No / Advances in antiemetic therapy for chemotherapy-induced emesis have resulted in improved protection against symptoms occurring within 24 h of chemotherapy. However, the vomiting which tends to occur beyond 24 h after chemotherapy (delayed-phase vomiting) is still relatively poorly controlled by the currently available drugs, suggesting that more than one mechanism may mediate these symptoms. The standard antiemetic regimen currently recommended for prevention of chemotherapy-induced emesis includes a serotonin (5-HT3) antagonist and a corticosteroid. The neurokinin-1 (NK1) antagonist aprepitant represents a new class of antiemetic currently in clinical development. Using data obtained in 2 Phase II clinical trials of aprepitant in patients receiving chemotherapy based on the highly emetogenic chemotherapeutic agent cisplatin, we compared the time course of antiemetic effect of aprepitant, a 5-HT3 antagonist, or a combination of both. Over the entire observation period (up to 7 days post-cisplatin), patients who received the NK1 antagonist had a superior prevention of emesis. However, in the first 24 h after cisplatin, emesis occurred in fewer patients who received the 5-HT3 antagonist than in patients who did not receive this class of drug. Furthermore, the majority of treatment failures in patients who received the NK1 antagonist occurred within the first 8¿12 h of chemotherapy, whereas the treatment failures in patients who received a 5-HT3 antagonist were more evenly distributed over time. Patients who received both drugs had superior control of symptoms compared with patients who received one or the other. The difference in the time course of emesis blockade observed with two different classes of receptor antagonists provides substantial evidence for involvement of separate pathophysiological mechanisms in chemotherapy-induced vomiting. Serotonin mediates the early vomiting process that occurs within 8¿12 h following cisplatin-based chemotherapy, after which time substance P acting at NK1 receptors becomes the dominant mediator of vomiting.

京都大学 / 0048 / 新制・課程博士 / 博士(社会健康医学) / 甲第22383号 / 社医博第105号 / 新制||社||医11(附属図書館) / 京都大学大学院医学研究科社会健康医学系専攻 / (主査)教授 古川 壽亮, 教授 川上 浩司, 教授 滝田 順子 / 学位規則第4条第1項該当 / Doctor of Public Health / Kyoto University / DFAM

Introduction: Nausea and vomiting are the most common and distressing side effects of chemotherapy because they negatively impact on quality of life and treatment compliance. Adequate control of nausea and vomiting in children receiving chemotherapy is imperative. Currently, the first-line drug for the prophylaxis and treatment of chemotherapy-induced nausea and vomiting (CINV) in paediatric patients is the serotonin (5HT3) receptor antagonist, ondansetron, administered intravenously. However, the parenteral route of administration of this drug is now being questioned as it is inconvenient for children and there is pressure to switch to an available oral formulation. The aim of this study was to evaluate the ease of administration, efficacy and cost-effectiveness of intravenous (IV) and oral tablet (OT) formulations of ondansetron in paediatric cancer patients receiving moderately emetogenic chemotherapy at the Steve Biko Academic Hospital in Pretoria, Gauteng (South Africa).Methods: It was an open-label, parallel, randomized trial. Thirty (30) patients scheduled to receive moderately emetogenic chemotherapy were recruited from the paediatric oncology department of the hospital. These patients were randomized to receive the same dose of either IV or OT ondansetron for the prophylaxis of CINV for one chemotherapy cycle. The efficacy of the agents was determined using a visual analogue scale (VAS) completed by the paediatric patients, which was compared to a one page questionnaire completed by the parents of the patients. Both questionnaires were completed at the end of chemotherapy (treatment period) as well as after a week without chemotherapy treatment (follow-up period). The patients’ plasma concentrations of ondansetron at four different time points were quantified by liquid chromatography tandem mass spectrometry (LC-MS/MS). The ondansetron plasma concentrations obtained in the IV group were compared to those obtained in the OT group. The cost-effectiveness calculations included the direct costs of antiemetic prophylaxis and treatment, the use of any rescue medication and the length of hospital stay. Results: The VAS revealed that patients who were given antiemetic prophylaxis with OT ondansetron experienced less acute and delayed nausea than the patients in the IV ondansetron group; however, these differences were not statistically significant (p=0.538). Vomiting was similar in the two groups (p=1). There was a statistically significant difference between the patients and their parents in the perception of acute nausea (p=0.018), with parents overstating the level of acute nausea felt by their children. The plasma concentrations of ondansetron in patients on the IV formulation were higher than the ones in patients on the OT formulation at all the time points investigated. At 30 minutes post-dosing the mean plasma concentration of ondansetron in the IV group was significantly higher than in the OT group (p=0.0015), but the differences in plasma concentrations between the two groups from 2 hours were fairly comparable. The cost of antiemetic prophylaxis for IV ondansetron was significantly higher than the cost of antiemetic prophylaxis using the equivalent OT dose (p=0.0351). Conclusion: For the prevention of CINV, OT ondansetron, a 5HT3 receptor antagonist, proved to be an easy to use and cost-effective alternative to IV ondansetron in paediatric cancer patients receiving moderately emetogenic chemotherapy treatment. / Dissertation (MSc)--University of Pretoria / Pharmacology / unrestricted

Published in Supportive Care in Cancer 2014;22(8):2161-6. DOI:10.1007/s00520-014-2182-7 / 京都大学 / 0048 / 新制・課程博士 / 博士(社会健康医学) / 甲第18548号 / 社医博第59号 / 新制||社医||8(附属図書館) / 31448 / 京都大学大学院医学研究科社会健康医学系専攻 / (主査)教授 武藤 学, 教授 佐藤 俊哉, 教授 千葉 勉 / 学位規則第4条第1項該当 / Doctor of Public Health / Kyoto University / DFAM

Symptoms after surgery and anaesthesia influence the patient´s ability to resume daily activities. If postoperative symptoms are controlled rehabilitation may be accelerated. The aims of this dissertation were to identify disturbing symptoms reported by patients after gynaecological surgery, to investigate what effect prohylactic treatment with antiemetics has on these symptoms and whether or not sensory simulation of the P6-acupressure has an effect on postoperative nausea and vomiting (PONV) and motion sickness. Methods: Total 1138 women participated in three clinical trials (Studies I, II, III) and one experimental study (Study IV). A questionnaire investigating postoperative symptoms was constructed and validated. The questionnaire was used in a prospective, consecutive, doubleblind, randomised, multicentre, and controlled study to identify incidence, and intensity of postoperative symptoms and the effect of common antiemetics (droperidol and granisetron) (Study III). The patients were followed for 24 h. In two studies (I, II) P6-acupressure was compared (prospective, double-blind, ransomised, controlled) with placebo acupressure and a reference group where the effect on PONV was followed over 24 h. The effect of P6-acupressure and placebo acupressure on motion sickness induced by a nauseogenic motion challenge was studied (Study III). Results: A high incidence and severity of postoperative symptoms were found after gynaecological surgery in a group with a high risk (>30%) for PONV. Sixty-four per cent (107/165) of the patients experienced disturbing symptoms after surgery and 46 % (76/165) scored their symptoms as moderate to very severe. Fourty-eight per cent (79/165) had two or more symptoms. A higher incidence of symptoms were reported in the groups with prophylactic treatment, granisetron 74% (123/165) and droperidol 80% (133/165) compared to the control group 41% (69/165) (P <0.05). The relative risk reduction for PONV with granisetron or droperidol prophylaxis is 27% respective 22%. The relative risk increase for headache is 63% after granisetron, and 44% for difficulty with accommodation after droperidol. Less PONV was seen after P6-acupressure, 33% (44/135) compared to reference group 46% (63/136) (p = 0.019), number needed to treat (NNT) was 7 [95% confidence interval (CI) 4- 6]. When comparing laparoscopic and vaginal surgery (subgroup analysis) the main effect was in the vaginal group (day-case surgery), 36% (27/75) in the reference group to 27% (23/86) in the placebo group and to 20% (17/84) in the P6-acupressure group, (P = 0.017), NNT for the vaginal group was 6 [95% CI 3-18]. P6-acupressure increased time to nausea after a laboratory motion challenge and reduced the total number of symptoms reported (p <0.009). Conclusions: There is no clinical efficacy in the form of reduced postoperative symptoms after prophylactic antiemetics (droperidol and granisetron) in females with a high risk (>30%) for PONV undergoing gynaecological surgery. P6-acupressure reduces the incidence of PONV after gynaecological surgery in females with a high (>30%) risk for PONV. The effect seems to be most prominent after vaginal surgery. P6-acupressure increased tolerance to experimental nausogenic stimuli and reduced the total number of symptoms reported in females with a history of motion sickness. / On the day of the public defence the status of article IV was: Submitted.

No description available.

Malgré le nombre important de spécialités pharmaceutiques mises sur le marché, certains patients hospitalisés ne peuvent bénéficier d’un traitement pour lequel aucun dosage et/ou forme pharmaceutique n’est disponible. Dans ce cas, la pharmacotechnie hospitalière peut être autorisée à formuler et contrôler des préparations.L’objectif de ces travaux a été de développer une forme transdermique semi-solide, à partir de véhicules prêts à l’emploi et contenant trois antiémétiques, pour traiter les nausées et vomissements chimio-induits. Pour ce faire, l’ondansétron, la dexaméthasone et l’aprépitant ont été formulés dans cinq véhicules commerciaux de composition liposomale (PLO®, Lipovan®, Pentravan® et Pentravan Plus®) ou phytosomale (Phytobase®). Après avoir protocolisé la formulation, un contrôle qualité a été réalisé sur chaque préparation finie. Il a essentiellement porté sur l’évaluation de la teneur en principes actifs dans les formulations et sur leur homogénéité. Dans ce but une méthode séparative utilisant la CLHP-UV et une méthode basée sur la PLS-UV ont été développées et validées selon les recommandations de la Société Française des Sciences Techniques et Pharmaceutiques pour doser simultanément les trois antiémétiques.Deux études in vitro ont ensuite été mises en œuvre sur des cellules de Franz. La première, menée à l’aide de membranes d’acétate de cellulose, a montré que le PLO® et le Pentravan Plus® sont les véhicules les plus performants pour libérer les trois principes actifs (PA) formulés séparément. La seconde visait à évaluer la perméation des mêmes PA à travers des épidermes de peau d’oreilles de cochon. Elle a mis en évidence les performances du Pentravan Plus® comme véhicule pour l’administration simultanée de l’ondansétron et de la dexaméthasone par voie transdermique. La perméation de l’aprépitant étant trop faible pour envisager son administration par voie transdermique, il n’a pas été intégré à la formulation finale. Différents promoteurs d’absorption ont été évalués afin d’améliorer le passage transcutanée : le tween 20 s’est révélé tout aussi performant que l’éthanol classiquement utilisé pour l’incorporation des PA dans ces véhicules. / Despite the high number of formulations available for a drug on the pharmaceutical market, it can arise that a patient needs a treatment for which none pharmaceutical form or dosage is available. In this case, pharmacy department of the hospital may have to prepare this form, in accordance with health agency.The goal of this work was to develop a semi-solid transdermic formulation from ready for use vehicle and containing three antiemetic drugs for the treatment of chemotherapy induced nausea and vomiting. Hence, ondansetron, dexamethasone and aprepitant have been formulated in five commercial vehicles of liposomal (PLO®, Lipovan®, Pentravan® and Pentravan Plus®) or phytosomal (Phytobase®) composition. After development of a formulation protocol, quality control was carried out on every finished preparation It focused on the evaluation of the content of active ingredients in formulations and their homogeneity. For this purpose a separation method using HPLC-UV and a method based on PLS-UV have been developed and validated according to the recommendations of the French Society of Pharmaceutical Science and Technology to assay the three antiemetics simultaneously.Two in vitro studies were then implemented on a Franz cell. The first, using cellulose acetate membranes, has shown that the PLO® and the Pentravan Plus® are the most efficient vehicles for releasing the three drugs formulated separately. The second one was performed to assess the permeation of the same drug through pig ears skin epidermis. It highlighted the performances of Pentravan Plus® as a vehicle for the simultaneous transdermal administration of ondansetron and dexamethasone. Nevertheless, as permeation of aprepitant is too poor to consider its transdermal administration, it has not been included in the final formulation. Different chemical enhancers were evaluated to improve the transcutaneous passage: tween 20 appeared to be as powerful as ethanol conventionally used for the incorporation of drugs in these vehicles.