ABSTRACT
Therapeutic monitoring of the potent, highly lipophilic glucocorticoid, fluticasone propionate (FP), was initially performed by a radioimmunoassay method. However an improved method with a lower limit of quantitation (LLOQ) of at least 25 pg per ml (pg/ml(-1)) was needed to measure the low levels of FP present in human plasma following inhalation administration of doses in the range 50-250 microg twice daily. A sensitive and specific liquid chromatographic, tandem mass spectrometric method (LC-MS/MS) with automated solid phase extraction (SPE) was developed and validated. Fluticasone propionate was extracted from plasma using Bond Elut C18 cartridges and analysed using reverse-phase chromatography with atmospheric pressure chemical ionisation followed by selective reaction monitoring. The method used a 13C-labelled internal standard and was validated over a concentration range of 25-500 pg/ml(-1). The method was shown to be specific, sensitive and reliable in the analysis of clinical samples. The main advantages of this method over the radioimmunoassay method previously used were improved sensitivity, specificity, ease of sample preparation and shortened analysis time.
Subject(s)
Androstadienes/blood , Anti-Inflammatory Agents/blood , Androstadienes/administration & dosage , Fluticasone , Gas Chromatography-Mass Spectrometry/methods , Humans , Radioimmunoassay , Reference Standards , Reproducibility of ResultsABSTRACT
1. The pharmacokinetics and disposition of picumeterol, a novel beta 2 receptor agonist agent, have been studied in the rat and dog following administration by inhalation, intravenous and oral routes at various dose levels. 2. Picumeterol was found to be transferred across the lung of the rat and dog following inhalation dosage. After i.v. dosage picumeterol was eliminated from plasma with a half-life of about 1 h in the rat and about 2 h in the dog. Plasma clearance in the rat was about twice liver blood flow and the plasma levels of picumeterol were low after oral administration. 3. Following instillation of 14C-picumeterol to the trachea of isolated respiring rat lung preparations radioactivity was transferred from the airways to perfusion media as unchanged drug within 2 min. After 2 h perfusion, no metabolites were detected in the recirculation perfusate or lung. 4. Picumeterol was extensively metabolized in vivo in the rat (about 95%) and dog (about 90%) and in vitro in microsomal preparations of rat, dog and human liver. O-dealkylation and beta-oxidation are important as routes of metabolism. 5. Radioactivity was largely excreted in the urine of the rat and dog (> 50% of dose), as metabolites, following i.v. administration. There was some excretion of radioactivity in dog bile. Extensive first-pass metabolism was found after oral administration in the rat.
Subject(s)
Adrenergic beta-2 Receptor Agonists , Microsomes, Liver/metabolism , Pyridines/pharmacokinetics , Administration, Inhalation , Administration, Oral , Animals , Carbon Radioisotopes , Dogs , Female , Injections, Intravenous , Male , Rats , Rats, WistarSubject(s)
Adrenergic beta-Agonists/therapeutic use , Albuterol/analogs & derivatives , Asthma/drug therapy , Bronchodilator Agents/therapeutic use , Acute Disease , Adrenergic beta-Agonists/administration & dosage , Albuterol/administration & dosage , Albuterol/adverse effects , Albuterol/therapeutic use , Bronchodilator Agents/administration & dosage , Clinical Trials as Topic , Drug Administration Schedule , Humans , Salmeterol XinafoateABSTRACT
Ataxia telangiectasia (AT) is a human autosomal recessive disorder in which patients show a marked predisposition to malignant disease and cytogenetic abnormalities. We report here the levels of spontaneously occurring chromosome aberrations and particularly the presence of cytogenetically marked clones of cells in peripheral lymphocytes of 13 patients. There is a variation between the patients with respect to frequency of different aberration types, and clones are present in 5/13 patients. Several of these patients appear to have more than a single clone, possible clones or subclones. There is no evidence for any malignant disease in any of these patients. A description is given from one of these patients, of the most complex clone so far reported in an AT patient without malignant disease. The development of such a complex clone might be important as a step in malignant change. Similarities between this clone and one reported in an AT patient with T-cell chronic lymphocytic leukaemia are discussed.
Subject(s)
Ataxia Telangiectasia/genetics , Chromosome Aberrations , Clone Cells/ultrastructure , Lymphocytes/ultrastructure , Adolescent , Adult , Ataxia Telangiectasia/pathology , Child , Child, Preschool , Female , Humans , KaryotypingABSTRACT
Clones of cytogenetically abnormal cells have been recognized in fibroblasts cultured from normal human adult skin. No such clones have been observed in human embryo skin fibroblasts cultured in the same way. Although the culture conditions may have played some part in the emergence of these clones, it is possible that the abnormal cells from which the clones were derived were present in vivo.
Subject(s)
Chromosome Aberrations , Chromosomes , Adult , Aged , Clone Cells , Female , Fetus , Fibroblasts , Humans , Karyotyping , Male , Middle AgedABSTRACT
Cytogenetic observations on seven cases of ataxia telangiectasia are presented. The aberration frequency was found to be increased in all of them with a specificity for the involvement of the D-group chromosomes in rearrangements. Clones of cytogenetically abnormal cells were observed in the lymphocytes of three cases and in the cultured skin fibroblasts of two cases, again with a specificity for D-group involvement. G-banding shows that chromosome 14 is frequently involved in rearrangements in clone cells and that the band 14q12 may be a highly specific exchange point. The significance of lymphocyte clones with a proliferative advantage in vivo is discussed. Cytogenetic studies of the parents and sibs of these cases are also reported.
