losartan-potassium and Cystic-Fibrosis

Once a rarely used subset of medical treatments, protein therapeutics have increased dramatically in number and frequency of use since the introduction of the first recombinant protein therapeutic--human insulin--25 years ago. Protein therapeutics already have a significant role in almost every field of medicine, but this role is still only in its infancy. This article overviews some of the key characteristics of protein therapeutics, summarizes the more than 130 protein therapeutics used currently and suggests a new classification of these proteins according to their pharmacological action.

Topics: Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Darbepoetin alfa; Diabetes Mellitus; Erythropoietin; Humans; Insulin; Protein Deficiency; Proteins; Recombinant Proteins

Hypoferremia is a marker of disease severity in cystic fibrosis (CF). The effect of systemic antibiotics on iron homeostasis during CF pulmonary exacerbation (CFPE) is unknown. Our central hypotheses were that, by the completion of treatment, serum iron would increase, serum concentrations of interleukin-6 (IL-6) and hepcidin-25, two mediators of hypoferremia, would decrease, and sputum iron would decrease.. Blood and sputum samples were collected from 12 subjects with moderate-to-severe CF (median percentage-predicted forced expiratory volume in 1 second (FEV(1) %) = 29%; median weight = 56 kg) within 24 hours of starting and completing a course of systemic antibiotics.. After treatment, subjects showed median FEV(1) % and body weight improvements of 4.5% and 2.0 kg, respectively (p < 0.05). Median serum iron rose by 2.4 μmol/L (p < 0.05), but 75% of patients remained hypoferremic. Median serum IL-6 and hepcidin-25 levels fell by 12.1 pg/mL and 37.5 ng/mL, respectively (p < 0.05). Median serum erythropoietin (EPO) and hemoglobin levels were unaffected by treatment. We observed a trend toward lower sputum iron content after treatment.. Hypoferremia is a salient characteristic of CFPE that improves with waning inflammation. Despite antibiotic treatment, many patients remain hypoferremic and anemic because of ineffective erythropoiesis.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Cystic Fibrosis; Disease Progression; Erythropoietin; Female; Forced Expiratory Volume; Hemoglobins; Hepcidins; Homeostasis; Humans; Interleukin-6; Iron; Male; Middle Aged; Sputum; Weight Gain; Young Adult

Angiogenesis is an important mechanism of airway remodeling in lung disease. We previously demonstrated that serum vascular endothelial growth factor (VEGF) is elevated in cystic fibrosis (CF) patients and declines with therapy for pulmonary exacerbation. We hypothesized that VEGF is elevated early in the course of CF and is associated with markers of tissue hypoxia. A prospective, single-visit evaluation of thirty stable infants and children with CF was performed. Serum was analyzed for VEGF and for other markers of tissue hypoxia (erythropoietin (EPO), insulin-like growth factor binding protein-1 (IGFBP-1)) and for inflammatory mediators (IL-1 beta, IL-6, IL-8, and tumor necrosis factor alpha (TNFα)) using Meso Scale multi-spot serum immunoassays. Measurements were correlated between assay groups; and with age in months and pulmonary function (FEV0.5 or FEV1). VEGF, EPO, TNFα and IL-8 were elevated compared to published normative values. VEGF levels were not significantly correlated with any inflammatory mediators. However, VEGF correlated with EPO (r=0.505; P<0.05). There was no correlation between lung function and markers of inflammation or tissue hypoxia. VEGF is elevated in young, stable infants and children suggesting angiogenesis as a contributing mechanism for early lung disease in CF. VEGF elevation does not show significant correlation with inflammatory mediators known to be increased in CF, but is significantly correlated with EPO levels. We propose that VEGF elevation and angiogenesis contribute to early lung disease and may result from a direct tissue hypoxia pathway in CF.

Topics: Age Factors; Child; Child, Preschool; Cohort Studies; Cystic Fibrosis; Cytokines; Erythropoietin; Female; Humans; Hypoxia; Inflammation Mediators; Lung; Male; Nutritional Status; Prospective Studies; Respiratory Function Tests; Vascular Endothelial Growth Factor A

Chronic lung disorders are usually associated with a hypoxia driven increase in red cell mass. However, patients with cystic fibrosis (CF) often have normal or decreased haemoglobin levels. The present prospective observational study in cystic fibrosis patients was performed to determine which factors were involved in alterations in the hematopoetic response to corresponding arterial oxygen pressure. Sixty adult patients (age 21-51) with stable CF were included. They all had vitamin A, D, E, and K but no vitamin B12 supplementation. Twenty-five patients were on oral Fe(2+) (100 mg/day). Resting arterial blood gases, lung function, complete blood counts, parameters of iron status, CRP, sputum microbiology and serum erythropoietin were measured at recruitment and after 3 and 6 months. Patients had varying degrees of pulmonary functional impairment and 9% were hypoxemic (arterial oxygen pressure <60 mm Hg). Low-grade systemic inflammation (CRP > 0.5 mg/dl) was present in 40% of the patients, who all had bacterial colonization. None of the patient had erythrocytosis and 12 patients had anemia. There was no significant difference in iron status between patients with or without chronic iron supplementation and erythropoietin levels were normal. During the 6 months observation period no significant changes occurred. The patients exhibited an impaired erythropoietic response to hypoxemia with normal or low hematocrit in spite of chronic lung disease which might be caused by chronic inflammation associated with CF. Linear multivariate regression analysis revealed CRP levels but neither iron substitution, nor erythropoietin levels nor lung function parameters as independent determinant of haemoglobin levels. CF may be associated with anemia of variable severity as expression of the chronic inflammation present in these patients. The therapeutic consequences are to treat the underlying inflammation rather than to supplement iron.

Topics: Adult; Anemia, Iron-Deficiency; Blood Gas Analysis; C-Reactive Protein; Cystic Fibrosis; Erythropoietin; Female; Follow-Up Studies; Forced Expiratory Flow Rates; Hemoglobins; Humans; Male; Middle Aged; Oxygen; Prognosis; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index

Chronic pulmonary disease and progressive tissue hypoxia are major causes of morbidity and mortality in cystic fibrosis (CF). Normally the body adapts to tissue hypoxia by increasing the red cell mass and decreasing the Hb-O(2) affinity. These adaptations are commonly observed in patients with cyanotic heart disease and individuals living at high altitude. However, patients with CF not only have an impaired erythroid response to hypoxia, but also are frequently anaemic.. In order to evaluate erythroid marrow activity and tissue oxygenation in 37 patients with CF we measured: the haematological and blood chemistry parameters; including red cell indices, ferritin, erythropoietin (Epo) and soluble transferrin receptors (sTfR) levels; arterial blood gases, P(50) and oxygen release to the tissues (O(2)(R)) and the 2,3-BPG levels.. The main results showed that a) patients with CF have a mild degree of tissue hypoxia which is expressed by the moderately decreased of P(50) and O(2)(R) values and the relative increase of Epo level, b) 2,3-BPG synthesis in patients with CF is normal and c) sTfR levels are significantly increased (3-fold normal) in patients with CF compared to normal controls.. The above observations indicate that erythroid marrow activity in patients with CF is increased.

Topics: Adolescent; Adult; Biomarkers; Blood Gas Analysis; Child; Child, Preschool; Cystic Fibrosis; Erythrocytes; Erythropoietin; Female; Ferritins; Humans; Hypoxia; Infant; Male; Oxygen Consumption; Receptors, Transferrin; Severity of Illness Index

Erythropoietin (EPO), a glycoprotein hormone, is the major physiological regulator of erythrocyte production in mammals. A cDNA clone containing the entire human EPO-coding region was used for Southern blot analysis of a series of human-Chinese hamster somatic cell hybrids containing different combinations of human chromosomes. Synteny analysis revealed 100% concordance between the EPO gene and human chromosome 7. Further localization to the region q11-q22 was accomplished by in situ hybridization of 3H-labeled human EPO cDNA to metaphase chromosomes prepared from both human lymphocytes and the cell hybrid 879-2a that contained human chromosomes 5, 7, 9, 12, and 21. In addition, restriction fragment length polymorphisms were detected at a frequency of approximately 20% in a Chinese population using restriction enzymes either HindIII or HinfI. These polymorphisms were inherited in a Mendelian fashion. Thus, the EPO marker is reasonably polymorphic and should be useful in linkage analysis with other genetic markers on chromosome 7, including the locus for cystic fibrosis.

Topics: Chromosome Mapping; Chromosomes, Human, 6-12 and X; Cystic Fibrosis; DNA; Erythropoietin; Genes; Humans; Hybrid Cells; Nucleic Acid Hybridization; Polymorphism, Genetic

An increase in hemoglobin concentration characterizes the normal compensatory response to chronic tissue hypoxia. We observed no such increase in 42 chronically hypoxic patients with cystic fibrosis, in whom the mean concentration was 12.6 gm/dl; one third of the patients were anemic. Compared with patients with cyanotic heart disease, patients with cystic fibrosis did not have a compensatory increase in P50 or 2,3-diphosphoglycerate. Despite anemia, erythropoietin levels in patients with cystic fibrosis were not significantly different from normal control values. The growth of colony-forming units-erythroid in patients with cystic fibrosis was similar to that in control subjects, and there was no inhibition of growth with the addition of autologous serum. Erythropoietin sensitivity, determined by measuring the CFUe dose response curve, was normal in both patients and controls. Results of iron studies were consistent with iron deficiency in the majority of patients. Impaired absorption of iron was observed in six of 13 iron-deficient patients with cystic fibrosis. An inverse correlation between erythrocyte sedimentation rate and peak serum iron was obtained during the iron absorption study. Eight patients who underwent a therapeutic trial of iron demonstrated a 1.8 gm/dl rise in hemoglobin concentration. Two patients with previously documented iron malabsorption responded to parenteral iron therapy after failure to respond to oral supplementation. These studies demonstrate that patients with cystic fibrosis not only have an impaired erythroid response to hypoxia, but are frequently anemic. Their inadequate erythroid response to hypoxia results in part from disturbances in erythropoietin regulation and iron availability.

Topics: 2,3-Diphosphoglycerate; Adolescent; Adult; Biological Availability; Blood Sedimentation; Child; Child, Preschool; Cystic Fibrosis; Diphosphoglyceric Acids; Erythropoietin; Heart Defects, Congenital; Hematopoietic Stem Cells; Hemoglobins; Humans; Hypoxia; In Vitro Techniques; Intestinal Absorption; Iron; Oxygen Consumption

We investigated 28 cystic fibrosis (CF) patients to determine why hypoxia from their obstructive pulmonary disease does not produce polycythemia. Oxygen saturation was lower and erythropoietin levels were higher in CF patients than in 25 age-comparable reference subjects (90.8% and 47 mimu vs. 94.7% and 29 mimu, p less than 0.01). Hematocrit and red blood cell (RBC) indices were not different between groups. Serum vitamin and iron levels, ferrokinetics, RBC volume, and RBC survival were studied in 10 of the 28 CF patients. Total iron-binding capacity and vitamin E levels were low, and serum iron, ferritin, vitamin B12, and folate levels were normal in these patients. Red blood cell survival was minimally decreased in six patients although there was no other evidence for hemolysis. Ferrokinetics (59Fe) indicated a reduction in total erythropoiesis in only two patients. Plasma volume was high-normal in five and above normal in four CF patients; RBC mass was increased appropriately for each patient's degree of hypoxia, when compared to healthy individuals living at different altitudes. These results suggest that CF patients are able to compensate for hypoxia by increasing RBC mass; however, an expanded plasma volume prevents a detectable rise in hematocrit.

Topics: 2,3-Diphosphoglycerate; Adolescent; Adult; Child; Chromium Radioisotopes; Cystic Fibrosis; Diphosphoglyceric Acids; Erythrocyte Aging; Erythrocyte Volume; Erythropoiesis; Erythropoietin; Hematocrit; Humans; Hypoxia; Iron; Iron Radioisotopes; Kinetics; Oxygen; Plasma Volume