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Antiemetic prophylaxis with aprepitant, a 5-hydroxytryptamine3 (5-HT3) receptor antagonist and dexamethasone is recommended for patients receiving intravenous cisplatin chemotherapy. Whether the same antiemetic regime is superior for hepatic transcatheter arterial infusion chemotherapy with cisplatin (CDDP-TAI) is unknown. We conducted a retrospective study of antiemetic prophylaxis protection against chemotherapy-induced nausea and vomiting (CINV) in CDDP-TAI at Nagasaki University Hospital. The rate of complete response (CR) to antiemetics in the acute (

To evaluate the antiemetic effects of 5-HT(3) receptor antagonists, we investigated the relationship between condition of food intake and occurrence of nausea and vomiting. We collected data such as sex, age, disease, combination of steroids and central antiemetic agents, eating condition, and vomiting condition from medical records in 33 hematologic cancer patients receiving chemotherapy; combination with 5-HT(3) receptor antagonists. The conditions of food intake and nausea/vomiting were checked at 4 mealtime points (lunch, supper, breakfast, and next lunch) after chemotherapy, and were recorded as 1, 3, or 5 as each condition score. To calculate eating scores and nausea/vomiting scores, the sum of scores from 4 mealtime points was used. We found a significant negative correlation between eating scores and nausea/ vomiting scores (n=62, p

The effects of three serotonin-3 (5-HT(3)) receptor antagonists, azasetron, ondansetron, and ramosetron, on cytochrome P450 (CYP) 1A2-mediated 7-ethoxyresorufin O-deethylation, CYP2C9-mediated tolbutamide hydroxylation, CYP2C19-mediated S-mephenytoin 4'-hydroxylation, CYP2D6-mediated debrisoquine 4-hydroxylation, CYP2E1-mediated chlorzoxazone 6-hydroxylation, CYP3A4-mediated nifedipine oxidation, and CYP3A4-mediated testosterone 6beta-hydroxylation activities in human liver microsomes were compared. Azasetron and ramosetron at a concentration of 1 or 10 muM neither inhibited nor stimulated any of the metabolic activities. On the other hand, ondansetron competitively inhibited CYP1A2 and CYP2D6 activities, and the inhibition constants (K(i)) were 3.2 and 21.0 muM, respectively, which are much higher than the reported plasma concentrations after clinical intravenous or oral dosing. The free fractions of the three 5-HT(3) receptor antagonists in the incubation mixture estimated by ultracentrifugation were more than 68.6%. These results suggest that azasetron, ondansetron, and ramosetron do not cause clinically significant interactions with other drugs that are metabolized by CYPs via the inhibition of metabolism.

EUFEPS conference on drug transporters at Copenhagen : integrative approaches in ADME research.

1. Experiments were carried out in conscious, chronically instrumented, male, Sprague-Dawley rats to delineate the regional haemodynamic effects of the putative endogenous cannabinoid, anandamide, (0.075 - 3 mg kg(-1)), and to dissect some of the mechanisms involved. 2. At all doses of anandamide, there was a significant, short-lived increase in mean arterial blood pressure associated with vasoconstriction in renal, mesenteric and hindquarters vascular beds. 3. The higher doses (2.5 and 3 mg kg(-1)), caused an initial, marked bradycardia accompanied, in some animals, by a fall in arterial blood pressure which preceded the hypertension. In addition, after the higher doses of anandamide, the hindquarters vasoconstriction was followed by vasodilatation. 4. Although some of the effects described above resembled those of 5-HT (25 microg kg(-1)), the bradycardia and hypotensive actions of the latter were abolished by the 5HT(3)-receptor antagonist, azasetron, whereas those of anandamide were generally unaffected. 5. None of the cardiovascular actions of anandamide were influenced by the CB(1)-receptor antagonist, AM 251, but its bradycardic effect was sensitive to atropine, and its hindquarters vasodilator action was suppressed by the beta(2)-adrenoceptor antagonist, ICI 118551. 6. The results differ, in several aspects, from those previously reported in anaesthetized animals, and underscore the important impact anaesthesia can have on responses to anandamide.

Neutrophil functions play an important role in the antibacterial or antitumor host defense system. Ondansetron, granisetron, ramosetron, and azasetron are often used in gynecological patients as a prophylaxis against postoperative emesis or chemotherapy-induced emesis. In this study, using an ex vivo system, we have shown that these antiemetics at clinically relevant concentrations had no effect on superoxide (O–2) and hydrogen peroxide (H2O2) production of neutrophils, although high doses of these drugs significantly inhibited it to a similar degree. The drugs failed to impair chemotaxis or phagocytosis and to scavenge O–2 or H2O2 generated by an acellular system. Inhibition of the reactive oxygen species production may be due to attenuation of calcium elevation in neutrophils with these antiemetics. Our findings suggest that we are able to use these antiemetics in gynecological patients with cancer or those undergoing surgery without great caution.

The occurrence of delayed emesis induced 24 h after the administration of a non-platina chemotherapeutic agent, doxorubicin hydrochloride (doxorubicin), as well as behaviors such as feeding, drinking and defecation were examined in dogs. A single intravenous administration of 2 mg/kg doxorubicin induced emesis within 24 h of administration in some dogs, while delayed emesis was observed 24 h after administration in all dogs. This delayed emesis emerged strongly at day 3 or 4 and decreased at day 5. Hypophagia, the decreased frequency of drinking and the increased frequency of defecation were induced shortly after delayed emesis. Twenty-four hours after the administration of doxorubicin, a daily dose of 0.3 and 1 mg/kg/day, p.o. azasetron, a 5-HT3 antagonist, was administered for 4 days. Doxorubicin-induced delayed emesis was observed to decrease by about 30 and 50%, respectively. This result suggests that 5-HT3 receptors play a role in the mechanism of delayed emesis. Azasetron was found to improve the increased frequency of defecation, but exerted no obvious effect on hypophagia or on the decreased frequency of drinking. Taken together, we suggest that doxorubicin-induced emesis in dogs is a useful method to study further the mechanisms of delayed emesis and to investigate novel therapeutic agents against delayed emesis.

Aseries of 4-amino-5-chloro-2-methoxy-N-(1-substituted piperidin-4-ylmethyl)benzamides was synthesized as novel gastroprokinetic agents. The affinity of these compounds for the 5-hydroxytryptamine 4 (5-HT4) receptor was evaluated. Among these compounds, 4-amino-5-chloro-2-methoxy-N-[1-[5-(1-methylindol-3-ylcarbonylamino)pentyl]piperidin-4-ylmethyl]benzamide (3f, Y-34959) showed a higher affinity for the 5-HT4 receptor (Ki = 0.30 nmol/L) than for other receptors, and was confirmed to be a potent 5-HT4 receptor agonist having contractile effects in the isolated guinea-pig ascending colon (EC50 = 1.2 nmol/L). In dogs, compound 3f increased gastroprokinetic motility of both the gastric antrum and the ascending colon. In addition, this effect on the colon was inhibited by azasetron, a selective 5-HT3 receptor antagonist, demonstrating that the effect of gastroprokinetic agents having 5-HT3 receptor antagonism on the colon were reduced compared with that of selective 5-HT4 receptor agonists.

5-HT(3) receptor antagonists are widely used as antiemetic agents in clinical setting, of which palonosetron, with a long elimination half life (t(1/2)), has recently become available. It is important to evaluate the concentration of serotonin when investigating the antiemetic effects of 5-HT(3) receptor antagonists, as those effects are not based solely on the t(1/2) value. We theoretically evaluated the antiemetic effects of three 5-HT(3) receptor antagonists (granisetron, azasetron, palonosetron) on cisplatin-induced nausea and vomiting by estimating the time course of the 5-HT(3) receptor occupancy of serotonin. We estimated the 5-HT(3) receptor occupancy of serotonin in the small intestine, based on the time course of plasma concentration of each 5-HT(3) receptor antagonist and the time course of concentration of serotonin near the 5-HT(3) receptor in the small intestine after administration of cisplatin. The antiemetic effect of each 5-HT(3) receptor antagonist was evaluated based on the normal level of 5-HT(3) receptor occupancy of serotonin. Our results suggest that an adequate antiemetic effect will be provided when a dose of 75 mg/m(2) of cisplatin is given to patients along with any single administration of granisetron, azasetron, or palonosetron at a usual dose. On the other hand, the 5-HT(3) receptor occupancy of serotonin was found to be significantly lower than normal for several days after administration of palonosetron, as compared to granisetron and azasetron, indicating that constipation may be induced. Our results show that granisetron, azasetron, and palonosetron each have an adequate antiemetic effect after administration of 75 mg/m(2) of cisplatin.

The aim of the present study was to develop a transdermal drug delivery system for azasetron and evaluate the correlation between in vitro and in vivo release. The effects of different adhesives, permeation enhancers, and loadings of azasetron used in patches on the penetration of azasetron through rabbit skin were investigated using two‐chamber diffusion cells in vitro . For in vivo studies, azasetron pharmacokinetic parameters in Bama miniature pigs were determined according to a noncompartment model method after topical application of transdermal patches and intravenous administration of azasetron injections. The best permeation profile was obtained with the formulation containing DURO‐TAK 87‐9301 as adhesive, 5% of isopropyl myristate as penetration enhancer, and 5% of azasetron. The optimal patch formulation exhibited sustained release profiles in vivo for 216 h. The in vivo absorption curve in Bama miniature pigs obtained by deconvolution approach using WinNonlin® program was correlated well with the in vitro permeation curve of the azasetron patch. These findings indicated that the developed patch for azasetron is promising for the treatment of delayed chemotherapy‐induced nausea and vomiting, and the in vitro skin permeation experiments could be useful to predict the in vivo performance of transdermal azasetron patches. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:4540–4548, 2012

Aseries of 4-amino-5-chloro-2-methoxy-N-(1-substituted piperidin-4-ylmethyl)benzamides was synthesized as novel gastroprokinetic agents. The affinity of these compounds for the 5-hydroxytryptamine 4 (5-HT4) receptor was evaluated. Among these compounds, 4-amino-5-chloro-2-methoxy-N-[1-[5-(1-methylindol-3-ylcarbonylamino)pentyl]piperidin-4-ylmethyl]benzamide (3f, Y-34959) showed a higher affinity for the 5-HT4 receptor (Ki = 0.30 nmol/L) than for other receptors, and was confirmed to be a potent 5-HT4 receptor agonist having contractile effects in the isolated guinea-pig ascending colon (EC50 = 1.2 nmol/L). In dogs, compound 3f increased gastroprokinetic motility of both the gastric antrum and the ascending colon. In addition, this effect on the colon was inhibited by azasetron, a selective 5-HT3 receptor antagonist, demonstrating that the effect of gastroprokinetic agents having 5-HT3 receptor antagonism on the colon were reduced compared with that of selective 5-HT4 receptor agonists.

Repeated intermittent administration of psychostimulants causes behavioral sensitization in rodents. Previous studies using serotonin (5-HT) receptor ligands show that the 5-HT system is involved in cocaine-induced behavioral sensitization in rats, but the role of the 5-HT system has not been studied in mice. The present study examined the effects of the 5-HT 1A receptor agonist osemozotan, the 5-HT 2 receptor antagonist ritanserin and the 5-HT 3 receptor antagonist azasetron on cocaine-induced behavioral sensitization in male ddY mice. Repeated administration of cocaine for 7 days enhanced cocaine-induced locomotor activity, and this sensitization was observed even after withdrawal for 7–14 days. Cocaine-induced behavioral sensitization after a 7-day withdrawal was significantly reduced with the coadministration of osemozotan, ritanserin or azasetron with cocaine repeatedly for 7 days. A single injection of osemozotan or ritanserin before cocaine challenge also reduced repeated cocaine-induced behavioral sensitization. However, none of these ligands inhibited cocaine-induced behavioral sensitization, when each drug was administered for 7 days after repeated cocaine administration. These results suggest that the central 5-HT system plays a role in the development and expression, but not maintenance, of behavioral sensitization in cocaine-treated mice.

The absorption characteristics of azasetron, a serotonin type 3 (5-HT3) receptor antagonist which is used for the treatment of chemotherapy-induced emesis and nausea, were investigated in rabbits. The serum concentrations of azasetron following rectal administration as a suppository increased rapidly and showed the mean tmax value of 0.18 h. The concentrations were greater after rectal administration than those after oral administration. The absolute bioavailability was significantly different between the rectal, 52.9% and oral doses, 21.6%. The mean Cmax and tmax values after the rectal dose were 904.8 ng/ml and 0.18 h, respectively, whereas those after the oral dose averaged 124.7 ng/ml and 0.85 h, respectively. These results indicate that azasetron is absorbed to a greater extent and more rapidly into the systemic circulation via the rectum than via the intestine in rabbits. Consequently, the suppository form of azasetron hydrochloride may be feasible for the treatment of chemotherapy-induced acute emesis and nausea.

5-Hydroxytryptamine3 (5-HT3)-receptor blocking activities of KB-R6933 (6-amino-5-chloro-1-isopropyl-2-(4-methyl-1-piperazinyl)-benzimidazole dimaleate) were assessed in vivo and in vitro. Intravenous administration of KB-R6933, granisetron, ondansetron and azasetron inhibited 5-HT-induced bradycardia (von Bezold-Jarisch reflex) in anesthetized rats, with ED50 values of 0.071, 0.71, 4.0 and 0.82 microg/kg, respectively. The inhibitory effect of KB-R6933 at a dose of 0.3 microg/kg lasted for at least 8 hr, whereas those of granisetron at 30 microg/kg, ondansetron at 100 microg/kg and azasetron at 30 microg/kg nearly disappeared within 2-4 hr. Oral administration of KB-R6933 and granisetron also inhibited the bradycardia, with ED50 values of 0.41 and 76.3 microg/kg, respectively. In guinea pig ileum, KB-R6933 concentration-dependently antagonized 5-HT-evoked contraction and reduced the maximal contraction (pK(B)=8.75). Granisetron, ondansetron and azasetron shifted the dose-response curve for 5-HT to higher concentrations with no reduction of maximal contraction, and their pK(B)s were 7.65, 7.00 and 6.29, respectively. In a radioligand receptor binding study, KB-R6933, granisetron, ondansetron and azasetron displaced [3H]GR65630 binding to rat entorhinal cortex membrane, with Ki values of 0.066, 0.99, 2.70 and 2.5 nM, respectively. On the other hand, KB-R6933 exhibited negligible affinities for other receptors or binding sites tested, except for a weak affinity for the cholinergic M1-receptor, even at concentrations up to 10 microM. These results suggest that KB-R6933 is a potent and selective 5-HT3-receptor antagonist with a longer duration of action than those of existing 5-HT3-receptor antagonists.

1. 1. We investigated 5-hydroxytryptamine3 (5-HT3) receptor-mediating contractions and relaxations in the guinea-pig isolated distal colon using various 5-HT3 receptor agonists and antagonists, including GK-128 (2-[(2-methylimidazol-l-yl) methyl]benzo[f]thiochromen-l-one monohy-drochloride hemihydrate). 2. 2. Selective 5-HT3 receptor agonists, 2-methyl-5-HT and m-chlorophenylbiguanide, produced spantide-insensitive contraction and atropine-insensitive contraction and the relaxation. These agonists showed a small, but significant, difference of potency between contraction and relaxation. 3. 3. GK-128 competitively blocked both 2-methyl-5-HT- and m-chlorophenylbiguanide-induced responses with similar potency. The affinities of GK-128 for spantide-insensitive contraction and atropine-insensitive contraction were tenfold higher than for relaxation. 4. 4. Other selective 5-HT3 receptor antagonists, azasetron and tropisetron, also exhibited higher affinity in contraction than in relaxation, but the extent of their affinity differences was smaller than that observed in GK-128. In contrast, granisetron, ramosetron and ondansetron exhibited no significant differences in their affinity values among the three responses. 5. 5. These results suggest that the 5-HT3 receptors which mediate contraction and relaxation in the guinea-pig distal colon may not be the same, and that GK-128 is a 5-HT3 receptor antagonist with a stronger potency for contraction.

Y-25130( (+/-)N-(1-azabicyclo[2.2.2]oct-3-yl)-6-chloro-4-methyl-3-oxo-3,4-dihydro - 2H-1,4-benzoxazine-8-carboxamide hydrochloride) is a potent and selective 5-HT3 receptor antagonist free of dopamine receptor blocking activity. This compound was effective against emesis induced in animals by cytotoxic drugs or by total body X-radiation. When given prophylactically, the doses required to completely inhibit cisplatin-induced emesis in dogs and doxorubicin and cyclophosphamide-induced emesis in ferrets were 0.1 and 0.3 mg/kg i.v., respectively. Y-25130, at the dose of 0.3 mg/kg i.v., almost completely inhibited X-radiation-induced emesis in ferrets. When given during emesis, the doses required to completely inhibit cisplatin-induced emesis in dogs and doxorubicin- and cyclophosphamide-induced emesis in ferrets were 0.1 and 0.3 mg/kg i.v., respectively. The i.v. dose of 0.3 mg/kg of Y-25130 was enough to almost completely inhibit cisplatin-induced emesis in dogs for 24 h. From these results, it is suggested that Y-25130 may become an effective antiemetic drug against emesis induced by anticancer therapy.