RESUMO
The bioavailability of propranolol from a matrix-in-cylinder system for sustained drug delivery, consisting of a hot-melt extruded ethylcellulose pipe surrounding a drug-containing HPMC-Gelucire 44/14 core, was determined. An oral dose of 80 mg propranolol hydrochloride was administered to healthy volunteers (n = 10) in a randomized cross-over study design either as a commercial pellet formulation (Inderal retard mitis) or as a matrix-in-cylinder system. The influence of concomitant food intake on drug release from the matrix-in-cylinder system was also studied. During the first 10 h after administration, the matrix-in-cylinder system resulted in similar plasma levels as the reference formulation Inderal. The concomitant intake of a high-fat, high-calorie breakfast did not cause dose-dumping. Between 10 h and 24 h after administration of the matrix-in-cylinder system, a remarkable increase of the propranolol plasma levels was noticed (compared to Inderal). This effect was even more pronounced under fed conditions. The matrix-in-cylinder system had a relative bioavailability of 156% (fasted conditions) and 222% (fed conditions) compared to the marketed reference product. In order to elucidate the origin of this increased bioavailability, Caco-2 experiments and dog lymph studies were performed. However, none of these experiments was able to provide a conclusive answer.
Assuntos
Antagonistas Adrenérgicos beta/administração & dosagem , Antagonistas Adrenérgicos beta/farmacocinética , Sistemas de Liberação de Medicamentos , Propranolol/administração & dosagem , Propranolol/farmacocinética , Adolescente , Adulto , Algoritmos , Animais , Área Sob a Curva , Disponibilidade Biológica , Transporte Biológico Ativo/fisiologia , Biotransformação , Células CACO-2 , Estudos Cross-Over , Excipientes , Feminino , Interações Alimento-Droga , Humanos , Técnicas In Vitro , Absorção Intestinal , Lactose/análogos & derivados , Masculino , Metilcelulose/análogos & derivados , Pessoa de Meia-Idade , Oxazinas , Polietilenoglicóis , RatosRESUMO
Ecteinascidin 743 (ET-743) is a new marine-derived agent with promising activity against a number of solid tumours. In four human tumour cell lines, the interaction between ET-743 and radiation was investigated in relation to the effects of ET-743 on the cell cycle, in vitro. Cell survival was measured based on quantitative staining of cellular protein by sulforhodamine B. A 24 h treatment with ET-743 before radiation resulted in a moderate increase in radiosensitivity in three out of four cell lines. Dose enhancement factors > or =1.8 were observed for concentrations resulting in 52, 46 and 30% cell kill in ECV304, H292 and CAL-27, respectively, whereas in A549 no radiosensitisation was observed (no significant increase in radiosensitivity). According to the combination index analysis, synergism was observed only in ECV304 and CAL-27 cells. A 24 h incubation with ET-743 resulted in a concentration-dependent G2/M block, which might explain the moderate radiosensitising effects in ECV304 and H292. The lack of radiosensitisation in A549 might be due to the S phase delay preceding the G2/M block at the moment of radiation, which only occurred in this cell line. In conclusion, ET-743 has moderate cell line-dependent radiosensitising properties; however, only when cytotoxic concentrations of ET-743 are used. In one of the four cell lines tested, no radiosensitisation was observed.
Assuntos
Antineoplásicos Alquilantes/farmacologia , Carcinoma/terapia , Ciclo Celular/efeitos dos fármacos , Dioxóis/farmacologia , Isoquinolinas/farmacologia , Radiossensibilizantes/farmacologia , Carcinoma/tratamento farmacológico , Carcinoma/radioterapia , Ciclo Celular/efeitos da radiação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Terapia Combinada , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/terapia , Tetra-Hidroisoquinolinas , Neoplasias da Língua/tratamento farmacológico , Neoplasias da Língua/radioterapia , Neoplasias da Língua/terapia , Trabectedina , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/radioterapia , Neoplasias da Bexiga Urinária/terapiaRESUMO
In this study, the radiosensitising effect of different concentrations of gemcitabine and the combination of gemcitabine/radiotherapy with the rescue agent amifostine was investigated in different human tumour cell lines. The cells were treated with gemcitabine (0-8 nM) for 24 h prior to radiation (0-8 Gy). Amifostine (ami) and alkaline phosphatase (AP) were added 30 min before radiation. Cell survival was determined 7 or 8 days after radiation treatment by the sulforhodamine B (SRB) test. For ECV304 cells, the dose enhancement factor (DEF) varied from 1.39 to 2.98 after treatment with 1-6 nM gemcitabine. FaDu, H292, A549 and CAL-27 seemed to be less sensitive, with DEFs ranging from 1.02 to 2.67. These cells were also less sensitive to the cytotoxic effects of single-agent gemcitabine. Amifostine with AP clearly showed a protective effect in combination with gemcitabine/radiotherapy. In H292 cells, the protection factor (PF) of amifostine after treatment with gemcitabine and radiotherapy varied from 1.64 to 1.86. In ECV304 cells, the PF varied from 2.20 to 2.29. In conclusion, a clear concentration- and cell line-dependent radiosensitising effect of gemcitabine was observed in all cell lines. Amifostine with AP showed protection against the radiosensitising effect of gemcitabine. If the protection in vivo indeed occurs selectively in normal tissues, then amifostine could prevent or strongly minimise the increased toxicity resulting from the radiosensitising effect of the combination of gemcitabine and radiotherapy, without influencing the antitumour effect.
Assuntos
Amifostina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Neoplasias/tratamento farmacológico , Radiossensibilizantes/uso terapêutico , Fosfatase Alcalina/farmacologia , Terapia Combinada , Relação Dose-Resposta a Droga , Interações Medicamentosas , Humanos , Dose Letal Mediana , Neoplasias/radioterapia , Células Tumorais Cultivadas , GencitabinaRESUMO
Amifostine (Ethyol, WR-2721) is in use in the clinic as a protector against platinum-induced toxicities. We have previously reported that amifostine induced a potentiation of the antitumour activity of carboplatin in human ovarian cancer xenografts. An influence of amifostine on the pharmacokinetics of carboplatin, resulting in higher platinum concentrations in plasma and tissues of the tumour-bearing nude mice, was thought to be the cause of enhancement of the antitumour activity. Therefore, the pharmacokinetics of cisplatin were investigated in tumour-bearing nude mice treated with cisplatin alone or in combination with amifostine. A significant increase in the area under the curve (AUC) of the total platinum concentration in mice treated with amifostine was only observed in the kidney (from 355 to 398 nmol h/g), whereas in the other tissues and plasma no significant changes were measured. The selective protection of normal tissues by amifostine was confirmed by a decrease in the AUC of the cisplatin-DNA adduct levels in normal tissues. The decrease was only significant in the liver (282-240 fmol h/microgram DNA), whereas in tumour tissue a slight increase in the AUC of the cisplatin-DNA adducts could be detected (91.3-110.1 fmol h/microgram DNA). The minor influence of amifostine on the pharmacokinetics of cisplatin may be the reason why amifostine did not potentiate the antitumour activity of cisplatin. The influence of amifostine on cisplatin-DNA adduct levels in normal tissues versus tumour tissues is further evidence for the usefulness of this toxicity modulator in cancer patients.
Assuntos
Amifostina/administração & dosagem , Antineoplásicos/farmacocinética , Cisplatino/farmacocinética , Neoplasias Ovarianas/metabolismo , Protetores contra Radiação/administração & dosagem , Animais , Cisplatino/administração & dosagem , Combinação de Medicamentos , Sinergismo Farmacológico , Feminino , Humanos , Rim/metabolismo , Fígado/metabolismo , Camundongos , Transplante de Neoplasias , Platina/análise , Transplante HeterólogoRESUMO
The pharmacokinetics of cisplatin was investigated in 13 patients receiving 18 courses of cisplatin alone or in combination with amifostine to investigate the influence of amifostine (WR 2721; Ethyol) on the pharmacokinetics of cisplatin. Cisplatin was administered as a 1-h i.v. infusion, whereas amifostine was given i.v. over 15 min just before the cisplatin infusion. An increase in the final half-life of ultrafilterable platinum was observed after treatment with cisplatin and amifostine (t1/2, 0.77 +/- 0.10 h; n = 8), compared to cisplatin alone (t1/2, 0.57 +/- 0.15 h; n = 8). This might be caused by an influence of amifostine on the kidney function, because an increase in the serum creatinine levels was also observed 24 h after treatment with cisplatin and amifostine (13.8 +/- 12.6%; n = 9), which was not observed after treatment with cisplatin alone (-0.1 +/- 6.8%; n = 9). Surprisingly, the final half-life of unchanged cisplatin did not increase, but even showed a slight decrease after treatment with amifostine. In vitro data would suggest that this might be due to a chemical interaction between cisplatin and amifostine. Because the AUC values of ultrafilterable platinum and unchanged cisplatin did not change significantly and no change in Pt-DNA adduct (Pt-GG) levels in leukocytes was observed upon addition of amifostine in the treatment schedule, the change in the pharmacokinetics of cisplatin is most probably of minor importance and has no significant impact on the efficacy of cisplatin, as already confirmed by clinical studies.
Assuntos
Amifostina/farmacologia , Antineoplásicos/farmacocinética , Cisplatino/farmacocinética , Neoplasias/metabolismo , Protetores contra Radiação/farmacologia , Adulto , Idoso , Antineoplásicos/sangue , Antineoplásicos/uso terapêutico , Cisplatino/sangue , Cisplatino/uso terapêutico , Adutos de DNA/sangue , Interações Medicamentosas , Feminino , Meia-Vida , Hemofiltração , Humanos , Leucócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/tratamento farmacológico , Platina/sangueRESUMO
The pharmacokinetics of the cytoprotective agent amifostine (EthyolR; WR 2721) and its main metabolites (WR 1065 and the disulphides) were studied in patients participating in two phase I trials concerning carboplatin or cisplatin in combination with amifostine. Patients were treated with a single dose or three doses of amifostine (740 or 910 mg/m2). The single or first dose was given as a 15 min i.v. infusion just before administration of the chemotherapeutic agent. The additional two infusions were administered 2 and 4 h thereafter. Amifostine was rapidly cleared from the plasma, due to, at least in part, the fast conversion into WR 1065. A biphasic decrease with a final half-life of 0.8 h was observed. The active metabolite WR 1065 was cleared from the plasma with a final half-life of 7.3 +/- 3.6 h. The short initial half-life of WR 1065 can be explained by its fast uptake in tissues and the formation of disulphides. The disulphides were cleared with a final half-life of 8.4-13.4 h and were detectable for at least 24 h after treatment. They may serve as an exchangeable pool of WR 1065. The amifostine peak values at the end of each 15 min infusion did not accumulate in the multiple dosing schedule. For WR 1065 a trend towards an increase in the peak levels was observed [C1,max: 47.5 +/- 11.9 microM, C2,max: 79.0 +/- 13.2 microM, C3,max: 84.8 +/- 15.1 microM, (n = 6)], whereas a trend towards a small decrease was observed for the peak levels of the disulphides [C1,max: 184.2 +/- 12.6 microM, C2,max: 175.0 +/- 23.7 microM, C3,max: 166.0 +/- 17.2 microM, (n = 6)]. This latter finding might suggest a saturation of the disulphide formation or a change in the uptake or elimination of WR 1065, which would result in higher WR 1065 levels in plasma and tissues, after multiple doses of amifostine.
Assuntos
Amifostina/farmacocinética , Dissulfetos/sangue , Mercaptoetilaminas/farmacocinética , Adulto , Amifostina/uso terapêutico , Antineoplásicos/uso terapêutico , Carboplatina/uso terapêutico , Cisplatino/uso terapêutico , Quimioterapia Combinada , Feminino , Meia-Vida , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
A high-performance liquid chromatographic (HPLC) method was developed for the combined analysis of the chemoprotective agent, amifostine, its active metabolite, WR 1065, and the (symmetrical and mixed) disulfides of WR 1065 in plasma. These three compounds were quantified by measuring WR 1065 after three different sample pretreatment procedures. During these procedures, amifostine and the disulfides were quantitatively converted into WR 1065, by incubating the sample either at a low pH or in the presence of dithiothreitol, respectively. The resulting amounts of WR 1065 were determined by HPLC with electrochemical detection (Au electrode, + 1.00 V). The lower limit of quantitation of WR 1065 was 0.15 microM. The within-day and between-day precision were < or =4.4 and < or =8.2% for WR 1065, < or =4.9 and < or =13.1% for amifostine and < or =8.5 and < or =5.5% for the disulfides, respectively. The within-day and between-day accuracy ranged from 97.2 to 109.8% and from 97.6 to 101.5% for WR 1065, from 88.3 to 110.7% and from 99.4 to 101.5% for amifostine and from 99.2 to 110.2% and from 103.3 to 104.9% for the disulfides, respectively. This method is superior to other described methods due to its simple and relatively rapid analysis of all three compounds in one system. Furthermore, it is at least as sensitive as earlier reported methods for one of the compounds and the application of the gold electrode requires only minor maintenance. Therefore, this method is very suitable for pharmacokinetic studies of amifostine and its metabolites. As an example, the plasma concentrations of amifostine, WR 1065 and the disulfides are shown in a patient after receiving an i.v. dose of 740 mg/m2 amifostine.
Assuntos
Amifostina/análise , Dissulfetos/sangue , Mercaptoetilaminas/sangue , Protetores contra Radiação/análise , Cromatografia Líquida de Alta Pressão , Eletroquímica , Humanos , Reprodutibilidade dos TestesRESUMO
We showed previously that amifostine (WR 2721; Ethyol), a protector against carboplatin-induced toxicities, changed the pharmacokinetics of carboplatin in tumor-bearing nude mice. In the present study, the influence of amifostine on the pharmacokinetics of carboplatin was studied in patients when carboplatin was given in combination with three doses of amifostine, administered just before the carboplatin infusion and 2-4 h thereafter. Compared with a control group of patients who received carboplatin alone, the patients receiving the combination had a longer final half-life of ultrafilterable platinum species [5.0 h versus 3.5 h in patients with a normal creatinine clearance (Clcr > 80 ml/min); 5.6 h versus 4.2 h in those with an impaired renal function (50 < Clcr < 80 ml/min)]. This might be caused by an influence of amifostine on the renal clearance of carboplatin as suggested by a transient increase in serum creatinine levels 24 h after treatment in the patients receiving the combination (mean +/- SD: 34.1% +/- 17.2% versus -1.8% +/- 16.5% in patients treated with carboplatin alone). The impact of these changes on the area under the concentration-time curves of the ultrafilterable platinum species was hardly noticeable in patients with a normal renal function but led to a significant increase in patients with an impaired renal function (395 +/- 59 micromol/l.h versus 280 +/- 62 micromol/l.h in patients receiving carboplatin alone). The clinical relevance of this influence is unclear, although theoretically it may result in an increase in the efficacy of carboplatin, as has been observed in tumor-bearing nude mice.
Assuntos
Amifostina/uso terapêutico , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Carboplatina/efeitos adversos , Carboplatina/farmacocinética , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/sangue , Carboplatina/sangue , Relação Dose-Resposta a Droga , Meia-Vida , Rim/efeitos dos fármacos , Testes de Função Renal , Taxa de Depuração Metabólica , Camundongos , Camundongos Nus , Neoplasias/sangueRESUMO
We have previously reported that amifostine potentiates the anti-tumour activity of carboplatin in mice. The present study was carried out in well-established human ovarian cancer xenografts OVCAR-3, A2780 and FMa grown subcutaneously in the nude mouse. It was found that a single dose of amifostine resulted in a higher increase in the anti-tumour activity of carboplatin than three doses of amifostine. A single dose of amifostine increased the AUC (area under the curve) values of total platinum in plasma ultrafiltrate (30.1 vs 18.2 microM x h), liver (307.7 vs 236.4 nmol g(-1) x h), kidney (500.8 vs 368.3 nmol g(-1) x h) and OVCAR-3 tumour tissue (184.0 vs 146.8 nmol g(-1) x h). Despite this increase in total platinum, a decrease in platinum (Pt)-DNA adduct levels was observed in liver, kidney and bone marrow, which was significant in liver. In tumour tissue an insignificant increase in Pt-DNA adduct levels, specifically the Pt-GG adduct, was observed after treatment with a single dose of amifostine, which may explain the increase in anti-tumour activity. The increase in the AUC of total platinum was probably caused by a reduction in body temperature, which was most severe after three doses of amifostine. The extreme hypothermia may be the reason that three doses of amifostine resulted in less potentiation of the efficacy of carboplatin.
Assuntos
Amifostina/farmacologia , Antineoplásicos/farmacocinética , Carboplatina/farmacologia , Protetores contra Radiação/farmacologia , Animais , Temperatura Corporal/efeitos dos fármacos , Adutos de DNA/biossíntese , Esquema de Medicação , Sinergismo Farmacológico , Feminino , Humanos , Camundongos , Camundongos Nus , Transplante de Neoplasias , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Platina/metabolismo , Transplante HeterólogoRESUMO
Amifostine (Ethyol) administered to cancer patients is rapidly cleared from plasma by a biphasic decay with an alpha half-life (T1/2 alpha) of 0.88 min and a T1/2 beta of 8.8 min. The result is that more than 90% of the drug has disappeared from the plasma compartment 6 min after intravenous (i.v.) administration. Only approximately 1% of the dose appears in the ascites. Animal studies indicate that amifostine is primarily excreted in urine-approximately 6% of the dose is excreted in the urine as amifostine and its metabolites WR-1065 and disulphides-which means that a large percentage of the dose is taken up by the tissues. Maximal tissue concentrations of WR-1065 and the disulphides were obtained between 10 and 30 min after an intraperitoneal injection of amifostine in mice, with the lowest concentrations in tumour tissues. Because WR-1065 gives protection to normal tissues rather than rescue, the pharmacokinetic data indicate that amifostine must be given shortly before administration of the cytostatic drug or radiation from which protection is required. For these reasons, amifostine is given to patients as a 15-min i.v. infusion before cisplatin and carboplatin to protect against their dose-limiting toxicities. In some regimens carboplatin is combined with three doses of amifostine because of the high concentration of the active carboplatin species during the first 4 h after administration. When carboplatin was administered as a 15-min i.v. infusion of 400 mg/m2 and amifostine as a 15-min i.v. infusion of 740 mg/m2 just before and 2 and 4 h after carboplatin, the area under the plasma concentration-time curve for ultrafilterable platinum increased from 253 +/- 45 microM.h (n = 6) for carboplatin alone to 305 +/- 63 microM.h (n = 11) for carboplatin+three doses of amifostine. Experiments in nude mice bearing OVCAR-3 xenografts showed that amifostine, given once before cisplatin or three times in combination with carboplatin, did not affect the antitumour effect of these drugs. When amifostine was only given just before carboplatin, it even stimulated the antitumour effect of carboplatin significantly.
Assuntos
Amifostina/farmacocinética , Antineoplásicos/farmacocinética , Carboplatina/farmacocinética , Cisplatino/farmacocinética , Amifostina/farmacologia , Animais , Antineoplásicos/farmacologia , Carboplatina/farmacologia , Cisplatino/farmacologia , Adutos de DNA/efeitos dos fármacos , Esquema de Medicação , Interações Medicamentosas , Feminino , Camundongos , Neoplasias Ovarianas/tratamento farmacológicoRESUMO
The pharmacokinetics of amifostine, a protector against chemotherapy and radiation-induced toxicities, was investigated in the plasma and ascites of a cancer patient. A high-performance liquid chromatography (HPLC) procedure with electrochemical detection was used to measure amifostine, its active metabolite, WR 1065, and the disulfides (symmetrical plus mixed disulfides). Both amifostine and WR 1065 were rapidly cleared from the plasma (95% and 50% of the peak concentration within 1 h, respectively). The disulfides, which were rapidly formed from WR 1065, were cleared much more slowly (final half-life 13.6 h). Multiple dosing resulted in a tendency toward increasing peak levels of WR 1065 and decreasing peak levels of the disulfides. Only 1% of the delivered dose appeared in the ascites. Therefore, it is not plausible that the presence of ascites or other third spaces would have an impact on the pharmacokinetics of amifostine.
Assuntos
Adenocarcinoma/metabolismo , Amifostina/farmacocinética , Ascite/metabolismo , Protetores contra Radiação/farmacocinética , Neoplasias Gástricas/metabolismo , Amifostina/metabolismo , Cromatografia Líquida de Alta Pressão , Dissulfetos/sangue , Meia-Vida , Humanos , Infusões Intravenosas , Masculino , Mercaptoetilaminas/farmacocinética , Pessoa de Meia-Idade , Protetores contra Radiação/metabolismoRESUMO
Measurements of bidirectional capillary permeability in the ASV tumor model revealed a heterogeneous distribution of transport rates for the small water-soluble molecules which are believed to be the driving force in perifocal edema formation. Mean K1 values were 8.1 +/- 5.5 microliters/g/min in whole tumor and 18.89 +/- 12.3 microliters/g/min in highly permeable areas. Tumor blood flow ranged between normal white matter and cortex, whereas the plasma vascular space in the tumors was increased as compared to the normal brain. The size of the extracellular space was depending on the regional capillary permeability, underlining the vasogenic nature of peritumoral edema which was capable of being studied using in vivo methods.
Assuntos
Volume Sanguíneo/fisiologia , Barreira Hematoencefálica/fisiologia , Edema Encefálico/fisiopatologia , Neoplasias Encefálicas/irrigação sanguínea , Espaço Extracelular/fisiologia , Glioma/irrigação sanguínea , Animais , Vírus do Sarcoma Aviário , Velocidade do Fluxo Sanguíneo/fisiologia , Cães , Fluxo Sanguíneo Regional/fisiologiaRESUMO
Ifosfamide is a member of the oxazaphosphorine class of cytostatic drugs. Ifosfamide has to be metabolized prior to expressing its cytotoxicity. This metabolism leads to a great variety of metabolites. An overview is given of the methods of analysis of ifosfamide and its metabolites as well as the current knowledge about its metabolism, toxicity and clinical use in relation to the bio-analysis. For ifosfamide and some of its metabolites reliable methods of analysis exist. However, for the most important metabolites, isofosforamide mustard and acrolein, progress has to be made in improving the simplicity and sensitivity of the existing methods.