RESUMEN
BACKGROUND: Hyperthermic intraperitoneal chemotherapy (HIPEC) is advised as a treatment option for epithelial ovarian cancer (EOC) with peritoneal carcinomatosis. This study was designed to define the pharmacokinetics of cisplatin (CDDP) and paclitaxel (PTX) administered together during HIPEC. METHODS: Thirteen women with EOC underwent cytoreductive surgery (CRS) and HIPEC, with CDDP and PTX. Blood, peritoneal perfusate and tissue samples were harvested to determine drug exposure by high-performance liquid chromatography and matrix-assisted laser desorption ionization imaging mass spectrometry (IMS). RESULTS: The mean maximum concentrations of CDDP and PTX in perfusate were, respectively, 24.8±10.4 µg ml(-1) and 69.8±14.3 µg ml(-1); in plasma were 1.87±0.4 µg ml(-1) and 0.055±0.009 µg ml(-1). The mean concentrations of CDDP and PTX in peritoneum at the end of HIPEC were 23.3±8.0 µg g(-1) and 30.1±18.3 µg(-1)g(-1), respectively. The penetration of PTX into the peritoneal wall, determined by IMS, was about 0.5 mm. Grade 3-4 surgical complications were recorded in four patients, five patients presented grade 3 and two patients presented grade 4 hematological complications. CONCLUSIONS: HIPEC with CDDP and PTX after CRS is feasible with acceptable morbidity and has a favorable pharmacokinetic profile: high drug concentrations are achieved in peritoneal tissue with low systemic exposure. Larger studies are needed to demonstrate its efficacy in patients with microscopic postsurgical residual tumours in the peritoneal cavity.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Carcinoma/tratamiento farmacológico , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Peritoneales/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Área Bajo la Curva , Carcinoma/secundario , Cisplatino/administración & dosificación , Femenino , Humanos , Hipertermia Inducida , Infusiones Parenterales , Masculino , Persona de Mediana Edad , Neoplasias Glandulares y Epiteliales/secundario , Neoplasias Ováricas/patología , Paclitaxel/administración & dosificación , Neoplasias Peritoneales/secundario , Peritoneo/metabolismoRESUMEN
BACKGROUND: Lucitanib is a potent, oral inhibitor fibroblast growth factor receptor types 1 and 2 (FGFR), vascular endothelial growth factor receptor types 1, 2, and 3 (VEGFR), platelet-derived growth factor receptor types α and ß (PGFRα/ß), which are essential kinases for tumor growth, survival, migration, and angiogenesis. Several tumor types, including breast carcinoma, demonstrate amplification of fibroblast growth factor (FGF)-related genes. There are no approved drugs for molecularly defined FGF-aberrant (FGFR1- or FGF3/4/19-amplified) tumors. METHODS: This open-label phase I/IIa study involved a dose-escalation phase to determine maximum tolerated dose (MTD), recommended dose (RD), and pharmacokinetics of lucitanib in patients with advanced solid tumors, followed by a dose-expansion phase to obtain preliminary evidence of efficacy in patients who could potentially benefit from treatment (i.e. with tumors harboring FGF-aberrant pathway or considered angiogenesis-sensitive). RESULTS: Doses from 5 to 30 mg were evaluated with dose-limiting toxic effects dominated by vascular endothelial growth factor (VEGF) inhibition-related toxic effects at the 30 mg dose level (one case of grade 4 depressed level of consciousness and two cases of grade 3 thrombotic microangiopathy). The most common adverse events (all grades, all cohorts) were hypertension (91%), asthenia (42%), and proteinuria (57%). Exposure increased with dose and t½ was 31-40 h, suitable for once daily administration. Seventy-six patients were included. All but one had stage IV; 42% had >3 lines of previous chemotherapy. Sixty-four patients were assessable for response; 58 had measurable disease. Clinical activity was observed at all doses tested with durable Response Evaluation Criteria In Solid Tumors (RECIST) partial responses in a variety of tumor types. In the angiogenesis-sensitive group, objective RECIST response rate (complete response + partial response) was 26% (7 of 27) and progression-free survival (PFS) was 25 weeks. In assessable FGF-aberrant breast cancer patients, 50% (6 of 12) achieved RECIST partial response with a median PFS of 40.4 weeks for all treated patients. CONCLUSION: Lucitanib has promising efficacy and a manageable side-effect profile. The spectrum of activity observed demonstrates clinical benefit in both FGF-aberrant and angiogenesis-sensitive populations. A comprehensive phase II program is planned.
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Relación Dosis-Respuesta a Droga , Naftalenos/análisis , Neoplasias/tratamiento farmacológico , Neovascularización Patológica/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Quinolinas/análisis , Adulto , Anciano , Supervivencia sin Enfermedad , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Femenino , Humanos , Persona de Mediana Edad , Neoplasias/clasificación , Neoplasias/patología , Neovascularización Patológica/patología , Inhibidores de Proteínas Quinasas/efectos adversos , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptores del Factor de Crecimiento Derivado de Plaquetas , Receptor 1 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidoresRESUMEN
There is no consensus on which drugs/techniques/strategies can affect mortality in the perioperative period of cardiac surgery. With the aim of identifying these measures, and suggesting measures for prioritized future investigation we performed the first International Consensus Conference on this topic. The consensus was a continuous international internet-based process with a final meeting on 28 June 2010 in Milan at the Vita-Salute University. Participants included 340 cardiac anesthesiologists, cardiac surgeons, and cardiologists from 65 countries all over the world. A comprehensive literature review was performed to identify topics that subsequently generated position statements for discussion, voting, and ranking. Of the 17 major topics with a documented mortality effect, seven were subsequently excluded after further evaluation due to concerns about clinical applicability and/or study methodology. The following topics are documented as reducing mortality: administration of insulin, levosimendan, volatile anesthetics, statins, chronic ß-blockade, early aspirin therapy, the use of pre-operative intra-aortic balloon counterpulsation, and referral to high-volume centers. The following are documented as increasing mortality: administration of aprotinin and aged red blood cell transfusion. These interventions were classified according to the level of evidence and effect on mortality and a position statement was generated. This International Consensus Conference has identified the non-surgical interventions that merit urgent study to achieve further reductions in mortality after cardiac surgery: insulin, intra-aortic balloon counterpulsation, levosimendan, volatile anesthetics, statins, chronic ß-blockade, early aspirin therapy, and referral to high-volume centers. The use of aprotinin and aged red blood cells may result in increased mortality.
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Procedimientos Quirúrgicos Cardíacos/mortalidad , Cuidados Críticos , Anestesia , HumanosRESUMEN
A simple, sensitive HPLC-MS/MS method was developed and validated for the determination of lidocaine in skin and plasma of rats. The methods were established and validated assessing lower limit of quantitation (LLOQ), linearity, intra and inter-day precision and accuracy, selectivity, recovery and matrix effect. Chromatography was done on a Gemini column embedded with C18 stationary phase (50 mm × 2.0 mm, 5 µm particle size), using a gradient with mobile phases consisting of 0.1% HCOOH in bidistilled water and 0.1% HCOOH in acetonitrile. The mass spectrometer worked with electrospray ionization in positive ion mode and selected reaction monitoring, using target ions m/z 235.10 for lidocaine and m/z 245.10 for lidocaine-d10, used as internal standard. RESULTS: The linearity of the method was in the ranges of lidocaine concentrations 10.0-200.0 ng/mL for skin homogenate (accuracy 94.1-105.5%; R2 ≥ 0.998) and 0.025-2 ng/mL for plasma (accuracy 96.2-104.8%; R2 ≥ 0.996). The intra- and inter-day precision and accuracy determined on three quality control samples (20, 75 and 170 ng/mL for skin and 0.075, 0.4 and 1.5 ng/mL for plasma) were ≤4.2% and 103.8-108.2% for skin and ≤12.4% and 95.5-101.4% for plasma. The LLOQ was 10 ng/mL in skin homogenate and 0.025 ng/mL in plasma. The applicability of the method was demonstrated by measuring lidocaine in skin and plasma after exposure to medicated patches containing 5% lidocaine.
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Cromatografía Líquida de Alta Presión/métodos , Lidocaína/análisis , Espectrometría de Masas en Tándem/métodos , Parche Transdérmico , Animales , Estabilidad de Medicamentos , Lidocaína/administración & dosificación , Lidocaína/farmacocinética , Límite de Detección , Modelos Lineales , Masculino , Ratas , Reproducibilidad de los Resultados , Piel/químicaRESUMEN
Trabectedin and its analogue lurbinectedin are effective drugs used in the treatment of ovarian cancer. Since the presence of ascites is a frequent event in advanced ovarian cancer we asked the question whether ascites could modify the activity of these compounds against ovarian cancer cells. The cytotoxicity induced by trabectedin or lurbinectedin against A2780, OVCAR-5 cell lines or primary culture of human ovarian cancer cells was compared by performing treatment in regular medium or in ascites taken from either nude mice or ovarian cancer patients. Ascites completely abolished the activity of lurbinectedin at up to 10nM (in regular medium corresponds to the IC90), strongly reduced that of trabectedin, inhibited the cellular uptake of lurbinectedin and, to a lesser extent, that of trabectedin. Since α1-acid glycoprotein (AGP) is present in ascites at relatively high concentrations, we tested if the binding of the drugs to this protein could be responsible for the reduction of their activity. Adding AGP to the medium at concentration range of those found in ascites, we reproduced the anticytotoxic effect of ascites. Erythromycin partially restored the activity of the drugs, presumably by displacing them from AGP. Equilibrium dialysis experiments showed that both drugs bind AGP, but the affinity of binding of lurbinectedin was much greater than that of trabectedin. KD values are 8±1.7 and 87±14nM for lurbinectedin and trabectedin, respectively. The studies intimate the possibility that AGP present in ascites might reduce the activity of lurbinectedin and to a lesser extent of trabectedin against ovarian cancer cells present in ascites. AGP plasma levels could influence the distribution of these drugs and thus they should be monitored in patients receiving these compounds.
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Ascitis/metabolismo , Carbolinas/metabolismo , Dioxoles/metabolismo , Compuestos Heterocíclicos de 4 o más Anillos/metabolismo , Orosomucoide/metabolismo , Neoplasias Ováricas/metabolismo , Tetrahidroisoquinolinas/metabolismo , Animales , Antineoplásicos Alquilantes/metabolismo , Antineoplásicos Alquilantes/farmacología , Antineoplásicos Alquilantes/uso terapéutico , Carbolinas/farmacología , Carbolinas/uso terapéutico , Línea Celular Tumoral , Dioxoles/farmacología , Dioxoles/uso terapéutico , Relación Dosis-Respuesta a Droga , Femenino , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Humanos , Ratones , Ratones Desnudos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/cirugía , Unión Proteica/fisiología , Tetrahidroisoquinolinas/farmacología , Tetrahidroisoquinolinas/uso terapéutico , Trabectedina , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
The toxicity profile and the pharmacokinetics of aphidicolin glycinate, a water-soluble analogue of aphidicolin, have been evaluated in two consecutive phase I clinical studies. In the first study, aphidicolin glycinate was given by 1-hour infusion for 5 consecutive days, every 3 weeks (daily x 5 study); in the second study, which was planned on the basis of the pharmacokinetic information obtained in the previous study, the drug was given by 24-hour continuous infusion. Treatment was repeated every 3 weeks. In the daily x 5 study, the daily dose was escalated from 12 mg/m2 to the maximum tolerated dose of 2250 mg/m2. Local toxicity was dose limiting. Elimination half-life was 2 +/- 0.2 hours (mean +/- SE) with aphidicolin being undetectable 6-8 hours after the end of the infusion. In the 24-hour continuous-infusion study, the dose was escalated from 435 mg/m2 to the maximum tolerated dose of 4500 mg/m2. Local toxicity was dose limiting, while other toxic effects were absent. The experimentally determined concentrations at the steady state were in agreement with those predicted on the basis of the available pharmacokinetic data. The targeted concentration at the steady state of 3 micrograms/mL was achieved at doses greater than or equal to 3000 mg/m2. Twenty-four-hour continuous infusion is the recommended schedule for clinical evaluations of aphidicolin glycinate as the synchronizing agent or in combination with cisplatin.
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Antineoplásicos/farmacocinética , Afidicolina/análogos & derivados , ADN Polimerasa II/antagonistas & inhibidores , Diterpenos/farmacocinética , Adulto , Anciano , Antineoplásicos/administración & dosificación , Diterpenos/administración & dosificación , Esquema de Medicación , Evaluación de Medicamentos , Femenino , Semivida , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Chronic myeloid leukemia is caused by a chromosomal translocation that results in an oncogenic fusion protein, Bcr-Abl. Bcr-Abl is a tyrosine kinase whose activity is inhibited by the antineoplastic drug STI571. This drug can cure mice given an injection of human leukemic cells, but treatment ultimately fails in animals that have large tumors when treatment is initiated. We created a mouse model to explore the mechanism of resistance in vivo. METHODS Nude mice were injected with KU812 Bcr-Abl(+) human leukemic cells. After 1 day (no evident tumors), 8 days, or 15 days (tumors >1 g), mice were treated with STI571 (160 mg/kg every 8 hours). Cells recovered from relapsing animals were used for in vitro experiments. Statistical tests were two-sided. RESULTS: Tumors regressed initially in all STI571-treated mice, but all mice treated 15 days after injection of tumor cells eventually relapsed. Relapsed animals did not respond to further STI571 treatment, and their Bcr-Abl kinase activity in vivo was not inhibited by STI571, despite high plasma concentrations of the drug. However, tumor cells from resistant animals were sensitive to STI571 in vitro, suggesting that a molecule in the plasma of relapsed animals may inactivate the drug. The plasma protein alpha1 acid glycoprotein (AGP) bound STI571 at physiologic concentrations in vitro and blocked the ability of STI571 to inhibit Bcr-Abl kinase activity in a dose-dependent manner. Plasma AGP concentrations were strongly associated with tumor load. Erythromycin competed with STI571 for AGP binding. When animals bearing large tumors were treated with STI571 alone or with a combination of STI571 and erythromycin, greater tumor reductions and better long-term tumor-free survival (10 of 12 versus one of 13 at day 180; P:<.001) were observed after the combination treatment. CONCLUSION: AGP in the plasma of relapsed animals binds to STI571, preventing this compound from inhibiting the Bcr/Abl tyrosine kinase. Molecules such as erythromycin that compete with STI571 for binding to AGP may enhance the therapeutic potential of this drug.
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Antineoplásicos/farmacología , Proteínas de Fusión bcr-abl/efectos de los fármacos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Orosomucoide/efectos de los fármacos , Orosomucoide/metabolismo , Piperazinas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirimidinas/farmacología , Animales , Benzamidas , Western Blotting , Resistencia a Antineoplásicos , Sinergismo Farmacológico , Quimioterapia Combinada , Inhibidores Enzimáticos/farmacología , Eritromicina/farmacología , Femenino , Proteínas de Fusión bcr-abl/metabolismo , Humanos , Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva/enzimología , Ratones , Ratones Desnudos , Fosforilación/efectos de los fármacos , Factores de Tiempo , Células Tumorales CultivadasRESUMEN
Etoposide (VP16) pharmacokinetics was investigated in three groups of cancer patients: a control group of 18 patients with renal and hepatic function tests in the normal range; a group of 8 patients with renal insufficiency; and a group of 15 patients with abnormal hepatic function. In the control group plasma clearance (Clp), volume of distribution (Vd), and elimination half-life (t1/2 beta) of VP16 were, respectively, 22.8 +/- 1.0 (SE) ml/min/m2, 11.4 +/- 0.8 liters/m2, and 5.6 +/- 0.4 h. In patients with renal insufficiency Clp was 12.8 +/- 1.1 ml/min/m2, Vd was 20.8 +/- 4.9 liters/m2, and t1/2 beta was 19.2 +/- 4.7 h. A statistically significant correlation (P = 0.0000001) was found between VP16 Clp and creatinine clearance. In 12 of 15 patients with abnormal liver tests Clp, Vd, and t1/2 beta were, respectively, 27.9 +/- 2.7 ml/min/m2, 12.4 +/- 1.5 liters/m2, and 5.4 +/- 0.6 h and are thus similar to those of the control group. In the other three cases with abnormal liver function VP16 plasma levels were very low. In these cases VP16 t1/2 beta values were similar (5.1, 4.4, and 5.1 h) whereas Clp values (320, 87, and 96 ml/min/m2) and Vd values (142, 33, and 42 liters/m2) were much larger than in controls. These results suggest that VP16 doses should be reduced in patients with renal function impairment but not necessarily in patients with liver impairment. The high VP16 Vd and Clp values found in a subset of patients with liver impairment require further elucidation.
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Etopósido/metabolismo , Enfermedades Renales/metabolismo , Hepatopatías/metabolismo , Podofilotoxina/análogos & derivados , Adulto , Anciano , Femenino , Humanos , Masculino , Tasa de Depuración Metabólica , Persona de Mediana EdadRESUMEN
IDN5109 is a new taxane, derived from 14beta-hydroxy-10-deacetylbaccatin III, selected for its lack of cross-resistance in tumor cell lines expressing the multidrug resistant phenotype. Because, unlike paclitaxel, IDN5109 is a poor substrate for P-glycoprotein, we hypothesized that IDN5109 given p.o. could improve bioavailability compared with paclitaxel. Here, we studied the p.o. and i.v. pharmacokinetics of IDN5109 together with its antitumor activity. Using a high-performance liquid chromatography method, the bioavailability of IDN5109 was determined to be 48% after oral delivery. IDN5109 given p.o. was highly active against the two human ovarian carcinoma xenografts 1A9 and HOC18 (90-100% tumor regressions) and showed significant activity on the paclitaxel-resistant MNB-PTX1 xenograft (10% tumor regressions). The p.o. administration was as active as the i.v. route at doses reflecting the pharmacokinetic data. IDN5109 is the first taxane with good oral bioavailability and potent antitumor activity and represents a potential candidate for clinical investigation.
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Antineoplásicos/farmacocinética , Hidrocarburos Aromáticos con Puentes/farmacocinética , Neoplasias Ováricas/tratamiento farmacológico , Paclitaxel/análogos & derivados , Taxoides , Administración Oral , Animales , Disponibilidad Biológica , Hidrocarburos Aromáticos con Puentes/administración & dosificación , Hidrocarburos Aromáticos con Puentes/uso terapéutico , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Ratones , Ratones DesnudosAsunto(s)
Vacunas contra la COVID-19/efectos adversos , COVID-19/prevención & control , Nanotecnología , SARS-CoV-2/efectos de los fármacos , Anafilaxia/inducido químicamente , COVID-19/inmunología , COVID-19/patología , COVID-19/virología , Hipersensibilidad a las Drogas/patología , Hipersensibilidad a las Drogas/virología , Humanos , Polietilenglicoles/efectos adversos , SARS-CoV-2/patogenicidad , Vacunación/efectos adversosRESUMEN
Mass Spectrometry Imaging (MSI) is a widespread technique used to qualitatively describe in two dimensions the distribution of endogenous or exogenous compounds within tissue sections. Absolute quantification of drugs using MSI is a recent challenge that just in the last years has started to be addressed. Starting from a two dimensional MSI protocol, we developed a three-dimensional pipeline to study drug penetration in tumors and to develop a new drug quantification method by MALDI MSI. Paclitaxel distribution and concentration in different tumors were measured in a 3D model of Malignant Pleural Mesothelioma (MPM), which is known to be a very heterogeneous neoplasm, highly resistant to different drugs. The 3D computational reconstruction allows an accurate description of tumor PTX penetration, adding information about the heterogeneity of tumor drug distribution due to the complex microenvironment. The use of an internal standard, homogenously sprayed on tissue slices, ensures quantitative results that are similar to those obtained using HPLC. The 3D model gives important information about the drug concentration in different tumor sub-volumes and shows that the great part of each tumor is not reached by the drug, suggesting the concept of pseudo-resistance as a further explanation for ineffective therapies and tumors relapse.
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Antineoplásicos Fitogénicos/análisis , Neoplasias/diagnóstico por imagen , Paclitaxel/análisis , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Animales , Antineoplásicos Fitogénicos/metabolismo , Antineoplásicos Fitogénicos/uso terapéutico , Línea Celular Tumoral , Cromatografía Líquida de Alta Presión , Femenino , Humanos , Imagenología Tridimensional , Mesotelioma/química , Mesotelioma/diagnóstico por imagen , Mesotelioma/tratamiento farmacológico , Mesotelioma/patología , Nanopartículas del Metal/química , Ratones , Ratones Desnudos , Neoplasias/química , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Paclitaxel/metabolismo , Paclitaxel/uso terapéutico , Titanio/química , Trasplante HeterólogoRESUMEN
PURPOSE: To determine the bioavailability (F) and the pharmacokinetic profile of both etoposide and its prodrug, etoposide phosphate, after oral and intravenous administration of etoposide phosphate, and to determine the maximum-tolerable dose (MTD) of oral etoposide phosphate administered daily for 5 consecutive days every 3 weeks. In addition, we sought to develop and validate two limited-sampling models (LSMs) to predict the etoposide area under the curve (AUC) 24 hours after administration of oral and intravenous etoposide phosphate. PATIENTS AND METHODS: In the F part of the study, patients were assessed for pharmacokinetic studies after one oral and one intravenous administration of the same dose of etoposide phosphate. Etoposide phosphate and etoposide plasma concentrations were assayed by high-performance liquid chromatography (HPLC). To develop LSMs after oral and intravenous administration, patients were randomized between the training and validation data sets. In the phase I part of the study, which followed the F part, the dose of etoposide phosphate was escalated from 50 mg/m2/d for etoposide equivalents for 5 days to 220 mg/m2/d for 5 days. RESULTS: Forty adult patients with solid tumors or lymphoma entered the study and 35 were assessable for toxicity. The MTDs were defined as 175 mg/m2 and 220 mg/m2 in previously treated and untreated patients, respectively. Neutropenia was dose-limiting, with high interpatient variability. Within 15 minutes after intravenous administration, etoposide phosphate was no longer detectable in plasma, and it was never detectable after oral administration. Plasma concentrations and pharmacokinetic parameters of etoposide following etoposide phosphate were comparable to those reported for etoposide. The relative F (mean +/- SD) of etoposide after oral etoposide phosphate was 76 +/- 27%, with a range of 37% to 144%. CONCLUSION: The clinical and pharmacokinetic results of this study confirm the prodrug hypothesis of etoposide phosphate. Although firm conclusions cannot be drawn, the F of oral etoposide phosphate seems to be comparable to or only slightly better than that of oral etoposide.
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Etopósido/análogos & derivados , Compuestos Organofosforados/administración & dosificación , Compuestos Organofosforados/farmacocinética , Profármacos/administración & dosificación , Profármacos/farmacocinética , Administración Oral , Adulto , Anciano , Análisis de Varianza , Disponibilidad Biológica , Esquema de Medicación , Etopósido/administración & dosificación , Etopósido/efectos adversos , Etopósido/sangre , Etopósido/farmacocinética , Humanos , Inyecciones Intravenosas , Linfoma/sangre , Persona de Mediana Edad , Modelos Biológicos , Neoplasias/sangre , Neutropenia/inducido químicamente , Compuestos Organofosforados/efectos adversos , Compuestos Organofosforados/sangre , Profármacos/efectos adversosRESUMEN
We aimed to evaluate the pharmacokinetics and pharmacodynamics of etoposide given chronically by the p.o. route to patients with small cell and non-small cell lung cancer. Single daily p.o. doses of 100 mg etoposide were given for 21 consecutive days every 4 weeks to 39 previously untreated patients with small cell lung cancer and 10 patients with non-small cell lung cancer. Bioavailability was studied after one i.v. and one p.o. dose of 100 mg etoposide given 48 h before and on day 1 of treatment, respectively. Etoposide plasma levels were measured using the HPLC method. Inter- and intrapatient variability of the area under the curve of the concentration versus time (AUC) during the first cycle were evaluated using a limited sampling model; the variability of etoposide plasma concentrations (Ecs) during the first cycle was assessed by weekly blood samples taken 24 h after dosing. The overall bioavailability of etoposide (mean +/- SD) was 67% +/- 22% and was not affected by fasting. A much higher inter- than intrapatient variability of both the AUC and 24-h Ec determined on days 8, 15, and 22 was found. Neutropenia was dose limiting and of varying degrees (mean +/- SD of absolute neutrophil count nadir at the first cycle: 1.5 +/- 1.2 x 10(3)/microliter). Neutropenia WHO grade >/=3 occurred in 38% of the patients after the first cycle. Pharmacodynamic analyses showed a significant relationship between the mean 24-h Ec and neutropenia, expressed as log- of absolute neutrophil count nadir or as a relative decrease of neutrophils. A correlation between a critical value of mean 24-h Ec (0.34 microgram/ml) and a high probability of achieving a greater than 80% decrease in absolute neutrophil count was found. Two pharmacodynamic models (one previously described and one developed in this study) were used to evaluate the possibility of predicting neutropenia on the basis of individual etoposide pharmacokinetics and baseline absolute neutrophil count. Pharmacokinetic studies have shown a high interpatient variability and a relatively low intrapatient variability of AUC and 24-h Ec. The application of the pharmacodynamic models and mean 24-h Ec cutoff values has proven statistically valid to predict the occurrence of severe neutropenia. However, it remains to be demonstrated in a prospective manner whether the application of pharmacokinetic/ pharmacodynamic knowledge can improve the overall therapeutic outcome of chronic p.o. treatment with etoposide.
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Antineoplásicos Fitogénicos/farmacocinética , Carcinoma de Pulmón de Células no Pequeñas/sangre , Carcinoma de Células Pequeñas/sangre , Etopósido/farmacocinética , Neoplasias Pulmonares/sangre , Administración Oral , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/efectos adversos , Disponibilidad Biológica , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Células Pequeñas/tratamiento farmacológico , Etopósido/administración & dosificación , Etopósido/efectos adversos , Femenino , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Neutropenia/inducido químicamente , Trombocitopenia/inducido químicamenteRESUMEN
A novel taxane (IDN 5109), originally selected for its ability to overcome P-glycoprotein-mediated drug resistance, is characterized by an improved preclinical profile in terms of efficacy and tolerability. Because P-glycoprotein may critically influence intestinal absorption and oral bioavailability of taxanes, the purpose of the study was to evaluate the bioavailability, the pharmacokinetic behavior, and the antitumor activity of the new taxane after oral administration. A comparative study of antitumor activity of Taxol and IDN 5109 given orally was performed in a human breast carcinoma model, MX-1, which is highly responsive to i.v. treatment with both of the taxanes. In contrast to Taxol, which was completely ineffective after administration to MX-1-bearing mice, oral IDN 5109 exhibited an activity comparable with that of i.v. treatment (ie., 100% cures). Again, the maximal tolerated doses were comparable (90 mg/kg, every 4 days for four doses) after i.v. and oral treatment. Three other tumor models (LoVo, IGROV/DDP, and U87) with a variable sensitivity to the drug were used to compare the antitumor effects of i.v. and oral treatment with IDN 5109. The efficacy after oral administration was only slightly lower than that found after i.v. treatment at equivalent doses; but optimal effects were comparable likely as a consequence of the long (>6 h) terminal half-life of oral IDN 5109. The bioavailability of IDN 5109 assessed by comparing area-under-the-curve values after oral and i.v. administrations was approximately 50%. The oral efficacy of the novel taxane, likely related to the inability of the P-glycoprotein to recognize the drug, which allowed an adequate intestinal absorption, is a unique feature among the taxanes and may represent a pharmacological breakthrough in their clinical use.
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Hidrocarburos Aromáticos con Puentes/farmacocinética , Hidrocarburos Aromáticos con Puentes/uso terapéutico , Taxoides , Administración Oral , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Área Bajo la Curva , Disponibilidad Biológica , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Inyecciones Intravenosas , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Paclitaxel/análogos & derivados , Paclitaxel/farmacocinética , Paclitaxel/uso terapéutico , Trasplante Heterólogo , Resultado del Tratamiento , Células Tumorales CultivadasRESUMEN
This report reviews published information on the clinical pharmacokinetics of antitumour agents in patients with liver dysfunction, associated with primary liver disease or liver metastases. Information was available for anthracyclines and their related compounds, antimetabolites, cyclophosphamide, vinca alkaloids, taxanes and epipodophyllotoxins. Changes in the pharmacokinetic profile or metabolism in patients with mild or severe hepatobiliary dysfunction are described and the relationships between serum levels, parameters employed for measuring hepatic function and toxic or therapeutic effects are examined. Current knowledge of the pharmacokinetics of antineoplastic agents in liver disease is far from complete, mostly obtained in small numbers of non-homogeneous patients often presenting only moderate liver dysfunction, and empirical guidelines for dose assessment are still largely applied in clinical practice. Because of the complex pathophysiological mechanisms of liver insufficiency in cancer patients, there is still doubt whether endogenous markers are useful. Although caution in treating cancer patients with liver insufficiency is compulsory, for most compounds there seems no need to recommend dose reductions for moderate impairment. However, for the tubulin acting agents, vincristine, vinblastine and possibly for paclitaxel and docetaxel, there is strong evidence that dose adjustment is mandatory in order to avoid excessive neutropenia and neurotoxicity.
Asunto(s)
Antraciclinas/farmacocinética , Antineoplásicos/farmacocinética , Hepatopatías/metabolismo , Antimetabolitos Antineoplásicos/farmacocinética , Ciclofosfamida/farmacocinética , Relación Dosis-Respuesta a Droga , Doxorrubicina/farmacocinética , Humanos , Paclitaxel/farmacocinética , Podofilotoxina/farmacocinética , Alcaloides de la Vinca/farmacocinéticaRESUMEN
The combination in clinical trials of taxoids with doxorubicin has focused attention on possible drug interactions. One specific finding requiring explanation is the relative lack of cardiotoxicity of the docetaxel (Taxotere; Rhône-Poulenc Rorer, Antony, France)/doxorubicin combination compared with that of the paclitaxel/doxorubicin combination. Data in mice demonstrate that epirubicin concentrations in cardiac tissue 24 hours after treatment are approximately doubled by the coadministration of paclitaxel. This effect appears to be less marked with docetaxel administered in its normal polysorbate vehicle or when the drug is given in Cremophor EL (Sigma, St Louis, MO). Both Cremophor EL or polysorbate appear to cause an increase in epirubicin tissue levels, although the levels were less than those seen with paclitaxel. Pharmacokinetic data from women being treated with combination therapy for advanced breast cancer demonstrate that the administration of docetaxel following doxorubicin does not alter doxorubicin's area under the plasma concentration-time, curve, maximum plasma concentration, or time until maximum plasma concentration is reached. However, the area under the curve of docetaxel is significantly increased by the prior administration of doxorubicin. These findings may explain both the low cardiotoxicity and the high clinical efficacy of the docetaxel/doxorubicin combination. Phase I clinical trials of combinations in which docetaxel was used together with vinorelbine, ifosfamide, or 5-fluorouracil have shown no evidence of relevant pharmacokinetic interactions.
Asunto(s)
Antibióticos Antineoplásicos/farmacocinética , Antineoplásicos Fitogénicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Paclitaxel/farmacocinética , Taxoides , Animales , Antraciclinas/administración & dosificación , Antraciclinas/farmacocinética , Antibióticos Antineoplásicos/administración & dosificación , Antineoplásicos Fitogénicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Área Bajo la Curva , Neoplasias de la Mama/tratamiento farmacológico , Docetaxel , Doxorrubicina/administración & dosificación , Doxorrubicina/farmacocinética , Interacciones Farmacológicas , Epirrubicina/administración & dosificación , Epirrubicina/farmacocinética , Femenino , Humanos , Ratones , Paclitaxel/administración & dosificación , Paclitaxel/análogos & derivadosRESUMEN
Temozolomide (8-carbamoyl-3-methylimidazo[5,1d]-1,2,3,5-tetrazin-4-(3H)-one), an experimental antitumor agent which spontaneously decomposes to 5-(3,3-methyl-1-triazeno) imidazole-4-carboxamide, the active metabolite of the antineoplastic drug DTIC, causes erythroid differentiation of K562 leukemia cells. The increase in epsilon and gamma globin gene expression after temozolomide treatment does not appear to be due to drug-induced hypomethylation of the genes. In other genes containing many methylated sequences such as the proto-oncogenes c-myc and C-Ha-ras, temozolomide caused no detectable change in methylation. In contrast, in the same genes 5-aza-2'-deoxycytidine induced hypomethylation. Temozolomide caused DNA alkali-labile sites and an arrest of the cell cycle in G2 phase. Ethazolastone (its 3-ethylimidazo analogue) which does not cause differentiation of K562 produced no significant DNA damage and G2 phase blockade. DNA damage rather than hypomethylation may be responsible for induction of differentiation.
Asunto(s)
ADN de Neoplasias/efectos de los fármacos , Dacarbazina/análogos & derivados , Genes ras/efectos de los fármacos , Proto-Oncogenes/efectos de los fármacos , Células Tumorales Cultivadas/efectos de los fármacos , Northern Blotting , Ciclo Celular/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Daño del ADN , Dacarbazina/metabolismo , Dacarbazina/farmacología , Citometría de Flujo , Humanos , Cinética , Leucemia Mielógena Crónica BCR-ABL Positiva , Metilación , Temozolomida , Células Tumorales Cultivadas/citologíaRESUMEN
The pharmacokinetics of cis-diamminedichloro platinum(II) (cisplatin), given as a continuous infusion with concurrent radiotherapy to patients with locally advanced inoperable non-small-cell lung carcinoma, was investigated in 16 cases. The regimen, repeated for 6 consecutive weeks, consisted of weekly 10-Gy radiotherapy given in five fractions from Monday to Friday, and concurrent 100-h infusion of cisplatin delivered at a daily dose of 4 mg/m2 by a central venous catheter and a portable pump. Throughout the weeks of therapy the platinum levels were determined in plasma and in ultrafiltered plasma by respectively inductively coupled plasma atomic emission spectrometry and inductively coupled plasma mass spectrometry. Mean levels of platinum in plasma ([Pt]tot ) increased from the 1st to the 6th week of infusion, while mean levels of platinum in ultrafiltered plasma ([Pt]uf), 110 microg/l, showed no marked variation throughout the therapy. [Pt]uf ranged from 16% to 22% of the total Pt. Mean levels of Pt in ultrafiltered plasma were of the same order of magnitude as those found to be active in vitro as radiopotentiators. Pt decay levels were measured for 24 h at the end of the 1st and 5th weeks of infusion, allowing the calculation of the Pt half-life and the area under the decay curves. The mean value of the area under the decay curve, plotting [Pt]tot against time (AUC), in the range 0-24 h from the end of the 5th week of infusion, was about twice that from the end of the 1st week; by contrast, the mean AUC values did not vary for the [Pt]uf against time curves. The mean values of the alpha half-life of Pt in the ultrafiltered plasma were in accordance with those published in the literature; however, an unexpected very long beta half-life was found (more than 100 h). Thus it was suggested that Pt species other than free cisplatin were present in the ultrafiltered plasma; such species probably involve metal bound to low-molecular-mass proteins. Throughout the therapy, the toxic effects in all patients were negligible, and 75% of them had an objective locoregional reduction of disease. In only 2 cases was progression of disease observed within the irradiated area. On the basis of these data, it can be concluded that cisplatin at a level of 110 microg/l in the ultrafiltered plasma, in the reported scheme of continuous intravenous infusion, has an enhancing effect on radiation and avoids concentration peaks of platinum not bound to protein.
Asunto(s)
Antineoplásicos/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/terapia , Cisplatino/farmacocinética , Neoplasias Pulmonares/terapia , Adulto , Anciano , Cisplatino/administración & dosificación , Terapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The metabolic effects of TPN were studied in a selected group of trauma patients. Nineteen patients were randomly divided into two groups: the first was treated with glucose and insulin, the second with glucose, insulin and amino acids. Each patient in both groups received TPN isocaloric with respect to daily energy output and the treatment lasted five days. Each group was further divided into two subsets (severe or moderate catabolism) according to fasting energy output with respect to the expected energy expenditure. During the acute flow phase, both in moderate as well as in severe catabolism, glucose and insulin were effective for protein sparing; the maximum protein sparing effect was reached when giving a caloric intake equal to 130% of daily energy output. Glucose, insulin and amino acids were effective in replacement of nitrogen losses. In moderately catabolic patients nitrogen balance was significantly better than in severely catabolic patients. This study shows that early and short-term TPN is effective in controlling the flow phase of trauma. Glucose and insulin appear to be the determinants of the protein sparing effect when given in amounts equal to those needed; amino acids provided protein replacement when given in amounts equal to about 20% of energy output. Energy supply higher than 120-130% of daily energy output does not increase protein sparing and protein replacement, the only effect being a further increase in metabolism, which is possibly dangerous in critically ill patients.