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.     

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.     

High throughput parallel analysis of hundreds of patient samples for more than 100 mutations in multiple disease genes

As more mutations are identified in genes of known sequence, there is a crucial need in the areas of medical genetics and genome analysis for rapid, accurate and cost-effective methods of mutation detection. We have developed a multiplex allele-specific diagnostic assay (MASDA) for analysis of large numbers of samples (> 500) simultaneously for a large number of known mutations (> 100) in a single assay. MASDA utilizes oligonucleotide hybridization to interrogate DNA sequences. Multiplex DNA samples are immobilized on a solid support and a single hybridization is performed with a pool of allele-specific oligonucleotide (ASO) probes. Any probes complementary to specific mutations present in a given sample are in effect affinity purified from the pool by the target DNA. Sequence-specific band patterns (fingerprints), generated by chemical or enzymatic sequencing of the bound ASO(s), easily identify the specific mutation(s). Using this design, in a single diagnostic assay, we tested samples for 66 cystic fibrosis (CF) mutations, 14 beta-thalassemia mutations, two sickle cell anemia (SCA) mutations, three Tay-Sachs mutations, eight Gaucher mutations, four mutations in Canavan disease, four mutations in Fanconi anemia, and five mutations in BRCA1. Each mutation was correctly identified. Finally, in a blinded study of 106 of these mutations in > 500 patients, all mutations were properly identified. There were no false positives or false negatives. The MASDA assay is capable of detecting point mutations as well as small insertion or deletion mutations. This technology is amenable to automation and is suitable for immediate utilization for high-throughput genetic diagnostics in clinical and research laboratories.      

Comparing sulindac with indomethacin for closure of ductus arteriosus in preterm infants

Objectives: A prospective study comparing the efficiacy and side-effects of oral sulindac with intravenous indomethacin in clinically stable preterm infants (<1750 g) requiring non-invasive closure of haemodynamically significant patent ductus arteriosus.
Methodology: As maturity and birthweight are the two major determinants of ductal closure, infants were matched as closely as possible for these parameters. An eligible patient was first assigned to the sulindac group and a subsequent patient with similar gestational age (± 1 week) and birthweight (±100 g) to the previously recruited infant would automatically receive indomethacin. A total of eight infants were enrolled in each group.
Results: The ductus arteriosus was successfully closed in all eight infants receiving indomethacin, and in seven of eight infants receiving sulindac. No significant differences were found with regards to the ductal size between the two groups at diagnosis or on each of the consecutive days of treatment ( P >0.25). More renal adverse effects were encountered in the indomethacin group. Significant differences in changes from baseline value for urine output, plasma sodium, urea and creatinine concentrations were noted at 24, 48 and 72 h after commencement of treatment between the two groups ( P <0.05). All the parameters returned to normal or pre-treatment levels 48 h after stopping therapy. Unexpectedly, severe gastrointestinal complications were encountered in the sulindac group.
Conclusions: Sulindac is capable of promoting ductal constriction in clinically stable preterm infants without compromising the renal function. The spectrum of gastrointestinal complications observed in sulindac treated infants were similar to those described for indomethacin. The use of sulindac for ductal closure in the preterm infant should remain experimental.     

Rapid Increase in Marrow Fat Content and Decrease in Marrow Perfusion in Lumbar Vertebra Following Bilateral Oophorectomy: An MR Imaging-Based Prospective Longitudinal Study

ObjectiveBilateral oophorectomy leads to reduced bone mineral density (BMD), and reduced BMD is associated with increased marrow fat and reduced marrow perfusion. Purpose of this study was to investigate how soon these changes occur following surgical oophorectomy.ResultsReduced BMD, increased marrow FF, and reduced marrow perfusion occurred synchronously post-oophorectomy. There was a sharp decrease of 12.5 ± 7.2% in BMD (n = 6), a sharp increase of 92.2 ± 46.3% (n = 6) in FF, a sharp decrease of 23.6 ± 3.9% in maximum contrast enhancement (n = 5), and of 45.4 ± 7.7% for enhancement slope (n = 5) during the initial 3 months post surgery. BMD and marrow perfusion continued to decrease, and marrow FF continued to increase at a slower rate during the following 18 months. Friedman test showed a significant trend for these changes (p < 0.05).ConclusionBilateral oophorectomy leads to a rapid decrease in lumbar BMD, an increase in marrow fat content, and a decrease in marrow blood perfusion.     

Legg‐Calvé‐Perthes Disease Produces Chronic Hip Synovitis and Elevation of Interleukin‐6 in the Synovial Fluid

Legg‐Calvé‐Perthes disease (LCPD) is a childhood hip disorder of ischemic osteonecrosis of the femoral head. Hip joint synovitis is a common feature of LCPD, but the nature and pathophysiology of the synovitis remain unknown. The purpose of this study was to determine the chronicity of the synovitis and the inflammatory cytokines present in the synovial fluid at an active stage of LCPD. Serial MRI was performed on 28 patients. T2‐weighted and gadolinium‐enhanced MR images were used to assess synovial effusion and synovial enhancement (hyperemia) over time. A multiple‐cytokine assay was used to determine the levels of 27 inflammatory cytokines and related factors present in the synovial fluid from 13 patients. MRI analysis showed fold increases of 5.0 ± 3.3 and 3.1 ± 2.1 in the synovial fluid volume in the affected hip compared to the unaffected hip at the initial and the last follow‐up MRI, respectively. The mean duration between the initial and the last MRI was 17.7 ± 8.3 months. The volume of enhanced synovium on the contrast MRI was increased 16.5 ± 8.5 fold and 6.3 ± 5.6 fold in the affected hip compared to the unaffected hip at the initial MRI and the last follow‐up MRI, respectively. In the synovial fluid of the affected hips, IL‐6 protein levels were significantly increased (LCPD: 509 ± 519 pg/mL, non‐LCPD: 19 ± 22 pg/mL; p = 0.0005) on the multi‐cytokine assay. Interestingly, IL‐1β and TNF‐α levels were not elevated. In the active stage of LCPD, chronic hip synovitis and significant elevation of IL‐6 are produced in the synovial fluid. Further studies are warranted to investigate the role of IL‐6 on the pathophysiology of synovitis in LCPD and how it affects bone healing. © 2015 American Society for Bone and Mineral Research