Effect of Dietary Fiber on the Level of Free Hypoglycemic Agents in Vitro.

We studied the effect of dietary fibers (DFs) on the levels of free hypoglycemic agents in vitro, i.e., glimepiride and the biguanides buformin and metformin. The levels of free buformin and free metformin were not affected by mixtures of DFs, i.e., cellulose, chitosan, pectin (PE), and glucomannan (GM), in fluids of pH 1.2 and 6.8 (similar to the pH of the stomach and intestines, respectively). However, the free biguanide level was significantly reduced by mixing with PE or sodium alginate (AL), in water. The free glimepiride level was reduced in the mixture of AL, PE, and GM (in a solution with a pH of 6.8). The changes in aqueous AL solution pH seemed to reflect the free metformin levels. Therefore, the effects of DFs on free drug levels were dependent on drug type, hypoglycemic agent, and mixing solution. In this study, the oral regimen concentrations of the drug and DFs were used. Based on these results, it is important to consider the interactions between hypoglycemic agents and DFs.

Effect of dietary fibers on losartan uptake and transport in Caco-2 cells.

The objective of this study was to assess the effect of dietary fibers on the transport of losartan, an angiotensin II type 1 receptor blocker, in small intestinal cells. Using Caco-2 cells in vitro, losartan uptake and transport were evaluated in the presence of various fibers (cellulose, chitosan, sodium alginate and glucomannan). Dietary fibers caused a decrease in the uptake of losartan, with chitosan causing a significant reduction. Chitosan and glucomannan significantly reduced the transport of losartan, while cellulose or sodium alginate did not. Dietary fibers also reduced the level of free losartan; however, this did not correlate with the observed reduction in losartan uptake and transport. In summary, chitosan had the greatest inhibitory effect on losartan uptake and transport, and this potential interaction should be considered in patients taking losartan. Copyright © 2016 John Wiley & Sons, Ltd.

Effect of dietary fiber on the level of free angiotensin II receptor blocker in vitro.

The interaction between angiotensin II type 1 (AT1) receptor blockers (ARBs), such as losartan potassium (LO), candesartan (CA), and telmisartan (TE), and dietary fiber was studied as to the level of free ARB in vitro. When ARB was incubated with soluble (sodium alginate, pectin, and glucomannan) or insoluble (cellulose and chitosan) dietary fiber, the levels of free LO, TE, and CA decreased. This resulted only from mixing the dietary fiber with the ARBs and differed among the types of dietary fiber, and the pH and electrolytes in the mixture. The levels of free LO and TE tended to decrease with a higher concentration of sodium chloride in pH 1.2 fluid. These results suggest that it is important to pay attention to the possible interactions between ARBs and dietary fiber.

Oral mucosal adhesive films containing royal jelly accelerate recovery from 5-fluorouracil-induced oral mucositis.

Oral mucositis induced by chemotherapy or radiotherapy has an impact upon quality-of-life, is dose-limiting for chemotherapy, and causes considerable morbidity. We evaluated the effect of royal jelly (RJ) on 5-fluorouracil (5-FU)-induced oral mucositis in hamsters. Oral mucositis was induced in hamsters through a combination of 5-FU treatment and mild abrasion of the cheek pouch. RJ was contained in chitosan-sodium alginate film (RJ film). Films were attached to the oral mucosa and the healing process examined by measuring the area of mucositis, myeloperoxidase (MPO) activity, microscopic aspects, and RT-PCR for detection of pro-inflammatory cytokines (tumor necrosis factor-α, interleukin-1ß). Furthermore, we evaluated the radical-scavenging activity of RJ and generation of keratinocyte growth factor from human periodontal ligament fibroblasts. RJ films (10%, 30%) significantly improved recovery from 5-FU-induced damage, reduced MPO activity and the production of pro-inflammatory cytokines. Additionally, RJ showed radical-scavenging activity. These data suggest that topical application of films that contain RJ had a healing effect on the severe oral mucositis induced by 5-FU and that the effect was caused by the anti-inflammatory or anti-oxidative activities of RJ.

Intravenously administered 2'-deoxycytidine suppresses mouse myeloma tumor growth.

We examined the in vivo effects of intravenously administered 2'-deoxycytidine (dCyd) on tumor growth and survival time in mice bearing SP2/0-Ag14 (SP2/0) myeloma tumors. Administration of dCyd tended to decrease the tumor volume and significantly decreased the tumor weight. A single intravenous administration of dCyd significantly increased survival time of the tumor-bearing mice. The effect of dCyd on tumor growth was maintained for at least 1 week after the final administration. The net amount of dCyd in the kidney, liver, and spleen of the tumor-bearing mice increased 2.5 to 5.3 fold compared with the amount in non-tumor-bearing mice. Our results suggest that the increase in dCyd in the mice inoculated SP2/0 myeloma cells plays an important role for the growth suppression of the tumor.

Comparison of contamination levels on the exterior surfaces of vials containing platinum anticancer drugs in Japan.

Contamination of the external surface of anticancer drug vials supplied to hospital pharmacies has been recognized as a potential health hazard. The aim of this study was to investigate the levels of contamination on the exterior surface of vials containing platinum anticancer drugs in Japan. Platinum contamination on the exterior surface of vials containing cisplatin or carboplatin was examined using products commercially available in Japan. Cisplatin vials from 42 batches (2 drug contents, 10 products and 5 manufacturers) and carboplatin vials from 28 batches (3 drug contents, 7 products and 3 manufacturers) were used. Five vials were randomly sampled from each batch. Exterior contamination levels of 0.070-144 ng/vial as cisplatin and 0.21-1630 ng/vial as carboplatin were detected. Significant differences in the levels of contamination among the batch numbers were observed in 6 of 10 cisplatin products and 6 of 7 carboplatin products. Significant differences in the levels of contamination were observed in 3 cisplatin products with different contents of drug within the vials and 1 carboplatin product with different contents of drug within the vials. Significant differences in the contamination levels among the cisplatin manufacturers but not carboplatin manufacturers were observed. The degree of contamination of the carboplatin products was significantly higher than that of the cisplatin products. In conclusion, external contamination was confirmed in all cisplatin and carboplatin vials tested. The degree of contamination was different among different batch numbers, drug contents, manufacturers, and platinum anticancer drug.

Population pharmacokinetics of afatinib and exposure-safety relationships in Japanese patients with EGFR mutation-positive non-small cell lung cancer.

To investigate the exposure-safety relationships of afatinib in Japanese population, we performed population pharmacokinetics (PK) analysis of afatinib in Japanese advanced non-small cell lung cancer patients harboring epidermal growth factor receptor mutation. Plasma samples were collected at 0.5-1, 2-3, 8-12, and 24 h after oral afatinib (40 mg) administration on day 1 and day 8. Plasma afatinib concentrations were determined using high-performance liquid chromatography. Data was analyzed following the population approach and using the software Phoenix® NLMETM Version 7.0 software (Certara USA, Inc., Princeton, NJ, USA). From 34 patients, a total of 354 afatinib plasma concentration values were available for the population PK analysis. Significant covariates in the population PK model included aspartate aminotransferase and creatinine clearance on CL/F, and age and body mass index on V/F. Results of simulation based on final PK model indicated that hepatic impairment had a significant effect on afatinib levels in plasma after multiple dosing. Afatinib trough plasma concentrations on day 8 were higher in patients with adverse events of grade 3 or higher. The population PK analysis showed that hepatic impairment affected afatinib PK parameters and contributed to the high inter-patient variability and high plasma concentrations of afatinib following multiple treatments.

Pharmacokinetic and pharmacodynamic studies of drug interaction following oral administration of imipramine and sodium alginate in rats.

Recently, the use of health foods has increased due to growing interest in health maintenance. Previous in vitro studies have shown some drugs to be adsorbed by sodium alginate, a dietary fiber, and that such adsorption was marked with tricyclic antidepressants, such as imipramine. This study investigated the pharmacokinetic and pharmacological interactions between imipramine and sodium alginate in rats. The simultaneous administration of imipramine (30 mg/kg, oral (p.o.)) and sodium alginate (3.0%, p.o.) decreased the antidepressant-like activity of imipramine in a forced swimming test. In the rats administrated imipramine and 0.3%, 1.0%, or 3.0% sodium alginate, the geometric mean ratio of the Cmax values of imipramine was 72% [90% confidence intervals (CI) = 53-91%], 64% (90% CI = 47-80%), and 58% (90% CI = 50-67%), respectively. The geometric mean ratio of the AUC(0-6) values of imipramine were 68% (90% CI = 56-80%), 74% (90% CI = 60-89%), and 87% (90% CI = 73-102%), respectively. The decrease in Cmax and AUC(0-6) was judged to be significant with a 90% CI outside the 80-125% boundaries. In addition, the Tmax value of imipramine significantly increased (P < 0.05) by coadministration with 3.0% sodium alginate. These results suggested that simultaneous administration of sodium alginate decreased the serum concentration and pharmacological action of imipramine, through a delay in its absorption. Although the clinical relevance of these findings is unclear, it is important to pay considerable attention to the interactions between imipramine and sodium alginate.

Cerebrospinal Fluid Penetration Rate and Efficacy of Afatinib in Patients with EGFR Mutation-positive Non-small Cell Lung Cancer with Leptomeningeal Carcinomatosis: A Multicenter Prospective Study.

BACKGROUND: Afatinib is an effective first-line treatment for epidermal growth factor receptor (EGFR) mutation-positive advanced non-small cell lung cancer (NSCLC). However, few reports have addressed the influence of cerebrospinal fluid (CSF) penetration rate on the efficacy of afatinib in patients with central nervous system metastases. Therefore, we conducted a prospective multicenter trial to evaluate the CSF penetration rate and efficacy of afatinib in patients with EGFR mutation-positive NSCLC with leptomeningeal carcinomatosis. PATIENTS AND METHODS: Eleven patients with histologically-proven EGFR mutation-positive NSCLC with leptomeningeal carcinomatosis were enrolled in the study between April 2014 and November 2015. They were treated with afatinib (40 mg/day), and blood and CSF levels of afatinib were analyzed on day 8. The primary endpoint was CSF penetration rate. Secondary endpoints included the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). RESULTS: The median age of patients was 66 years. Five patients harbored an exon 19 deletion, three harbored a p.L858R point mutation, and three harbored an uncommon exon 18 mutation. The levels of afatinib in blood and CSF (mean±SD) were 233.26±195.40 nM and 3.16±1.95 nM, respectively. The CSF penetration rate was 2.45±2.91%. The ORR was 27.3% (three out of 11 patients), and two out of these three responders had uncommon EGFR mutations. The median PFS and OS were 2.0 and 3.8 months, respectively. CONCLUSION: The median CSF penetration rate of afatinib was higher than previously reported. Afatinib was effective against leptomeningeal carcinomatosis particularly in patients with NSCLC harboring uncommon EGFR mutations. The criteria for selecting a specific EGFR tyrosine kinase inhibitor for therapy of NSCLC should include its ability to penetrate CSF and its efficacy against specific mutation types.

[Acid-neutralizing capacity of over-the-counter gastrointestinal medications].

  There is little information regarding the acid-neutralizing capacity of over-the-counter (OTC) gastrointestinal medicines. In this study, we assessed the acid-neutralizing capacity of OTC and prescribed gastrointestinal drugs based on the Japanese Pharmacopoeia 16th Edition. The acid-neutralizing capacity of the OTC drugs was calculated using experimental results for the crude materials found in the prescribed drugs based on OTC antacid quantity. The measured acid-neutralizing capacities of the OTC drugs agreed with the respective calculated values. These results indicate that the acid-neutralizing capacity of OTC drugs labeled as an antacid without information on their capacity can be estimated based on the quantity and capacity of the antacid components.

Validated method using liquid chromatography-electrospray ionization tandem mass spectrometry for the determination of contamination of the exterior surface of vials containing platinum anticancer drugs.

Contamination of the exterior surface of vials of cytostatic drugs by the drugs themselves is a potential hazard to human health. This study developed a validated method using liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) for the determination of contamination of the exteriors of vials of cisplatin and carboplatin. Large Alpha® sampling swabs were employed to wipe the vial exterior. Cisplatin or carboplatin and gold(III) as an internal standard were derivatized by N,N-diethyldithiocarbamate (DDTC). Pt(DDTC)(3)(+) and Au(DDTC)(2)(+) were monitored by the respective transitions of m/z 639.3-490.9 and 493.0-345.0, respectively. Each separation was completed within 9 min using a 3 µm particle ODS-column. Calibration curves for cisplatin and carboplatin were linear over concentration ranges of 30-10,000 and 30-30,000pgvial(-1), respectively. The accuracies and precisions were 96.1-102.5% and within 8.2% for intra-assay and 99.6-103.3% and within 7.6% for inter-assay, respectively. Their lower limit of quantification was 30 pg vial(-1). Amounts of 0.17-17.0 ng vial(-1) as cisplatin and 0.48-794 ng vial(-1) as carboplatin were detected from the exterior surface of the vials. This validated method using LC-ESI-MS/MS for the determination of platinum anticancer drugs is helpful for monitoring contamination of the exterior surface of drug vials.

Changes in 2'-deoxycytidine levels in various tissues of tumor-bearing mice.

The nucleoside 2'-deoxycytidine (dCyd) increases in the plasma of cancer patients with poor prognoses. 5-fluorouracil (5FU) is one of the anti-cancer agents used in chemotherapy for patients whose plasma dCyd is elevated. We examined the free dCyd level in various tissues of mice, with and without tumors, and in mice with and without the administration of 5FU or of dCyd, and investigated the effects of dCyd in tumor-bearing animals. SP2/0-Ag14 mouse myeloma cells were transplanted subcutaneously into mice and 5FU or dCyd was administered intraperitoneally. Free dCyd was measured in blood and tissues by HPLC at two time points, once when mouse body weight was maximally decreased (1 day after the last administration of 5FU, day 16) and again when it returned to control level at 1 week after the last 5FU treatment (day 22). Results showed that in tumor-bearing mice, the level of dCyd (per g wet weight) increased in the spleen. The change in liver weight caused by the administration of 5FU correlated with the level of dCyd in the liver. Notably, the relative tumor volume and tumor weight was decreased in dCyd-treated animals in comparison with controls. In conclusion, the levels of dCyd were markedly altered in the tissues of the reticuloendothelial and lymphatic systems, such as liver and spleen, and dCyd apparently had the ability to inhibit tumor growth in the body.