An update on overcoming MDR1-mediated multidrug resistance in cancer chemotherapy

The intrinsic or acquired resistance to anticancer drugs remains one of the most significant factors impeding the progress of cancer chemotherapy. This phenomenon often involves simultaneous resistance to other anticancer drugs that differ in their chemical structure and mode of action and are not even used in chemotherapy. This phenotype has been called multidrug resistance (MDR). Although the cellular basis underlying MDR is not fully understood, several factors mediating therapy resistance in tumors have been proposed. One of the mechanisms leading to chemoresistance of tumor cells is the increased activity of transporter proteins. The best-characterized transporter protein is MDR1/P-glycoprotein, and a number of clinical investigations have suggested that its intrinsic or acquired overexpression resulted in a poor clinical outcome of chemotherapy. Various types of compounds and techniques for the reversal of MDR1/P-glycoprotein-mediated MDR have been developed, and efforts have concentrated on the inhibition of function and suppression of expression. This review summarizes the current state of knowledge of MDR1/P-glycoprotein and the modulation of MDR by targeting MDR1/P-glycoprotein.     

MDR1 C3435T polymorphism is predictive of later onset of ulcerative colitis in Japanese

Recently, a silent polymorphism of C3435T of the MDR1 gene, encoding the multidrug resistant transporter MDR1/P-glycoprotein, has been found to be associated with susceptibility to ulcerative colitis (UC), but this remains controversial. This study was conducted to find a possible reason for the discrepancies, and it was suggested that the age of onset was important for the association, namely, C3435T was predictive of susceptibility to later onset UC, but not for early onset UC. Linkage disequilibrium of C3435T with T-129C, C1236T and G2677A, T was suggested to be altered in UC, but the analysis of their haplotype provided no advantage in terms of prediction over that with only C3435T. The effect of C3435T on susceptibility could not be explained by that on mRNA expression in rectal mucosa, but it was greater in the C(3435)-noncarriers in the early onset group, allowing the individualization of steroid-based pharmacotherapy.     

Comparison of In Vivo Transportability of Anti-Methicillin-Resistant Staphylococcus aureus (MRSA) Agents Into Intracellular and Extracellular Tissue Spaces in Rats

The pathogenic bacterium Staphylococcus aureus can penetrate host cells. However, intracellular S. aureus is not considered during antimicrobial agent selection in clinical chemotherapy because of the lack of information about drug transportability into cells in vivo. We focused on agents used to treat methicillin-resistant S. aureus (MRSA) (vancomycin, arbekacin, linezolid, and daptomycin) and indirectly assessed the drug levels in intracellular compartment using plasma, tissue homogenates, and interstitial fluid (ISF) samples from the skin of rats using the microneedle array technique. Lower drug levels were observed in the ISF than in the plasma for daptomycin but extracellular and intracellular drug levels were comparable. In contrast, vancomycin, arbekacin, and linezolid showed higher concentrations in the ISF than in the plasma. Intracellular transport was estimated only for arbekacin. Stasis of vancomycin in the ISF was also observed. These results suggest that both low vancomycin exposure against intracellular S. aureus infection and long-term subinhibitory drug levels in the ISF contribute to the failure of treatment and emergence of antibiotic resistance. Based on its pharmacokinetic characteristics in niche extravascular tissue spaces, arbekacin may be suitable for achieving sufficient clinical outcomes for MRSA infection because the drug is widely distributed in extracellular and intracellular compartments.     

Change in pharmacokinetics of model compounds with different elimination processes in rats during hypothermia

We compared the pharmacokinetics of model compounds with different elimination processes between hypothermic and normothermic rats, to obtain basic information concerning drug therapy during hypothermia. Male Wistar rats were anesthetized with sodium pentobarbital and kept at temperatures of 37 degrees C (normothermic group) by heat lamp, and 32 degrees C or 28 degrees C (hypothermic group) by external cooling. We chose phenolsulfonphthalein (PSP), indocyanine green (ICG) and fluorescein isothiocyanate (FITC)-dextran (FD-4, Mw 4400) as model compounds to determine changes in clearance pathways during hypothermia therapy. The plasma concentrations of PSP as biliary, urinary and metabolic elimination type were increased significantly in the hypothermic group (32 degrees C, 28 degrees C) after i.v. administration at a dose of 1 mg, compared to the normothermic group (37 degrees C). Each PSP clearance (bile, urine and metabolites) in the hypothermic group was decreased, suggesting an influence of hypothermia on the active elimination process. The decreasing tendency was marked at a temperature of 28 degrees C. Moreover, the plasma concentrations of ICG as the biliary excretion type after i.v. administration to the hypothermic rats at a dose of 1 mg were higher with more than 50% decrease in the total body clearance compared to normothermic rats. On the other hand, there was almost no difference in the i.v. pharmacokinetics of FD-4 as the urinary excretion type between 37 degrees C and 32 degrees C. However, renal clearance of FD-4 was significantly decreased at a temperature of 28 degrees C. Accordingly, the change in pharmacokinetics of a drug in the hypothermic group could differ with the elimination processes.     

Association of cumulative cyclosporine dose with its irreversible nephrotoxicity in Japanese patients with pediatric-onset autoimmune diseases

Cyclosporine (CsA)-induced nephrotoxicity can become a major obstacle to continuous use. The aim of this study was to optimize CsA dose to avoid its irreversible nephrotoxicity. Twenty-three Japanese patients with pediatric-onset systemic lupus erythematosus or idiopathic nephrotic syndrome, who were maintained in a stable condition by oral dosing of CsA microemulsion, were enrolled in this study. The patients were stratified into 3 groups; those with no, reversible, and irreversible nephrotoxicity, according to periodically performed renal pathohistological examinations. A higher concentration of CsA in blood (p=0.002-0.011) and a longer duration of CsA treatment (p=0.002) were risk factors for irreversible nephrotoxicity, and the cumulative CsA dose, the product of the maintenance dose and duration of CsA treatment, was predictive of nephrotoxicity (p=0.036). The maximum target blood concentration at 2 h post-dose, C(2), to avoid CsA-induced irreversible nephrotoxicity was 700 ng/ml, although the cumulative CsA dose of 4850 mg/kg would result in a 50% probability of nephrotoxicity.     

Adverse event profiles of 5-fluorouracil and capecitabine: data mining of the public version of the FDA Adverse Event Reporting System, AERS, and reproducibility of clinical observations

Objective: The safety profiles of oral fluoropyrimidines were compared with 5-fluorouracil (5-FU) using adverse event reports (AERs) submitted to the Adverse Event Reporting System, AERS, of the US Food and Drug Administration (FDA).Methods: After a revision of arbitrary drug names and the deletion of duplicated submissions, AERs involving 5-FU and oral fluoropyrimidines were analyzed. Standardized official pharmacovigilance tools were used for the quantitative detection of signals, i.e., drug-associated adverse events, including the proportional reporting ratio, the reporting odds ratio, the information component given by a Bayesian confidence propagation neural network, and the empirical Bayes geometric mean.Results: Based on 22,017,956 co-occurrences, i.e., drug-adverse event pairs, found in 1,644,220 AERs from 2004 to 2009, it was suggested that leukopenia, neutropenia, and thrombocytopenia were more frequently accompanied by the use of 5-FU than capecitabine, whereas diarrhea, nausea, vomiting, and hand-foot syndrome were more frequently associated with capecitabine. The total number of co-occurrences was not large enough to compare tegafur, tegafur-uracil (UFT), tegafur-gimeracil-oteracil potassium (S-1), or doxifluridine to 5-FU.Conclusion: The results obtained herein were consistent with clinical observations, suggesting the usefulness of the FDA''s AERS database and data mining methods used, but the number of co-occurrences is an important factor in signal detection.     

Fulminant Japanese spotted fever--the second fatal case in Japan

A 77-year-old woman who have no past history, was admitted in a local hospital in Muroto City, Kochi, Japan, after several days of fever and severe general fatigue and generalized skin erythema. She was suspected to have Japanease spotted fever, which was a local pandemic disease. She was treated with minocycline immediately. The next day, she had consciousness disturbance and low blood pressure. Laboratory findings indicated disseminated intravascular coagulation (DIC) and multiple organ failure. She was referred to our hospital. An eschar was identified in the back of It. femur. Treatment included minocycline, ciprofloxain, gabexate mesilate, methylprednisolone, hemodialysis and mechanical ventilation. In spite of the avobe treatment, she died 3 days after admission of the local hospital. Though the serological test showed no positive antibody titer against Rickettsia japonica, Rickettsia japonica was isoleted from blood culture, to confirm Japanese spotted fever, Japanese spotted fever is generaly a curative disease with early diagnosis and minocycline. In this case, the patient died 3 days after proper diagnosis and treatment was started. We reported the second fatal Japanese spotted fever case in Japan.     

Impact of clarithromycin resistance and CYP2C19 genetic polymorphism on treatment efficacy of Helicobacter pylori infection with lansoprazole- or rabeprazole-based triple therapy in Japan

OBJECTIVE: Helicobacter pylori treatment failure is thought to be due mainly to polymorphic cytochrome P450 2C19 (CPY2C19) genetic polymorphism, associated with proton pump inhibitor metabolism, and antimicrobial susceptibility. This report has ascertained which was more important, CPY2C19 polymorphism or antimicrobial susceptibility, when using 1-week lansoprazole-based or rabeprazole-based triple therapy in Japan. DESIGN: An open, randomized, parallel group study. SETTING: One hundred and forty-five subjects with H. pylori-positive gastritis or peptic ulcers were randomly assigned to receive 30 mg lansoprazole twice daily (LAC group), 10 mg rabeprazole twice daily (RAC20 group), or 20 mg rabeprazole twice daily (RAC40 group), with 1000 mg amoxicillin twice daily and 400 mg clarithromycin twice daily for 1 week. Antimicrobial resistance testing was performed by E-test. More than 4 weeks after completion of treatment, H. pylori status was assessed by 13C-urea breath test, histology, and culture. RESULTS: Cure rates expressed as intention-to-treat and per-protocol analyses, respectively, were 79.6 and 83.0% with LAC, 85.4 and 89.1% with RAC20, and 83.3 and 88.9% with RAC40. In the case of clarithromycin-sensitive strains, the cure rates were more than 97%, regardless of CPY2C19 polymorphism. However, treatment succeeded in only one out of 16 clarithromycin-resistant strains. CONCLUSIONS: The key to successful eradication of H. pylori, using lansoprazole or rabeprazole with clarithromycin and amoxicillin, is clarithromycin susceptibility, not CPY2C19 polymorphism.     

Pharmacokinetics-based optimal dose-exploration of mycophenolate mofetil in allogeneic hematopoietic stem cell transplantation

For better clinical outcomes of mycophenolate mofetil (MMF) in allogeneic hematopoietic stem cell transplantation (alloSCT), higher mycophenolic acid (MPA) plasma levels are proposed to be desirable. Here, we investigate the optimal MMF dosing strategy based on pharmacokinetic studies in 20 Japanese alloSCT patients. The first 11 patients received MMF twice daily at an escalated dose from 15 mg/kg, according to real-time pharmacokinetic monitoring of the total MPA area under the curve (AUC). In the subsequent nine patients, MMF was given at a fixed dose of 1,000 mg three-times daily. The pharmacokinetic data revealed that the dose escalation in each individual did not always increase the AUC. In contrast, the increase of dosing frequency could statistically keep higher MPA plasma levels, as reflected in higher concentration at steady state (C (ss)) or trough value (C (trough)). There was no symptomatic adverse event in both groups. These results suggest that MMF administration of every 8 h after alloSCT would be better to maintain higher MPA plasma levels than that of every 12 h even in the same daily dose. Further studies are necessary to confirm the clinical benefit of MMF to prevent graft failure, as well as severe aGVHD.