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NOEL S. STURM ANN MARIE HUTZLER CLINTON S. DAVID BASSEM Y. AZIZEH DEV TRIVEDI VICTOR J. HRUBY 《Chemical biology & drug design》1997,49(4):293-299
We have designed and synthesized eight compounds 2-9 which incorporate neutral, hydrophobic amino acid residues in positions 9, 11 and 16 of the glucagon molecule: (2) [desHis1,Va19,11e11,16] glucagon amide, (3) [desHis1,Val9,11,16]glucagon amide, (4) [desHis1,Va19,Leu11,16]glucagon amide, (5) [desHis1,Nle9,11e11,16]glucagon amide, (6) [desHis1,Nle9,Val11,16]glucagon amide, (7) [desHis1,Nle9,Leu11,16]glucagon amide, (8) [desHis1,Val9,Leu11,16,Lys17,18,Glu21]glucagon amide and (9) [desHis1,Nle9,Leu11,16,Lys17,18,Glu21]glucagon amide. The effect of neutral, hydrophobic residues at positions 9, 11 and 16 led to good binding to the glucagon receptor. Compared to glucagon (IC50= 1.5 nM), analogues 2-9 were found to have IC50 values of 6.0, 6.0, 11.0, 9.0, 2.5, 2.8, 6.5 and 7.0 nM, respectively. When these compounds were tested for their ability to block adenylate cyclase (AC) activity, they were found to be antagonists having no stimulation of adenyl cyclase, with PA2, values of 6.15, 6.20, 6.30, 7.25, 6.10, 7.30, 6.25 and 7.25, respectively. © Munksgaard 1997. 相似文献
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Anti-inflammatory activity of phosphodiesterase (PDE)-IV inhibitors in acute and chronic models of inflammation 下载免费PDF全文
L. SEKUT D. YARNALL S. A. STIMPSON L. S. NOEL R. BATEMAN-FITE R. L. CLARK M. F. BRACKEEN J. A. MENIUS K. M. CONNOLLY 《Clinical and experimental immunology》1995,100(1):126-132
Inhibitors of cyclic nucleotide phosphodiesterases are known to suppress lipopolysaccharide (LPS)-induced tumour necrosis factor-alpha (TNF-α) production in vitro in human monocytes. The most potent of these have selectivity for type IV PDEs, suggesting that this class of PDE is the major type involved in the regulation of human TNF-α production. Using compounds of two distinct chemical structural classes, a quinazolinedione (CP-77 059) and a 4 arylpyrrolidinone (rolipram). we show here that PDE-IV-specific inhibitors are also potent in suppressing LPS-induced TNF-α production in vitro in sodium periodate-elicited murine macrophages (IC50s of 1 and 33, respectively). We then report the in vivo anti-inflammatory effect of PDE-IV inhibition in five murine models of inflammation: (i) elevation of serum TNF-α induced by a subtethal LPS injection; (ii) LPS-induced endotoxic shock; (iii) LPS/galactosamine-induced endotoxic shock; (iv) carrageenan-induced paw oedema; and (v) adjuvant arthritis. Following a sublethal (5 μg/mouse) injection of LPS, serum TNF-α levels in mice peaked sharply, reaching concentrations of 3–12 ng/ ml 90 min after injection. In this sublethal LPS assay, CP-77 059 was about 30 times more potent than rolipram, with a minimum effective dose of 0.1 mg/kg versus 3 mg/kg for rolipram. This rank order is in keeping with the relative in vitro IC50S for CP-77059 and rolipram, as well as their relative Ki against the human PDE-IV enzyme (46 nM and 220 nM, respectively). In LPS-induced endotoxic shock, rolipram and CP-77 059 at relatively high doses of 30 and 10 mg/kg, respectively, significantly reduced serum TNF-α levels, and also inhibited mortality 66%. In the LPS/galactosamine shock model, in which mice are rendered exquisitely sensitive to LPS by co-injection with galactosamine, only 0.1 μg of LPS/mouse Is necessary for serum TNF-α elevation and death. Both rolipram and the CP-77059 caused dose-dependent reduction of serum TNF-α and lethality. In the carrageenan-induced paw oedema model, in which there is a pronounced local TNF-α response (without a serum TNF-α elevation), rolipram significantly inhibited paw swelling as well as localized TNF-α levels in the paw. In the adjuvant arthritis model, a chronic model of inflammation also possessing localized TNF-α elevation in the inflamed paw, rolipram and CP-77059 suppressed ankle swelling and radiological evidence of joint damage. These data are consistent with a major role for PDE-IV in regulation of TNF-α production and inflammatory responses in murine systems. It suggests a potential therapeutic use for PDE-IV-specific inhibitors in inflammatory disease such as rheumatoid arthritis, septic shock and other inflammatory diseases where TNF-α has been postulated to be a contributing factor in the pathology of the disease. 相似文献
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JASON BRADFIELD M.D. SHELLEY SHAPIRO M.D. Ph.D. WILLIAM FINCH B.S. RODERICK TUNG M.D. NOEL G. BOYLE M.D. Ph.D. ERIC BUCH M.D. NILESH MATHURIA M.D. RAVI MANDAPATI M.D. KALYANAM SHIVKUMAR M.D. Ph.D. MALCOLM BERSOHN M.D. Ph.D. 《Journal of cardiovascular electrophysiology》2012,23(11):1185-1190
Atrial Flutter and Pulmonary Hypertension. Background: Radiofrequency ablation is first‐line therapy for atrial flutter (AFL). There are no studies of ablation in patients with severe pulmonary arterial hypertension (PAH). Methods: Consecutive patients with severe PAH (systolic pulmonary artery pressure >60 mmHg) and AFL referred for ablation were evaluated. Patients with complex congenital heart disease were excluded. Results: A total of 14 AFL ablation procedures were undertaken in 12 patients. A total of 75% of patients were female; mean age 49 ± 12 years. SPAP prior to ablation was 99 ± 35 mmHg. Baseline 6‐minute walk distance was 295 ± 118 m. ECG demonstrated a typical AFL pattern in only 42% of cases. Baseline AFL cycle length was longer in PAH patients compared to controls (295 ± 53 ms vs 252 ± 35 ms, P = 0.006). Cavotricuspid isthmus dependence was verified in 86% of cases. Acute success was obtained in 86% of procedures. SPAP decreased from 114 ± 44 mmHg to 82 ± 38 mmHg after ablation (P = 0.004). BNP levels were lower postablation (787 ± 832 pg/mL vs 522 ± 745 pg/mL, P = 0.02). Complications were seen in 14%. A total of 80% (8/10) of patients were free of AFL at 3 months; 75% (6/8) at 1 year. Conclusion: Ablation of AFL in severe PAH patients is feasible, with good short‐ and intermediate‐term success rates. The ECG pattern is not a reliable marker of isthmus dependence. The SPAP and BNP levels may decrease postablation. AFL may be a marker of poor outcomes in patients with PAH with a 1‐year mortality rate of 42% in this study. This rate is higher than expected in the general PAH population. (J Cardiovasc Electrophysiol, Vol. 23, pp. 1185–1190, November 2012) 相似文献
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CAMILLE J. KOLOTYLO RN MScN NORA I. PARKER RN PHD JACQUELINE S. CHAPMAN R N PHD 《Journal of obstetric, gynecologic, and neonatal nursing : JOGNN / NAACOG》1991,20(2):146-153
This study explored mothers' perceptions of their neonates' in-hospital transfers from a neonatal intensive-care unit. A convenience sample of 15 mothers was selected, and the researchers interviewed each mother once within a week after her neonate's transfer. Three themes emerged from the data: (1) the mothers expressed feelings of relief accompanied by concern, fear of the unknown, and feelings of alienation; (2) the mothers depended on familiar things and people; and (3) the mothers experienced feelings of helplessness. The mothers' perceptions of their preparation for transfer and continuity of care were mainly negative. 相似文献
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Use of spiral and non-spiral computed tomography arterial portography in the detection of potentially malignant liver masses 总被引:2,自引:0,他引:2
NOEL YOUNG TOM SING KAI PING WONG MICHAEL HOLLANDS NOEL TAIT 《Journal of gastroenterology and hepatology》1997,12(5):385-391
The present study assesses the usefulness of computed tomography (CT) arterial portography (CTAP) in detecting and defining the number and anatomy of potentially malignant liver lesions. One hundred and one adults studied in 1993 and 1994 were retrospectively reviewed, including patients with primary or secondary tumours for possible resection and patients with non-hepatic malignancies in whom the detection of liver metastases would preclude surgery. Twenty-three patients underwent non-spiral CT studies and 78 had studies on a spiral unit, with 22 of these having single phase and 56 having dual phase studies to overcome artefact problems. The relationship between lesion size and detection sensitivity is critical. On non-spiral studies, the overall lesion detection sensitivity and positive predictive value was 69 and 90%, respectively. Detection sensitivity was 100 and 20% for lesions > 1 cm and < 1 cm, respectively. On single phase spiral CTAP the overall detection sensitivity and positive predictive value was 80 and 66%, respectively. Detection sensitivity for lesions > 1 cm and < 1 cm was 100 and 0%, respectively. On dual phase spiral CTAP the overall detection sensitivity and positive predictive value was 76 and 71%, respectively. For lesions > 1 cm and < 1 cm the sensitivity was 81 and 55%, respectively. Eighteen patients with non-hepatic malignancies with unsuspected metastatic spread did not proceed to major surgery because of liver metastases detected on CTAP. Perfusion artefacts occurred in 30 and 64% of non-spiral and of initial portal venous spiral CTAP studies, respectively. By using the double-phase technique, these artefacts were substantially diminished. In conclusion, CTAP is a valuable tool for assessing the presence, site and size of possible liver tumours and confers a benefit even when previous ultrasound and conventional CT have already been used. In addition, CTAP has a lower limit of useful resolution of approximately 1 cm. Perfusion artefacts can be reduced by a dual phase protocol. 相似文献
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Wide QRS Rhythm Due to Taxine Toxicity 总被引:1,自引:0,他引:1
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