RESUMO
BACKGROUND: Respiratory tract infections (RTIs) are a common reason for children to consult in general practice. Antibiotics are often prescribed, in part due to miscommunication between parents and GPs. The duration of specific respiratory symptoms has been widely studied. Less is known about illness-related symptoms and the impact of these symptoms on family life, including parental production loss. Better understanding of the natural course of illness-related symptoms in RTI in children and impact on family life may improve GP-parent communication during RTI consultations. OBJECTIVE: To describe the general impact of RTI on children and parents regarding illness-related symptoms, absenteeism from childcare, school and work, use of health care facilities, and the use of over-the-counter (OTC) medication. METHODS: Prospectively collected diary data from two randomized clinical trials in children with RTI in primary care (n = 149). Duration of symptoms was analysed using survival analysis. RESULTS: Disturbed sleep, decreased intake of food and/or fluid, feeling ill and/or disturbance at play or other daily activities are very common during RTI episodes, with disturbed sleep lasting longest. Fifty-two percent of the children were absent for one or more days from childcare or school, and 28% of mothers and 20% of fathers reported absence from work the first week after GP consultation. Re-consultation occurred in 48% of the children. OTC medication was given frequently, particularly paracetamol and nasal sprays. CONCLUSION: Appreciation of, and communication about the general burden of disease on children and their parents, may improve understanding between GPs and parents consulting with their child.
Assuntos
Efeitos Psicossociais da Doença , Pais , Atenção Primária à Saúde , Encaminhamento e Consulta , Infecções Respiratórias/fisiopatologia , Absenteísmo , Antibacterianos/uso terapêutico , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Estimativa de Kaplan-Meier , Masculino , Países Baixos , Medicamentos sem Prescrição/uso terapêutico , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Infecções Respiratórias/tratamento farmacológico , Índice de Gravidade de Doença , Fatores de TempoRESUMO
PURPOSE: This study used longitudinal data to examine the influence of the religiosity of pre-adolescents with psychiatric problems on the course of mental health during adolescence. METHODS: In the TRAILS clinical cohort of 543 pre-adolescents (10-12 years), mental health problems were assessed using self-report at baseline, T2 (12-14 years), T3 (14-17 years), and T4 (17-21 years). The Youth Self Report (YSR) was used at baseline, T2, and T3, and the Adult Self Report (ASR) was used at T4. Religiosity was assessed at baseline using self-report and information from mothers and fathers, resulting in three categorical religiosity variables and six SOCON (Social Cultural Developments Questionnaire) religiosity scales that assess religiosity in greater detail. Repeated measure ANOVA analyses were performed for each independent religiosity variable with internalizing and externalizing problem behavior as dependent variables, gender as a factor and time (T1, T2, T3 and T4) as within factor. Results were adjusted for marital status of parents and socioeconomic status and corrected for multiple testing. RESULTS: There were main effects of the self-report SOCON scale "Humanistic beliefs" and gender and gender "by Humanistic beliefs" interaction effect on internalizing problems. Follow-up tests revealed that among females "high" scores on "Humanistic beliefs" were associated with increased internalizing problems. CONCLUSIONS: There were hardly any associations between religiosity and mental health in a clinical cohort of pre-adolescents up to adolescence. The exception being that among females strong humanistic beliefs were associated with internalizing problems. Implications of these findings are discussed.
Assuntos
Comportamento do Adolescente/psicologia , Depressão/psicologia , Saúde Mental/estatística & dados numéricos , Psicologia do Adolescente , Religião e Psicologia , Autorrelato , Adolescente , Adulto , Feminino , Humanos , Estudos Longitudinais , Masculino , Classe Social , Inquéritos e Questionários , Adulto JovemRESUMO
BACKGROUND: This study investigated the association between the religiosity of parents and pre-adolescents, and pre-adolescents' psychiatric problems. METHOD: In a clinic-referred cohort of 543 pre-adolescents at least once referred to a mental health outpatient clinic mental health problems were assessed using self-reports (Youth Self-Report; YSR), parent reports (Child Behavior Checklist; CBCL), and teacher reports (Teacher's Report Form; TRF) of child behavioral and emotional problems. Paternal, maternal, and pre-adolescent religiosity were assessed by self-report. MANCOVAs were performed for internalizing and externalizing problems as dependent variables, with maternal religiosity, paternal religiosity, pre-adolescent religiosity, parental religious harmony, and gender as independent variables, and socioeconomic status and divorce as covariates. RESULTS: Internalizing problems. Pre-adolescents of actively religious mothers had more internalizing symptoms than pre-adolescents of nonreligious mothers. Harmony and gender did not significantly affect the association between maternal religiosity and internalizing problems. Externalizing problems. No associations between religiosity of pre-adolescents, religiosity of mothers, religiosity of fathers and/or harmony of parents and externalizing problem behavior have been found. DISCUSSION AND CONCLUSIONS: Overall, associations between mental health and religiosity were modest to absent. Results are discussed in the context of a clinic-referred cohort, the quest phase of internalizing religious beliefs and role modeling of parents.
Assuntos
Transtornos do Comportamento Infantil/psicologia , Comportamento Infantil/psicologia , Saúde Mental/estatística & dados numéricos , Mães/psicologia , Relações Pais-Filho , Religião e Psicologia , Adolescente , Criança , Transtornos do Comportamento Infantil/diagnóstico , Feminino , Humanos , Masculino , Relações Mãe-FilhoRESUMO
Indibulin (ZIO-301/D-24851) is an orally applied small molecule with antitumor activity based upon destabilization of microtubule polymerization. The purpose of this phase I study was to determine the maximum tolerated dose (MTD) as well as the dose limiting toxicity (DLT), the pharmacokinetics, safety and tolerability of orally administered indibulin as capsule formulation in patients with advanced solid tumors. Patients received a single dose of indibulin. Seven dose-levels were evaluated: 100 mg, 150 mg, 250 mg, 350 mg and 600 mg once daily (QD), 450 mg and 600 mg twice daily (BID). After a washout period, patients received indibulin at the pre-defined daily dose for 14 days every 3 weeks (multiple dose part). A total of 28 patients entered the study. Indibulin administered as capsules was generally well tolerated. The MTD was not reached. There was a disproportionate increase of the area under the plasma concentration-time curve (AUC) with dose, with declining AUC corrected for dose starting at the 250 mg dose-level. There was no significant difference in AUC of indibulin after multiple dosing (day 1-14) compared to single administration (day-4). Inter-patient variability in AUC (102% CV) was high. A plateau in drug exposure was observed prior to reaching the MTD. Continued dose-escalation was unlikely to yield any increase in exposure of indibulin. The formulation needs optimization to increase the systemic exposure upon oral administration.
Assuntos
Acetamidas/farmacocinética , Acetamidas/uso terapêutico , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Indóis/farmacocinética , Indóis/uso terapêutico , Neoplasias/tratamento farmacológico , Acetamidas/administração & dosagem , Acetamidas/efeitos adversos , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Área Sob a Curva , Relação Dose-Resposta a Droga , Feminino , Humanos , Indóis/administração & dosagem , Indóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Neoplasias/patologia , Fatores de TempoRESUMO
Indibulin is a synthetic small molecule which antitumor activity is based upon destabilization of microtubules. The primary study objectives were to determine the impact of fasted and fed condition on pharmacokinetic parameters, as well as the maximum tolerated dose of the oral drinking solution of indibulin administered once daily for 14 days every 3 weeks in patients with solid tumors. In the pilot food effect part, patients received a single dose of 20 mg indibulin on day-8 and -4, fasted or fed, in a randomized crossover design. In the dose-escalation part, patients received a single dose of indibulin on day-4. Three dose levels were evaluated: 20, 40 and 80 mg. After a washout period, patients received indibulin once daily for 14 days every 3 weeks (multiple dose part). Blood samples were collected in the pilot food effect- and in the dose escalation study. A total of 14 patients entered, of which 6 completed the food effect study. The ratio of indibulin (fed/fasted) in the food effect study for AUC(0-72) was estimated as 1.24 (P=0.082, 95%CI 0.96-1.41) and C(max) ratio was 0.89 (P=0.54, 95%CI 0.55-1.44). Interpatient variability was high. Higher peak plasma concentrations were reached under fasting conditions which was undesired regarding tolerability. Therefore the dose escalation study was continued under fed conditions. Dose limiting toxicities, nausea and vomiting, appeared to be related to the increased volume of the solvent lactic acid. This study is continued, evaluating indibulin administered as capsules on the recommended dose level of 60 mg daily for 14 days.
Assuntos
Acetamidas/administração & dosagem , Acetamidas/farmacocinética , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Indóis/administração & dosagem , Indóis/farmacocinética , Neoplasias/tratamento farmacológico , Moduladores de Tubulina/administração & dosagem , Moduladores de Tubulina/farmacocinética , Acetamidas/efeitos adversos , Acetamidas/sangue , Administração Oral , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Estudos Cross-Over , Relação Dose-Resposta a Droga , Esquema de Medicação , Jejum/sangue , Feminino , Interações Alimento-Droga , Humanos , Indóis/efeitos adversos , Indóis/sangue , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/metabolismo , Neoplasias/patologia , Países Baixos , Projetos Piloto , Período Pós-Prandial , Resultado do Tratamento , Moduladores de Tubulina/efeitos adversos , Moduladores de Tubulina/sangueRESUMO
Paclitaxel is an important chemotherapeutic agent for breast cancer. Paclitaxel has high affinity for the P-glycoprotein (P-gp) (drug efflux pump) in the gastrointestinal tract causing low and variable oral bioavailability. Previously, we demonstrated that oral paclitaxel plus the P-gp inhibitor cyclosporin (CsA) is safe and results in adequate exposure to paclitaxel. This study evaluates the activity, toxicity and pharmacokinetics of paclitaxel combined with CsA in breast cancer patients. Patients with measurable metastatic breast cancer were given oral paclitaxel 90 mg m-2 combined with CsA 10 mg kg-1 (30 min prior to each paclitaxel administration) twice on one day, each week. Twenty-nine patients with a median age of 50 years were entered. All patients had received prior treatments, 25 had received prior anthracycline-containing chemotherapy and 19 had three or more metastatic sites. Total number of weekly administrations was 442 (median: 15/patient) and dose intensity of 97 mg m-2 week-1. Most patients needed treatment delay and 17 patients needed dose reductions. In intention to treat analysis, the overall response rate was 52%, the median time to progression was 6.5 months and overall survival was 16 months. The pharmacokinetics revealed moderate inter- and low intrapatient variability. Weekly oral paclitaxel, combined with CsA, is active in patients with advanced breast cancer.
Assuntos
Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Ciclosporina/administração & dosagem , Metástase Neoplásica/tratamento farmacológico , Paclitaxel/administração & dosagem , Administração Oral , Adulto , Idoso , Antraciclinas/uso terapêutico , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Ciclosporina/efeitos adversos , Ciclosporina/farmacocinética , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Humanos , Pessoa de Meia-Idade , Paclitaxel/efeitos adversos , Paclitaxel/farmacocinética , Análise de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: Pharmacokinetic study has shown that co-administration of cyclosporin A (CsA), which acts as a P-glycoprotein (P-gp) and CYP-3A blocker, resulted in an 8-fold increase in the systemic exposure of oral paclitaxel. Two doses of oral paclitaxel on 1 day in combination with CsA resulted in higher systemic exposure than single dose administration. PATIENTS AND METHODS: In this phase II study, chemonaïve patients with advanced gastric cancer received oral paclitaxel weekly in two doses of 90 mg/m(2) on the same day; CsA (10 mg/kg) was given 30 min before each dose of oral paclitaxel. RESULTS: In 25 patients, the main toxicities were: nausea CTC grade 2/3, 10 patients (40%); vomiting grade 2/3, 4 patients (20%); diarrhea grade 2/3, 6 patients (24%); neutropenia grade 3/4, 5 patients (20%). In the 24 evaluable patients, eight partial responses were observed, resulting in an overall response rate (ORR) of 33% [95% confidence interval (CI) 18% to 52%]. Eleven patients had stable disease (46%) and 5 patients showed progressive disease (21%). The ORR in the total population was 32% (95% CI 17% to 50%). The median time to progression was 16 weeks (95% CI 9-22). Pharmacokinetic analyses revealed that the mean area under the plasma concentration-time curve (AUC) of orally administered paclitaxel (+/- standard deviation) was 3757.6 +/- 939.4 ng.h/ml in week 1 and 3928.4 +/- 1281 ng.h/ml in week 2. The intrapatient variability in the AUC was 12%. CONCLUSIONS: Oral paclitaxel in combination with CsA is both active and safe in chemonaïve patients with advanced gastric cancer. Toxicities were mainly gastrointestinal.
Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos Fitogênicos/farmacologia , Ciclosporina/administração & dosagem , Inibidores Enzimáticos/administração & dosagem , Paclitaxel/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/patologia , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/farmacocinética , Terapia Combinada , Ciclosporina/farmacologia , Diarreia/induzido quimicamente , Esquema de Medicação , Inibidores Enzimáticos/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Paclitaxel/farmacocinética , Neoplasias Gástricas/patologia , Resultado do Tratamento , Vômito/induzido quimicamenteRESUMO
In the present study, the consequences of individual rearing during the play period on adult responses to aggression were investigated in a complex social setting. In a group of either socially or individually reared rats, an aggressor was repeatedly introduced. Separate control groups of individually and socially reared rats were not exposed to an aggressor. To allow an interpretation of the altered reactivity to aggression in terms of (in)efficient or (in)adequate behavior, not only the responses in the presence of the aggressor but also the consequences of the altered reactivity on subsequent behavior in the absence of the aggressor were observed. We demonstrated that a higher number of injuries, more agitation of the aggressor, and more ultrasonic distress vocalizations accompanied the altered responses of individually reared rats in the presence of the aggressor. In the absence of the aggressor, individually reared rats displayed less social stress-reducing behaviors (play and social grooming) than socially reared rats. It was concluded that individually reared rats display a less adequate response to aggression in this social context.
Assuntos
Agressão/psicologia , Comportamento Animal/fisiologia , Abrigo para Animais , Jogos e Brinquedos/psicologia , Comportamento Social , Isolamento Social/psicologia , Estresse Fisiológico/psicologia , Análise de Variância , Animais , Peso Corporal/fisiologia , Masculino , Ratos , Ratos WistarRESUMO
PURPOSE: We discovered that breast cancer resistance protein (BCRP), a recently identified adenosine triphosphate-binding cassette drug transporter, substantially limits the oral bioavailability of topotecan in mdr1a/1b(-/-) P-glycoprotein (P-gp) knockout and wild-type mice. GF120918 is a potent inhibitor of BCRP and P-gp. The aim was to increase the bioavailability of topotecan by GF120918. PATIENTS AND METHODS: In cohort A, eight patients received 1.0 mg/m(2) oral topotecan with or without coadministration of one single oral dose of 1,000 mg GF120918 (day 1 or day 8). In cohort B, eight other patients received 1.0 mg/m(2) intravenous topotecan with or without 1,000 mg oral GF120918 to study the effect of GF120918 on the systemic clearance of topotecan. RESULTS: After oral topotecan, the mean area under the plasma concentration-time curve (AUC) of total topotecan increased significantly from 32.4 +/- 9.6 microg.h/L without GF120918 to 78.7 +/- 20.6 microg.h/L when GF120918 was coadministered (P =.008). The mean maximum plasma concentration of total topotecan increased from 4.1 +/- 1.5 microg/L without GF120918 to 11.5 +/- 2.4 microg/L with GF120918 (P =.008). The apparent bioavailability in this cohort increased significantly from 40.0% (range, 32% to 47%) to 97.1% (range, 91% to 120%) (P =.008). Interpatient variability of the apparent bioavailability was 17% without and 11% with GF120918. After intravenous administration of topotecan, coadministration of oral GF120918 had a small but statistically significant effect on the AUC and systemic clearance of total topotecan but no statistically significant effect on maximum plasma concentration and terminal half-life of total topotecan. CONCLUSION: Coadministration of the BCRP and P-gp inhibitor GF120918 resulted in a significant increase of the systemic exposure of oral topotecan. The apparent oral bioavailability increased from 40.0% without to 97.1% with GF120918.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Acridinas/uso terapêutico , Antineoplásicos/farmacocinética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Inibidores Enzimáticos/farmacocinética , Isoquinolinas/uso terapêutico , Tetra-Hidroisoquinolinas , Topotecan/farmacocinética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Acridinas/farmacologia , Administração Oral , Adulto , Antineoplásicos/administração & dosagem , Disponibilidade Biológica , Esquema de Medicação , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Inibidores Enzimáticos/administração & dosagem , Feminino , Humanos , Isoquinolinas/farmacologia , Pessoa de Meia-Idade , Proteínas de Neoplasias/antagonistas & inibidores , Topotecan/administração & dosagemRESUMO
The purpose of this study was to investigate the effect of the co-solvents Cremophor EL and polysorbate 80 on the absorption of orally administered paclitaxel. 6 patients received in a randomized setting, one week apart oral paclitaxel 60 mg m(-2) dissolved in polysorbate 80 or Cremophor EL. For 3 patients the amount of Cremophor EL was 5 ml m(-2), for the other three 15 ml m(-2). Prior to paclitaxel administration patients received 15 mg kg(-1) oral cyclosporin A to enhance the oral absorption of the drug. Paclitaxel formulated in polysorbate 80 resulted in a significant increase in the maximal concentration (C(max)) and area under the concentration-time curve (AUC) of paclitaxel in comparison with the Cremophor EL formulations (P = 0.046 for both parameters). When formulated in Cremophor EL 15 ml m(-2), paclitaxel C(max) and AUC values were 0.10 +/- 0.06 microM and 1.29 +/- 0.99 microM h(-1), respectively, whereas these values were 0.31 +/- 0.06 microM and 2.61 +/- 1.54 microM h(-1), respectively, when formulated in polysorbate 80. Faecal data revealed a decrease in excretion of unchanged paclitaxel for the polysorbate 80 formulation compared to the Cremophor EL formulations. The amount of paclitaxel excreted in faeces was significantly correlated with the amount of Cremophor EL excreted in faeces (P = 0.019). When formulated in Cremophor EL 15 ml m(-2), paclitaxel excretion in faeces was 38.8 +/- 13.0% of the administered dose, whereas this value was 18.3 +/-15.5% for the polysorbate 80 formulation. The results show that the co-solvent Cremophor EL is an important factor limiting the absorption of orally administered paclitaxel from the intestinal lumen. They highlight the need for designing a better drug formulation in order to increase the usefulness of the oral route of paclitaxel
Assuntos
Antineoplásicos Fitogênicos/farmacocinética , Glicerol/análogos & derivados , Glicerol/farmacologia , Absorção Intestinal/efeitos dos fármacos , Neoplasias/metabolismo , Paclitaxel/farmacocinética , Administração Oral , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/uso terapêutico , Área Sob a Curva , Ciclosporina/administração & dosagem , Ciclosporina/farmacocinética , Ciclosporina/farmacologia , Combinação de Medicamentos , Fezes/química , Humanos , Neoplasias/tratamento farmacológico , Paclitaxel/administração & dosagem , Paclitaxel/uso terapêutico , Veículos Farmacêuticos , Polissorbatos/farmacologia , Solventes/farmacologiaRESUMO
Intravenous administration of paclitaxel is hindered by poor water solubility of the drug. Currently, paclitaxel is dissolved in a mixture of ethanol and Cremophor EL; however, this formulation (Taxol) is associated with significant side effects, which are considered to be related to the pharmaceutical vehicle. A new polymer-conjugated derivative of paclitaxel, PNU166945, was investigated in a dose-finding phase I study to document toxicity and pharmacokinetics. A clinical phase I study was initiated in patients with refractory solid tumors. PNU16645 was administered as a 1-h infusion every 3 weeks at a starting dose of 80 mg/m(2), as paclitaxel equivalents. Pharmacokinetics of polymer-bound and released paclitaxel were determined during the first course. Twelve patients in total were enrolled in the study. The highest dose level was 196 mg/m(2), at which we did not observe any dose-limiting toxicities. Hematologic toxicity of PNU166945 was mild and dose independent. One patient developed a grade 3 neurotoxicity. A partial response was observed in one patient with advanced breast cancer. PNU166945 displayed a linear pharmacokinetic behavior for the bound fraction as well as for released paclitaxel. The study was discontinued prematurely due to severe neurotoxicity observed in additional rat studies. The presented phase I study with PNU166945, a water-soluble polymeric drug conjugate of paclitaxel, shows an alteration in pharmacokinetic behavior when paclitaxel is administered as a polymer-bound drug. Consequently, the safety profile may differ significantly from standard paclitaxel.
Assuntos
Anemia/induzido quimicamente , Doenças do Sistema Nervoso/induzido quimicamente , Paclitaxel/farmacocinética , Paclitaxel/toxicidade , Polímeros/farmacocinética , Polímeros/toxicidade , Adulto , Idoso , Área Sob a Curva , Neoplasias da Mama/tratamento farmacológico , Carcinoma de Células Pequenas/tratamento farmacológico , Neoplasias do Colo/tratamento farmacológico , Relação Dose-Resposta a Droga , Portadores de Fármacos , Feminino , Gastroenteropatias/induzido quimicamente , Humanos , Infusões Intravenosas , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Dose Máxima Tolerável , Metacrilatos/química , Pessoa de Meia-Idade , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/análogos & derivados , Paclitaxel/síntese química , Paclitaxel/química , Polímeros/síntese química , Polímeros/química , Pró-Fármacos/síntese química , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Pró-Fármacos/toxicidade , Indução de Remissão , Neoplasias Cutâneas/secundário , Solubilidade , Taxoides/análogos & derivadosRESUMO
PURPOSE: Oral bioavailability of docetaxel is very low, which is, at least in part, due to its affinity for the intestinal drug efflux pump P-glycoprotein (P-gp). In addition, metabolism of docetaxel by cytochrome P450 (CYP) 3A4 in gut and liver may also contribute. The purpose of this study was to enhance the systemic exposure to oral docetaxel on coadministration of cyclosporine (CsA), an efficacious inhibitor of P-gp and substrate for CYP 3A4. PATIENTS AND METHODS: A proof-of-concept study was carried out in 14 patients with solid tumors. Patients received one course of oral docetaxel 75 mg/m(2) with or without a single oral dose of CsA 15 mg/kg. CsA preceded oral docetaxel by 30 minutes. During subsequent courses, patients received intravenous (IV) docetaxel 100 mg/m(2). RESULTS: The mean (+/- SD) area under the concentration-time curve (AUC) in patients who received oral docetaxel 75 mg/m(2) without CsA was 0.37 +/- 0.33 mg.h/L and 2.71 +/- 1.81 mg.h/L for the same oral docetaxel dose with CsA. The mean AUC of IV docetaxel 100 mg/m(2) was 4.41 +/- 2.10 mg.h/L. The absolute bioavailability of oral docetaxel was 8% +/- 6% without and 90% +/- 44% with CsA. The oral combination of docetaxel and CsA was well tolerated. CONCLUSION: Coadministration of oral CsA strongly enhanced the oral bioavailability of docetaxel. Interpatient variability in the systemic exposure after oral drug administration was of the same order as after IV administration. These data are promising and form the basis for the further development of a clinically useful oral formulation of docetaxel.
Assuntos
Ciclosporina/administração & dosagem , Paclitaxel/análogos & derivados , Paclitaxel/metabolismo , Taxoides , Administração Oral , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Disponibilidade Biológica , Docetaxel , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversosRESUMO
PURPOSE: To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of 9-aminocamptothecin (9-AC) in a colloidal dispersion (CD) formulation administered as a 30-minute intravenous (IV) infusion over 5 consecutive days every 3 weeks. PATIENTS AND METHODS: Patients with solid tumors refractory to standard therapy were entered onto the study. The starting dose was 0.4 mg/m(2)/d. The MTD was assessed on the first cycle and was defined as the dose at which > or = two of three patients or > or = two of six patients experience DLT. Pharmacokinetic measurements were performed on days 1 and 5 of the first cycle and on day 4 of subsequent cycles using high-performance liquid chromatography. RESULTS: Thirty-one patients received 104+ treatment courses at seven dose levels. The DLT was hematologic. At a dose of 1.3 mg/m(2)/d, three of six patients experienced grade 3 thrombocytopenia. Grade 4 neutropenia that lasted less than 7 days was observed in four patients. At a dose of 1.1 mg/m(2)/d, four of nine patients had grade 4 neutropenia of brief duration, which was not dose limiting. Nonhematologic toxicities were relatively mild and included nausea/vomiting, diarrhea, obstipation, mucositis, fatigue, and alopecia. Maximal plasma concentrations and area under the concentration-time curve (AUC) increased linearly with dose, but interpatient variation was wide. Lactone concentrations exceeded 10 nmol/L, the threshold for activity in preclinical tumor models, at all dose levels. Sigmoidal E(max) models could be fit to the relationship between AUC and the degree of hematologic toxicity. A partial response was observed in small-cell lung cancer. CONCLUSION: 9-AC CD administered as a 30-minute IV infusion daily times 5 every three weeks is safe and feasible. The recommended phase II dose is 1. 1 mg/m(2)/d.
Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Camptotecina/análogos & derivados , Neoplasias/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Área Sob a Curva , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Camptotecina/sangue , Camptotecina/farmacocinética , Coloides , Relação Dose-Resposta a Droga , Esquema de Medicação , Portadores de Fármacos , Feminino , Hematopoese/efeitos dos fármacos , Humanos , Infusões Intravenosas , Lactonas/sangue , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Neutropenia/induzido quimicamente , Trombocitopenia/induzido quimicamenteRESUMO
PURPOSE: To evaluate the pharmacokinetics of paclitaxel and cisplatin administered in combination with bleomycin and etoposide and Granulocyte Colony-Stimulating Factor (G-CSF) in patients with advanced solid tumours. METHODS: Patients were recruited to a phase I trial where escalating doses of paclitaxel (125 to 200 mg/m(2)) were administered in combination with etoposide 100 or 120 mg/m(2), and fixed dose of cisplatin 20 mg/m(2) and bleomycin 30 mg, with the concomitant use of G-CSF. Paclitaxel (3-h infusion) was followed by 1-h etoposide, 4-h cisplatin and 30-min bleomycin infusions, respectively. Pharmacokinetics sampling for paclitaxel analysis was performed in ten patients from dose levels II-V. RESULTS: The mean paclitaxel area under the plasma concentration-versus-time curves (AUC) for the 125-mg/m(2) dose level (II) was 7.0 +/- 3.6 h micromol(-1) l(-1), for the 175-mg/m(2) dose level (III) 10.6 +/- 2. 8 h micromol(-1) l(-1), for the 200-mg/m(2) dose level (IV) it was 16.0 +/- 5.0 h micromol(-1) l(-1), and for the 175-mg/m(2) dose level (V) it was 12.5 +/- 6.1 h micromol(-1) l(-1). The mean peak plasma concentration (C(max)) values for dose levels II-V were 1.9 +/- 1.1 micromol/l, 3.4 +/- 1.2 micromol/l, 4.3 +/- 1.0 micromol/l and 3.8 +/- 1.2 h micromol/l, respectively. CONCLUSION: In this study, relevant pharmacokinetic parameters of paclitaxel like AUC, C(max) and the paclitaxel plasma concentration above the pharmacologically relevant 0.1-micromol/l threshold concentration (t > 0.1 microM) when administered in combination with cisplatin, etoposide and bleomycin (PEB) were not statistically different from paclitaxel data of historical controls. However, given the trial design, pharmacokinetic interactions between the agents cannot be excluded.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Neoplasias/metabolismo , Paclitaxel/farmacocinética , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bleomicina/administração & dosagem , Carcinoma/tratamento farmacológico , Carcinoma/metabolismo , Cisplatino/administração & dosagem , Relação Dose-Resposta a Droga , Esquema de Medicação , Etoposídeo/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Humanos , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Paclitaxel/administração & dosagem , Paclitaxel/sangueRESUMO
Preclinical schedule dependency suggests that prolonged maintenance of low plasma levels of topotecan, a specific inhibitor of the nuclear enzyme topoisomerase I, results in optimal antitumor activity. The pharmacokinetics and pharmacodynamics of topotecan, administered as single agent in second-line therapy as a continuous low-dose infusion for 21 days, were evaluated in nine patients with small cell lung cancer (SCLC). Topotecan was administered i.v. as a 21 day continuous infusion every 28 days via an ambulatory pump. Dosages ranged from 0.4 to 0.6 mg/m2/day. Plasma levels of topotecan, the sum of topotecan, and its hydroxy acid congener and the N-desmethyl metabolite were determined at 1, 7, 14 and 21 days during infusion, using a validated high-performance liquid chromatography method with fluorescence detection. Myelosuppression was the most important toxicity. All patients experienced anemia, being severe (grade 3/4) in 55% of all courses. Other adverse effects were relatively mild and reversible, and included nausea, vomiting, diarrhea and fatigue. Three patients achieved a partial response. Mean steady-state concentrations of topotecan (C(ss)) in the first course were 0.46+/-0.17 and 0.47+/-0.19 ng/ml after doses of 0.4 and 0.5 mg/m2/day, respectively. Steady-state levels of the total of topotecan and hydroxy acid (C(ss,tot)) were 1.28+/-0.25 (range 0.93-1.58) and 1.57+/-0.19 (range 1.43-1.70) ng/ml at doses of 0.4 and 0.5 mg/m2/day, respectively. The percentage of the administered topotecan dose excreted in the urine within 24 h was 40+/-14 and 1.2+/-1.0% for total topotecan and N-desmethyltopotecan, respectively. During the second course, C(ss,tot) was significantly higher (p=0.032, paired t-test), which suggests altered topotecan disposition. A sigmoidal relationship was found between C(ss,tot) and the percent decrease in platelets (r=0.76, p=0.018). We conclude that topotecan administered as a 21 day continuous low-dose infusion has activity as single-agent, second-line therapy in patients with SCLC. There was considerable interpatient and intrapatient variability in systemic exposure to topotecan. Differences in organ function might contribute to this variation. Serum aspartate aminotransferase and albumin levels were predictive of topotecan pharmacokinetics.