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Pharmacologic correction of dominant-negative GH1 deficiency causing mutations.
Poling JS, Phillips JA, Cogan JD, Hamid R
(2011) Clin Transl Sci 4: 175-9
MeSH Terms: Cell Line, Dexamethasone, Digoxin, Family Health, Genes, Dominant, Growth Hormone, Humans, Leukocytes, Mononuclear, Mutation, Phenotype, Pituitary Diseases, RNA, Messenger, Reverse Transcriptase Polymerase Chain Reaction, Sodium Oxybate, Tubercidin
Show Abstract · Added March 27, 2014
PURPOSE - Dominant-negative growth hormone gene (GH1) mutations cause familial isolated growth hormone deficiency type II (IGHD II), which is characterized by GH deficiency, occasional multiple anterior pituitary hormone deficiencies, and anterior pituitary hypoplasia. We have previously shown that 17.5-/22-kDa GH1 transcript ratios correlate with the severity of the IGHD II phenotype. We hypothesized that different pharmaceutical agents could affect the GH1 transcript ratio by modulating alternative splicing.
METHODS - We exposed peripheral blood mononuclear cells from IGHD II patients and unaffected family members to different pharmacologic agents and then determined the 17.5-/22-kDa transcript ratios by real-time PCR.
RESULTS - Dexamethasone and digoxin significantly increased the 17.5-/22-kDa transcript ratio, while sodium butyrate and 5-iodotubericidin significantly decreased the ratio.
CONCLUSION - Since we have previously shown that the ratio of the 17.5-/22-kDa GH1 transcripts correlates with severity of the IGHD II phenotype, our findings here suggest that selected previously unconsidered agents could possibly reduce the severity of IGHD II, while other agents could possibly exacerbate the disease phenotype.
© 2011 Wiley Periodicals, Inc.
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15 MeSH Terms
Digoxin associates with mortality in ESRD.
Chan KE, Lazarus JM, Hakim RM
(2010) J Am Soc Nephrol 21: 1550-9
MeSH Terms: Aged, Cardiotonic Agents, Digoxin, Female, Humans, Kidney Failure, Chronic, Male, Middle Aged, Potassium, Renal Dialysis
Show Abstract · Added May 20, 2014
The safety of prescribing digoxin in ESRD is unknown. Hypokalemia, which frequently occurs among dialysis patients, may enhance the toxicity of digoxin. Here, we analyzed the association between digoxin prescription and survival in a retrospective cohort using covariate- and propensity score-adjusted Cox models to minimize the potential for confounding by indication. Among 120,864 incident hemodialysis patients, digoxin use associated with a 28% increased risk for death (hazard ratio [HR] 1.28; 95% confidence interval 1.25 to 1.31). Increasing serum digoxin level was also significantly associated with mortality (HR 1.19 per ng/ml increase; 95% confidence interval 1.05 to 1.35). This increased mortality risk with level was most pronounced in patients with lower predialysis serum potassium (K) levels (HR 2.53 [P = 0.01] for K <4.3 mEq/L versus HR 0.86 [P = 0.35] for K >4.6 mEq/L). In conclusion, digoxin use among patients who are on hemodialysis associates with increased mortality, especially among those with low predialysis K concentrations.
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10 MeSH Terms
"Inactive" excipients such as Cremophor can affect in vivo drug disposition.
Wandel C, Kim RB, Stein CM
(2003) Clin Pharmacol Ther 73: 394-6
MeSH Terms: ATP Binding Cassette Transporter, Subfamily B, Member 1, Cardiotonic Agents, Digoxin, Excipients, Humans, Pharmaceutical Preparations, Pharmacokinetics, Polyethylene Glycols
Added December 10, 2013
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8 MeSH Terms
Identification of functionally variant MDR1 alleles among European Americans and African Americans.
Kim RB, Leake BF, Choo EF, Dresser GK, Kubba SV, Schwarz UI, Taylor A, Xie HG, McKinsey J, Zhou S, Lan LB, Schuetz JD, Schuetz EG, Wilkinson GR
(2001) Clin Pharmacol Ther 70: 189-99
MeSH Terms: ATP Binding Cassette Transporter, Subfamily B, Member 1, Africa, African Continental Ancestry Group, Alleles, Anti-Allergic Agents, Area Under Curve, Cloning, Molecular, DNA Primers, Digoxin, Enzyme Inhibitors, Europe, European Continental Ancestry Group, Genes, MDR, Genetic Variation, Genotype, Haplotypes, Humans, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Sequence Analysis, DNA, Terfenadine, Time Factors
Show Abstract · Added March 27, 2014
MDR1 (P-glycoprotein) is an important factor in the disposition of many drugs, and the involved processes often exhibit considerable interindividual variability that may be genetically determined. Single-strand conformational polymorphism analysis and direct sequencing of exonic MDR1 deoxyribonucleic acid from 37 healthy European American and 23 healthy African American subjects identified 10 single nucleotide polymorphisms (SNPs), including 6 nonsynonymous variants, occurring in various allelic combinations. Population frequencies of the 15 identified alleles varied according to racial background. Two synonymous SNPs (C1236T in exon 12 and C3435T in exon 26) and a nonsynonymous SNP (G2677T, Ala893Ser) in exon 21 were found to be linked (MDR1*2 ) and occurred in 62% of European Americans and 13% of African Americans. In vitro expression of MDR1 encoding Ala893 (MDR1*1 ) or a site-directed Ser893 mutation (MDR1*2 ) indicated enhanced efflux of digoxin by cells expressing the MDR1-Ser893 variant. In vivo functional relevance of this SNP was assessed with the known P-glycoprotein drug substrate fexofenadine as a probe of the transporter's activity. In humans, MDR1*1 and MDR1*2 variants were associated with differences in fexofenadine levels, consistent with the in vitro data, with the area under the plasma level-time curve being almost 40% greater in the *1/*1 genotype compared with the *2/*2 and the *1/*2 heterozygotes having an intermediate value, suggesting enhanced in vivo P-glycoprotein activity among subjects with the MDR1*2 allele. Thus allelic variation in MDR1 is more common than previously recognized and involves multiple SNPs whose allelic frequencies vary between populations, and some of these SNPs are associated with altered P-glycoprotein function.
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22 MeSH Terms
Inhibition of P-glycoprotein-mediated drug transport: A unifying mechanism to explain the interaction between digoxin and quinidine [seecomments].
Fromm MF, Kim RB, Stein CM, Wilkinson GR, Roden DM
(1999) Circulation 99: 552-7
MeSH Terms: ATP Binding Cassette Transporter, Subfamily B, Member 1, Animals, Biological Transport, Active, Caco-2 Cells, Cardiovascular Agents, Digoxin, Drug Interactions, Drug Resistance, Multiple, Humans, Mice, Quinidine, Tissue Distribution
Show Abstract · Added December 10, 2013
BACKGROUND - Although quinidine is known to elevate plasma digoxin concentrations, the mechanism underlying this interaction is not fully understood. Digoxin is not extensively metabolized, but it is known to be transported by the drug efflux pump P-glycoprotein, which is expressed in excretory tissues (kidney, liver, intestine) and at the blood-brain barrier. Accordingly, we tested the hypothesis that inhibition of P-glycoprotein-mediated digoxin transport by quinidine contributes to the digoxin-quinidine interaction.
METHODS AND RESULTS - First, we demonstrated active transcellular transport of both digoxin and quinidine in cultured cell lines that express P-glycoprotein in a polarized fashion. In addition, 5 micromol/L quinidine inhibited P-glycoprotein-mediated digoxin transport by 57%. Second, the effect of quinidine on digoxin disposition was studied in wild-type and in mdr1a(-/-) mice, in which the gene expressing the major digoxin-transporting P-glycoprotein has been disrupted. Because the in vitro data showed that quinidine itself is a P-glycoprotein substrate, quinidine doses were reduced in mdr1a(-/-) mice to produce plasma concentrations similar to those in wild-type control animals. Quinidine increased plasma digoxin concentrations by 73.0% (P=0.05) in wild-type animals, compared with 19.5% (P=NS) in mdr1a(-/-) mice. Moreover, quinidine increased digoxin brain concentrations by 73.2% (P=0.05) in wild-type animals; by contrast, quinidine did not increase digoxin brain concentrations in mdr1a(-/-) mice but rather decreased them (-30.7%, P<0.01).
CONCLUSIONS - Quinidine and digoxin are both substrates for P-glycoprotein, and quinidine is a potent inhibitor of digoxin transport in vitro. The in vivo data strongly support the hypothesis that inhibition of P-glycoprotein-mediated digoxin elimination plays an important role in the increase of plasma digoxin concentration occurring with quinidine coadministration in wild-type mice and thus support a similar mechanism in humans.
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12 MeSH Terms
A randomized controlled trial of epoprostenol therapy for severe congestive heart failure: The Flolan International Randomized Survival Trial (FIRST).
Califf RM, Adams KF, McKenna WJ, Gheorghiade M, Uretsky BF, McNulty SE, Darius H, Schulman K, Zannad F, Handberg-Thurmond E, Harrell FE, Wheeler W, Soler-Soler J, Swedberg K
(1997) Am Heart J 134: 44-54
MeSH Terms: Aged, Angiography, Angiotensin-Converting Enzyme Inhibitors, Antihypertensive Agents, Cardiac Output, Cardiotonic Agents, Cause of Death, Digoxin, Diuretics, Epoprostenol, Exercise Tolerance, Female, Heart Failure, Humans, Infusions, Intravenous, Male, Middle Aged, Proportional Hazards Models, Pulmonary Wedge Pressure, Quality of Life, Risk Factors, Stroke Volume, Survival Rate, Vascular Resistance, Ventricular Dysfunction, Left, Walking
Show Abstract · Added February 28, 2014
This trial evaluated the effects of epoprostenol on patients with severe left ventricular failure. Patients with class IIIB/IV congestive heart failure and decreased left ventricular ejection fraction were eligible for enrollment if angiography documented severely compromised hemodynamics while the patient was receiving a regimen of digoxin, diuretics, and an angiotensin-converting enzyme inhibitor. We randomly assigned 471 patients to epoprostenol infusion or standard care. The primary end point was survival; secondary end points were clinical events, congestive heart failure symptoms, distance walked in 6 minutes, and quality-of-life measures. The median dose of epoprostenol was 4.0 ng/kg/min, resulting in a significant increase in cardiac index (1.81 to 2.61 L/min/m2), a decrease in pulmonary capillary wedge pressure (24.5 to 20.0 mm Hg), and a decrease in systemic vascular resistance (20.76 to 12.33 units). The trial was terminated early because of a strong trend toward decreased survival in the patients treated with epoprostenol. Chronic intravenous epoprostenol therapy is not associated with improvement in distance walked, quality of life, or morbid events and is associated with an increased risk of death.
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26 MeSH Terms
Effects of ATPase inhibitors on the response of HeLa cells to Helicobacter pylori vacuolating toxin.
Cover TL, Reddy LY, Blaser MJ
(1993) Infect Immun 61: 1427-31
MeSH Terms: Adenosine Triphosphatases, Anti-Bacterial Agents, Bacterial Toxins, Digoxin, Drug Synergism, HeLa Cells, Helicobacter pylori, Humans, In Vitro Techniques, Macrolides, Ouabain, Vacuoles
Show Abstract · Added March 5, 2014
Approximately 50% of Helicobacter pylori strains produce a toxin in vitro that induces vacuolation of eukaryotic cells. To determine whether ion transport pathways are important in the formation of toxin-induced vacuoles, HeLa cells were incubated with H. pylori toxin in the presence of nine different inhibitors of ion-transporting ATPases. Oligomycin, an inhibitor of predominantly F1F0-type ATPases, had no effect on toxin activity. Inhibitors of predominantly V-type ATPases, exemplified by bafilomycin A1, inhibited the formation of vacuoles in response to the H. pylori toxin and reversed the vacuolation induced by the toxin. In contrast, at concentrations of > or = 100 nM, ouabain and digoxin, inhibitors of the Na(+)-K+ ATPase, potentiated the activity of H. pylori toxin. The inhibitory effects of bafilomycin A1 could not be overcome by the potentiating effects of ouabain. These data suggest that intact activity of the vacuolar ATPase of eukaryotic cells is a critical requirement in the pathogenesis of cell vacuolation induced by H. pylori toxin and that vacuole formation by this toxin is associated with altered cation transport within eukaryotic cells.
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12 MeSH Terms
Prognostic implications of ventricular arrhythmias during 24 hour ambulatory monitoring in patients undergoing cardiac catheterization for coronary artery disease.
Califf RM, McKinnis RA, Burks J, Lee KL, Harrell FE, Behar VS, Pryor DB, Wagner GS, Rosati RA
(1982) Am J Cardiol 50: 23-31
MeSH Terms: Adrenergic beta-Antagonists, Ambulatory Care, Angina Pectoris, Arrhythmias, Cardiac, Cardiac Catheterization, Cardiac Output, Coronary Disease, Death, Sudden, Digoxin, Electrocardiography, Female, Heart Ventricles, Humans, Male, Middle Aged, Myocardial Contraction, Myocardial Infarction, Prognosis
Show Abstract · Added February 28, 2014
The prognostic importance of ventricular arrhythmias detected during 24 hour ambulatory monitoring was evaluated in 395 patients with and 260 patients without significant coronary artery disease. Ventricular arrhythmias were found to be strongly related to abnormal left ventricular function. A modification of the Lown grading system (ventricular arrhythmia score) was the most useful scheme for classifying ventricular arrhythmias according to prognostic importance. When only noninvasive characteristics were considered, the score contributed independent prognostic information, and the complexity of ventricular arrhythmias as measured by this score was inversely related to survival. However, when invasive measurements were included, the ventricular arrhythmia score did not contribute independent prognostic information. Furthermore, ejection fraction was more useful than the ventricular arrhythmia score in identifying patients at high risk of sudden death.
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18 MeSH Terms