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OBJECTIVES: Uric acid may activate an innate immune response in osteoarthritis (OA), contributing to disease pathology and progression. We evaluated the effectiveness of colchicine on pain and function in symptomatic knee OA (KOA) and the underlying mechanism of action. METHODS: Colchicine effectiveness in symptoms and inflammation modification in knee osteoarthritis (COLKOA) was a double-blind, placebo-controlled, randomized trial comparing 16 weeks of treatment with 0.5 mg twice-daily oral colchicine to placebo for knee osteoarthritis (KOA). The primary endpoint was ≥30% improvement in total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score at week 16. Secondary endpoints included improvement in pain (0-10 Likert scales); WOMAC pain; patient global assessment (0-100); physical function; the OARSI-OMERACT response; quality of life; and change in serum, urine, synovial fluid (SF) biomarkers of cartilage metabolism and inflammation, and plasma/SF colchicine concentrations. RESULTS: Of 109 randomly assigned participants, 39% (95% confidence interval (CI) 27-52%) and 49% (95% CI 36-62%) in the colchicine and placebo arms respectively met the primary endpoint at study end (P = 0.284, odds ratio 0.66, 95% CI 0.31-1.41). No strong evidence of treatment differences was identified on clinical secondary endpoints. Treatment significantly reduced mean serum hs-CRP (P = 0.008) and SF CTXI (P = 0.002); treatment tended to reduce inflammatory markers (SF IL-6, IL8, TNFα, CD14 and IL-18), but these differences were not statistically significant. CONCLUSION: Colchicine (0.5 mg twice-daily orally) reduced inflammation and high bone turnover biomarkers known to be associated with OA severity and progression risk, but did not reduce KOA symptoms over a 16-week study period. A longer-term study to evaluate for slow-acting disease modifying effects is warranted. TRIAL REGISTRATION: The trial has been registered at clinicaltrials.gov as NCT02176460. Date of registration: June 26, 2014.
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Colchicina/administración & dosificación , Citocinas/metabolismo , Inflamación/tratamiento farmacológico , Osteoartritis de la Rodilla/tratamiento farmacológico , Líquido Sinovial/metabolismo , Administración Oral , Adulto , Anciano , Biomarcadores/metabolismo , Progresión de la Enfermedad , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Inflamación/metabolismo , Masculino , Persona de Mediana Edad , Osteoartritis de la Rodilla/complicaciones , Osteoartritis de la Rodilla/metabolismo , Resultado del Tratamiento , Adulto JovenRESUMEN
This study investigated the impact of ABCB5, ABCC5 and RLIP76 polymorphisms on doxorubicin pharmacokinetics in Asian breast cancer patients (N=62). Direct sequencing was performed to screen for previously identified ABCC5 polymorphisms as well as polymorphisms in the exons and exon-intron boundaries of ABCB5 and RLIP76 genes. Genotype-phenotype correlations were analyzed using Mann-Whitney U-test. The homozygous variant allele at the ABCC5 g.+7161G>A (rs1533682) locus was significantly associated with higher doxorubicin clearance (g.+7161AA vs g.+7161GG, CL/BSA (Lh-1m-2): 30.34 (25.41-33.60) vs 22.46 (15.04-49.4), P=0.04). Homozygosity for the reference allele at the ABCC5 g.-1679T>A locus was associated with significantly higher doxorubicinol exposure (g.-1679TT vs g.-1679TA, AUC0-∞/dose/BSA (hm-5): 15.48 (6.18-67.17) vs 8.88 (3.68-21.71), P=0.0001). No significant influence of the three newly identified ABCB5 polymorphisms (c.2T>C, c.343A>G and c.1573G>A) on doxorubicin pharmacokinetics was observed. No polymorphisms were identified in the RLIP76 gene. These findings suggest that ABCC5 polymorphisms may explain partially the interpatient variability in doxorubicin disposition.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/genética , Pueblo Asiatico/genética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Doxorrubicina/farmacocinética , Proteínas Activadoras de GTPasa/genética , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Subfamilia B de Transportador de Casetes de Unión a ATP , Adulto , Anciano , Alelos , Antibióticos Antineoplásicos/farmacocinética , Antibióticos Antineoplásicos/uso terapéutico , Doxorrubicina/uso terapéutico , Exones/genética , Femenino , Frecuencia de los Genes/genética , Estudios de Asociación Genética , Genotipo , Haplotipos/genética , Humanos , Persona de Mediana Edad , Farmacogenética/métodos , Polimorfismo Genético/genéticaRESUMEN
Tamoxifen is the standard-of-care treatment for estrogen receptor-positive premenopausal breast cancer. We examined tamoxifen metabolism via blood metabolite concentrations and germline variations of CYP3A5, CYP2C9, CYP2C19 and CYP2D6 in 587 premenopausal patients (Asians, Middle Eastern Arabs, Caucasian-UK; median age 39 years) and clinical outcome in 306 patients. N-desmethyltamoxifen (DM-Tam)/(Z)-endoxifen and CYP2D6 phenotype significantly correlated across ethnicities (R(2): 53%, P<10(-77)). CYP2C19 and CYP2C9 correlated with norendoxifen and (Z)-4-hydroxytamoxifen concentrations, respectively (P<0.001). DM-Tam was influenced by body mass index (P<0.001). Improved distant relapse-free survival (DRFS) was associated with decreasing DM-Tam/(Z)-endoxifen (P=0.036) and increasing CYP2D6 activity score (hazard ratio (HR)=0.62; 95% confidence interval (CI), 0.43-0.91; P=0.013). Low (<14 nM) compared with high (>35 nM) endoxifen concentrations were associated with shorter DRFS (univariate P=0.03; multivariate HR=1.94; 95% CI, 1.04-4.14; P=0.064). Our data indicate that endoxifen formation in premenopausal women depends on CYP2D6 irrespective of ethnicity. Low endoxifen concentration/formation and decreased CYP2D6 activity predict shorter DRFS.
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Antineoplásicos Hormonales/sangre , Neoplasias de la Mama/sangre , Neoplasias de la Mama/diagnóstico , Detección Precoz del Cáncer , Premenopausia/sangre , Tamoxifeno/sangre , Adulto , Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Estudios de Cohortes , Femenino , Humanos , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Prospectivos , Tamoxifeno/uso terapéutico , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND & AIMS: Preclinical studies have demonstrated the additive effect of rapamycin with bevacizumab for hepatocellular carcinoma treatment. We conducted a Phase 1 study to evaluate the safety and pharmacokinetics of the combination in patients with hepatocellular carcinoma. METHODS: Adult participants with advanced hepatocellular carcinoma received intravenous bevacizumab (5mg/kg every 14 days) and oral rapamycin (1-6 mg/day; 3+3 dose escalation design). Computed tomography assessed tumour response and treatment safety. Pharmacokinetics assessment established rapamycin blood concentrations pre- and post-dose. Dynamic contrast-enhanced computed tomography analysed the tumour region for blood flow, permeability surface area product, fractional intravascular blood volume and extracellular-extravascular volume. RESULTS: Twenty-four participants were treated. There were two dose limiting toxicities with rapamycin 5mg: grade 3 thrombocytopenia and grade 3 mucositis. The maximally tolerated dose of rapamycin was 4 mg. Adverse events (grade 1-2) included hyperglycaemia (83%), thrombocytopenia (75%), fatigue (46%), mucositis (46%), anorexia (42%), diarrhoea (33%) and proteinuria (12.5%). Of 20 evaluable participants, one reached complete response that lasted 4.5 months, two reached partial response, 14 reached stable disease and three had progressive disease. Median overall survival was 9.4 months; progression-free survival was 5.5 months. Dose level and steady state area under the concentration time curve for hour zero to infinity of rapamycin correlated inversely with blood flow rate and change in permeability-surface area. After 22 days of treatment, there were significant reductions from baseline in blood flow rate, permeability-surface area and fractional intracellular blood volume. CONCLUSIONS: The recommended Phase 2 dose of rapamycin is 4 mg in combination with bevacizumab. Evidence of anti-vascular activity was observed together with promising clinical activity.
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Anticuerpos Monoclonales Humanizados/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Sirolimus/farmacocinética , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Relación Dosis-Respuesta a Droga , Femenino , Hepatectomía , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Sirolimus/administración & dosificación , Sirolimus/efectos adversos , Resultado del TratamientoRESUMEN
A systematic review and a meta-analysis were performed to quantify the accumulated information from genetic association studies investigating the impact of the CYP4F2 rs2108622 (p.V433M) polymorphism on coumarin dose requirement. An additional aim was to explore the contribution of the CYP4F2 variant in comparison with, as well as after stratification for, the VKORC1 and CYP2C9 variants. Thirty studies involving 9,470 participants met prespecified inclusion criteria. As compared with CC-homozygotes, T-allele carriers required an 8.3% (95% confidence interval (CI): 5.6-11.1%; P < 0.0001) higher mean daily coumarin dose than CC homozygotes to reach a stable international normalized ratio (INR). There was no evidence of publication bias. Heterogeneity among studies was present (I(2) = 43%). Our results show that the CYP4F2 p.V433M polymorphism is associated with interindividual variability in response to coumarin drugs, but with a low effect size that is confirmed to be lower than those contributed by VKORC1 and CYP2C9 polymorphisms.
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Cumarinas/administración & dosificación , Sistema Enzimático del Citocromo P-450/genética , Polimorfismo Genético/genética , Anciano , Anciano de 80 o más Años , Algoritmos , Alelos , Hidrocarburo de Aril Hidroxilasas/genética , Estudios de Cohortes , Cumarinas/uso terapéutico , Estudios Transversales , Citocromo P-450 CYP2C9 , Familia 4 del Citocromo P450 , Etnicidad , Humanos , Relación Normalizada Internacional , Persona de Mediana Edad , Oxigenasas de Función Mixta/genética , Sesgo de Publicación , Factores Sexuales , Vitamina K Epóxido ReductasasRESUMEN
We performed a single institution retrospective analysis of 114 patients treated with BU-based pretransplant conditioning regimens. Oral BU was administered to 76 patients (total dose 16 mg/kg or 8 mg/kg) and i.v. BU to 38 others (total dose 12.8 mg/kg or 6.4 mg/kg). Either CY (n=74) or fludarabine (n=40) was given in combination with BU. Median age was 35 years in the oral BU group and 48.5 years with i.v. BU (P<0.001). OS and PFS rates at 3-years post HSCT were not different in patients who received either i.v. or oral BU (OS: 41.3 vs 44.0% (P=0.981); PFS: 52.7 vs 54.7% (P=0.526), respectively). The i.v. BU, however, was associated with a significantly shorter time to engraftment (13.5 days vs 16 days, respectively; P<0.001). There were no significant differences in survival or 100-day mortality for patients who received either CY or fludarabine, in combination with BU. After adjustment for confounders, multivariate analysis showed that age of transplant (P=0.002), donor type (sibling or unrelated; P=0.003), GVHD (P<0.05) and route of administration (P=0.023) were significant risk factors for OS. The i.v. BU used in an older age group yielded equivalent survival compared with oral BU used in a younger population.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/métodos , Acondicionamiento Pretrasplante/métodos , Adolescente , Adulto , Anciano , Busulfano/administración & dosificación , Femenino , Humanos , Leucemia/tratamiento farmacológico , Leucemia/cirugía , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/cirugía , Estudios Retrospectivos , Trasplante Homólogo , Vidarabina/administración & dosificación , Vidarabina/análogos & derivados , Adulto JovenRESUMEN
BACKGROUND: To evaluate the efficacy and toxicity of single-agent docetaxel (Taxotere) as therapy in patients with disseminated nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS: Patients with histologically confirmed metastatic or recurrent NPC who have failed at least one line of palliative chemotherapy regimen but no prior docetaxel were eligible. Patients received weekly docetaxel every 28 days (docetaxel 30 mg/m(2) on days 1, 8 and 15) and were evaluated every two cycles of treatment of response assessment. Quality-of-life (QoL) assessments during the treatment period were done using the European Organization for Research and Treatment of Cancer QoL questionnaire QLQ-C30; version 3.0. RESULTS: Thirty patients were assessable for toxicity and response. The median age of the patients was 47 years (range 25-68 years) and the majority of patients had good performance status (Eastern Cooperative Oncology Group 0-1). Grade 3 or 4 toxicity included fatigue (13%), anemia (10%) and diarrhea (3%) of patients. Eleven (37%) and four (13.3%) patients achieved partial response and stable disease, respectively. The median progression-free survival was 5.3 months and median overall survival of 12.8 months. The partial responders had a mean duration of response of 4.1 months. Docetaxel caused a significant decline in QoL scores during treatment of patients responding or progressing with the treatment. CONCLUSIONS: Our findings suggest that weekly docetaxel is well tolerated and is an active agent in patients with disseminated NPC who were previously exposed and largely refractory to platinum-based chemotherapy but can cause a significant decline in QoL during treatment.
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Antineoplásicos/uso terapéutico , Neoplasias Nasofaríngeas/tratamiento farmacológico , Taxoides/uso terapéutico , Adulto , Anciano , Carcinoma , Supervivencia sin Enfermedad , Docetaxel , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/mortalidad , Neoplasias Nasofaríngeas/patología , Metástasis de la Neoplasia , Cuidados Paliativos , Calidad de Vida , Insuficiencia del TratamientoRESUMEN
BACKGROUND: The aim of this study was to determine the maximum tolerated dose (MTD) and the pharmacokinetic profile of Genexol-PM in Asian cancer patients. MATERIALS AND METHODS: Patients (N = 24) refractory to previous chemotherapy received Genexol-PM as an 1-h infusion on a weekly basis for 3 weeks followed by a resting week. The starting dose was 80 mg/m(2) and the maximum administered dose was 200 mg/m(2). RESULTS: The majority of patients had lung, nasopharyngeal and breast cancers and in eleven patients (46%), taxane-based chemotherapy had previously failed. The MTD was defined at 180 mg/m(2). The most common grade 3 non-hematologic adverse events in cycle 1 were fatigue (4%) and neuropathy (4%) occurring mainly at 200 mg/m(2). Five (21%) patients had partial response, nine (38%) had stable disease and seven (29%) had disease progression. Five of 11 previously taxane-refractory patients showed clinical benefit to Genexol-PM. The pharmacokinetics of Genexol-PM displayed dose-proportionality, with both the maximum concentration (C(max)) and the area under the concentration-time curve from zero to infinity (AUC(0-infinity)) increasing by approximately four- and threefold, respectively, as the dose of Genexol-PM was escalated from 80 to 200 mg/m(2). The median total-body clearance of Genexol-PM for all patients was 43.9 l/h. CONCLUSION: The weekly regimen of Genexol-PM was well tolerated and responses were observed in patients with refractory tumors, including patients who had failed taxane-based chemotherapy previously.
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Neoplasias/tratamiento farmacológico , Paclitaxel/administración & dosificación , Paclitaxel/farmacocinética , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Química Farmacéutica , Esquema de Medicación , Femenino , Humanos , Liposomas/efectos adversos , Liposomas/farmacocinética , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias/metabolismo , Neoplasias/patología , Paclitaxel/efectos adversos , Terapia Recuperativa , Resultado del TratamientoRESUMEN
Genetic polymorphisms in hepatically expressed UGT1A1 and UGT1A9 contribute to the interindividual variability i-n irinotecan disposition and toxicity. We screened UGT1A1 (UGT1A1*60, g.-3140G>A, UGT1A1*28 and UGT1A1*6) and UGT1A9 (g.-118(T)(9>10) and I399C>T) genes for polymorphic variants in the promoter and coding regions, and the genotypic effect of UGT1A9 I399C>T polymorphism on irinotecan disposition in Asian cancer patients was investigated. Blood samples were collected from 45 patients after administration of irinotecan as a 90 min intravenous infusion of 375 mg/m(2) once in every 3 weeks. Genotypic-phenotypic correlates showed that cancer patients heterozygous or homozygous for the I399C>T allele had approximately 2-fold lower systemic exposure to SN-38 (P<0.05) and a trend towards a higher relative extent of glucuronidation (REG) of SN-38 (P>0.05). UGT1A1-1A9 diplotype analysis showed that patients harbouring the H1/H2 (TG6GT(10)T/GG6GT(9)C) diplotype had 2.4-fold lower systemic exposure to SN-38 glucuronide (SN-38G) compared with patients harbouring the H1/H5 (TG6GT(10)T/GG6GT(10)C) diplotype (P=0.025). In conclusion, this in vivo study supports the in vitro findings of Girard et al. and suggests that the UGT1A9 I399C>T variant may be an important glucuronidating allele affecting the pharmacokinetics of SN-38 and SN-38G in Asian cancer patients receiving irinotecan chemotherapy.
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Camptotecina/análogos & derivados , Glucurónidos/metabolismo , Glucuronosiltransferasa/genética , Intrones , Neoplasias/genética , Polimorfismo Genético , Adulto , Anciano , Pueblo Asiatico , Camptotecina/metabolismo , Camptotecina/uso terapéutico , Femenino , Haplotipos , Humanos , Irinotecán , Hígado/enzimología , Masculino , Persona de Mediana Edad , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , UDP Glucuronosiltransferasa 1A9RESUMEN
INTRODUCTION: Not much is known about how Singaporeans perceive and react to risk presentation. There is no consensus on whether the European Union guidelines for describing the risk of side effects are valid. This study investigated the effect of different modes of risk presentation on how Singaporeans perceive and react to medical risk. Furthermore, we investigated the practical usage of qualitative phrases, the European Union's adjectives in particular, in describing levels of risk. MATERIALS AND METHODS: A hypothetical situation about the risk of side effects of an influenza vaccine was presented in either a probability format (i.e., 5%; n = 42) or a frequency format (i.e., 1 out of 20; n = 43). The 2 versions of questionnaire were handed out in an alternate order to a convenience sample of 47 healthcare professionals and 38 university students. RESULTS: Respondents presented with a "5% risk" were more likely to describe the risk as "uncommon" or "rare", as compared to respondents presented with a risk of "one out of twenty" (P <0.01). Furthermore, the former showed more willingness to accept the influenza vaccine described in the hypothetical situation than in the latter, but this was not statistically different (67% versus 54%; P >0.1). CONCLUSIONS: Modes of risk presentation affect how people perceive risk, even among people who are highly educated.