AIM: To investigate across multiple cycles the efficacy and safety of palonosetron in the prevention of chemotherapy-induced nausea and vomiting in pediatric cancer patients receiving highly or moderately emetogenic chemotherapy (HEC/MEC). PATIENTS & METHODS: Patients were randomly assigned to 10, 20 μg/kg palonosetron or 3 × 150 μg/kg ondansetron for up to four cycles of HEC/MEC. RESULTS: In all on-study chemotherapy cycles, complete response rates were higher in patients in the 20 μg/kg palonosetron group than the ondansetron group. Treatment-emergent adverse events were comparable between the palonosetron 20 μg/kg and ondansetron groups. CONCLUSION: Over four cycles of HEC/MEC, 20 μg/kg palonosetron was an efficacious and safe treatment for the prevention of chemotherapy-induced nausea and vomiting in pediatric cancer patients.

• Klíčová slova
• antiemetic, chemotherapy, palonosetron, pediatric cancer,
• MeSH
• antiemetika aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• chinuklidiny aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• dítě MeSH
• isochinoliny aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• nádory komplikace   farmakoterapie   MeSH
• nauzea farmakoterapie   etiologie   MeSH
• novorozenec MeSH
• ondansetron aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• palonosetron MeSH
• předškolní dítě MeSH
• protinádorové látky škodlivé účinky   terapeutické užití   MeSH
• výsledek terapie MeSH
• zvracení farmakoterapie   etiologie   MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• antiemetika MeSH
• chinuklidiny MeSH
• isochinoliny MeSH
• ondansetron MeSH
• palonosetron MeSH
• protinádorové látky MeSH

BACKGROUND: 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. METHODS: 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 complete response rates had to be superior to -15%. Safety was assessed, according to treatment received. This study is registered with ClinicalTrials.gov, number NCT01442376, and has been completed. FINDINGS: Between Sept 12, 2011, and Oct 26, 2012, we randomly assigned 502 patients; 169 were assigned to receive 10 μg/kg palonosetron, 169 to receive 20 μg/kg palonosetron, and 164 to receive 3 × 150 μg/kg ondansetron, of whom 166, 165, and 162, respectively, were included in the efficacy analysis. In the acute phase, complete responses were recorded in 90 (54%) patients in the 10 μg/kg palonosetron group, 98 (59%) in the 20 μg/kg palonosetron group, and 95 (59%) in the ondansetron group. Non-inferiority versus ondansetron was shown for 20 μg/kg palonosetron in the acute phase (weighted sum of the differences in complete response rates 0·36% [97·5% CI -11·7 to 12·4]; p=0·0022). Non-inferiority versus ondansetron was not shown for 10 μg/kg palonosetron in the acute phase (weighted sum of the differences in complete response rates -4·41% [97·5% CI -16·4 to 7·6]). In the first on-study treatment cycle, treatment-emergent adverse events were reported in 134 (80%) of 167 patients who received 10 μg/kg palonosetron, 113 (69%) of 163 who received 20 μg/kg palonosetron, and 134 (82%) of 164 who received ondansetron. The most common drug-related treatment-emergent adverse events were nervous system disorders, mainly headache, which occurred in three (2%) patients who received 10 μg/kg palonosetron, one (<1%) patient who received 20 μg/kg palonosetron, and two (1%) patients who received ondansetron. The incidence of serious adverse events in the first on-study treatment cycle was lower in the 20 μg/kg palonosetron group (43 [26%]) than in the 10 μg/kg palonosetron group (52 [31%]) and the ondansetron group (55 [34%]). INTERPRETATION: Non-inferiority was shown for 20 μg/kg palonosetron during the acute phase of the first on-study chemotherapy cycle. 20 μg/kg palonosetron is now indicated by the European Medicines Agency and the US Food and Drug Administration for the prevention of chemotherapy-induced nausea and vomiting in paediatric patients aged 1 month to younger than 17 years. FUNDING: Helsinn Healthcare.

• MeSH
• antiemetika terapeutické užití   MeSH
• chinuklidiny terapeutické užití   MeSH
• dítě MeSH
• dvojitá slepá metoda MeSH
• internacionalita MeSH
• interval spolehlivosti MeSH
• isochinoliny terapeutické užití   MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• nádory farmakoterapie   mortalita   patologie   MeSH
• následné studie MeSH
• nauzea chemicky indukované   prevence a kontrola   MeSH
• nežádoucí účinky léčiv farmakoterapie   MeSH
• ondansetron terapeutické užití   MeSH
• palonosetron MeSH
• předškolní dítě MeSH
• protinádorové látky aplikace a dávkování   škodlivé účinky   MeSH
• rozvrh dávkování léků MeSH
• výsledek terapie MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvracení chemicky indukované   prevence a kontrola   MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• antiemetika MeSH
• chinuklidiny MeSH
• isochinoliny MeSH
• ondansetron MeSH
• palonosetron MeSH
• protinádorové látky MeSH

OBJECTIVES: Ondansetron is an antagonist of 5-HT3 receptors mostly used as an antiemetic yet known to modulate metabolism and appetite. We tested the metabolic effects of ondansetron in newly derived congenic rat strain, carrying limited chromosome 8 regions of (PD) Brown Norway (BN) and polydactylous (PD) strain origins (including variant serotonin receptor Htr3b gene) within the genomic background of highly inbred model of metabolic syndrome, the spontaneously hypertensive rat (SHR). METHODS: Adult, standard diet-fed male rats of SHR and the congenic SHR.(PD/BN)8 strains received ondansetron (2mg/kg body weight/day) or vehicle (n=6/strain/treatment) via oral gavage for 14 days while we followed their metabolic and morphometric profiles including glucose tolerance and triacylgycerol and cholesterol concentrations in 20 lipoprotein fractions. RESULTS: We fine-mapped the chromosome 8 differential segment in the new SHR.(PD/BN)8 congenic strain: it comprises BN-derived region together with an adjacent 422kb stretch of PD origin. The SHR.(PD/BN)8 rats were heavier than SHR, the fasting glucose was significantly higher in ondansetron-treated congenic than in SHR (post-hoc Tukey's HSD p=0.02). Compared to SHR, ondansetron induced significantly more robust increases of cholesterol and triacylglycerol concentrations in total, chylomicron, VLDL and HDL particles in the SHR.(PD/BN)8 congenic strain. CONCLUSION: We established new congenic model with distinct pharmacogenetic profile related to metabolic effects of ondansetron, facilitating thus the search for responsible genetic variants within the limited genomic region demarcated by the differential segment.

• MeSH
• antagonisté serotoninových receptorů 5-HT3 farmakologie   MeSH
• hypertenze farmakoterapie   genetika   metabolismus   MeSH
• krysa rodu Rattus MeSH
• lipidy krev   MeSH
• metabolický syndrom farmakoterapie   genetika   metabolismus   MeSH
• modely nemocí na zvířatech * MeSH
• ondansetron farmakologie   MeSH
• polydaktylie genetika   MeSH
• porucha glukózové tolerance farmakoterapie   genetika   metabolismus   MeSH
• potkani inbrední BN MeSH
• potkani inbrední SHR * MeSH
• receptory serotoninové 5-HT3 genetika   metabolismus   MeSH
• savčí chromozomy MeSH
• zvířata kongenní MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antagonisté serotoninových receptorů 5-HT3 MeSH
• lipidy MeSH
• ondansetron MeSH
• receptory serotoninové 5-HT3 MeSH

Improvements in stationary phase stability have been and remain a great task for research of new stationary phases. Metal oxide-based stationary phases appear as one of perspective alternatives to classical silica based stationary phases regarding to their similar effectiveness, different selectivity, different retention mechanism and mainly better chemical and thermal stability. In this study, the retention behaviour of ondansetron and its five pharmacopoeial impurities on TiO(2)-based reversed phase was investigated. The influence of buffer type, pH and concentration on retention was studied. Different types and amount of organic solvent in mobile phase were tested. The effect of temperature and flow rate on separation was investigated. The separation conditions were optimized and developed method validated. The retention parameters - retention time (t(R)), retention factor (k'), theoretical plate number (N), resolution between peaks due to nearby peaks (R(s)) and symmetry factor (A(s)) have been compared to parameters achieved on polybutadiene-coated zirconia column. The thermodynamic parameters of retention of analysed compounds - enthalpy, entropy and Gibbs free energy - were calculated and compared to those achieved on polybutadiene-coated zirconia column. This work proves similarity of retention behaviour of ondansetron and its five related compounds on zirconia-based and titania-based stationary phases and potential utilisation of polyethylene covered TiO(2)-based reversed stationary phase as an alternative to polybutadiene-coated ZrO(2) stationary phase in pharmaceutical analysis of ondansetron.

• MeSH
• molekulární struktura MeSH
• ondansetron chemie   izolace a purifikace   MeSH
• titan chemie   MeSH
• vysokoúčinná kapalinová chromatografie metody   MeSH
• zirkonium chemie   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ondansetron MeSH
• titan MeSH
• titanium dioxide MeSH Prohlížeč
• zirconium oxide MeSH Prohlížeč
• zirkonium MeSH

The absolute majority of the HPLC applications use silica-based columns for the separation of active substance and its impurities. However, stationary phases based on metal oxides appear as an interesting alternative. The aim of our study was to investigate the potential utilization of metal oxide-based stationary phases in analytical evaluation of ondansetron and its five pharmacopoeial impurities. In our study commercially available ZrO(2)-based columns (e.g. Zr-PBD, Zr-PS, Zr-C18) and TiO(2)-based column were used. The effect of an organic modifier (type and ratio), a buffer (type, pH and concentration) and the influence of temperature was investigated. The separation of ondansetron and its five pharmacopoeial impurities was successfully accomplished on a Zirchrom-PBD column using a mobile phase consisting of acetonitrile-ammonium phosphate (25 mM, pH 7.0) (18:82, v/v). Detection was performed at 216 nm and the analysis was completed within 7.5 min. The paper proves metal oxide-based stationary phases as an alternative to classical silica-based stationary phases in pharmaceutical analysis.

• MeSH
• acetonitrily chemie   MeSH
• antagonisté serotoninových receptorů 5-HT3 * MeSH
• časové faktory MeSH
• fosfáty chemie   MeSH
• koncentrace vodíkových iontů MeSH
• kontaminace léku prevence a kontrola   MeSH
• léčivé přípravky analýza   chemie   MeSH
• molekulární struktura MeSH
• ondansetron analýza   chemie   MeSH
• oxid křemičitý chemie   MeSH
• pufry MeSH
• referenční standardy MeSH
• roztoky chemie   MeSH
• teplota MeSH
• titan chemie   MeSH
• vysokoúčinná kapalinová chromatografie metody   MeSH
• zirkonium chemie   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• acetonitrile MeSH Prohlížeč
• acetonitrily MeSH
• ammonium phosphate MeSH Prohlížeč
• antagonisté serotoninových receptorů 5-HT3 * MeSH
• fosfáty MeSH
• léčivé přípravky MeSH
• ondansetron MeSH
• oxid křemičitý MeSH
• pufry MeSH
• roztoky MeSH
• titan MeSH
• titanium dioxide MeSH Prohlížeč
• zirkonium MeSH

The aim of this study was to compare antiemetic efficacy of three serotonin antagonists, granisetron, tropisetron and ondansetron, during conditioning for autologous stem cell transplantation (ASCT). Forty-five malignant lymphoma patients (mean age 38 years, M:F 30:15), undergoing the highly emetogenic regimen BEAM prior to ASCT, were randomized to receive IV granisetron (G) 3 mg once a day, IV tropisetron (T) 5 mg once a day, or IV ondansetron (0) 8 mg twice daily, for six days. The treatment groups were comparable with respect to age, sex and previous experience of nausea and/or vomiting. Nausea and/or emesis control failure was defined as a nausea lasting > or = 4 hours and/or > or = 3 episodes of vomiting/24 h, emesis control failure as > or = 3 episodes of vomiting/24 h. Both the period of chemotherapy (6 days) and the whole period of observation (10 days) were evaluated. Nausea and/or emesis control failure occurred in 24% of patients during the period of chemotherapy and in 51% of patients throughout the whole period of observation, while emesis control failed in 2% and 27% of patients, respectively. The efficacy of three serotonin antagonists was comparable during the chemotherapy period (5 patients with nausea and/or emesis control failure in the granisetron group, 2 in the tropisetron group and 4 in the ondansetron group,p = 0.40). When evaluating the whole period of observation, the antiemetic response to G and T was significantly better than to O, nausea and/or emesis control failure having occurred in 7 (47%) patients treated with G, 5 (33%) patients treated with T, and 12 (80%) patients treated with O, p = 0.03. The results concerning emesis control failures were similar, G 4 (27%), T 1 (7%), O 7 (47%), p = 0.04. Headache was the only frequent side effect of serotonin antagonists (30% incidence). All three serotonin antagonists sufficiently controlled nausea and vomiting during high-dose chemotherapy (BEAM) administration in 67-87% of patients. In comparison with ondansetron, both tropisetron and granisetron proved to be more effective after ASCT, when emetogenic factors other than chemotherapy alone participated.

• MeSH
• antagonisté serotoninu terapeutické užití   MeSH
• antiemetika terapeutické užití   MeSH
• autologní transplantace MeSH
• cytarabin aplikace a dávkování   MeSH
• dospělí MeSH
• etoposid aplikace a dávkování   MeSH
• granisetron terapeutické užití   MeSH
• indoly terapeutické užití   MeSH
• karmustin aplikace a dávkování   MeSH
• kombinovaná terapie MeSH
• lidé MeSH
• lymfom farmakoterapie   terapie   MeSH
• melfalan aplikace a dávkování   MeSH
• nauzea prevence a kontrola   MeSH
• ondansetron terapeutické užití   MeSH
• protokoly protinádorové kombinované chemoterapie aplikace a dávkování   terapeutické užití   MeSH
• transplantace hematopoetických kmenových buněk škodlivé účinky   MeSH
• tropisetron MeSH
• zvracení prevence a kontrola   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH
• Názvy látek
• antagonisté serotoninu MeSH
• antiemetika MeSH
• cytarabin MeSH
• etoposid MeSH
• granisetron MeSH
• indoly MeSH
• karmustin MeSH
• melfalan MeSH
• ondansetron MeSH
• tropisetron MeSH

The relaxations mediated by the activation of 5-HT receptors in the guinea pig proximal colon were investigated. Longitudinal strips were cut from the colon segment and placed into the bath. In the presence of atropine (0.2 microM), the relaxations were evoked by adding increasing concentrations of 5-HT (1-100 microM). Noncumulative concentration-response curves were established in the absence and presence of either 5-HT or nitric oxide synthase (NOS) antagonists. Selective 5-HT3 antagonists tropisetron (10 and 100 nM) and ondansetron (1 microM) inhibited the relaxations and shifted the concentration-response curves to the right. Similar effects were observed in the presence of the NOS inhibitor N(G)-nitro-L-arginine (3.2, 10, 32 microM) and partly reversed with L-arginine (100, 320 microM). N(G)-nitro-D-arginine, serving as a negative control, was ineffective. The relaxations were further inhibited in the presence of the soluble guanylate cyclase blocker methylene blue (10 microM) or NO scavenger hemoglobin (32 microM). These results suggest that the 5-HT3 receptor plays a role in neurogenic relaxations of guinea pig proximal colon, which are at least partly mediated via release of NO from nerve endings.

• MeSH
• antagonisté serotoninu farmakologie   MeSH
• hemoglobiny farmakologie   MeSH
• hladké svalstvo účinky léků   inervace   MeSH
• indoly farmakologie   MeSH
• inhibitory enzymů farmakologie   MeSH
• kolon účinky léků   inervace   MeSH
• methylenová modř farmakologie   MeSH
• morčata MeSH
• nitroarginin farmakologie   MeSH
• ondansetron farmakologie   MeSH
• oxid dusnatý antagonisté a inhibitory   fyziologie   MeSH
• receptory serotoninové 5-HT3 MeSH
• receptory serotoninové aplikace a dávkování   účinky léků   fyziologie   MeSH
• relaxace svalu účinky léků   MeSH
• synthasa oxidu dusnatého, typ I MeSH
• synthasa oxidu dusnatého antagonisté a inhibitory   MeSH
• techniky in vitro MeSH
• tropisetron MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• morčata MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antagonisté serotoninu MeSH
• hemoglobiny MeSH
• indoly MeSH
• inhibitory enzymů MeSH
• methylenová modř MeSH
• nitroarginin MeSH
• ondansetron MeSH
• oxid dusnatý MeSH
• receptory serotoninové 5-HT3 MeSH
• receptory serotoninové MeSH
• synthasa oxidu dusnatého, typ I MeSH
• synthasa oxidu dusnatého MeSH
• tropisetron MeSH

Concentration-dependent 5-hydroxytryptamine (5-HT) relaxations of guinea pig proximal colon were evoked in the presence of atropine (0.2 microM). 5-HT effect was neuronally mediated since it was blocked by tetrodotoxin (TTX) (0.5 microM). The type of 5-HT receptor mediating the relaxations was investigated using both 5-HT agonists and antagonists. Selective 5-HT3 antagonists tropisetron (10, 50, 500 nM) and ondansetron (1 microM) shifted the concentration-response curves for 5-HT to the right. Another 5-HT3 antagonist MDL 72222 (0.5 microM), 5-HT1/5-HT2 antagonists methiothepin (0.1 microM) and metergoline (0.1 microM), 5-HT(1A,B) antagonist propranolol (l microM) and 5-HT1B antagonist isamoltane (10 nM) were ineffective. Specific agonist of 5-HT3 receptors 2-methyl-5-hydroxytryptamine (2-methyl-5-HT) and agonist of 5-HT1 receptors 5-carboxamidotryptamine (5-CT) also relaxed the preparation, although the relaxation was not 5-HT relaxation. Neither was it neurogenic because it persisted in the presence of TTX (0.5 microM). The concentration-response curve for 2-methyl-5-HT was not affected by ondansetron (1 microM) or tropisetron (0.5 microM), but it was shifted to the right in the presence of 5-HT1/5-HT2 receptor antagonists methiothepin (0.1 microM) and metergoline (0.1 microM) and in the presence of 5-HT(1Da)/5-HT2A receptor antagonist ketanserin (1 microM). Methiothepin (0.1 microM) also inhibited the relaxations evoked in the presence of 5-CT. Specific agonist of 5-HT4 receptors 5-methoxytryptamine did not exert any effect on the preparation. It is suggested that there are two different mechanisms of relaxation in the guinea pig proximal colon. One is neurogenic and involves the activation of 5-HT3 receptors located on inhibitory neurons to the muscle; the other is myogenic and might be mediated via yet unclassified 5-HT receptors located on the muscle.

• MeSH
• agonisté serotoninových receptorů farmakologie   MeSH
• antagonisté serotoninu farmakologie   MeSH
• hladké svalstvo * chemie   účinky léků   MeSH
• indoly farmakologie   MeSH
• ketanserin farmakologie   MeSH
• kolon chemie   účinky léků   MeSH
• metergolin farmakologie   MeSH
• methiothepin farmakologie   MeSH
• morčata MeSH
• ondansetron farmakologie   MeSH
• receptory serotoninové fyziologie   MeSH
• relaxace svalu * účinky léků   MeSH
• serotonin analogy a deriváty   farmakologie   MeSH
• svalová kontrakce účinky léků   MeSH
• techniky in vitro MeSH
• tetrodotoxin farmakologie   MeSH
• tropisetron MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• morčata MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 2-methyl-5-HT MeSH Prohlížeč
• 5-carboxamidotryptamine MeSH Prohlížeč
• agonisté serotoninových receptorů MeSH
• antagonisté serotoninu MeSH
• indoly MeSH
• ketanserin MeSH
• metergolin MeSH
• methiothepin MeSH
• ondansetron MeSH
• receptory serotoninové MeSH
• serotonin MeSH
• tetrodotoxin MeSH
• tropisetron MeSH