Subject(s)
Antineoplastic Agents/pharmacokinetics , Benzenesulfonates/pharmacokinetics , Kidney Diseases/therapy , Protein Kinase Inhibitors/pharmacokinetics , Pyridines/pharmacokinetics , Renal Dialysis , Antineoplastic Agents/metabolism , Antineoplastic Agents/therapeutic use , Benzenesulfonates/metabolism , Benzenesulfonates/therapeutic use , Blood Specimen Collection , Clinical Trials as Topic , Dose-Response Relationship, Drug , Drug Administration Schedule , Humans , Kidney Diseases/blood , Kidney Diseases/physiopathology , Niacinamide/analogs & derivatives , Phenylurea Compounds , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/therapeutic use , Pyridines/chemistry , Pyridines/metabolism , Pyridines/therapeutic use , Sorafenib , Time FactorsSubject(s)
Antimetabolites, Antineoplastic/therapeutic use , Oxonic Acid/pharmacokinetics , Oxonic Acid/therapeutic use , Tegafur/pharmacokinetics , Tegafur/therapeutic use , 2-Pyridinylmethylsulfinylbenzimidazoles/administration & dosage , Administration, Oral , Anti-Ulcer Agents/administration & dosage , Antimetabolites, Antineoplastic/blood , Antimetabolites, Antineoplastic/pharmacokinetics , Area Under Curve , Biological Availability , Clinical Trials as Topic , Dihydrouracil Dehydrogenase (NADP)/blood , Drug Combinations , Fasting , Fluorouracil/analogs & derivatives , Fluorouracil/metabolism , Food , Gastric Acidity Determination , Half-Life , Humans , Hydrogen-Ion Concentration , Oxonic Acid/blood , Oxonic Acid/metabolism , Pantoprazole , Pyridines/metabolism , Pyridines/pharmacokinetics , Pyridines/therapeutic use , Tegafur/blood , Tegafur/metabolism , Triazines/metabolism , Uracil/analogs & derivatives , Uracil/metabolism , beta-Alanine/analogs & derivatives , beta-Alanine/metabolismSubject(s)
Biopsy , Carcinoma , Neoplasms , Oxygen , Tissue Preservation , Cell Line, Tumor , Cell Survival , DNA, Neoplasm/analysis , Humans , Nanostructures , RNA, Neoplasm/analysis , Solutions , TemperatureSubject(s)
Benzenesulfonates/pharmacology , Neoplasms/drug therapy , Proto-Oncogene Proteins c-raf/antagonists & inhibitors , Pyridines/pharmacology , Adult , Area Under Curve , Benzenesulfonates/administration & dosage , Benzenesulfonates/adverse effects , Diarrhea/chemically induced , Drug Administration Schedule , Exanthema/chemically induced , Humans , Niacinamide/analogs & derivatives , Phenylurea Compounds , Phosphorylation/drug effects , Pyridines/administration & dosage , Pyridines/adverse effects , SorafenibSubject(s)
Cell Culture Techniques , Cell Line, Tumor , Cell Survival , Humans , Solutions , Specimen Handling/methodsSubject(s)
Benzenesulfonates/pharmacology , Biomarkers/analysis , Circadian Rhythm , MAP Kinase Signaling System/physiology , Mitogen-Activated Protein Kinase Kinases/analysis , Mitogen-Activated Protein Kinases/analysis , Pyridines/pharmacology , Blotting, Western , Humans , Niacinamide/analogs & derivatives , Phenylurea Compounds , Phosphorylation , Signal Transduction , Sorafenib , p38 Mitogen-Activated Protein KinasesSubject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Benzenesulfonates/pharmacology , Benzenesulfonates/pharmacokinetics , Neoplasms/drug therapy , Pyridines/pharmacology , Pyridines/pharmacokinetics , Administration, Oral , Area Under Curve , Aspartate Aminotransferases/pharmacology , Benzenesulfonates/administration & dosage , Doxorubicin/administration & dosage , Humans , Liver Neoplasms/complications , Liver Neoplasms/drug therapy , Niacinamide/analogs & derivatives , Phenylurea Compounds , Pyridines/administration & dosage , Sorafenib , Treatment OutcomeSubject(s)
Benzenesulfonates/pharmacology , Enzyme Inhibitors/pharmacology , Proto-Oncogene Proteins c-raf/antagonists & inhibitors , Pyridines/pharmacology , Benzenesulfonates/adverse effects , Benzenesulfonates/pharmacokinetics , Dose-Response Relationship, Drug , Drug Administration Schedule , Enzyme Inhibitors/adverse effects , Enzyme Inhibitors/pharmacokinetics , Humans , Maximum Tolerated Dose , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3 , Mitogen-Activated Protein Kinases/metabolism , Neoplasms/metabolism , Niacinamide/analogs & derivatives , Phenylurea Compounds , Phosphorylation , Proto-Oncogene Proteins c-raf/metabolism , Pyridines/adverse effects , Pyridines/pharmacokinetics , SorafenibABSTRACT
PURPOSE: Treosulfan (L-threitol-1,4-bis-methanesulfonate, Ovastat) is a prodrug of a bifunctional alkylating agent with activity in ovarian carcinoma and other solid tumors. In a pharmacologic study of the bioavailability of treosulfan in a capsule formulation, patients with relapsed ovarian carcinoma were treated with alternating doses of oral and intravenous (i.v.) treosulfan of 1.5 or 2.0 g daily for 5 to 8 days. METHODS: A sensitive method for the determination of treosulfan in plasma and urine by reversed-phase high-performance liquid chromatography had previously been developed. Pharmacokinetic analyses of treosulfan were carried on plasma and urine samples from 20 i.v. courses and 20 courses of oral administration. RESULTS: The bioavailability ratio (f) of oral to i.v. administration was calculated as 0.97 +/- 0.18 (mean +/- SD) using the values AUC oral = 82.1 +/- 39.4 microg/ml h and AUC i.v. = 85.4 +/- 30.3 microg/ml h. The peak plasma concentration cmax (29 +/- 14 microg/ml vs 65 +/- 23 microg/ml) was significantly (P < 0.01) higher after i.v. administration and the tmax after oral administration was 1.5 +/- 0.34 h. The terminal half-life of treosulfan was about 1.8 h. The mean urinary excretion of the parent compound was about 15% of the administered total dose over 24 h (range 6-26%). CONCLUSIONS: The high and relatively constant bioavailability of treosulfan indicates that capsules provide a satisfactory noninvasive treatment alternative. A feasible and reliable oral treosulfan formulation could provide the basis for the development of long-term low-dose outpatient treatment of patients with malignant diseases.
Subject(s)
Antineoplastic Agents, Alkylating/pharmacokinetics , Busulfan/analogs & derivatives , Ovarian Neoplasms/metabolism , Administration, Oral , Aged , Antineoplastic Agents, Alkylating/administration & dosage , Antineoplastic Agents, Alkylating/therapeutic use , Biological Availability , Busulfan/administration & dosage , Busulfan/pharmacokinetics , Busulfan/therapeutic use , Dose-Response Relationship, Drug , Drug Evaluation , Female , Humans , Middle Aged , Neoplasm Recurrence, Local , Ovarian Neoplasms/drug therapyABSTRACT
A cosmid library has been constructed from a hamster x human hybrid cell line and gridded into 270 microtiter plates containing a total of 25,920 single colonies. Approximately 84% of the recombinants contain human material, with an average length of 29 kb. This library represents a nearly three-fold coverage of human chromosome 4. We investigated this library for presumptive genes, using a set of oligonucleotides detecting SpI and splice-site consensus sequences. The presence of simple repeat motifs was investigated in the cosmids using the oligonucleotides (GGATTT)3, (GGAT)4, (CAC)5, (GCC)5, (AGC)5, (GATA)4, (GACA)4, and (CA)8 as hybridization probes.
