digoxin and Cystic-Fibrosis

This review mainly summarizes selected aspects of the present knowledge of drug elimination kinetics independent of developmental changes, with special attention given to clinical situations. The effects of different disease states, drug interactions, changes in urinary pH, induction of microsomal enzymes, competition for renal excretory mechanisms, possible enterohepatic recirculation, binding of drugs to tissues, effects of a drug on another drug's metabolizing organ, and dose-dependent elimination, on increase or decrease of drug elimination rates in children, have been presented. Based on the available data it seems that one may postulate the following conclusions: (1) that the distribution factors as well as changes in drug elimination capacities seem to play a role, perhaps with differing relative importance, during each of the maturational periods; (2) that the physicochemical properties of a drug and its dosage, as well as changes in the volume of distribution in children, in the course of certain disease states may have a significant effect on kinetics of drug disposition in the body; (3) that systemic clearance, a model independent parameter, rather than elimination half-life, a hybrid pharmacokinetic parameter, more accurately reflects elimination of some drugs from the body; (4) that each drug and every clinical situation may require the evaluation of the direct effect on pharmacokinetic processes, since general principles may not always apply; (5) that drug disposition studies should also be performed, if possible, on patients under actual clinical situations and receiving the usual therapeutic regime, and (6) that the half-life of colistin is independent of postnatal age which should serve as a warning not to generalize about drug excretion in the young infant.

Topics: Adult; Anti-Bacterial Agents; Brain Injuries; Child; Child, Preschool; Colistin; Cystic Fibrosis; Digoxin; Dose-Response Relationship, Drug; Drug Interactions; Female; Half-Life; Heart Failure; Humans; Hydrogen-Ion Concentration; Hypothermia, Induced; Infant; Infant, Newborn; Kidney; Kinetics; Liver; Nephrotic Syndrome; Nutrition Disorders; Pharmaceutical Preparations; Phenobarbital; Reye Syndrome; Serum Albumin; Urine

Topics: Acute Disease; Cardiac Catheterization; Cardiomegaly; Child; Child, Preschool; Chronic Disease; Cystic Fibrosis; Digoxin; Electrocardiography; Female; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Lung; Male; Pulmonary Heart Disease; Radiography; Vectorcardiography

1. Airway epithelium in cystic fibrosis is characterized by a defect in chloride secretion across the apical membrane and an increase in sodium absorption. The increased rate of sodium absorption can be inhibited in vitro by ouabain, a Na(+)-K(+)-ATPase inhibitor, and in cystic fibrosis patients the number and activity of nasal epithelial Na(+)-K(+)-ATPase pumps is increased. 2. We have performed a series of studies to determine whether drugs which modify airway epithelial Na(+)-K(+)-ATPase activity in vitro can modify nasal potential in cystic fibrosis patients in vivo. As transepithelial nasal potential difference measurements were used to study the effect of drug modulation of airway epithelial ion transport in vivo, the repeatability of the technique was first evaluated. In order to assess the effectiveness of the technique used for measuring nasal potential difference, a pilot study was carried out using topical amiloride, a drug which has previously been shown to inhibit airway epithelium sodium transport in vivo. We then studied the effects of ouabain and digoxin, two inhibitors of Na(+)-K(+)-ATPase, on nasal potential difference. 3. In study 1, nasal potential difference measurements were repeated on non-consecutive days in 20 patients with cystic fibrosis and 20 healthy individuals. Healthy subjects had a mean (SEM) potential difference value of -19.5 (0.9) mV with a 95% range for a single estimate of 75-133%. In patients with cystic fibrosis, the mean (SEM) potential difference was -40.4, (2.1) mV, with a 95% range for a single estimate of 74-136%.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Albuterol; Amiloride; Cystic Fibrosis; Digoxin; Double-Blind Method; Enzyme Inhibitors; Epithelium; Female; Humans; Male; Nasal Mucosa; Ouabain; Pilot Projects; Sodium-Potassium-Exchanging ATPase

The ability of digoxin to increase exercise capacity and stroke volume (SV) during exercise was evaluated in ten patients with cystic fibrosis (CF) ages 12 to 20 years with moderate to severe degrees of airway obstruction but no history of heart failure. A double-blind crossover trial of digoxin versus placebo was carried out. An evaluation of exercise performance was undertaken upon entry into the study, and after each of the one-week periods in which digoxin 0.25 mg/day or placebo was taken. Exercise testing consisted of a progressive exercise test on a cycle ergometer to measure maximum work capacity (Wmax) and a steady state test at 2/3 of the baseline Wmax. During the steady state test, the oxygen consumption and carbon dioxide production were measured and cardiac output (Q) was calculated by the indirect Fick (CO2) method. From Q and heart rate (HR), SV was derived. After digoxin, Wmax was unchanged. On steady state exercise HR was unchanged, but there was a slight but significant fall in Q due to a fall in SV. The decrease in SV was associated with exercising hypoxemia. We conclude that digoxin did not increase exercise capacity or improve exercising cardiac function in patients with moderate to severe airway obstruction due to CF.

Topics: Adolescent; Adult; Blood Gas Analysis; Cardiac Output; Child; Cystic Fibrosis; Digoxin; Double-Blind Method; Heart; Heart Rate; Humans; Physical Exertion; Respiratory Function Tests; Stroke Volume

Small molecules that correct the folding defects and enhance surface localization of the F508del mutation in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) comprise an important therapeutic strategy for cystic fibrosis lung disease. However, compounds that rescue the F508del mutant protein to wild type (WT) levels have not been identified. In this report, we consider obstacles to obtaining robust and therapeutically relevant levels of F508del CFTR. For example, markedly diminished steady state amounts of F508del CFTR compared to WT CFTR are present in recombinant bronchial epithelial cell lines, even when much higher levels of mutant transcript are present. In human primary airway cells, the paucity of Band B F508del is even more pronounced, although F508del and WT mRNA concentrations are comparable. Therefore, to augment levels of "repairable" F508del CFTR and identify small molecules that then correct this pool, we developed compound library screening protocols based on automated protein detection. First, cell-based imaging measurements were used to semi-quantitatively estimate distribution of F508del CFTR by high content analysis of two-dimensional images. We evaluated ~2,000 known bioactive compounds from the NIH Roadmap Molecular Libraries Small Molecule Repository in a pilot screen and identified agents that increase the F508del protein pool. Second, we analyzed ~10,000 compounds representing diverse chemical scaffolds for effects on total CFTR expression using a multi-plate fluorescence protocol and describe compounds that promote F508del maturation. Together, our findings demonstrate proof of principle that agents identified in this fashion can augment the level of endoplasmic reticulum (ER) resident "Band B" F508del CFTR suitable for pharmacologic correction. As further evidence in support of this strategy, PYR-41-a compound that inhibits the E1 ubiquitin activating enzyme-was shown to synergistically enhance F508del rescue by C18, a small molecule corrector. Our combined results indicate that increasing the levels of ER-localized CFTR available for repair provides a novel route to correct F508del CFTR.

Topics: Alleles; Benzoates; Cells, Cultured; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Endoplasmic Reticulum; Furans; Gene Deletion; HEK293 Cells; HeLa Cells; High-Throughput Screening Assays; Humans; Hydroxamic Acids; Microscopy, Fluorescence; Protein Folding; Protein Structure, Tertiary; Pyrazoles; RNA, Messenger; Small Molecule Libraries; Ubiquitination; Vorinostat

Topics: Adolescent; Adult; Anti-Bacterial Agents; Cyclic AMP; Cystic Fibrosis; Digoxin; Female; Granulocytes; Heterozygote; Homozygote; Humans; Isoproterenol; Leukocytes; Male; Middle Aged; Pancreatic Extracts; Prostaglandins E; Receptors, Adrenergic, beta

The absorption of digoxin in cystic fibrosis was evaluated in 16 subjects by assessing the relationship between dosage expressed in mug/kg/day and serum digoxin concentration. The results indicate that the same relationship exists between maintenance dosage and serum levels in these patients and in patients without cystic fibrosis. Thus, no evidence of impaired absorption was found.

Topics: Adolescent; Adult; Child; Child, Preschool; Cystic Fibrosis; Digoxin; Humans; Pulmonary Heart Disease

Topics: Calcium; Cystic Fibrosis; Digitalis Glycosides; Digoxin; Heart Diseases; Humans; Hyperaldosteronism; Potassium; Prospective Studies; Saliva

Topics: Cardiac Catheterization; Cystic Fibrosis; Digoxin; Electrocardiography; Humans; Oxygen; Pulmonary Heart Disease; Vectorcardiography