonized the effect of 5-HT in the rat oesophagus in a non-surmountable fashion. SC 53116 relaxed the rat oesophagus with an EC50 value of 91 +/- 4 nM, with an efficacy less than that observed to 5-HT; however, at 200 nM it did not antagonize the 5-HT-induced relaxation of the rat

Obsessive-compulsive disorder, impulse control disorders and drug addiction: common features and potential treatments.

PubMed

Fontenelle, Leonardo F; Oostermeijer, Sanne; Harrison, Ben J; Pantelis, Christos; Yücel, Murat

2011-05-07

), glutamate (e.g. topiramate), serotonin (e.g. ondansetron) or γ-aminobutyric acid (e.g. baclofen and topiramate) systems, may prove to show some benefit in certain forms of OCD. Based on the available evidence, we suggest that the treatment of patients with these disorders must account for alterations in the underlying motivations and neurobiology of the condition. We provide an initial guide to the specific treatments that future clinical trials might consider in patients with OCD. For example, it might be wise to test naltrexone in patients with co-morbid SUD and ICD, topiramate in patients with co-morbid ICD and eating disorders, and baclofen in patients with co-morbid Tourette's syndrome. These trials could also include scales aimed at assessing underlying impulsivity (e.g. Barratt Impulsiveness Scale) to check whether this construct might predict response to drugs acting on the reward system. © 2011 Adis Data Information BV. All rights reserved.

A comparative study of functional 5-HT4 receptors in human colon, rat oesophagus and rat ileum.

PubMed

McLean, P G; Coupar, I M; Molenaar, P

1995-05-01

1. The pharmacological properties of 5-hydroxytryptamine (5-HT), the 5-HT4 receptor agonists, DAU 6236 and SC 53116 and the 5-HT4 receptor antagonist, GR 1130808, were studied in the rat oesophagus, rat ileum and human colon. 2. 5-HT relaxed the longitudinal muscle of the rat oesophagus and rat ileum and the circular muscle of the human colon. Absolute values of relaxation were measured and showed the order of the maximum responses, rat oesophagus > human colon > rat ileum with EC50 values of 189 +/- 15 nM, 157 +/- 4 nM, 306 +/- 72 nM, respectively. 5-HT also inhibited the spontaneous contractions of the human colon with an EC50 value of 119 +/- 1 nM. The effect of 5-HT on the human colon was not affected by methysergide (10 microM) or ondansetron (1 microM). 3. The use of the uptake and metabolism inhibitors, cocaine (30 microM) and pargyline (100 microM), did not increase the potency of 5-HT in the rat oesophagus or human colon. In the rat oesophagus, cocaine (30 microM) produced a reduction in carbachol-induced tone of 22.2 +/- 0.6% and reduced the 5-HT maximum effect by 52.0 +/- 0.4%. 4. The compounds, DAU 6236 and SC 53116, showed a different pattern of potencies and efficacies in the rat oesophagus, rat ileum and human colon compared to 5-HT. DAU 6236 relaxed the human colonic circular muscle with an EC50 value of 129 +/- 16 nM but its efficacy was less than that of 5-HT. DAU 6236 (1 microM) also antagonized the 5-HT-induced relaxation of the human colon with a dose-ratio of 9.9. In the rat oesophagus and rat ileum, DAU 6236 was inactive in the majority of tissues. In the minority of oesophagus tissues that did respond the EC50 value was 1.2 +/- 0.7 microM. DAU 6236 also antagonized the effect of 5-HT in the rat oesophagus in a non-surmountable fashion. SC 53116 relaxed the rat oesophagus with an EC50 value of 91 +/- 4 nM, with an efficacy less than that observed to 5-HT; however, at 200 nM it did not antagonize the 5-HT-induced relaxation of the rat

The Development of Countermeasures for Space Radiation Induced Adverse Health Effects

NASA Astrophysics Data System (ADS)

Kennedy, Ann

human trials necessary to demonstrate "efficacy" for a beneficial effect on the long term adverse health effects of radiation, such as the development of cancer, cataracts, etc., is expected to take particularly long periods of time. To avoid the long time delay in the development of new drugs as countermeasures for radiation induced adverse health effects, the NSBRI Center for Acute Radiation Research (CARR) is currently focused on the use of drugs that have already been approved for human use by the FDA. Currently there are no approved countermeasures for external radiation exposure by the US Army or by NASA. The appropriate medications for symptoms of the Acute Radiation Syndrome (ARS) due to exposure to solar particle event (SPE) radiation are unknown, but there are medications appropriate for ARS symptoms caused by exposure to conventional ra-diation. The Armed Forces Radiobiology Research Institute (AFRRI) has medical guidelines for ARS medications (http://www.afrri.usuhs.mil/outreach/guidance.htm#policies), as does the US Dept. of Health and Human Services (the REMM (Radiation Event Medical Manage-ment) site (http://www.remm.nlm.gov). Supportive care when ARS symptoms develop include the administration of antimicrobial agents (which can include systemic antibiotics [especially those directed at gram-negative bacteria]), antiemetic agents, antidiarrheal agents, fluids, elec-trolytes, analgesic agents and topical burn creams (Waselenko, J.K. et al. Ann. Intern. Med. 140: 1037, 2004). For nausea and vomiting, serotonin receptor antagonists (5HT3 receptor antagonists) are very effective prophylaxis. There are two drugs that have been approved by the FDA (Zofran and Kytril) for radiation induced nausea and vomiting. Kytril (granisetron) is preferred by the US Army and is currently maintained in the US National Stockpile. Both of these drugs are known to stop retching and vomiting when given either before or after irradi-ation, even when vomiting and/or retching are

Cannabinoids for nausea and vomiting in adults with cancer receiving chemotherapy.

PubMed

Smith, Lesley A; Azariah, Fredric; Lavender, Verna T C; Stoner, Nicola S; Bettiol, Silvana

2015-11-12

Cannabis has a long history of medicinal use. Cannabis-based medications (cannabinoids) are based on its active element, delta-9-tetrahydrocannabinol (THC), and have been approved for medical purposes. Cannabinoids may be a useful therapeutic option for people with chemotherapy-induced nausea and vomiting that respond poorly to commonly used anti-emetic agents (anti-sickness drugs). However, unpleasant adverse effects may limit their widespread use. To evaluate the effectiveness and tolerability of cannabis-based medications for chemotherapy-induced nausea and vomiting in adults with cancer. We identified studies by searching the following electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PsycINFO and LILACS from inception to January 2015. We also searched reference lists of reviews and included studies. We did not restrict the search by language of publication. We included randomised controlled trials (RCTs) that compared a cannabis-based medication with either placebo or with a conventional anti-emetic in adults receiving chemotherapy. At least two review authors independently conducted eligibility and risk of bias assessment, and extracted data. We grouped studies based on control groups for meta-analyses conducted using random effects. We expressed efficacy and tolerability outcomes as risk ratio (RR) with 95% confidence intervals (CI). We included 23 RCTs. Most were of cross-over design, on adults undergoing a variety of chemotherapeutic regimens ranging from moderate to high emetic potential for a variety of cancers. The majority of the studies were at risk of bias due to either lack of allocation concealment or attrition. Trials were conducted between 1975 and 1991. No trials involved comparison with newer anti-emetic drugs such as ondansetron. Comparison with placebo People had more chance of reporting complete absence of vomiting (3 trials; 168 participants; RR 5.7; 95% CI 2.6 to 12.6; low quality evidence