Omeprazole- and Esomeprazole-associated Hypomagnesaemia: Data Mining of the Public Version of the FDA Adverse Event Reporting System

Objective: Case reports showing that proton-pump inhibitors (PPIs), omeprazole and esomeprazole, can cause hypomagnesaemia have been accumulating since 2006. In this study, the reports submitted to the Adverse Event Reporting System (AERS) of the US Food and Drug Administration (FDA) were evaluated to assess omeprazole and esomeprazole in terms of susceptibility to hypomagnesaemia

Oxaliplatin up-regulated the function and expression of P-glycoprotein/MDR1 in porcine kidney epithelial LLC-PK cells

The purpose of this study was to clarify the effects of oxaliplatin on the function and expression of the multidrug efflux transporter P-glycoprotein/MDR1 in a porcine kidney epithelial cell line, LLC-PK, as a renal tubular epithelial model. LLC-PK cells were pretreated with or without oxaliplatin for 48 h, and the growth inhibitory effects of a MDR1 substrate, paclitaxel, and the transport of a MDR1 substrate, Rhodamine123, were assessed. The level of MDR1 mRNA and protein was also examined in the cells treated with or without oxaliplatin for 48 h using RT-PCR and immunoblotting. In the present study, the pretreatment with oxaliplatin tended to suppress the growth inhibitory effects of paclitaxel in LLC-PK cells, presumably by accelerating the functions of MDR1. In addition, the uptake of Rhodamine123 was reduced significantly by pretreatment with oxaliplatin, and the efflux of Rhodamine123 from LLC-PK cells was enhanced significantly. These accelerated functions were supported by the suppression of Rhodamine123 s transport by a representative MDR1 substrate/inhibitor, ciclosporin, at 10 µM. The exposure to oxaliplatin for 48 h resulted in an increase in the expression of MDR1 in LLC-PK cells. These findings were similar to those obtained with cisplatin, a nephrotoxic drug. In conclusion, the present findings suggested that transient exposure for 48 h to oxaliplatin caused the up-regulation of MDR1 function and expression in LLC-PK cells, as was the case for cisplatin

TNFRSF1B A1466G genotype is predictive of clinical efficacy after treatment with a definitive 5-fluorouracil/cisplatin-based chemoradiotherapy in Japanese patients with esophageal squamous cell carcinoma

<p>Abstract</p> <p>Background</p> <p>Currently definitive 5-fluorouracil (5-FU)/cisplatin (CDDP) -based chemotherapy is recognized as one of the most promising treatments for esophageal cancer. A series of studies performed found genetic polymorphisms and the plasma concentration of 5-FU to be predictive of acute severe toxicities and clinical response. Genetic polymorphisms of <it>tumor necrosis factor (TNF) -α </it>and its surface receptors, <it>TNFRSF1A </it>and <it>TNFRSF1B </it>have been examined in terms of susceptibility to various cancers. In this study, genetic polymorphisms of <it>TNFRSF1B </it>gene were evaluated Japanese esophageal squamous cell carcinoma (ESCC) patients treated with the definitive 5-FU/CDDP-based chemoradiotherapy and their predictive values of prognosis or severe acute toxicities were assessed.</p> <p>Methods</p> <p>Forty-six patients with ESCC were treated with the definitive 5-FU/CDDP-based chemoradiotherapy, one course of which consisted of the continuous infusion of 5-FU for days 1-5 and 8-12, the infusion of CDDP on days 1 and 8, and the radiation at 2 Gy/day on days 1-5, 8-12, and 15-19, with a second course repeated after 2-week interval. Genetic polymorphisms of a TNF-α receptor <it>TNFRSF1B </it>gene were determined by a TaqMan^®MGB probe-based polymerase chain reaction.</p> <p>Results</p> <p>The genotype of <it>TNFSR1B </it>A1466G, but not M196R/T587G or C1493T, was found to be predictive of clinical response, i.e., a complete response or not (p = 0.040). Clinical response was predicted by tumor size (p = 0,002), lymph node metastasis (p = 0.007), distant metastasis (p = 0.001) and disease stage (p < 0.001), but <it>TNFRSF1B </it>A1466G genotype was independent of these factors.</p> <p>Conclusions</p> <p>Genetic polymorphism of <it>TNFRSF1B </it>A1466G was found to be predictive response in Japanese ESCC patients with a definitive 5-FU/CDDP-based chemoradiotherapy. Further clinical investigation with a large number of patients or experiments in vitro should be performed to assess the predictive value of <it>TNFRSF1B </it>A1466G genotype after chemoradiotherapy.</p

Effects of plasma concentrations of 5-fluorouracil on long-term survival after treatment with a definitive 5-fluorouracil/cisplatin-based chemoradiotherapy in Japanese patients with esophageal squamous cell carcinoma

<p>Abstract</p> <p>Background</p> <p>A substantial body of literature has accumulated during the past 20 years showing the plasma concentrations of 5-fluorouracil (5-FU) to correlate with clinical response and/or toxicity in colorectal cancer, and head and neck cancer, but little information is available concerning effects on long-term survival. Here, Japanese patients with esophageal squamous cell carcinoma (ESCC) were followed up for 5 years after treatment with a definitive 5-FU/cisplatin (CDDP)-based chemoradiotherapy (CRT), and the association between prognosis and the plasma concentration of 5-FU was evaluated.</p> <p>Methods</p> <p>Forty-nine patients with ESCC, who were treated with a definitive 5-FU/CDDP-based CRT, were enrolled. A course consisted of the continuous infusion of 5-FU at 400 mg/m²/day for days 1-5 and 8-12, the infusion of CDDP at 40 mg/m²/day on days 1 and 8, and the radiation at 2 Gy/day on days 1 to 5, 8 to 12, and 15 to 19, with a second course repeated after a 2-week interval. Plasma concentrations of 5-FU were determined by high performance liquid chromatography at 5:00 PM on days 3, 10, 38 and 45, and at 5:00 AM on days 4, 11, 39 and 46.</p> <p>Results</p> <p>The overall 5-year survival rate was 42.9%. Age (P = 0.020), body weight (P = 0.019), and disease stage (P = 0.048) affected the survival, and the survival depended on the clinical response assessed at 1 month after the treatment (P = 0.001). Higher plasma concentrations of 5-FU resulted in a better clinical response (P = 0.043), and trended to prolong survival (P = 0.321).</p> <p>Conclusions</p> <p>The long-term survival after treatment with a definitive 5-FU/CDDP-based CRT possibly depends on the plasma concentrations of 5-FU, and further clinical studies with a larger number of cases are needed to clarify the relationship between them.</p

Replacement of cisplatin with nedaplatin in a definitive 5-fluorouracil/cisplatin-based chemoradiotherapy in Japanese patients with esophageal squamous cell carcinoma

Objective: The effects of replacing cisplatin (CDDP) with cis-diammineglycolatoplatinum (nedaplatin, NDP), a second-generation platinum complex, on the pharmacokinetics of 5-fluorouracil (5-FU) were investigated in Japanese patients with esophageal squamous cell carcinoma, who were treated with a definitive 5-FU/CDDP-based chemoradiotherapy

Effect of instillation method on the absorption of phenolsulphonphthalein as a model drug from the liver and small intestinal serosal surface in rats

The aim of this study is to examine the effect of the instillation method on absorption of a drug from the liver and small intestinal serosal surface in rats. We performed continuous microinstillation via an infusion pump and bolus instillation via a syringe. Phenol red as a model was absorbed after continuous microinstillation of 2.35 mg in 235 ?L for 5 min on the liver and small intestinal serosal surface in rats with a significantly higher AUC of the plasma concentration profile until 60 min, compared with that after bolus instillation. A similar trend was observed after continuous microinstillation of 2.35 mg in 117.5 ?L for 2.5 min. The calculated absorption rate constants Ka after continuous microinstillation of phenol red based on a two-compartment model with first-order absorption were higher than those after bolus instillation on the liver and small intestinal serosal surface at either instillation concentration. Moreover, Ka was increased after continuous microinstillation of 2.35 mg in 117.5 ?L on either instillation site. In the comparison between instillation sites, instillation of phenol red on the liver surface resulted in 1.2 to 2.3-fold higher Ka, compared to small intestinal serosal surface. This tendency was marked after continuous microinstillation of 2.35 mg in 117.5 ?L. In conclusion, absorption could be enhanced by instilling a small amount of drug solution on the liver surface gradually and continuously, suggesting a promising approach for instillation site-selective drug delivery in the peritoneal cavity