The in vitro pharmacological profile of KR31080, a nonpeptide AT1 receptor antagonist

Summary— KR31080 (2-butyl-5-methyl-6-(1-oxopyridin-2-yl)-3-[[2'-(1H-tetrazol-5-yl) biphenyl-4-yl]methyl]-3H-imidazo[4,5-b] pyridine) is a potent inhibitor of angiotensin type 1 (AT₁) receptors in rabbit aorta and human recombinant AT₁ receptors. In the isolated rabbit thoracic aorta, KR31080 caused a nonparallel shift to the right of the concentration-response curves to angiotensin II (All) with decreased maximal response (pD'₂ = 10.1 ± 0.1), but had no effect on the contractile response induced by norepinephrine. KR31080 inhibited specific [¹²⁵I]AII binding to rabbit aortic membranes (AT, receptors) and [¹²⁵I][Sar¹, Ile⁸]AII binding to human recombinant AT₁ receptors in a concentration-dependent manner with IC₅₀ values of 0.84 ± 0.08 nM and 1.92 ± 0.15 nM, respectively, but did not inhibit specific [¹²⁵I)AII binding to bovine cerebellum membranes (ÀT₂ receptors). In the Scatchard analysis, KR31080 interacted with rabbit aortic AT₁ receptors in a competitive manner, similar to losartan. These results demonstrate that KR31080 is a potent and AT₁ selective angiotensin receptor antagonist which exerts a competitive antagonism in the [¹²⁵I]AII binding assay and insurmountable AT₁ receptor antagonism in the functional study.     

A Chinese adolescent girl with Fechtner-like syndrome

We describe a 15-y-old girl with Fechtner-like syndrome, who is the first Chinese reported to have this rare syndrome. She presented with left homonymous hemianopia and neuroimaging revealed haemorrhage in both parietal and occipital lobes. Peripheral blood smear showed macrothrombocytopenia and intracytoplasmic inclusion bodies inside leucocytes. Thrombocytopenia and proteinuria responded to intravenous immunoglobulin and pulsed methylprednisolone. This case illustrates that life-threatening haemorrhage can occur in patients with Fechtner syndrome. Although there was no effective treatment reported in the literature, high dose steroid and immunoglobulin seemed to be useful in our patient. Our patient also had nephritic-nephrotic syndrome with renal insufficiency, which is unusual in adolescent female patients.     

Noninvasive Nasal Mask BiPAP Management for Prolonged Respiratory Failure Following Cardiovascular Surgery

A bstract The purpose of this study was to assess the efficacy of nasal mask bi-level positive airway pressure (BiPAP) support in managing respiratory failure following cardiovascular surgery. A total of 20 patients requiring postoperative prolonged respiratory support of 72 hours or longer were studied. BiPAP support was used for eight patients (BiPAP group); the other 12 patients were managed using ordinary oxygen mask treatment (control group). The mean age of the BiPAP group and control group was 65 and 58 years of age, respectively. The mean period of postoperative endotracheal intubation of the BiPAP group and control group was 12 ± 5 days and 7 ± 1 days, respectively. Reintubation was necessary in two patients of the control group. The BiPAP group patients required no reintubation. BiPAP support was discontinued within 48 hours in 6 out of 8 patients. The respiratory rates of control group increased (p < 0.1) 24 hours after extubation, however, the respiratory rates of the BiPAP group remained unchanged. The values of the respiratory index of the BiPAP group improved significantly (p < 0.01) after BiPAP management (from 1.5 ± 0.2 to 0.9 ± 0.2). The values of the control group, however, remained unchanged. A-aDO₂ and Qs/Qt decreased (p < 0.1) in the BiPAP group. There were no significant differences in central venous pressure or circulatory status between the two groups. In conclusion, BiPAP support is a noninvasive management technique for postoperative respiratory failure and may also prevent prolonged endotracheal intubation.     

Solid and papillary epithelial neoplasms of the pancreas: CT findings

Five female patients and one male patient with solid and papillary epithelial neoplasms of the pancreas were examined with computed tomography (CT). The mean age of the patients was 27 years (range, 13-46 years). All cases showed well-encapsulated, round or lobulated masses consisting of both cystic and solid areas. Cystic portions showed CT numbers that suggested hemorrhagic necrosis. There were no internal septations within the masses. In three tumors located in the head of the pancreas, dilatation of the biliary tree was absent or minimal, although the masses were large. Two tumors contained calcifications. One tumor demonstrated metastatic deposits in liver and lymph nodes. Metastatic masses appeared similar to the primary pancreatic mass. Solid and papillary neoplasm of the pancreas should be the primary diagnostic consideration when characteristic CT findings are detected in a young female patient.     

Analysis of the non-sense mutants of varicella-zoster virus thymidine kinase

Summary.  Three non-sense mutants of varicella-zoster virus (VZV) thymidine kinase (TK) gene, VZTK₃₂₅, VZTK₂₇₈ and VZTK₂₂₄, were isolated. The mutants had a single nucleotide substitution at codons 326, 279 and 225, which changed the codon of TGG (tryptophan) to the stop codon TGA. The wild type (WT) and mutant TKs were expressed in E. coli cells and their characteristics were evaluated. VZTK₂₂₄ lost TK activity, but VZTK₃₂₅ and VZTK₂₇₈ maintained 74.8% and 21.2% of the WT TK activity. On the other hand, all mutants lost the thymidylate kinase activity. Moreover, VZTK₃₂₅ and VZTK₂₇₈ polypeptides were heat-labile. These data suggest that the carboxy-terminal portion of herpesvirus TK plays an important role in the stable folding of TK and thymidylate kinase activity. Received April 21, 1997 Accepted June 16, 1997     

Detection of reactive oxygen species (ROS) and apoptosis in human fragmented embryos

In human in-vitro fertilization (IVF)-embryo transfer, the in-vitro culture environment differs from in-vivo conditions in that the oxygen concentration is higher, and in such conditions the mouse embryos show a higher concentration of reactive oxygen species (ROS) in simple culture media. ROS are believed to cause damage to cell membranes and DNA fragmentation in somatic cells. This study was conducted to ascertain the level of H2O2 concentration within embryos and the morphological features of cell damage induced by H2O2. A total of 62 human oocytes and embryos (31 fragmented, 15 non-fragmented embryos, 16 unfertilized oocytes) was obtained from the IVF-embryo transfer programme. The relative intensity of H2O2 concentrations within embryos was measured using 2',7'-dichlorodihydrofluorescein diacetate by Quanti cell 500 fluorescence imaging and DNA fragmentation was observed with transmission electron microscopy and an in-situ apoptosis detection kit. The H2O2 concentrations were significantly higher in fragmented embryos (72.21 +/- 9.62, mean +/- SEM) compared to non-fragmented embryos (31.30 +/- 3.50, P < 0.05) and unfertilized oocytes (30.75 +/- 2.67, P < 0.05). Apoptosis was observed only in fragmented embryos, and was absent in non-fragmented embryos. Electron microscopic findings confirmed apoptotic bodies and cytoplasmic condensation in the fragmented blastomeres. We conclude that there is a direct relationship between increased H2O2 concentration and apoptosis, and that further studies should be undertaken to confirm these findings.