tacrolimus and Atrial-Fibrillation

Digoxin toxicity is a major public health issue in the United States. Often this is due to drug interactions, and renal transplant recipients are at particularly high risk for drug-drug interactions. We present cases of 2 renal transplant recipients who received itraconazole and digoxin concomitantly and experienced digoxin toxicity. We have also reviewed the relevant literature to elicit the mechanisms, signs, and symptoms of digoxin toxicity in the presence of itraconazole. When clinicians know the potential drug-drug interactions that may lead to digoxin toxicity, the mechanisms of interaction, the signs and symptoms of digoxin toxicity, and appropriate monitoring, digoxin toxicity is largely preventable.

Topics: Anti-Arrhythmia Agents; Antifungal Agents; Atrial Fibrillation; Digoxin; Drug Interactions; Humans; Immunosuppressive Agents; Itraconazole; Kidney Transplantation; Male; Middle Aged; Tacrolimus

Autologous bone marrow-derived mesenchymal stromal cell (MSC) therapy and withdrawal of calcineurin inhibitors (CNIs) has been shown to improve systemic blood pressure control and left ventricular hypertrophy regression in kidney transplant recipients. In the current subanalysis, we aimed to evaluate the impact of this novel immunosuppressive regimen on the longitudinal changes of left atrial (LA) structure and function after kidney transplantation.. Kidney transplant recipients randomized to MSC therapy-infused at weeks 6 and 7 after transplantation, with complete discontinuation at week 8 of tacrolimus (MSC group)-or standard tacrolimus dose (control group) were evaluated with transthoracic echocardiography at weeks 4 and 24 after kidney transplantation. The changes in echocardiographic parameters were compared between the randomization arms using an analysis of covariance model adjusted for baseline variable.. Fifty-four participants (MSC therapy = 27; tacrolimus therapy = 27) were included. There was no significant interaction between the allocated treatment and the changes of indexed maximal LA volume (LAVImax) over the study period. Conversely, between 4 and 24 weeks post-transplantation, an increase in indexed minimal LA volume (LAVImin) was observed in control subjects, while it remained unchanged in the MSC group, leading to a significant difference between groups (P = .021). Additionally, patients treated with MSC therapy showed a benefit in LA function, assessed by a significant interaction between changes in LA emptying fraction and LA reservoir strain and the randomization arm (P = .012 and P = .027, respectively).. The combination of MSC therapy and CNIs withdrawal prevents progressive LA dilation and dysfunction in the first 6 months after kidney transplantation. LAVImin and LA reservoir strain may be more sensitive markers of LA reverse remodeling, compared with LAVImax.

Topics: Atrial Fibrillation; Heart Atria; Humans; Kidney Transplantation; Mesenchymal Stem Cells; Tacrolimus

Apixaban is metabolized by cytochrome P450 (CYP) 3A4 in the liver and intestine, undergoes direct intestinal excretion, and is a substrate to permeability glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transporters. We examined the drug interactions between cyclosporine and tacrolimus (combined inhibitors of CYP3A4, P-gp, and BCRP) with apixaban in 12 healthy adult male volunteers. Apixaban 10 mg was administered orally alone, in combination with 100 mg cyclosporine or 5 mg tacrolimus. Co-administration with cyclosporine resulted in increase in apixaban maximum plasma concentration (C

Topics: Adult; Anticoagulants; Area Under Curve; Atrial Fibrillation; Calcineurin Inhibitors; Cross-Over Studies; Cyclosporine; Drug Interactions; Graft Rejection; Healthy Volunteers; Humans; Male; Middle Aged; Organ Transplantation; Pyrazoles; Pyridones; Tacrolimus; Venous Thromboembolism; Young Adult

Topics: Aged; Antithrombins; Atrial Fibrillation; Conjunctival Diseases; Dabigatran; Drug Interactions; Drug Substitution; Eye Hemorrhage; Female; Humans; Immunosuppressive Agents; International Normalized Ratio; Liver Transplantation; Renal Insufficiency; Tacrolimus; Treatment Outcome

Topics: Aged; Amiodarone; Anti-Arrhythmia Agents; Atrial Fibrillation; Coronary Artery Bypass; Diabetic Nephropathies; Drug Interactions; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Long QT Syndrome; Male; Tacrolimus; Treatment Outcome

Topics: Aged; Amiodarone; Anti-Arrhythmia Agents; Atrial Fibrillation; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Follow-Up Studies; Glomerulonephritis; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Tacrolimus

Aging and pulmonary veins (PVs) play a critical role in the pathophysiology of atrial fibrillation. Abnormal Ca(2+) regulation and ryanodine receptors are known to contribute to PV arrhythmogenesis.. The purpose of this study was to investigate whether aging alters PV electrophysiology, Ca(2+) regulation proteins, and responses to rapamycin, FK-506, ryanodine, and ouabain.. Conventional microelectrodes were used to record action potential and contractility in isolated PV tissue samples in 15 young (age 3 months) and 16 aged (age 3 years) rabbits before and after drug administration. Expression of sarcoplasmic reticulum Ca(2+) ATPase (SERCA2a), ryanodine receptor, and Na(+)/Ca(2+) exchanger was evaluated by western blot.. Aged PVs had larger amplitude of delayed afterdepolarizations, greater depolarized resting membrane potential, longer action potential duration, and higher incidence of action potential alternans and contractile alternans with increased expression of Na(+)/Ca(2+) exchanger and ryanodine receptor and decreased expression of SERCA2a. Rapamycin (1,10,100 nM), FK-506 (0.01, 0.1, 1 microM), ryanodine (0.1, 1 microM), and ouabain (0.1, 1 microM) concentration-dependently increased PV spontaneous rates and the incidence of delayed afterdepolarizations in young and aged PVs. Compared with results in young PVs, rapamycin and FK-506 in aged PVs increased PV spontaneous rates to a greater extent and exhibited a larger delayed afterdepolarization amplitude. In PVs without spontaneous activity, rapamycin and FK-506 induced spontaneous activity only in aged PVs, but ryanodine and ouabain induced spontaneous activity in both young and aged PVs.. Aging increases PV arrhythmogenesis via abnormal Ca(2+) regulation. These findings support the concept that ryanodine receptor dysfunction may result in high PV arrhythmogenesis and aging-related arrhythmogenic vulnerability.

Topics: Age Factors; Animals; Atrial Fibrillation; Blotting, Western; Calcium; Dose-Response Relationship, Drug; Electrocardiography; Heart Atria; Microelectrodes; Myocardial Contraction; Ouabain; Pulmonary Veins; Rabbits; Ryanodine; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Signal Processing, Computer-Assisted; Sirolimus; Sodium-Calcium Exchanger; Tacrolimus; Tissue Culture Techniques