digoxin and Tuberculosis--Pulmonary

Topics: Adult; Aged; Chronic Disease; Digoxin; Drug Therapy, Combination; Female; Hemodynamics; Humans; Male; Middle Aged; Nitroglycerin; Pulmonary Heart Disease; Tuberculosis, Pulmonary

Accumulating evidence supports the use of higher doses of rifampicin for tuberculosis (TB) treatment. Rifampicin is a potent inducer of metabolic enzymes and drug transporters, resulting in clinically relevant drug interactions. To assess the drug interaction potential of higher doses of rifampicin, we compared the effect of high-dose rifampicin (40 mg/kg daily, RIF40) and standard-dose rifampicin (10 mg/kg daily, RIF10) on the activities of major cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp). In this open-label, single-arm, two-period, fixed-order phenotyping cocktail study, adult participants with pulmonary TB received RIF10 (days 1-15), followed by RIF40 (days 16-30). A single dose of selective substrates (probe drugs) was administered orally on days 15 and 30: caffeine (CYP1A2), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), midazolam (CYP3A), and digoxin (P-gp). Intensive pharmacokinetic blood sampling was performed over 24 hours after probe drug intake. In all, 25 participants completed the study. Geometric mean ratios (90% confidence interval) of the total exposure (area under the concentration versus time curve, RIF40 versus RIF10) for each of the probe drugs were as follows: caffeine, 105% (96%-115%); tolbutamide, 80% (74%-86%); omeprazole, 55% (47%-65%); dextromethorphan, 77% (68%-86%); midazolam, 62% (49%-78%), and 117% (105%-130%) for digoxin. In summary, high-dose rifampicin resulted in no additional effect on CYP1A2, mild additional induction of CYP2C9, CYP2C19, CYP2D6, and CYP3A, and marginal inhibition of P-gp. Existing recommendations on managing drug interactions with rifampicin can remain unchanged for the majority of co-administered drugs when using high-dose rifampicin. Clinical Trials registration number NCT04525235.

Topics: Adult; Caffeine; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP2C9; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Dextromethorphan; Digoxin; Drug Interactions; Humans; Midazolam; Omeprazole; Rifampin; Tolbutamide; Tuberculosis, Pulmonary

New data on the pathogenesis of chronic cor pulmonale were obtained. The reduction of pulmonary capillaries at the site of the tuberculosis process beyond this site was found to contribute much to the development of pulmonary artery hypertension. Irreversible injuries to the vessels are due to both the pneumosclerotic changes and the specific circulating immune complexes (CIC) effects. Acting on the peripheral veins (in Koch's test), CICs influence the central hemodynamics, decreasing circulating blood volume by 30-40% and reducing cardiac output, thus resulting in deficit of the blood inflow to the right compartments of the heart. In this case the atrium functions at a higher load, like a suction pump, thus leading to cardiac hypertrophy. Peripheral vasodilators (apressin, nitrong) combined with cardiac glycosides (digoxin), favorably influencing the central hemodynamics, are recommended for the prevention and treatment of chronic cor pulmonale.

Topics: Chronic Disease; Digoxin; Drug Therapy, Combination; Hemodynamics; Humans; Nitrates; Pulmonary Heart Disease; Tuberculosis, Pulmonary

Serum drug concentration data from the first of the two patients described herein suggest that rifampin may directly increase the metabolism of quinidine and thereby negate the influence of quinidine on the serum digoxin concentration (SDC). Data on the second patient suggest that rifampin may directly increase the metabolism of digoxin producing lower SDC values. In both cases, the discontinuation of rifampin therapy appears to have allowed reversion toward prerifampin metabolism of both quinidine and digoxin.

Topics: Aged; Arrhythmias, Cardiac; Digoxin; Drug Interactions; Drug Therapy, Combination; Female; Humans; Kinetics; Middle Aged; Quinidine; Rifampin; Tuberculosis, Pulmonary

Topics: Adult; Digoxin; Drug Interactions; Female; Heart Failure; Humans; Renal Dialysis; Rifampin; Tuberculosis, Pulmonary

Topics: Antitubercular Agents; Child; Child, Preschool; Diagnosis, Differential; Digoxin; Diuretics; Endomyocardial Fibrosis; Female; Humans; Infant; Male; Pericardial Effusion; Prednisone; Tuberculosis, Cardiovascular; Tuberculosis, Pulmonary; Uganda

Topics: Chronic Disease; Digoxin; Humans; Hypertension, Pulmonary; Pulmonary Heart Disease; Tuberculosis; Tuberculosis, Pulmonary