ABSTRACT
Imatinib (IMT) is a selective tyrosine kinase inhibitor, used in the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors. Its strong plasma protein binding was found to belong to the F1*S genetic variant of α(1)-acid glycoprotein (AGP). In this work, comparative AGP binding studies were performed with IMT fragment molecules to reveal which parts of the molecule are important in the high-affinity interaction provoking specific spectral changes. Molecular modeling calculations indicated that IMT docked into the X-ray structure of AGP/F1 adopts a bent, compact conformation. This binding mode is similar to those found in its complexes with some low-affinity kinases and a quinone reductase, being strikingly different from the extended conformation of IMT in its high-affinity kinase targets.
Subject(s)
Orosomucoid/metabolism , Piperazines/metabolism , Protein Kinase Inhibitors/metabolism , Pyrimidines/metabolism , Benzamides , Humans , Imatinib Mesylate , Models, Molecular , Orosomucoid/chemistry , Piperazines/chemistry , Protein Binding , Protein Conformation , Protein Kinase Inhibitors/chemistry , Pyrimidines/chemistry , Spectrum AnalysisABSTRACT
The measurement of carbamylated haemoglobin is a useful indicator of uraemic state during the preceding few weeks in patients with renal failure. In diabetic uraemic patients with hyperglycaemia, glycation of haemoglobin may interfere with its carbamylation, as both reactions involve the free amino groups of the protein. The aim of this study was to investigate the carbamylation of haemoglobin in the presence of hyperglycaemia. The study included 29 patients with chronic renal failure on regular haemodialysis, 14 diabetic and 15 non-diabetic patients, and 10 healthy controls. We found a significant correlation between the degree of haemoglobin carbamylation and mean blood urea concentration in both uraemic and control subjects. Carbamylation of haemoglobin was higher in both diabetic and non-diabetic chronic renal failure patients, but there were no significant differences between the groups regarding mean blood urea concentration or level of haemoglobin carbamylation. Carbamylated haemoglobin per unit of blood urea concentration was lower in the diabetic patients. Using a correction formula to account for the degree of haemoglobin glycation, there was no longer a significant difference in carbamylation per unit of blood urea concentration. In vitro incubation of red blood cells from six healthy and six diabetic non-uraemic patients in 70 mmol/L urea showed a significantly lower carbamylation in the diabetic patients, but there was no significant difference when using corrected carbamylated haemoglobin values. We conclude that glycation of haemoglobin affects its carbamylation and that monitoring of uraemia in a diabetic patient necessitates the use of carbamylated haemoglobin value corrected for the degree of glycation.
Subject(s)
Cyanates/metabolism , Diabetic Nephropathies/blood , Hemoglobins/analysis , Uremia/blood , Adult , Blood Glucose/analysis , Female , Glycated Hemoglobin/metabolism , Glycosylation , Hemoglobins/metabolism , Humans , Hyperglycemia/blood , In Vitro Techniques , Kidney Failure, Chronic/blood , Male , Middle Aged , Reference Values , Renal Dialysis , Urea/bloodABSTRACT
The authors conducted a single blind, placebo controlled local therapy trial on a total of 190 patients involving the use of materials (i) topically and (ii) by iontophoresis for pain and/or inflammation of the organs of movement. The materials used comprised of the following: (i) purified propolis and propolis saturated with antiinflammatory trace metal elements and (ii) propolis saturated with trace metal elements and poplar bud ointment saturated with trace metal elements also. Both methods of application using all the three preparations significantly improved symptoms. The preparations saturated with metallic ions were more effective. The mild effect of the placebo treatment is explained by the treatment procedure itself. Side effects were not observed.
Subject(s)
Plants, Medicinal , Propolis/therapeutic use , Rheumatic Diseases/drug therapy , Trace Elements/therapeutic use , Administration, Cutaneous , Humans , Iontophoresis , Ointments , Plant Extracts/therapeutic use , Propolis/administration & dosage , Single-Blind MethodABSTRACT
Metabolism of 3-trifluoromethyl-alpha-ethyl-benzhydrol (I), hepatic enzyme inducer has been studied in rats. Five metabolites in bile and four in urine, as well as minute amounts of the original drug (I) were identified. The only major metabolite in bile and one of the two major metabolites in urine were found to be aromatic hydroxylated products of I, i.e., 3-trifluoro-methyl-4'-hydroxy-alpha-ethylbenzhydrol (II). The results of enzymatic hydrolysis with beta-glucuronidase/arylsulfatase suggest that hydroxyl groups of metabolites are conjugated. Considering the structure of metabolites isolated a probable order of metabolite formation is outlined.
