Differential effect of grapefruit juice on intestinal absorption of statins due to inhibition of organic anion transporting polypeptide and/or P-glycoprotein

The purpose of this study is to examine the contributions of organic anion transporting polypeptide (Oatp) and/or P-glycoprotein (P-gp) to grapefruit juice (GFJ) interaction with two statins, pravastatin and pitavastatin, which undergo negligible metabolism in rats. The two statins were found to be substrates of both Oatp1a5 and Oatp2b1, whereas pitavastatin, but not pravastatin, was a substrate of P-gp. The plasma concentration of pravastatin after oral administration was significantly decreased by GFJ and naringin, whereas that of pitavastatin was significantly increased. Naringin inhibited Oatp1a5- and Oatp2b1-mediated uptake of pravastatin and Oatp1a5-mediated, but not Oatp2b1-mediated, uptake of pitavastatin. Naringin also inhibited P-gp-mediated transport of pitavastatin. These results suggested that the decrease of pravastatin absorption in the presence of GFJ is due to the inhibitory effect of naringin on Oatp, whereas the increase of pitavastatin is due to the inhibition of P-gp. These observations are consistent with the results of in situ absorption studies. In conclusion, Oatp and/or P-gp contribute to the intestinal absorption of statins, and the differential effect of GFJ on pravastatin and pitavastatin absorption is at least partly accounted for by the different inhibitory effects of naringin on these transporters.     

S-1-induced, prolonged complete regression of lung metastasis from gastric cancer refractory to 5'-DFUR: a case report with pharmacokinetic study

S-1 is an oral fluoropyrimidine reported to be most active for gastric cancer. However, few studies have documented a complete response (CR) of lung metastasis to S-1 treatment. We describe a 66-year-old woman in whom S-1 induced complete regression of lung metastasis from gastric cancer, that had been refractory to another oral fluoropyrimidine, 5'-deoxy-5-fluorouridine (5'-DFUR). After preoperative chemotherapy with a combination of etoposide, adriamycin and cisplatin and with methotrexate plus 5-fluorouracil, the patient underwent a total gastrectomy with lower esophagectomy for advanced diffuse-type gastric cancer with invasion of the esophagus in May 1993. She received postoperative adjuvant chemotherapy with 5'-DFUR (600 mg/day) for 3 years. However, a solitary metastasis to the left lung was detected in November 1996 and she underwent partial resection of the left lung. Chemotherapy with 5'-DFUR was reinitiated after operation, but re-metastasis to the left lung with elevation of the serum carcinoembryonic antigen (CEA) level was diagnosed in June 1999. Treatment with S-1 was started in August. S-1 was given orally in a dose of 100 mg/day for 28 consecutive days, followed by a 14-day recovery; treatment was repeated every 6 weeks. The metastatic lesion in the left lung completely regressed after two courses of S-1 and the serum CEA level returned to the normal range. The patient received a total of 10 courses of S-1. The dose of S-1 was reduced to 80 mg/day from the sixth course because of grade 2 skin rash. Pharmacokinetic studies after administration of S-1 revealed high and prolonged plasma 5-FU levels. Nearly 4 years have passed since complete regression of the lung metastasis. This may be the first report to document a prolonged complete response of lung metastasis from gastric cancer induced by single-agent chemotherapy with S-1.     

Molecular analysis of the BCR-ABL1 kinase domain in chronic-phase chronic myelogenous leukemia treated with tyrosine kinase inhibitors in practice: Study by the Nagasaki CML Study Group

An appropriate trigger for BCR-ABL1 mutation analysis has not yet been established in unselected cohorts of chronic-phase chronic myelogenous leukemia patients. We examined 92 patients after 12 months of tyrosine kinase inhibitor (TKI) treatment in Nagasaki Prefecture, Japan. Univariate analysis revealed that significant factors associated with not attaining a major molecular response (MMR) were the presence of the minor BCR-ABL1 fusion gene, a low daily dose of TKI, and the emergence of BCR-ABL1 kinase domain mutations conferring resistance to imatinib. Factors associated with the loss of sustained MMR were a low daily dose of TKI and the emergence of alternatively spliced BCR-ABL1 mRNA with a 35-nucleotide insertion. Taken together, our results suggest that the search for BCR-ABL1 mutations should be initiated if patients have not achieved MMR following 12 months of TKI treatment.     

Stem cell therapy: social recognition recovery in a FASD model

To better understand the cellular pathogenetic mechanisms of fetal alcohol spectrum disorder (FASD) and the therapeutic benefit of stem cell treatment, we exposed pregnant rats to ethanol followed by intravenous administration of neural stem cells (NSCs) complexed with atelocollagen to the new born rats and studied recovery of GABAergic interneuron numbers and synaptic protein density in the anterior cingulate cortex, hippocampus and amygdala. Prenatal ethanol exposure reduced both parvalbumin-positive phenotype of GABAergic interneurons and postsynaptic density protein 95 levels in these areas. Intravenous NSC treatment reversed these reductions. Furthermore, treatment with NSCs reversed impaired memory/cognitive function and social interaction behavior. These experiments underscore an important role for synaptic remodeling and GABAergic interneuron genesis in the pathophysiology and treatment of FASD and highlight the therapeutic potential for intravenous NSC administration in FASD utilizing atelocollagen.     

Acute pancreatic damage associated with convulsive status epilepticus: A report of three cases

Three cases involving a previously unreported association of acute pancreatic damage following convulsive status epilepticus (SE) are presented. A review of literature failed to reveal a similar association between SE and acute pancreatic damage. As possible pathophysiological mechanisms of this so far unknown sequel of SE, increased intraduodenal pressure during SE leading to the reflux of the duodenal contents into the pancreatic duct, along with altered metabolism of oxygen-derived free radicals during a prolonged seizure with hypoxia and ischemia resulting in acinar cell injury are suggested. We believe that SE should be considered as an additional risk factor of acute pancreatitis and that pancreatic enzymes should be monitored in patients who have prolonged seizures.     

Biochemical modulation therapy for pancreatic cancer

It is well known that the clinical course in most patients with advanced pancreatic cancer is not influenced substantially by chemotherapy and/or radiotherapy. However, new chemotherapy, based on the synergistic antitumor activities of 5-fluorouracil (5-FU) and cisplatin (CDDP) producing biochemical modulation in solid cancers diagnosed as adenocarcinoma, has recently been reported to be effective. In gastrointestinal cancers, the optimal concentrations of each drug and the duration of the anticancer effects, as well as adverse effects have been confirmed in pharmacodynamic studies. Our experience of this treatment for advanced pancreatic cancer (stage IV) indicates the usefulness of the antitumor effect in terms of both effect on the tumor size in unresectable patients and prognosis in resectable patients. These results were remarkable in patients diagnosed as stage IV b and/or curability C. Although there were adverse effects, none were severe. However, anything compromising the patient's quality of life must be prevented. Randomized prospective studies of the combination of 5-FU and CDDP are expected in the near future. Received for publication on July 29, 1998; accepted on July 31, 1998