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.     

Masked hyperprolactinemia: tumor-derived factors inhibiting prolactin secretion caused by pituitary-stalk damage

Tumor-induced secondary hyperprolactinemia in patients with non-prolactin (PRL)-secreting pituitary tumors has traditionally been ascribed to pituitary stalk damage. We conducted a retrospective analysis of secondary hyperprolactinemia in 106 patients who underwent surgery for non-PRL-secreting pituitary adenoma. The incidence of hyperprolactinemia was evaluated, and pituitary-stalk damage was assessed radiographically using MRI (size of tumor and extension type) and endocrinologically by monitoring hormonal function using a provocation test. The effect of a tumor-derived intrasellar factor, leukemia inhibitory factor (LIF), on hyperprolactinemia was also investigated. Hyperprolactinemia was observed in 31 of the 106 (29.2%) patients. It was not correlated with either physical stalk compression or endocrinological dysfunction. However, LIF expression was negatively correlated with the incidence of secondary hyperprolactinemia (p<0.01). Although secondary hyperprolactinemia might be caused by pituitary stalk damage, it is possible that LIF masks the effect.     

Alternate-day treatment with S-1 in patients with gastric cancer: a retrospective study of strategies for reducing toxicity

Background

In patients with adverse events of S-1, the dose is generally reduced or the treatment cycle is shortened. Whether the therapeutic effectiveness of modified regimens is similar to that of the standard dosage remains unclear.

Methods

We retrospectively studied patients with gastric cancer who received S-1 on alternate days.

Results

A total of 266 patients received S-1 on alternate days. In 116 patients, S-1 was initially given at the standard dosage but was switched to alternate-day treatment because of toxicity within 28 days on average. The other 150 patients initially received alternate-day treatment because of poor general condition. In the adjuvant chemotherapy group (n = 96), the 3-year survival rate was 88% in patients with stage II, 73% in stage IIIA, and 67% in stage IIIB who underwent D2 lymph-node dissection. In the palliative surgery group (n = 96), the response rate was 13%, with a median survival time (MST) of 624 days. In patients with unresectable/recurrent disease (n = 74), the response rate was 25%, with an MST of 338 days. Among the 116 patients who initially received treatment on consecutive days, 100% had grade 1, 53% had grade 2, and 5.2% had grade 3 adverse events. When S-1 was switched to alternate-day treatment, toxicity decreased in all patients. In the 266 patients who received alternate-day treatment, 8% had grade 1, 6% had grade 2, and 0% had grade 3 adverse events.

Conclusion

Alternate-day treatment with S-1 may have milder adverse events without compromising therapeutic effectiveness.     

Comparison of Amrubicin and Weekly Cisplatin/Etoposide/Irinotecan in Patients With Relapsed Small-cell Lung Cancer

Background

Although several agents have been introduced for the treatment of relapsed small-cell lung cancer (SCLC), there is still only limited evidence regarding second- and later-line chemotherapies for these patients.

Feasibility of low-radiation-dose CT for abdominal examinations with hybrid iterative reconstruction algorithm: low-contrast phantom study

Our purpose in this study was to evaluate the image quality of low-radiation-dose CT using hybrid iterative reconstruction (HIR), and to compare the results with those of filtered back projection (FBP) at routine doses. We measured the mean values and standard deviation of the CT numbers within and outside a 15-mm low-contrast object cylinder at 1.0 % contrast level. The noise reduction levels of the HIR were 1 (weak) to 7 (strong). Visual inspection of the low-contrast detectability was done by six radiologic technologists. The low-contrast detectability of the cylinder at the 1.0 % contrast level with HIR at all mAs levels was equal to that obtained with FBP, and thus the use of HIR did not result in any improvement of low-contrast detectability.     

Superior antitumour activity of S-1 in tumours with a high dihydropyrimidine dehydrogenase activity

To elucidate the mechanism of the enhanced antitumour activity of S-1 (1 M tegafur, 0.4 M 5-chloro-2, 4-dihydroxypyridine, and 1 M potassium oxonate) in terms of the phosphorylation and degradation pathways of 5-fluorouracil (5-FU) metabolism, we investigated tumoral thymidylate synthase (TS) content, dihydropyrimidine dehydrogenase (DPD) activity, the TS inhibition rate (TS-IR), and 5-FU incorporated into RNA (F-RNA) in four human gastric cancer xenografts (MKN-28, MKN-74, GCIY and GT3TKB) and compared the results obtained with S-1 with those obtained with 5-FU and UFT (1 M tegafur, 4 M uracil). 5-FU was administered intraperitoneally (i.p.) to mice at a dose of 50 mg/kg, three times, on days 0, 4 and 8. S-1 and UFT were administered orally at doses of 10 and 24 mg/kg, respectively, once a day, for 9 consecutive days. Antitumour activity was evaluated as the maximum inhibition of tumour growth in each animal. S-1 showed a better antitumour activity than 5-FU and UFT in tumours with a high DPD activity (GCIY and GT3TKB). There were inverse correlations between the antitumour activity and both TS content and DPD activity in the 5-FU and UFT groups. However, no such correlations were observed in the S-1 group. In GCIY and GT3TKB xenografts, TS-IR was significantly higher in the S-1 group than in the 5-FU or UFT groups. In GT3TKB xenografts, the F-RNA level was significantly higher in the S-1 group than in the 5-FU or UFT groups. The superior cytotoxicity of S-1 appears to be attributable to both an increased inhibition of DNA synthesis and an enhanced blockade of RNA function against tumours with a high DPD activity.     

Induced oscillatory responses during the Sternberg's visual memory task in patients with Alzheimer's disease and mild cognitive impairment

In this study we used magnetoencephalography during a modified version of the Sternberg's memory recognition task performed by patients with early Alzheimer's disease (AD), mild cognitive impairment (MCI), and by age-matched healthy controls to identify differences in induced oscillatory responses. For analyses, we focused on the retention period of the working memory task. Multiple-source beamformer and Brain Voyager were used for localization of source-power changes across the cortex and for statistic group analyses, respectively. We found significant differences in oscillatory response during the task, specifically in beta and gamma frequency bands: patients with AD showed reduced beta event-related desynchronization (ERD) in the right central area compared to controls, and reduced gamma ERD in the left prefrontal and medial parietal cortex compared to patients with MCI. Our findings suggest that reduced oscillatory responses over certain brain regions in high frequency bands (i.e., beta, gamma), and especially in the beta band that was significantly different between AD patients and healthy subjects, may represent brain electromagnetic changes underlying visual-object working memory dysfunction in early AD, and a neurophysiological indicator of cognitive decline.