Granisetron: an update on its clinical use in the management of nausea and vomiting. (41/162)

Nausea and vomiting are typical side effects of cytotoxic therapy and some surgical procedures. These symptoms can represent a major therapeutic challenge and, if inadequately controlled by antiemetic treatment, will result in increased mortality, morbidity, and health care costs. However, the management of nausea and vomiting has improved greatly in recent years following the introduction of the 5-HT3-receptor antagonists, known as 'setrons.' In light of recent developments in antiemetic care, including the approval of the first neurokinin-1-receptor antagonist aprepitant (Emend; Merck and Company, Inc.; West Point, PA) and a new 5-HT3 receptor antagonist palonosetron (Aloxi; MGI Pharma; Minneapolis, MN), this article provides an update on the clinical experience gained with the 5-HT3-receptor antagonist granisetron (Kytril; Roche Laboratories, Inc.; Nutley, NJ) for the management of chemotherapy-induced, radiation-induced, and postoperative nausea and vomiting, and also reviews its use in special patient populations. Granisetron is a potent and highly selective 5-HT3-receptor antagonist that has little or no affinity for other receptors, a characteristic that is thought to underlie the favorable side-effect and safety profiles of this agent. Extensive clinical trial data have shown granisetron to be an effective and well-tolerated agent for the treatment of nausea and vomiting in the oncology and surgical settings. Granisetron has also been shown to be effective and well tolerated in special populations, such as patients refractory to antiemetic treatment, patients with hepatic or renal impairment, and children. Data also suggest that its safety profile and minimal potential for drug-drug interactions would make it an antiemetic agent of choice for elderly cancer patients.  (+info)

Functional interaction between nucleus tractus solitarius NK1 and 5-HT3 receptors in the inhibition of baroreflex in rats. (42/162)

OBJECTIVE: Previous data showed that in the nucleus tractus solitarius (NTS), 5-HT(3) receptors are critically involved in the inhibition of cardiac baroreceptor reflex response occurring during the defense reaction. Since stimulation of NTS NK(1) receptors has been found to inhibit the baroreflex bradycardia, we examined in this study whether this reflex response is inhibited during the defense reaction via an interaction between NK(1) and 5-HT(3) receptors. METHODS: For this purpose, we analyzed in urethane-anaesthetized rats the effects of intra-NTS GR205171, a selective NK(1) receptor antagonist, on the baroreflex bradycardia inhibition observed either during the defense reaction triggered by electrical stimulation of the dorsal periaqueductal grey matter (dPAG) or after NTS 5-HT(3) receptor activation. RESULTS: Intra-NTS GR205171, reversed, in dose-dependent manner, the inhibitory effect of dPAG stimulation on baroreflex bradycardia. This reversion was of 49% when both sinus carotid and aortic baroreceptors were stimulated by phenylephrine, and of 84% when aortic depressor nerve was stimulated. Similarly, intra-NTS GR205171 reversed partially or almost totally the inhibitory effect of local microinjections of phenylbiguanide, a 5-HT(3) receptor agonist, on baroreflex bradycardia induced either by phenylephrine administration or aortic nerve stimulation, respectively. CONCLUSION: These results strongly suggest that NK(1) receptors contribute downstream to the 5-HT(3) receptor-mediated inhibition of the aortic but not carotid cardiac baroreflex response occurring during the defense reaction, therefore implying that baroreceptor afferent inputs may be differentially modulated depending on their origin. This differentiation may be useful for a better understanding of baroreflex dysfunction in disease-induced conditions.  (+info)

Influence of serotonin on the analgesic effect of granisetron on temporomandibular joint arthritis. (43/162)

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.  (+info)

Locating an antagonist in the 5-HT3 receptor binding site using modeling and radioligand binding. (44/162)

We have used a homology model of the extracellular domain of the 5-HT(3) receptor to dock granisetron, a 5-HT(3) receptor antagonist, into the binding site using AUTODOCK. This yielded 13 alternative energetically favorable models. The models fell into 3 groups. In model type A the aromatic rings of granisetron were between Trp-90 and Phe-226 and its azabicyclic ring was between Trp-183 and Tyr-234, in model type B this orientation was reversed, and in model type C the aromatic rings were between Asp-229 and Ser-200 and the azabicyclic ring was between Phe-226 and Asn-128. Residues located no more than 5 A from the docked granisetron were identified for each model; of 26 residues identified, 8 were found to be common to all models, with 18 others being represented in only a subset of the models. To identify which of the docking models best represents the ligand-receptor complex, we substituted each of these 26 residues with alanine and a residue with similar chemical properties. The mutant receptors were expressed in human embryonic kidney (HEK)293 cells and the affinity of granisetron determined using radioligand binding. Mutation of 2 residues (Trp-183 and Glu-129) ablated binding, whereas mutation of 14 other residues caused changes in the [(3)H]granisetron binding affinity in one or both mutant receptors. The data showed that residues both in and close to the binding pocket can affect antagonist binding and overall were found to best support model B.  (+info)

Spatial orientation of the antagonist granisetron in the ligand-binding site of the 5-HT3 receptor. (45/162)

The serotonin type 3 receptor (5-HT(3)R) is a member of the cys-loop ligand-gated ion channel (LGIC) superfamily. Like almost all membrane proteins, high-resolution structural data are unavailable for this class of receptors. We have taken advantage of the high degree of homology between LGICs and the acetylcholine binding protein (AChBP) from the freshwater snail Lymnea stagnalis, for which high-resolution structural data are available, to create a structural model for the extracellular (i.e., ligand-binding) domain of the 5-HT(3)R and to perform a series of ligand docking experiments to delineate the architecture of the ligand-binding site. Structural models were created using homology modeling with the AChBP as a template. Docking of the antagonist granisetron was carried out using a Lamarckian genetic algorithm to produce models of ligand-receptor complexes. Two energetically similar conformations of granisetron in the binding site were obtained from the docking simulations. In one model, the indazole ring of granisetron is near Trp90 and the tropane ring is near Arg92; in the other, the orientation is reversed. We used double-mutant cycle analysis to determine which of the two orientations is consistent with experimental data and found that the data are consistent with the model in which the indazole ring of granisetron interacts with Arg92 and the tropane ring interacts with Trp90. The combination of molecular modeling with double-mutant cycle analysis offers a powerful approach for the delineation of the architecture of the ligand-binding site.  (+info)

Comparative clinical study of the anti-emetic effects of oral ramosetron and injected granisetron in patients with malignant glioma undergoing ACNU chemotherapy. (46/162)

The effectiveness of ramosetron tablets and granisetron injection was compared for reducing the frequency of nausea, vomiting, and anorexia in patients with malignant glioma undergoing ACNU chemotherapy. Patients with malignant glioma to be treated with ACNU chemotherapy were randomly assigned to receive oral ramosetron (20 patients) or intravenous granisetron (19 patients) prior to ACNU injection. Gastrointestinal toxicity within 48 hours of ACNU injection was compared to that in patients who had received ACNU chemotherapy with dopamine D2 receptor-blocker as a historical control group. Within 24 hours of the administration of ACNU, 15 of the 20 patients treated with ramosetron and 16 of the 19 treated with granisetron were nausea-free, and 14 of the former and 14 of the latter regained their normal appetite. There was no significant difference in the anti-emetic effects. Ten of the 17 controls experienced no vomiting within 6 hours of the injection of ACNU, five were nausea-free within 24 hours, and two retained their normal appetite within 24 hours. Oral ramosetron has the same anti-anorectic and anti-emetic effects as intravenous granisetron. Ramosetron tablets are less expensive and are easy to take, so should be on the list of first-choice anti-emetic drugs for patients treated with ACNU chemotherapy.  (+info)

The efficacy of granisetron for cancer patients undergoing platinum-based chemotherapy: comparison of 1 miligram versus 3 miligram doses in preventing nausea and vomiting. (47/162)

AIM: To compare the efficacy of anti-emetic and prophylactic effects of 1 milligram (mg) versus 3 mg granisetron in cancer patients. METHODS: In this double blind, randomized, parallel study, 2-dose regimens of intra venous (IV) granisetron were evaluated in 39 cancer patients who were treated with platinum-based chemotherapy. Patients who met the inclusion criteria were randomized to receive granisetron 1 mg IV plus dexamethasone 20 mg (group A) or granisetron 3 mg iv plus dexamethasone 20 mg (group B). A questionnaire was used to evaluate the anti-emetic effects of granisetron. RESULTS: Subjects consisted of 31 men and 8 women. In group A (19 patients) 57.9% showed complete response from vomiting, 10.5% of major response, and 31.6% of failure to anti-emetic therapy. There were 47.4% of patients free from nausea and 52.6% complained of nausea (mild, moderate, and severe nausea). Among group B (20 patients), 90% showed complete response from vomiting, 5% of major response, and 5% of failure to anti-emetic therapy. Eighty percent of patients were free from nausea, while 15% complained of mild nausea and 5% of moderate nausea. The differences were statistically significant for vomiting (p = 0.02) as well as for nausea (p = 0.03). CONCLUSION: Intravenous granisetron 3 mg has better efficacy than granisetron 1 mg in preventing cisplatin- induced acute emesis.  (+info)

Comparison of ramosetron and granisetron for the prevention of acute and delayed emesis in Cisplatin-based chemotherapy: a randomized controlled trial. (48/162)

OBJECTIVE: A clinical study of ramosetron was carried out to evaluate its efficacy in preventing both acute and delayed emesis in cisplatin-based chemotherapy by using a double-blind method with granisetron as the comparative drug. METHODS: Cisplatin at a dose of > or =70 mg/m(2) was administered as a single intravenous (i.v.) infusion over 4 h. Patients were randomly assigned to receive either ramosetron (0.3 mg i.v. bolus 30 min before cisplatin on Day 1 and a 0.1 mg tablet in the morning for Days 2 to 5 after completion of chemotherapy; n = 36) or granisetron (3 mg i.v. infusion 30 min before cisplatin on Day 1 and a 1 mg tablet in the morning for Days 2 to 5 after completion of chemotherapy; n = 37). The observation period started with the initiation of chemotherapy (0 h) and continued for 24 h after completion of the chemotherapy for acute emesis, and on Days 2 to 5 for delayed nausea and vomiting. RESULTS: A total of 73 patients were eligible for evaluation, with 36 patients in the ramosetron group and 37 in the granisetron group. The efficacy of both drugs was analyzed in terms of the degree of achievement in each day of treatment. Ramosetron was as effective as granisetron in preventing nausea and vomiting (both acute and delayed emesis). The two drugs had a similar safety profile and adverse events were generally mild and transient. CONCLUSIONS: Ramosetron is effective and safe for the control of acute and delayed emesis induced by cisplatin.  (+info)