The inability of opioid peptides to be transported through epithelial membranes in the gastrointestinal tract and pass the blood-brain barrier limits their effectiveness for oral application in an antinociceptive treatment regime. To overcome this limitation, we enhanced the hydrophobicity while maintaining the aqueous solubility properties in a class of opioid-mimetic substances by inclusion of two identical N-termini consisting of Dmt (2',6'-dimethyl-l-tyrosine) coupled to a pyrazinone ring platform by means of alkyl chains to yield the class of 3,6-bis[Dmt-NH-(CH(2))(n)]-2(1H)-pyrazinones. These compounds displayed high micro-opioid receptor affinity (K(i)micro = 0.042-0.115 nM) and selectivity (K(i)delta/K(i)micro = 204-307) and functional micro-opioid receptor agonism (guinea-pig ileum, IC(50) = 1.3-1.9 nM) with little or undetectable bioactivity toward delta-opioid receptors (mouse vas deferens) and produced analgesia in mice in a naloxone reversible manner when administered centrally (intracerebroventricular, i.c.v.) or systemically (subcutaneously and orally). Furthermore, the most potent compound, 3,6-bis(3'-Dmt-aminopropyl)-5-methyl-2(1H)-pyrazinone (7'), lacked functional delta-opioid receptor bioactivity and was 50-63-fold and 18-21-fold more active than morphine by icv administration as measured analgesia using tail-flick (spinal involvement) and hot-plate (supraspinal effect) tests, respectively; the compound ranged from 16 to 63% as potent upon systemic injection. These analgesic effects are many times greater than unmodified opioid peptides. The data open new possibilities for the rational design of potential opioid-mimetic drugs that pass through the epithelium of the gastrointestinal tract and the blood-brain barrier to target brain receptors.

The minimum anesthetic concentration for sevoflurane in chickens was within the range of minimum alveolar concentration reported in mammals. When the concentration of sevoflurane is increased during controlled ventilation in chickens, decrease in arterial pressure should be expected.

"What is the latest news on TV or papers?" was highly effective in identifying AD and MCI. The present study suggests that the "saving appearances answer" is associated with the onset or awareness of memory impairment, the maintenance of the frontal lobe function and other characteristics of the patient.

Cisplatin is used widely for the treatment of multiple solid tumors. Cisplatin‐induced nephrotoxicity is caused by renal accumulation of cisplatin via human organic cation transporter 2 (hOCT2). As lansoprazole, a proton pump inhibitor, is known to inhibit hOCT2 activity, lansoprazole might ameliorate cisplatin‐induced nephrotoxicity. A previous study showed that concomitant lansoprazole administration ameliorated nephrotoxicity in patients receiving cisplatin. However, the detailed mechanism remains to be clarified. In the present study, the drug–drug interaction between lansoprazole and cisplatin was examined using hOCT2‐expressing cultured cells and rat renal slices. Moreover, the effect of lansoprazole on cisplatin‐induced nephrotoxicity and the pharmacokinetics of cisplatin in rats was investigated. In the uptake study, lansoprazole potently inhibited the uptake of cisplatin in hOCT2‐expressing cultured cells and rat renal slices. The in vivo rat study showed that concomitant lansoprazole significantly ameliorated cisplatin‐induced nephrotoxicity and reduced the renal accumulation of platinum up to approximately 60% of cisplatin alone at 72 h after cisplatin intraperitoneal administration. Furthermore, the renal uptake of platinum at 3 min after intravenous cisplatin administration in rats with cisplatin and lansoprazole decreased to 78% of rats with cisplatin alone. In addition, there was no significant difference in the plasma platinum concentration between rats treated with and without lansoprazole at 3 min after cisplatin intravenous administration. These findings suggested that concomitant lansoprazole ameliorated cisplatin‐induced nephrotoxicity by inhibiting rOCT2‐mediated cisplatin uptake in rats, thus decreasing cisplatin accumulation in the kidney. The present findings provided important information for the establishment of novel protective approaches to minimize cisplatin‐induced nephrotoxicity.

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BackgroundPrevious clinical studies have revealed the potential of [18F]-fluoro-L-α-methyltyrosine (18F-FAMT) for the differential diagnosis of malignant tumours from sarcoidosis. However, one concern regarding the differential diagnosis with 18F-FAMT is the possibility of false negatives given the small absolute uptake of 18F-FAMT that has been observed in some malignant tumours. The aim of this study was to evaluate a usefulness of dynamic 18F-FAMT positron emission tomography (PET) for differentiating malignant tumours from granulomas.MethodsRats bearing both granulomas (Mycobacterium bovis bacillus Calmette-Guérin (BCG)-induced) and tumours (C6 glioma cell-induced) underwent dynamic 2-deoxy-2-[18F]-fluoro-D-glucose (18F-FDG) PET and 18F-FAMT PET for 120 min on consecutive days. Time-activity curves, static images, mean standardized uptake values (SUVs) and the SUV ratios (SUVRs; calculated by dividing SUV at each time point by that of 2 min after injection) were assessed.ResultsIn tumours, 18F-FAMT showed a shoulder peak immediately after the initial distribution followed by gradual clearance compared with granulomas. Although the mean SUV in the tumours (1.00 ± 0.10) was significantly higher than that in the granulomas (0.88 ± 0.12), a large overlap was observed. In contrast, the SUVR was markedly higher in tumours than in granulomas (50 min/2 min, 0.72 ± 0.06 and 0.56 ± 0.05, respectively) with no overlap. The dynamic patterns, SUVR, and mean SUV of 18F-FDG in the granulomas were comparable to those in the tumours.ConclusionsDynamic 18F-FAMT and SUVR analysis might compensate for the current limitations and help in improving the diagnostic accuracy of 18F-FAMT.

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