Effects Of Granisetron Research Articles

The Effect of Granisetron on Sensory Detection and Pain Thresholds in Facial Skin of Healthy Young Males.

Background: The specific serotonin type 3 (5-HT3)-receptor antagonist granisetron effectively reduces clinical as well as experimental muscle pain and hyperalgesia and with a duration that exceeds that of lidocaine. Hence, it may be an alternative to lidocaine as a local anesthetic. There are also some indications that granisetron in addition to 5-HT3 receptors blocks sodium channels. Thus, the local anesthetic effect by granisetron may resemble that of lidocaine, but this has not been tested. The aim of this study was therefore to compare the effect granisetron has on facial skin sensitivity to the effect of lidocaine and isotonic saline.Methods: This was a randomized, controlled, and double-blind study, in which 1 ml of either granisetron (test-substance), lidocaine (positive control), or isotonic saline (negative control) was injected into the skin over the masseter muscle at three different occasions in 18 healthy males (27.2 ± 5.8 years old). Skin detection thresholds and pain thresholds for thermal stimuli as well as mechanical detection thresholds and sensitivity to a painful mechanical (pinprick) stimulus were assessed before (baseline) and 5, 20, 40, and 60 min after injection. The quality and area of subjective sensory change over the cheek were assessed 20 min after injection.Results: All substances increased the mechanical detection threshold (granisetron: p = 0.011; lidocaine: p = 0.016; saline: p = 0.031). Both granisetron and lidocaine, but not isotonic saline, increased the heat detection thresholds (p < 0.001 and p < 0.02, respectively), but not the cold detection thresholds. Granisetron and lidocaine also reduced pinprick pain (p = 0.001 for each comparison). There were no significant differences between granisetron and lidocaine for any of these variables. There was no effect on thermal pain thresholds for any substance.Conclusion: The similar analgesic patterns on mechanical sensory and pain thresholds as well as thermal sensory thresholds over the facial skin by subcutaneous injection of granisetron and lidocaine shown in this study and the absence of paresthesia, in combination with the reduced pain intensity and pressure pain sensitivity shown in previous studies, indicate that granisetron might be a novel candidate as a local anesthetic.

The Effect of Granisetron and Ondansetron on Hemodynamic During Cesarean Section Under Spinal Anesthesia

The Effect of Granisetron and Ondansetron on Hemodynamic During Cesarean Section Under Spinal Anesthesia

Granisetron protects polymicrobial sepsis-induced acute lung injury in mice

Sepsis is a serious condition with a high mortality rate worldwide. Granisetron is an anti-nausea drug for patients undergoing chemotherapy. Here we aimed to identify the novel effect of granisetron on sepsis-induced acute lung injury (ALI). Our results showed that mice treated with granisetron displayed less severe lung damage than controls. Granisetron administration reduced pulmonary neutrophil recruitment after CLP. Moreover, the expressions of Cxcl1 and Cxcl2 were diminished in the presence of granisetron in THP-1 macrophages after lipopolysaccharide exposure. Additionally, granisetron could inhibit the activation of p38 MAPK and NLRP3 inflammasome both in vivo and in vitro. Collectively, granisetron protects against sepsis-induced ALI by suppressing macrophage Cxcl1/Cxcl2 expression and neutrophil recruitment in the lung.

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

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.

Effects of Granisetron on Postoperative Nausea and Vomiting in Non-smoking Women Undergoing Thyroidectomy: A Prospective Randomized Double Blind Placebo Controlled Study

Background: Postoperative nausea and vomiting is a relatively common complication after thyroidectomy. The aim of this study was to determine the effectiveness of granisetron for the prevention of postoperative nausea and vomiting in non-smoking women undergoing elective thyroidectomy. Material and Methods: In this prospective, randomized, double-blind, placebo-controlled study, 260 non-smoking female patients ASA physical status I-II, who had undergone elective thyroidectomy under general anesthesia, received granisetron 40µg/kg in 3ml saline or placebo as 3ml saline IV 30 min before operation end. Patients were observed at 0, 2, 4, 6, 12 and 24. hours after anesthesia. Age, weight, operation and anesthesia duration, a total amount of fentanyl dose, nausea, and vomiting episodes and adverse effects were recorded. Results: 234 patients were analyzed statistically. Demographic characteristics, including age, height, and body weight were comparable in both groups. In addition, there were no differences in the preoperative total amounts of fentanyl and fluid, operation and anesthesia duration. The overall incidence of PONV differed significantly among the two groups (p

Systemic granisetron can minimize hypotension and bradycardia during spinal anesthesia in patients undergoing elective lower-abdominal surgeries: a prospective, double-blind randomized controlled study

Introduction Although it is considered safe, spinal anesthesia has many side effects, including hypotension, and bradycardia. Increased activity of chemoreceptors (Bezold–Jarisch reflex) may play a role in this. The release of serotonin has been suggested as a possible trigger for Bezold–Jarisch reflex. Granisetron, a selective 5-HT3 receptor antagonist, may play a role in preventing hypotension and bradycardia. Aim The aim of this study was to assess the effects of granisetron on hypotension, bradycardia, shivering, nausea, and vomiting after spinal anesthesia in patients undergoing elective lower-abdominal surgeries. Patients and methods This study was designed as a randomized, double-blind, placebo-controlled trial. Fifty-four American Society of Anesthesiologists I–III patients, ages 25–55 years, scheduled for elective lower-abdominal surgeries under spinal anesthesia were included in this prospective study and were divided into two equal groups. Group G received 1 mg intravenous granisetron diluted in 0.9% normal saline to a total volume of 5 ml, and group C received 5 ml normal saline 5 min before undergoing spinal anesthesia. The mean arterial blood pressure, the heart rate, nausea, vomiting, and shivering were assessed. Results The reduction in mean arterial blood pressure and heart rate was significantly lower in group G compared with group C. Regarding the incidence of complications, hypotension, bradycardia, nausea, and shivering were significantly lower in group G compared with group C. No significant difference was observed with regard to the incidence of vomiting. Conclusion In lower-abdominal surgery, intravenously 1 mg granisetron before subarachnoid block decreased the incidence of hypotension and bradycardia significantly, besides being effective for the prevention of nausea, vomiting, and shivering.

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

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.

Stimulation of contractions in pregnant human myometrium is associated with 5-HT3 receptors

BackgroundSerotonin (5-HT) is known to play an important role in regulating uterine contractions. However, the specific receptors involved have not been well characterized. We evaluated whether 5-HT3 receptors exist in human myometrium, and their effects on myometrial contractility when stimulated by a 5-HT3 agonist. MethodsFour tissue samples taken from patients undergoing hysterectomy (n=2) and elective cesarean delivery (n=2) were used to detect expression of 5-HT3 receptors on the myometrium using western blotting. For isometric tension measurement, another 12 myometrial strips obtained from patients undergoing elective cesarean delivery were randomly divided into a control group (Group CON) and an RS56812 group (Group RG). In increasing doses from 10−7M to 10−4M, RS56812, a 5-HT3 receptor agonist, was used to investigate the contractile effects after bonding to the 5-HT3 receptor, following which the effects of granisetron were assessed. Amplitude, interval and duration of myometrial contractions were recorded. ResultsProteins with a molecular mass of 55kDa, consistent with 5-HT3 receptors, were detected both on non-pregnant and late-pregnant human uteri. RS56812 increased the contractile amplitude at concentrations of 10−6M, 10−5M and 10−4M, achieving maximum effect at 10−5M. A prolonged contractile interval was detected at the concentration of 10−4M. However, RS56812 showed no significant effect on contraction duration. Granisetron did not reverse the contractile effects induced by RS56812. Conclusion5-HT3 receptors are expressed on non-pregnant and pregnant uteri. RS56812 enhanced myometrial contractions, but this was not affected by granisetron, the mechanism of which requires further investigation.

Effect of granisetron in attenuation of hypotension following spinal anaesthesia in parturients undergoing elective caesarean section - a double blind randomized controlled trial

Background: Spinal anaesthesia has side effects like hypotension and bradycardia, which may be induced by sympathetic blockade and Bezold-Jarisch reflex (mediated by peripheral serotonin receptor, 5-HT3 type). The objective of the study was to evaluate the effects of type 3 serotonin receptors blockade by intravenous granisetron pre-treatment in spinal induced hypotension in parturient undergoing elective caesarean section.Methods: Fifty six parturient with American Society of Anaesthesiologists Physical Status I and II undergoing elective caesarean section were assigned randomly to receive either Normal Saline (control) or Granisetron 1mg intravenously five minutes before spinal anaesthesia. Spinal anaesthesia was performed with 2.2 ml 0.5% hyperbaric bupivacaine solution and then heart rates, systolic blood pressure, diastolic blood pressure, mean arterial pressure were recorded every two and half minutes for ten minutes and then every five minutes for till end of surgery after. Hemodynamic parameters were compared with baseline in each group.Results: Change in mean, systolic and diastolic arterial pressure compared with baseline value were comparable in both the groups, but use of ephedrine as rescue vasopressor drug was significantly reduced in granisetron group. The episodes of hypotension, nausea/vomiting and shivering were comparable in both groups.Conclusions: Type 3 serotonin blockade by intravenous granisetron pre-treatment does not reduce spinal induced hypotension in parturient undergoing elective caesarean section; however there is reduction in need of rescue vasopressor.

The role of granisetron in the enhancement of recovery and home discharge in ambulatory surgery performed under spinal anesthesia

Background The popularity of day-care surgery has increased worldwide due to reduced costs and remarkable safety profile. Neuraxial anesthesia is a popular technique for day-case surgeries. Anesthetist should modify his/her techniques to optimize patient’s chance of early discharge. 5-Hydroxytryptamine type 3 receptor antagonists used to prevent and treat postoperative nausea and vomiting may affect the course of spinal anesthesia and prevent its associated hypotension. Aim The aim of this study was to evaluate the effects of granisetron in the reversal of hyperbaric bupivacaine spinal anesthesia and enhancement of home discharge in day surgeries. Patients and methods Sixty adult patients scheduled for elective day surgery under spinal anesthesia were randomly divided into two equal groups to receive either 1 mg of granisetron (the G group) intravenously diluted in 5 ml normal saline over 30 s, 5 min before spinal anesthesia, or an equal volume of intravenous normal saline (the S group) at the same time. Heart rate, mean arterial pressure, oxygen saturation, and sensory and motor block levels were monitored and recorded. Results Time to regression of sensory level by two dermatomes, time to regression of sensory level to S2, time to first void, and time to discharge readiness were significantly lower in group G. Moreover, the incidence of nausea and shivering was significantly lower in group G. Conclusion Administration of 1 mg of granisetron before spinal anesthesia in ambulatory surgeries resulted in a statistically faster sensory regression and earlier home discharge from the day-surgery unit.

Effects of Selective Blockade of 5-HT3 Receptors on Physiological Markers of Abdominal Pain in Conscious Dogs

Experiments on conscious dogs addressed the effects of blockade of type 3 serotonin receptors on visceromotor reactions and changes in heart rate (HR) initiated by nociceptive distension of the rectum. Distension of the rectal walls with pressures of 20–60 mmHg were found not to produce significant changes in the electromyographic activity of the abdominal muscles or HR. Distension of the intestine with a pressure of 80 mmHg and greater produced marked visceromotor reactions (contractions of the abdominal muscles) and increases in HR (tachycardia), which are regarded as markers for the occurrence of pain sensations. Use of these indicators allowed the first demonstration in conscious dogs of the dose-dependent antinociceptive effect of blockade of 5-HT3 receptors with granisetron. Administration of granisetron at doses of 0.25, 0.5, and 1.0 mg/kg was accompanied by prolonged (at least 90 min) decreases in visceromotor reactions to nociceptive rectal distension by 33.6 ± 9.2%, 58.0 ± 8.6%, and 76.7 ± 5.5% of baseline, respectively. In turn, the inhibitory effect of granisetron on tachycardia induced by painful rectal stimulation was seen only immediately after administration. Thus, studies on conscious dogs demonstrated the antinociceptive effect of granisetron in relation to abdominal pain, which may be relevant in the development of pharmacological agents to treat pain in patients with irritable bowel syndrome.

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

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.

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

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.

Hemin and Zinc Protoporphyrin IX Affect Granisetron Constipating Effects In Vitro and In Vivo

Granisetron is a 5-HT3 receptors antagonist used in the management of emesis associated with anticancer chemotherapy. It affects intestinal motility with constipating effect. Since the pathway heme oxygenase/carbon monoxide (HO/CO) is involved in gastrointestinal motility, we evaluated the possible interplay between granisetron and agents affecting HO/CO pathways such as zinc protoporphyrin IX (ZnPPIX), an HO inhibitor, or hemin, an HO-1 inducer. ZnPPIX (10 µM) or hemin (10 µM), but not granisetron (0.1, 0.3, 1 µM), affected spontaneous basal activity recorded in rat duodenal strips, in noncholinergic nonadrenergic conditions. Granisetron restored spontaneous basal activity after ZnPPIX, but not after hemin. ZnPPIX decreased and hemin increased the inhibition of activity after electrical field stimulation (EFS), but they did not affect the contraction that follows the relaxation induced by EFS called off contraction. Granisetron did not alter the response to EFS per se but abolished both ZnPPIX and hemin effect when coadministered. In vivo study showed constipating effect of granisetron (25, 50, 75 µg/kg/sc) but no effect of either ZnPPIX (50 µg/kg/i.p.) or hemin (50 µM/kg/i.p.). When coadministered, granisetron effect was abolished by ZnPPIX and increased by hemin. Specimens from rats treated in vivo with hemin (50 µM/kg/i.p.) showed increased HO-1 protein levels. In conclusion, granisetron seems to interact with agents affecting HO/CO pathway both in vitro and in vivo.

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

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.

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

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.

3087 The NK-1 antagonist aprepitant (APR) in combination with granisetron and dexamethasone in high dose chemotherapy (HDC)

We have previously reported that intramuscular injection of serotonin (5-HT) into the masseter muscle elicits pain and allodynia/hyperalgesia in healthy subjects. The aim of this study was to investigate whether the 5-HT3 receptor antagonist granisetron or 5-HT1A receptor antagonist propranolol can reduce 5-HT induced pain and allodynia/hyperalgesia in the masseter muscle. Twenty-four healthy individuals (12 males and 12 females) without pain from the masseter muscle region participated. They were examined clinically including tenderness to digital palpation (TDP) and pressure pain threshold (PPT) of the masseter muscle. 5-HT in combination with granisetron or propranolol was randomly injected on one side in a double-blind manner. 5-HT in combination with saline was used on the contralateral side. After the injections the pain intensity and PPT were recorded 10 times during 30 min. After the last recording the TDP was assessed again. The injections were repeated with the other antagonist within 1 week. All three combinations of substances elicited pain after injection, which lasted for 5–8 min. 5-HT induced significantly more pain than granisetron+5-HT and propranolol+5-HT. The TDP increased significantly after injection of all combinations of substances, but there was no significant difference between them. The PPT decreased significantly after injection of 5-HT and increased significantly after injection of granisetron+5-HT, while it did not change significantly after injection of propranolol+5-HT. The difference between 5-HT and granisetron+5-HT was significant. In conclusion, the results of this study indicate that injection of granisetron and propranolol into the human masseter muscle reduces pain induced by local administration of 5-HT, but that the effect of granisetron is stronger than that of propranolol. In addition, granisetron totally abolishes allodynia/hyperalgesia.

Antiemetic effects of granisetron and dexamethasone combination therapy during cisplatin-containing chemotherapy for head and neck cancer: dexamethasone dosage verification trial

Chemotherapy-induced nausea and vomiting (CINV) remains a significant problem for patients and is associated with a substantial deterioration in quality of life; appropriate use of antiemetic drugs is crucial in maintaining the quality of life in patients undergoing chemotherapy. This randomized, crossover trial evaluated the antiemetic efficacy and safety of 8 mg per day (low-dose) and 16 mg per day (standard-dose) dexamethasone, in combination with the 5-HT(3) receptor antagonist granisetron, in 36 patients receiving cisplatin (CDDP)-containing chemotherapy for head and neck cancer. Following chemotherapy, the antinausea/vomiting inhibition rate for each dexamethasone dose was measured. During the 24-h period following administration of chemotherapy (acute phase), the antinausea/vomiting inhibition rates (no nausea and no episodes of vomiting) for 8 mg and 16 mg dexamethasone were comparably high (58.3% and 63.8%, respectively; P = 0.8092). Similar results were seen on days 2-5 following chemotherapy. Efficacy during the acute phase, based on the number of instances of vomiting and degree of nausea, was also comparably high for the two dexamethasone doses (overall efficacy rates were 94.4% and 88.8%, respectively, for 8 mg and 16 mg dexamethasone; P = 0.7637). Both doses maintained an 80% or higher response rate until day 3, and neither dose produced severe side effects. The results suggest that granisetron and dexamethasone combination therapy is useful in controlling acute and delayed nausea and vomiting induced by CDDP-containing chemotherapy for head and neck cancer. Furthermore, 8 mg and 16 mg dexamethasone have equivalent antiemetic efficacy.

Ligand-Induced 5-HT3 Receptor Internalization in Enteric Neurons in Rat Ileum

Release of 5-hydroxytryptamine (5-HT) from mucosal enterochromaffin cells and activation of 5-HT(3) receptors (5-HT(3)Rs) on neurons in the gut wall is important in the response of the gut to the luminal environment. Intestinal inflammation is associated with increased levels of mucosal 5-HT. The aims of the study were to determine the following: (1) if 5-HT(3)R undergoes ligand-induced internalization in myenteric neurons, and (2) the effect of long-term increase of mucosal 5-HT on 5-HT(3)Rs. Acute effects of exogenous 5-HT or endogenous release of 5-HT by luminal glucose on cellular localization of 5-HT(3)Rs was determined by immunohistochemistry and confocal microscopy. Treatment with the serotonin re-uptake inhibitor, fluoxetine, for 6 days (20 mg/kg daily orally) was used to increase mucosal 5-HT chronically in rats. Net ileal fluid movement was measured in anesthetized rats by the weight change of a 2.5% agarose cylinder. Acute increases in 5-HT induced by exogenous or endogenous 5-HT decreased 5-HT(3)R immunoreactivity at the neuronal cell membrane by 70% and 60%, respectively. Chronic fluoxetine treatment increased mucosal levels of 5-HT and decreased membrane 5-HT(3)R immunoreactivity by 27%. Net fluid absorption was decreased by a 5-HT(3)R agonist or by luminal glucose; this was attenuated 88% and 99%, respectively, by fluoxetine treatment. Long-term increase in 5-HT in the intestinal mucosa results in increased 5-HT(3)R internalization in myenteric neurons. Chronic changes in mucosal 5-HT may alter gastrointestinal secretory and motor function via ongoing loss of receptor from neuronal membrane, causing a mismatch between luminal content and absorption.

The effects of granisetron with droperidol or dexamethasone on prevention of postoperative nausea and vomiting after general anesthesia for cesarean section

This prospective, placebo-controlled, double-blinded, and randomized study was undertaken to compare the efficacy of granisetron, droperidol, and combinations of granisetron with droperidol or dexamethasone on postoperative nausea and vomiting in patients undergoing general anesthesia for cesarean section. Patients (n = 150) who were scheduled for cesarean section under general anesthesia were randomly assigned to one of the five groups: physiological saline 5 ml in Group A, granisetron 40 microg/kg + dexamethasone 8 mg in Group B, granisetron 40 microg/kg + droperidol 1.25 mg in Group C, droperidol 1.25 mg in Group D, and granisetron 40 microg/kg in Group E were administered intravenously after clamping of the fetal umbilical cord. Postoperative nausea and vomiting was observed for 024 h after the anesthesia. Cesarean sections were all performed under general anesthesia. Postoperative nausea and vomiting was more common in placebo group (56.7%) than the others during the 0-24 h after the anesthesia (p < 0.05). All granisetron groups were more effective than placebo and droperidol groups during the postoperative 3-24 h (p < 0.01). Although this trial lacks statistical power, granisetron alone and combinations with droperidol or dexamethasone were effective similarly. All treatment groups, except droperidol during the postoperative 3-24 h, were effective for prevention of postoperative nausea and vomiting during the postoperative 0-24 h.