QT PRODACT: evaluation of the potential of compounds to cause QT interval prolongation by action potential assays using guinea-pig papillary muscles

Certain compounds that prolong QT interval in humans have little or no effect on action-potential (AP) duration used traditionally, but they inhibit rapidly-activated-delayed-rectifier potassium currents (IKr) and/or human ether-a-go-go-related gene (hERG) currents. In this study using isolated guinea-pig papillary muscles, we investigated whether new parameters in AP assays can detect the inhibitory effects of various compounds on IKr and/or hERG currents with high sensitivity. The difference in AP duration between 60% and 30% repolarization, 90% and 60% repolarization, and 90% and 30% repolarization (APD30-60, APD60-90, and APD30-90, respectively) were calculated as the new parameters. All the 15 IKr and/or hERG current inhibitors that have been reported (9 compounds) or not reported (6 compounds) to inhibit calcium currents prolonged APD30-60, APD60-90, and/or APD30-90; and 8 of the 15 inhibitors prolonged APD30-60, APD60-90, and/or APD30-90 more potently than APD90. The APD30-60, APD60-90, and APD30-90 measurements revealed no difference in sensitivity when evaluating the effects of the IKr and/or hERG current inhibitors on the three parameters. On the other hand, compounds with little or no effect on hERG currents had no effect on APD30-60, APD60-90, or APD30-90. Therefore, it is concluded that in AP assays using isolated guinea-pig papillary muscles, APD30-60, APD60-90, and APD30-90 are useful indexes for evaluating the inhibitory effects of compounds including mixed ion-channel blockers on IKr and/or hERG currents.     

Eleven novel single nucleotide polymorphisms in the NR1I2 (PXR) gene, four of which induce non-synonymous amino acid alterations

Eleven novel single nucleotide polymorphisms (SNPs) were found in the NR1I2 (PXR/SXR) gene from 205 Japanese subjects. The detected SNPs were as follows: 1) SNP, MPJ6_1I2001; GENE NAME, NR1I2; ACCESSION NUMBER, AF364606; LENGTH, 25 bases; 5'-TTTCTACCTCTAC/TTATTGAAAGGGC-3'. 2) SNP, MPJ6_1I2004; GENE NAME, NR1I2; ACCESSION NUMBER, AF364606; LENGTH, 25 bases; 5'-AGGCCCAAATGTG/AAGTGATGCATAG-3'. 3) SNP, MPJ6_1I2007; GENE NAME, NR1I2; ACCESSION NUMBER, AF364606; LENGTH, 25 bases; 5'-TGCCAGGCCTGCC/TGCCTGCGCAAGT-3'. 4) SNP, MPJ6_1I2008; GENE NAME, NR1I2; ACCESSION NUMBER, AF364606; LENGTH, 25 bases; 5'-GAGTGAGCAGTGG/CGCGCGCGGGCGG-3'. 5) SNP, MPJ6_1I2010; GENE NAME, NR1I2; ACCESSION NUMBER, AF364606; LENGTH, 25 bases; 5'-CAGAGGAGCAGCG/AGATGATGATCAG-3'. 6) SNP, MPJ6_1I2011; GENE NAME, NR1I2; ACCESSION NUMBER, AF364606; LENGTH, 25 bases; 5'-CTGGAAGTGGCCA/GGGAGGTTCAAAG-3'. 7) SNP, MPJ6_1I2013; GENE NAME, NR1I2; ACCESSION NUMBER, AF364606; LENGTH, 25 bases; 5'-TCTTCCTCTCGCC/TCCCAACTTCTGG-3'. 8) SNP, MPJ6_1I2017; GENE NAME, NR1I2; ACCESSION NUMBER, AF364606; LENGTH, 25 bases; 5'-ATTGAATGCAATC/TGGCCCCAGCCTG-3'. 9) SNP, MPJ6_1I2018; GENE NAME, NR1I2; ACCESSION NUMBER, AF364606; LENGTH, 25 bases; 5'-GGTGAGCACAGCA/GGGGGGTGAGGAC-3'. 10) SNP, MPJ6_1I2019; GENE NAME, NR1I2; ACCESSION NUMBER, AF364606; LENGTH, 25 bases; 5'-GAGCTCCGCAGCA/GTCAATGCTCAGC-3'. 11) SNP, MPJ6_1I2021; GENE NAME, NR1I2; ACCESSION NUMBER, AF364606; LENGTH, 25 bases; 5'-GGTGACACCTCCG/AAGAGGCAGCCAG-3'. The frequencies were 0.0293 for MPJ6_1I2021, 0.0073 for MPJ6_1I2011, and 0.0024 for the other 9 SNPs. All SNPs were found as heterozygous. Among these SNPs, MPJ6_1I2007, MPJ6_1I2010, MPJ6_1I2017 and MPJ6_1I2019 induce non-synonymous amino acid alterations (R98C, R148Q, R381W and I403V, respectively, in PAR1).     

Relationship between progression of visual field damage and choroidal thickness in eyes with normal-tension glaucoma

Background: To measure choroidal thickness in normal eyes and in patients with normal‐tension glaucoma using enhanced depth imaging optical coherence tomography and evaluate the association between choroidal thickness and progression of visual field damage. Design: Cross‐sectional comparative study. Participants: A total of 62 eyes of 62 normal subjects and 45 eyes of 45 normal‐tension glaucoma patients were examined. Methods: The choroid was measured at the fovea and 3 mm nasal and temporal from the fovea. In the separate study, both eyes of the patients with normal‐tension glaucoma were included in the analyses. Visual fields were measured with automated perimetry. Changes in mean deviation per year (dB/year), that is, mean deviation slope, were calculated. Main Outcome Measures: Difference in the choroidal thickness between the normal subjects and the patients with normal‐tension glaucoma. The relationship between mean deviation slope and the choroidal thickness in eyes with normal‐tension glaucoma was analysed. Results: Compared with normal subjects, the choroidal thickness was significantly thinner in eyes with normal‐tension glaucoma at 3 mm nasal from the fovea (P = 0.02). There was a significant correlation between the choroidal thickness at 3 mm nasal from the fovea and the mean deviation slope (Pearson's r = 0.413; P < 0.001). Conclusion: The decrease in the thickness of the choroid at 3 mm nasal from the fovea in eyes with normal‐tension glaucoma may be associated with progressive visual field loss. Thus, choroidal abnormalities may play a role in the pathogenesis of normal‐tension glaucoma.     

Inequality in the health status of workers in small-scale enterprises

BACKGROUND: Small-scale enterprises (SSEs) usually share poorer resources for promoting occupational health. AIM: To investigate inequality of health status among SSEs in Japan. METHOD: A cross-sectional, multiple-centred study was carried out using the periodical health check-up data for the fiscal year 2000 to compare the age-adjusted proportions of workers with hypertension (HT), hyperlipidaemia, impaired glucose tolerance (IGT) and obesity and of current smokers by size of enterprise, i.e. or=1000 employees in Japan. RESULTS: From five leading occupational health organizations, data were collected for 9833 enterprises with a total of 436 729 subjects, 302 383 males and 134 346 females. The proportions of workers in SSEs with or=50 male employees. The prevalence of smokers in SSEs with or=50 male employees. These proportions showed a significantly increasing tendency with decreasing size of male workforce. CONCLUSION: Despite the cross-sectional design and only adjusting age as a potential confounder, higher proportions of HT, IGT, obesity and smoking in male workers were found in SSEs compared to larger organizations.     

Successful treatment with chemotherapy of vinorelbine and gemcitabine for an elderly patient with advanced non-small cell lung cancer

A 74-year-old man with non-small cell lung cancer was referred to our hospital for chemotherapy. On admission, he suffered from high fever and left upper back pain. Laboratory data showed marked leukocytosis and increased CRP. He was treated with chemotherapy of weekly vinorelbine and gemcitabine. After the second cycle, the levels of leukocytes and CRP were remarkably decreased, and the severe back pain was also alleviated. He has been given an additional 4 cycles as an outpatient. He is now doing well. This regimen seems to be effective in alleviating symptoms and improving QOL.     

Highly efficient in vivo gene transfection by plasmid/PEI complexes coated by anionic PEG derivatives bearing carboxyl groups and RGD peptide.

A new class of an anionic poly (ethylene glycol) derivative, PEG-Suc, bearing 17.7 pairs of carboxylic acid-side chains was synthesized. PEG-Suc deposited onto the DNA/polyethyleneimine complexes without destroying them even at high dose ratio. Coating of the DNA complexes by PEG-Suc recharged their surface to negative, and effectively protected them from the albumin-induced aggregation. Paired carboxyl groups in the side chains showed higher proton sponge effect. Negatively charged surface would diminish the electrostatic binding of the complexes to the cells, and the transfection efficiency on the cultured cells was not high. RGD peptide side chain as a ligand to malignant cell surfaces was then introduced to compensate the reduced electrical adhesion. RGD-PEG-Suc-coated plasmid/PEI complex brought about more than 3 times higher reporter protein activity on the cultured B16 cells. Those bio-compatible DNA complexes with ligand attained very high gene expression in tumor, lung, and liver after injection into mouse tail vein.     

Pharmacokinetics of calcitriol and maxacalcitol administered into peritoneal dialysate bags in peritoneal dialysis patients.

OBJECTIVES: It is well known that injection of calcitriol (CT) or maxacalcitol (OCT) is very effective in hemodialysis patients with secondary hyperparathyroidism (2HPT). However, it is difficult to use these drugs with peritoneal dialysis (PD) patients with 2HPT because these drugs must be injected two or three times per week. The objective of the present study was to evaluate the stability of physiological activities of CT and OCT in PD bags and to determine the CT or OCT dosage for intraperitoneal (IP) administration. MATERIALS AND METHODS: We added CT 1.5 microg or OCT 10 microg to Dianeal PD-2 (approximate pH = 5.0, calcium = 0.87 mmol/L; Baxter,Tokyo, Japan), Midpeliq 250 (approximate pH = 7.0, Ca = 1.0 mmol/L;Terumo Corporation, Tokyo, Japan), and Peritoliq 250 (approximate pH = 5.5, Ca = 1.0 mmol/L; Terumo Corp.). Dialysis solutions were collected from the PD bags at 0, 1, 4, 8, 12, 24, 48, and 72 hours after addition of CT and OCT. The activities of CT and OCT in the dialysis effluent were measured by radioimmunoassay. The levels of serum and effluent OCT after a single IP administration of 10 microg OCT were examined in 4 PO patients with advanced 2HPT. RESULTS: Although the levels of CT and OCT in PD bags made of polyvinyl resins decreased by 70% - 75% immediately after injection, levels in PD bags made of polypropylene resins decreased only slightly. The concentration of CT mixed into the acidic solution in glass containers was stable; the decreased concentration of CT in the PD solution might be due to adsorption onto polyvinyl resins. The maximum serum concentration after IP administration of 10 microg OCT was 750 pg/mL after 5 minutes, and remained at 500 pg/mL at 60 minutes. These results show good peritoneal transport of OCT but not rapid disappearance, unlike intravenous administration. CONCLUSIONS: If peritoneal administration of vitamin D derivatives is contemplated, it is important to select the composition of PD bag resins, type of vitamin D analog, and time lag to use when deciding the dosage of injectable vitamin D preparations, such as OCT or CT, for IP administration to PD patients. It appears that IP administration in overnight dwells might be useful for PD patients as a complementary vitamin D preparation.