Interaction of miconazole oral gel with warfarin and cyclosporine in a patient with nephrotic syndrome.

It is well known that miconazole inhibits cytochrome P450 (CYP). However, this drug in oral gel form is believed not to absorb into systemic circulation, and therefore not to inhibit CYP. We experienced a case of increased oral bioavailability of warfarin and cyclosporine with this gel for treatment of oral candidiasis in a patient with nephrotic syndrome. Her prothrombin time-international normalized ratio (PT-INR) increased from 2 to 7.25, and the cyclosporine concentration at 2 h after final dosing (C2) increased from 633.8 to 1396.5 ng/ml 6 days after the coadministration. These problems were resolved by termination of the gel and switching to amphotericin B gargle. We further detected a significant amount of miconazole in her plasma, directly showing for the first time in a patient with this interaction that oral miconazole gel was actually absorbed into systemic circulation. Because warfarin and cyclosporine are often used simultaneously by nephrologists, caution should be applied with combined use of these drugs and oral miconazole gel to avoid adverse reaction.

Statins inhibited erythropoietin-induced proliferation of rat vascular smooth muscle cells.

Erythropoietin (EPO) directly stimulates the proliferation of vascular smooth muscle cells, and this is believed to be one of the mechanisms of vascular access failure of hemodialysis patients. However, precise mechanisms of the EPO-induced proliferation of vascular smooth muscle cells are not certain. HMG-CoA reductase inhibitors (statins) are primarily used to reduce cholesterol levels, but also exert other effects, including reno-protective effects. We evaluated the effect of several statins with various hydrophilicities on the EPO-induced proliferation of primary cultured rat vascular smooth muscle cells (VSMCs) in vitro. EPO significantly and concentration-dependently increased DNA synthesis as assessed by [³H]thymidine incorporation, cell proliferation as assessed by WST-1 assay, and activation of the p44/42MAPK pathway. Therapeutic doses of statins (pravastatin, simvastatin, atorvastatin and fluvastatin) in patients with hypercholesterolemia almost completely suppressed all of the EPO-induced effects in a concentration-dependent manner. Co-addition of mevalonic acid almost completely reversed the effects of statins. Statin alone did not affect the basal proliferation capacity of the cells. The effects were almost similar among the statins. We concluded that statins inhibited EPO-induced proliferation in rat VSMCs at least partly through their inhibition of HMG-CoA reductase activity. In the future, statins might prove useful for the treatment of EPO-induced hyperplasia of vascular access. Because the statins all showed comparable effects irrespective of their hydrophilicities, these effects might be a class effect.

Cranberry juice suppressed the diclofenac metabolism by human liver microsomes, but not in healthy human subjects.

AIM: To investigate a potential interaction between cranberry juice and diclofenac, a substrate of CYP2C9. METHODS: The inhibitory effect of cranberry juice on diclofenac metabolism was determined using human liver microsome assay. Subsequently, we performed a clinical trial in healthy human subjects to determine whether the repeated consumption of cranberry juice changed the diclofenac pharmacokinetics. RESULTS: Cranberry juice significantly suppressed diclofenac metabolism by human liver microsomes. On the other hand, repeated consumption of cranberry juice did not influence the diclofenac pharmacokinetics in human subjects. CONCLUSIONS: Cranberry juice inhibited diclofenac metabolism by human liver microsomes, but not in human subjects. Based on the present and previous findings, we think that although cranberry juice inhibits CYP2C9 activity in vitro, it does not change the pharmacokinetics of medications metabolized by CYP2C9 in clinical situations.

Dosing time-dependent effect of raloxifene on plasma fibrinogen concentration in ovariectomized rats.

The chronopharmacological effect of raloxifene, a selective estrogen-receptor modulator, was evaluated by repeated dosing of ovariectomized rats. Bilateral ovariectomy or sham operation was performed at age 12 wks, and animals were kept in rooms with a 12 h light-12 h dark cycle. Raloxifene (3 mg/kg, once daily for 10 wks) or vehicle was given repeatedly at either 2 h after lights-on (2 HALO) or 14 h after lights-on (14 HALO). Plasma fibrinogen concentration at the end of the study was reduced by the drug, and the reduction was significantly prominent in rats in whom the drug was dosed at 2 HALO rather than 14 HALO. Femur bone density decreased, and urinary excretion of deoxypyridinoline, an index of bone resorption capacity of osteoclasts, increased in ovariectomized animals at the end of the study. Treatment with raloxifene ameliorated these changes in a dosing time-independent manner. Serum calcium, ALT, and total protein concentrations at the end of the study also did not differ according to treatment regime, which indicates that protein synthesis and liver function may not contribute to the effects. This is the first study to determine dosing time-dependent changes in the efficacy of raloxifene in an animal model of osteoporosis. Because fibrinogen concentration is reported to be a marker of cardiovascular events, consideration of dosing time of raloxifene may be important to obtain a better cardioprotective effect of this medication when it is prescribed to postmenopausal women with osteoporosis.

Dosing time-dependent variation of bone resorption by cyclosporin A in rats' femurs.

The dosing time-dependent difference of bone resorption by cyclosporin A was determined in normal rats. Rats were kept in rooms with a 12-h light/dark cycle. Cyclosporin A (3 mg/kg, once a day) or vehicle was given at either 2 h after light on (2 HALO) or 8 HALO, 14 HALO, 20 HALO for 24 weeks. Serum and 4-h urine samples were obtained before and at 12 and 24 weeks after the treatment. Body weight, creatinine clearance, serum parathyroid hormone, the trough level of cyclosporin A in whole blood and urinary excretion of Ca and P were not changed by the drug at every any dosing time. Serum Ca and P concentrations by the vehicle treatment differed with the dosing time. Furthermore, increases of these two parameters by the drug varied with dosing time; most prominently at the 2 HALO dosing, and were not seen at the 8 and 14 HALO dosings. Degree of bone resorption of the femur determined by dual-energy X-ray absorption, also varied with dosing time, most prominently at 2 HALO and less prominently at 14 HALO. Increase of urine deoxypyridinoline excretion, a marker of osteoclast activity, by the drug was highest at 2 HALO and lowest at 14 HALO, however parathyroid hormone and osteocalcin concentrations after cyclosporin A treatment did not vary with dosing time. Reduction of urinary nitric oxide (NO) was most prominent at 2 HALO and negligible at 14 HALO. We concluded that cyclosporin A-induced bone resorption and serum Ca and P increases were varied with dosing time. Sensitivity of osteoclasts by the drug was the major mechanisms of the phenomenon, while differences in pharmacokinetics, the parathyroid gland, osteoblasts and renal handling of Ca and P did not contribute to the phenomenon.