Pharmacokinetic analysis of the cardioprotective effect of 3-(2,2, 2-trimethylhydrazinium) propionate in mice: inhibition of carnitine transport in kidney

The site of action of 3-(2,2,2-trimethylhydrazinium) propionate (THP), a new cardioprotective agent, was investigated in mice and rats. I.p. administration of THP decreased the concentrations of free carnitine and long-chain acylcarnitine in heart tissue. In isolated myocytes, THP inhibited free carnitine transport with a Ki of 1340 microM, which is considerably higher than the observed serum concentration of THP. The major cause of the decreased free carnitine concentration in heart was found to be the decreased serum concentration of free carnitine that resulted from the increased renal clearance of carnitine by THP. The estimated Ki of THP for inhibiting the reabsorption of free carnitine in kidneys was 52.2 microM, which is consistent with the serum THP concentration range. No inhibition of THP on the carnitine palmitoyltransferase activity in isolated mitochondrial fractions was observed. These results indicate that the principal site of action of THP as a cardioprotective agent is the carnitine transport carrier in the kidney, but not the carrier in the heart.     

P-Glycoprotein-Mediated Transport of Itraconazole across the Blood-Brain Barrier

The mechanism for the accumulation of itraconazole (ITZ) in its elimination from the brain was studied in rats and mice. The concentration of ITZ in liver tissue declined in parallel with the plasma ITZ concentration until 24 h after intravenous injection of the drug (half-life, 5 h); however, the ITZ in brain tissue rapidly disappeared (half-life, 0.4 h). The time profiles of the brain/plasma ITZ concentration ratio (K_p value) showed a marked overshooting, and the K_p value increased with increasing dose; these phenomena were not observed in the liver tissue. This finding indicates the occurrence of a nonlinear efflux of ITZ from the brain to the blood. Moreover, based on a pharmacokinetic model which hypothesized processes for both nonlinear and linear effluxes of ITZ from the brain to the blood, we found that the efflux rate constant in the saturable process was approximately sevenfold larger than that in the nonsaturable process. The K_p value for the brain tissue was significantly increased in the presence of ketoconazole or verapamil. The brain K_p value for mdr1a knockout mice was also significantly increased compared with that of control mice. Moreover, the uptake of vincristine or vinblastine, both of which are substrates of the P glycoprotein (P-gp), into mouse brain capillary endothelial cells was also significantly increased by ITZ or verapamil. In conclusion, P-gp in the brain capillary endothelial cells participates in a process of active efflux of ITZ from the brain to the blood at the blood-brain barrier, and ITZ can be an inhibitor of various substrates of P-gp.     

Cost-effectiveness analysis of screening for colorectal cancer in Japan.

To clarify the best cost-effective screening strategy for colorectal cancer in Japan, the cost-effectiveness ratio was compared among six currently performed procedures. The analysis was made using a simulation model to estimate long-term cost and effectiveness of the screening programs. In the screening by the immunological fecal occult blood test (FOBT), a comparison between the one- and two-day fecal collection methods indicated that the latter was more cost-effective than the former. A comparison was also made on the four workup methods: barium enema (BE) alone, a combination of BE and sigmoidoscopy (BE + SIG), total colonoscopy (TCF) alone, and a combination of BE and TCF (BE + TCF). The cost-effectiveness ratio was the lowest in the method using TCF alone, followed by those based on BE alone and BE + TCF, and the highest in the BE + SIG method. The superiority of TCF alone strategy was stable over a range of estimates such as the sensitivity of diagnostic tests, the probability of complications due to TCF, etc. It is concluded that a combination of the two-day FOBT and TCF yields the best cost-effectiveness.     

An electric field induced in the retina and brain at threshold magnetic flux density causing magnetophosphenes

For magnetic field exposures at extremely low frequencies, the electrostimulatory response with the lowest threshold is the magnetophosphene, a response that corresponds to an adult exposed to a 20 Hz magnetic field of nominally 8.14 mT. In the IEEE standard C95.6 (2002), the corresponding in situ field in the retinal locus of an adult-sized ellipsoidal was calculated to be 53 mV m(-1). However, the associated dose in the retina and brain at a high level of resolution in anatomically correct human models is incompletely characterized. Furthermore, the dose maxima in tissue computed with voxel human models are prone to staircasing errors, particularly for the low-frequency dosimetry. In the analyses presented in this paper, analytical and quasi-static finite-difference time-domain (FDTD) solutions were first compared for a three-layer sphere exposed to a uniform 50 Hz magnetic field. Staircasing errors in the FDTD results were observed at the tissue interface, and were greatest at the skin-air boundary. The 99th percentile value was within 3% of the analytic maximum, depending on model resolution, and thus may be considered a close approximation of the analytic maximum. For the adult anatomical model, TARO, exposed to a uniform magnetic field, the differences in the 99th percentile value of in situ electric fields for 2 mm and 1 mm voxel models were at most several per cent. For various human models exposed at the magnetophosphene threshold at three orthogonal field orientations, the in situ electric field in the brain was between 10% and 70% greater than the analytical IEEE threshold of 53 mV m(-1), and in the retina was lower by roughly 50% for two horizontal orientations (anterior-posterior and lateral), and greater by about 15% for a vertically oriented field. Considering a reduction factor or safety factors of several folds applied to electrostimulatory thresholds, the 99th percentile dose to a tissue calculated with voxel human models may be used as an estimate of the tissue's maximum dose.     

Intrahepatic micrometastases around liver metastases from gastric cancer

Background/Purpose  We aimed to clarify the association between the presence of micrometastases around liver metastases from gastric cancer and the results of hepatic resection. In addition, we investigated the influence of E-cadherin and matrix metalloproteinase (MMP)-7 expression on the development of micrometastases. Methods  Micrometastases around liver metastases were examined microscopically in 31 metastatic liver tumor specimens resected from 17 patients who had undergone hepatic resection for liver metastases from gastric cancer. E-cadherin and MMP-7 expression in the primary gastric tumor, the liver metastases, and the micrometastases were examined immunohistochemically. Results  Hepatic micrometastases were present in around 48% of the liver metastases, accounting for 59% of the patients. The tumor recurrence rate in the remnant liver after hepatic resection was significantly higher, and survival significantly poorer, in patients with such micrometastases than in those without. Micrometastases tended to appear around the liver metastases that had reduced E-cadherin expression. Most of the micrometastases in the lymph ducts and sinusoids showed reduced E-cadherin expression. MMP-7 expression was not correlated with the presence of micrometastases. Conclusions  About half of the hepatic metastases from gastric cancer had seeded off micrometastases, and the presence of these micrometastases was associated with a poorer result of hepatic resection. Reduced E-cadherin expression in metastatic liver tumors may be associated with the development of micrometastases.     

Spleen-preserving distal pancreatectomy with conservation of the splenic artery and vein

Preservation of the spleen at distal pancreatectomy has recently attracted considerable attention.Since our first successful trial,spleen-preserving distal pancreatectomy with conservation of the splenic artery and vein for tumors of the pancreas and chronic pancreatitis has been performed more frequently.The technique for spleen-preserving distal pancreatectomy with conservation of the splenic artery and vein are outlined.The splenic vein is identified behind the pancreas and within the thin connective tissue membrane.The connective tissue membrane is cut longitudinally above the splenic vein.An important issue is to remove the splenic vein from the body of the pancreas toward the spleen,since a different approach may be very difficult.The pancreas is preferably removed from the splenic artery toward the head of the pancreas itself.This procedure is much easier than removing the pancreas from the vein side.One patient had undergone distal gastrectomy for duodenal ulcer,with reconstruction by Billroth Ⅱ tehcnique.If distal pancreatectomy with splenectomy had been performed for the lesion of the distal pancreas at the time,the residual stomach would also have to be resected.The potential damage done to the patient by reconstruction of the gastrointestinal tract in combination with distal pancreatectomy and splenectomy would have been much greater than with distal pancreatectomy only with preservation of the spleen and residual stomach.Benign lesions as well as low-grade malignancy of the body and tail of the pancreas may be a possible indication for this procedure.     

Production of recombinant channel catfish (Ictalurus punctatus) FSH and LH in S2 Drosophila cell line and an indication of their different actions

Due to the lack of purified, native gonadotropins (GtH) for almost all species of fish, we designed a system for the production of recombinant bioactive luteinizing hormone (LH) and follicle stimulating hormone (FSH) using the channel catfish (Ictalurus punctatus) as a model animal. The strategy was to produce the three subunits composing FSH and LH, i.e. the common alpha-subunit (alpha-glycoprotein hormone (alpha-GP)), beta-FSH, and beta-LH subunit, individually in stable recombinant insect cells (S2) with C-terminal His-tag. This expression system was also used to co-express the alpha-subunit without the His-tag with each of the His-tagged beta-subunits. The recombinant S2 cells were capable of secreting FSH and LH heterodimers and alpha-GP in abundance; however, expression of the individual beta-subunits was much less successful. The recombinant GtHs were partially purified from the cell medium by immobilized metal affinity chromatography to ~15% purity with a yield of 7 and 4 mg per liter of medium for FSH and LH respectively. These recombinant GtHs activated their receptors in vitro, enhanced estrogen secretion, up-regulated several steroidogenic enzyme genes in channel catfish ovarian follicles, and increased androgen secretion from African catfish testis. Interestingly, the FSH and LH dose-response curves for each of these biological activities clearly demonstrate differences in their cellular action and physiological roles. This expression system may be an important development for the production of species-specific GtHs so that FSH- and LH-specific mechanisms of actions within the reproductive endocrine processes can finally be examined with homologous, albeit recombinant, hormones.