Background:Persistent hypoalbuminemia is a predictor of death in long-term maintenance hemodialysis patients, although cardiovascular diseases remain the leading cause of death. A decreased serum antioxidant activity in maintenance hemodialysis patients may contribute to increased oxidative damage, and may be associated with accelerated atherosclerotic changes. Methods:The aim of this study was to examine the redox state of human serum albumin in maintenance hemodialysis patients by high-performance liquid chromatography (HPLC) using a fluorescence detector. Results: HPLC of human serum albumin on a Shodex-Asahipak ES-502N column at pH 4.85 showed a clear resolution of human mercaptalbumin (HMA) and nonmercaptalbumin (HNA), which are the reduced and oxidized forms of human serum albumin, respectively. The mean ± SD percentage of the HMA fraction of human serum albumin was significantly lower in maintenance hemodialysis patients than in age-matched normal subjects. The percentage of HMA increased 3–5 h after starting the hemodialysis and then decreased to subnormal levels. Conclusion: This suggests that serum albumin may be a major extracellular antioxidant in maintenance hemodialysis patients, and that hemodialysis may rescue serum albumin reduction by inducing intermolecular sulfhydryl-disulfide exchange reaction.
Purpose: Cytochrome P450 (CYP)2C19 polymorphisms may partly explain the variability of thalidomide concentration and adverse drug effects by altering its metabolism. To compare the genetic and clinical factors responsible for the adverse effects and efficacy of thalidomide treatment, we investigated CYP2C19 genetic polymorphisms in Japanese subjects. Materials and Methods: Variations in the CYP2C19 gene in 6 patients treated with thalidomide were analyzed. The dosage of thalidomide, concentrations of (R)-and (S)-thalidomide in whole blood, and clinical laboratory test results were used as pharmacokinetic and pharmacodynamic indices. Using genomic DNA, CYP2C19*2 and *3 allele frequencies were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays. Results: The frequencies of CYP2C19 PM and hetero EM (hetEM) genotypes in Japanese patients taking thalidomide were 2 (33.3%) and 4 (66.7%), respectively. The areas under the curve (AUC) of (R)-thalidomide were 3.42 and 5.33 μg·h/L, and those of (S)-thalidomide were 1.64 and 2.46 μg·h/L for hetEM and PM, respectively. Conclusions: This study provided new insights regarding the contribution of CYP2C19 gene variations to adverse responses to thalidomide. Genotyping of CYP2C19*2 and *3 can be considerably simplified by using KOD FX as a polymerase for prediction of adverse effects to thalidomide by the PCR-RFLP method. CYP2C19 PM patients tend to have high serum thalidomide concentrations.
The teratogenic effects of thalidomide have been studied for more than 50 years. However, there have been few studies of the pharmacokinetic changes occurring during thalidomide therapy. Thalidomide was originally developed as a sedative. However, thalidomide induces multiple birth defects when used in pregnant women. Thalidomide is now used in the treatment of multiple myeloma (MM) and erythema nodosum leprosum (ENL) in Japan. Rational use of thalidomide is problematic due to a lack of basic research regarding its mechanism of action and serum concentration/effect relationships. There are a number of hypotheses for pharmacokinetic changes in thalidomide therapy. Genetic factors including single nucleotide polymorphisms (SNPs) that change cytochrome P450 (CYP) activity and epigenetic regulation that modifies CYP expression levels may contribute to the changes in pharmacokinetics and adverse drug reactions (ADRs) of thalidomide. Environmental factors include the pharmacological context of drug-drug interactions and the physiological context of liver diseases. Liver and kidney diseases do not play important roles in pharmacokinetic changes or ADRs in thalidomide therapy. To date, most research has focused on teratogenic activity, while the impact of polymorphisms in genes encoding drug metabolic enzymes and drug-drug interactions could mediate ADRs. Here, we discuss clinical evidence of pharmacokinetic changes in thalidomide therapy.
Summary
What is known and objective
Azole antifungal drugs are often co‐administered with tacrolimus after allogeneic hematopoietic stem cell transplantation (HSCT). However, the influence of azole antifungal drugs on variation in tacrolimus pharmacokinetics when switching from intravenous tacrolimus (Tac‐iv) to once‐daily modified release tacrolimus (Tac‐MR) remains to be elucidated. This study was performed to evaluate the effects of oral azole antifungal drugs on variation in tacrolimus pharmacokinetics after conversion to Tac‐MR in HSCT patients.
Methods
Patients concomitantly receiving fluconazole (FLCZ) or voriconazole (VRCZ) along with tacrolimus were evaluated retrospectively. Blood tacrolimus concentrations before and after changing to oral administration were compared between FLCZ and VRCZ groups.
Results and discussion
A total of 52 patients (34 FLCZ and 18 VRCZ) were included in the analysis. There were no significant differences in the most recent daily dose (Div) and blood level (Civ) of Tac‐iv, Civ/Div, and ratio of daily dose of tacrolimus on the first to second day after changing to Tac‐MR (Dpo1‐2) to Div between FLCZ and VRCZ groups (P > 0.2). The trough levels of tacrolimus on the first to second day after switching to Tac‐MR (Cpo1‐2) and on the third to fifth day after the switch (Cpo3‐5) were significantly higher in the VRCZ group than the FLCZ group (P < 0.05). The values of (Civ/Div)/(Cpo1‐2/Dpo1‐2) and (Civ/Div)/(Cpo3‐5/Dpo3‐5) in the VRCZ group were significantly lower compared with those in the FLCZ group (P < 0.05). Furthermore, individual values of (Civ/Div)/(Cpo3‐5/Dpo3‐5) in the FLCZ group varied widely.
What is new and conclusion
Voriconazole increased blood tacrolimus level more markedly than FLCZ after switching to Tac‐MR, whereas FLCZ caused a large variation in tacrolimus blood level. These results suggest that therapeutic monitoring of tacrolimus after the switch may need to be performed carefully considering that orally co‐administered VRCZ and FLCZ exhibit different change in blood tacrolimus level just after the switch.
Vaginal calculi are rarely encountered and are often misdiagnosed as bladder calculi because of the difficulty in achieving an appropriate diagnosis. Most vaginal calculi result from the presence of a urethrovaginal fistula; those occurring in the absence of such fistulas are extremely rare. We present a case of a 42-year-old bedridden woman with mental and physical disabilities who had been misdiagnosed for a decade as having a bladder calculus. We removed the calculus nonsurgically and the analyzed the components. Results demonstrated the presence of a primary vaginal calculus. Vaginal calculi may occasionally occur in disabled women, but further investigation of the etiology of such calculi is required.
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