Pharmacogenetics oriented therapeutic drug monitoring of digoxin in critically ill patients

This study was performed to outline the different MDR-1 [Multi-Drug Resistance-1] genotypes in a sample of 37 Egyptian patients suffering from atrial fibrillation [AF] and/or congestive heart failure [CHF] and are using digoxin, to assess the role of MDR-1 genotypes polymorphism in affecting steady state serum digoxin therapeutic levels, and studying the consequences on patients' clinical outcome. Two venous blood samples were drawn from each patient; the 1[st] sample was taken, on admission, for DNA extraction and genotyping and the 2 [nd] was taken, 6 hours post dose after reaching steady state concentration, for serum digoxin assay. Serum digoxin. levels were assayed using EMIT 2000 analyzer, and MDR-1 genotyping was done using polymerase chain reaction-restriction fragment length polymorphism [PCR-RFLP] technique. Twenty patients [54.1%] showed serum digoxin levels within the therapeutic range, 12 patients [32.4%] showed serum digoxin levels under the minimum effective concentration [p< 0.9 ng/ml], while 5 patients [13.5%] showed serum digoxin levels over maximum safety concentration [> 2 ng/ml], with P value of 0.0001 among the three groups. MDR-1 genotyping revealed ten patients [27%] carrying the homozygous mutant TT genotype, 27 patients [73%] carrying the heterozygous mutant CT genotype, with no patient showing the wild CC genotype. Allelic distribution showed 42% for the wild type C allele while 58% for the homozygous mutant T allele. Patients carrying the homozygous mutant TT genotype showed significantly lower serum digoxin levels compared with those carrying the heterozygous mutant CT genotype [P value: 0.009]. Patients with significant improvement carried the CT genotype and had serum digoxin levels within the therapeutic range. In conclusion, patients with different MDR-1 genotypes had variations in their serum digoxin levels and identification of MDR-1 variations was found useful in predicting therapy outcome. We recommend further extensive work on large samples to study the important role of MDR-1 gene in affecting the disposition of different substrates, to be able for individualizing them according to the patients' genetic profile in order to improve drug therapy and reduce inter-patient variability

Clinical evaluation of aceis in treatment of congestive heart failure

This trial was performed to evaluate and compare the efficacy of angiotensin converting enzyme inhibitors [ACEIs] in the treatment of congestive heart failure [CHF]. The selected ACEIs were captopril [as an example of direct acting drugs with short duration], lisinopril [as an example of direct acting drugs with long duration] and ramipril [as an example of prodrugs]. The drugs were evaluated in sixty two patients with New York Heart Association functional class Ill and IV despite treatment with digoxin and diuretics. After baseline assessment and adjustment of digoxin and diuretic dosages to the optimal regimen, patients were randomly assigned to treatment with 25mg captopril [increased to 50mg] as 2 divided doses [20 patients], 5mg lisinopril [increased to 10mg] as a single dose [13 patients], 2.5mg ramipril [increased to 5mg] as 2 divided doses [18 patients] or placebo [11 patients] in a blind fashion for a period of 3 months. Lisinopril after the treatment period although, it improved dyspnea and fatigue, it didn't produce any significant changes as regards orthopnea or echocardiography. Both captopril and ramipril after the treatment period significantly improved dyspnea, fatigue and orthopnea. Also, they significantly increased each of the left ventricular ejection fraction and shortening fraction. Captopril didn't influence renal function, however, ramipril unlike captopril significantly increased serum creatinine and blood urea nitrogen. In conclusion, we prefer the short acting ACEI captopril as adjuvant therapy in the treatment of CHF as it was clinically effective and tolerable