Tacrolimus successfully used to control refractory eosinophilic granulomatosis with polyangiitis complicated by invasive aspergillosis and chronic hepatitis B

While several alternatives to cyclophosphamide have been proposed for refractory eosinophilic granulomatosis with polyangiitis (EGPA), therapeutic options are limited in patients with chronic infections. We report a case of refractory EGPA complicated by invasive aspergillosis and chronic hepatitis B. Although multiple immunosuppressants, including cyclophosphamide, were not effective, tacrolimus was used successfully to control disease without exacerbating concomitant infections in the long term. Tacrolimus could be an alternative choice in the treatment of EGPA, especially when aggressive immunosuppression is unfeasible.     

Novel evidence‐based colchicine dose‐reduction algorithm to predict and prevent colchicine toxicity in the presence of cytochrome P450 3A4/P‐glycoprotein inhibitors

Objective

Drug–drug interactions can limit the safety of colchicine for treating rheumatic diseases. Seven separate drug–drug interaction (DDI) studies were performed to elucidate the in vivo effects of concomitant treatment with colchicine and known inhibitors of cytochrome P450 3A4 (CYP3A4)/P‐glycoprotein (cyclosporine, ketoconazole, ritonavir, clarithromycin, azithromycin, verapamil ER [extended release]), and diltiazem ER) on the pharmacokinetics of colchicine. The objective was to develop colchicine‐dosing algorithms with improved safety.

Methods

All studies were open‐label, non‐randomized, single‐center, one‐sequence, two‐period DDI experiments, using two 0.6‐mg doses of colchicine, separated by a minimum 14‐day washout period, followed by administration of the approved on‐label regimen of known CYP3A4/P‐glycoprotein inhibitors. Plasma concentrations of colchicine, but not the reference CYP3A4/P‐glycoprotein inhibitors, were determined, and the pharmacokinetic parameters were calculated.

Results

The ratios of the maximum concentration and area under the curve from time 0 to infinity for colchicine plus CYP3A4/P‐glycoprotein inhibitors versus colchicine alone were >125% across all studies, with the exception of studies involving azithromycin. Significant DDIs were present when single doses of colchicine were coadministered with most of the selected CYP3A4/P‐glycoprotein inhibitors. Recommended colchicine dose reductions of 33–66% for the treatment of acute gout and 50–75% for prophylaxis were calculated for concomitant therapy with each agent, with the exception of no dose adjustment when colchicine is used in combination with azithromycin.

Conclusion

These studies provide quantitative evidence regarding drug interactions and necessary adjustments in the dose of colchicine if colchicine treatment is continued during therapy with multiple CYP3A4/P‐glycoprotein inhibitors. We demonstrated the need for specific reductions in the dose of colchicine when it is used in combination with 2 broadly prescribed calcium channel blockers (verapamil ER and diltiazem ER) and that the dose of colchicine does not need to be adjusted when it is used in combination with azithromycin.

     

Early down‐regulation of cytochrome P450 3A and 2E1 in the regenerating rat liver is not related to the loss of liver mass or the process of cellular proliferation

Abstract: Aims/Background: Conflicting data have been reported concerning the modification of cytochrome P450 expression in the regenerating liver. Ligation of branches of the portal vein (PBL) perfusing 70% of the liver parenchyma, which produces regeneration and atrophy within the same liver, constitutes an ideal model to study the relative specificity of the early events in the regenerating liver and their relationship to the loss of liver mass. Methods: In this PBL model and in sham models, we studied the expression and the metabolic activities of two major cytochromes, CYP3A and CYP2E1, and the expression of inducible nitric oxide synthase protein (iNOS). They were simultaneously measured in the atrophying and regenerating liver lobes following PBL using Western Blot and HPLC methods. Results: The metabolic activities of both cytochromes were transiently and simultaneously down‐regulated in the regenerating and atrophying lobes during the first 2–5 h after PBL. No significant modification was observed at the protein level. In contrast, iNOS protein was significantly induced in both lobes. Similar results were observed after sham operation. Conclusions: The reduction of these CYP activities in both lobes after PBL and in sham livers suggests that other mechanisms than the regenerating process itself or the reduction of the liver mass might account for such down‐regulation during the early phase of liver regeneration. The activation of nitric oxide (NO) and/or pro‐inflammatory cytokine production provides clues to pathways liable to affect the CYP activities in the regenerating liver.