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51.
A Martin M State K Koenig R Schultz EM Dykens SB Cassidy JF Leckman 《Canadian Metallurgical Quarterly》1998,155(9):1265-1273
52.
DC Underwood S Bochnowicz RR Osborn CJ Kotzer MA Luttmann DW Hay PD Gorycki SB Christensen TJ Torphy 《Canadian Metallurgical Quarterly》1998,287(3):988-995
We evaluated the airway activity of the novel phosphodiesterase type 4 inhibitor SB 207499 [Ariflo; c-4-cyano-4-(3-cyclopentyloxy-4-methoxyp henyl-r-1-cyclohexane carboxylic acid)], in the guinea pig. Ovalbumin (OA)-induced contractions of guinea pig isolated tracheal strips were inhibited by SB 207499 with an EC50 of 1 microM but had little or no effect on exogenous agonist-induced contraction, which suggests that its effect on OA-induced contraction in vitro is primarily due to inhibition of mediator release from mast cells. In anesthetized guinea pigs, SB 207499 inhibited OA-induced bronchoconstriction with i.v. and p.o. ID50 values of 1.7 and 17 mg/kg, respectively. At 1, 3 and 6 hr after SB 207499 (30 mg/kg p.o.), OA-induced bronchospasm was inhibited by 92%, 70% and 58%, respectively, corresponding to elevated plasma concentrations of 1.62 +/- 0.19, 1.65 +/- 0.29 and 0. 93 +/- 0.24 microg/ml, respectively, of SB 207499. SB 207499 also inhibited house dust mite-induced bronchoconstriction (ID50 = 0.9 mg/kg i.v. and 8.9 mg/kg p.o.). In contrast to its lack of bronchorelaxant activity in vitro, SB 207499 inhibited bronchospasm induced by i.v. leukotriene D4 (LTD4) [ID50 = 3 mg/kg i.v.]. The bronchorelaxant effect of i.v.-administered SB 207499 was at least additive with that of salbutamol in reversing infused histamine-enhanced airway tone, but it did not alter base line or enhance salbutamol-induced cardiovascular effects. In conscious guinea pigs, SB 207499 (10 or 30 mg/kg p.o.), 1 hr before antigen or LTD4 challenge, markedly reduced bronchospasm and subsequent eosinophil influx as measured by bronchoalveolar lavage 24 hr after provocation. SB 207499 administered after OA or LTD4 challenge also reduced airway eosinophilia measured at 24 hr after OA challenge or 96 hr after LTD4 challenge. These results, coupled with the broad anti-inflammatory activity of SB 207499 previously described (Barnett et al., 1998), suggest that SB 207499 will be useful in the treatment of asthma and other inflammatory disorders. 相似文献
53.
J Heller AC Kolbert R Larsen M Ernst T Bekker M Baldwin SB Prusiner A Pines DE Wemmer 《Canadian Metallurgical Quarterly》1996,5(8):1655-1661
Conformational changes in the prion protein (PrP) seem to be responsible for prion diseases. We have used conformation-dependent chemical-shift measurements and rotational-resonance distance measurements to analyze the conformation of solid-state peptides lacking long-range order, corresponding to a region of PrP designated H1. This region is predicted to undergo a transformation of secondary structure in generating the infectious form of the protein. Solid-state NMR spectra of specifically 13C-enriched samples of H1, residues 109-122 (MKHMAGAAAAGAVV) of Syrian hamster PrP, have been acquired under cross-polarization and magic-angle spinning conditions. Samples lyophilized from 50% acetonitrile/50% water show chemical shifts characteristic of a beta-sheet conformation in the region corresponding to residues 112-121, whereas samples lyophilized from hexafluoroisopropanol display shifts indicative of alpha-helical secondary structure in the region corresponding to residues 113-117. Complete conversion to the helical conformation was not observed and conversion from alpha-helix back to beta-sheet, as inferred from the solid-state NMR spectra, occurred when samples were exposed to water. Rotational-resonance experiments were performed on seven doubly 13C-labeled H1 samples dried from water. Measured distances suggest that the peptide is in an extended, possibly beta-strand, conformation. These results are consistent with the experimental observation that PrP can exist in different conformational states and with structural predictions based on biological data and theoretical modeling that suggest that H1 may play a key role in the conformational transition involved in the development of prion diseases. 相似文献
54.
We describe two unusual cases in sheep of subclinical mastitis caused by Streptococcus parasanguinis. This bacterium has been associated with the development of experimental endocarditis; its presence at relatively high concentrations in apparently healthy sheep milk may pose a health risk in persons with predisposing heart lesions. 相似文献
55.
AE Fidler SB Lawrence DM Vanmontfort DJ Tisdall KP McNatty 《Canadian Metallurgical Quarterly》1998,20(3):345-353
Substantial evidence has accumulated to suggest that in the near future implementation of the veto-cell-suppressor concept in the treatment of kidney allograft recipients might lead to the establishment of life-long specific allograft tolerance in the absence of further immunosuppressive therapy. Veto suppression prevents the generation of antigen-specific T-helper and cytotoxic T lymphocytes in vitro provided that the T-lymphocyte precursors specifically recognize antigenic peptides associated with the major histocompatibility complex molecules class II and class I, respectively, expressed on the surface of the veto-active cell. Data from a large number of experimental and clinical studies strongly indicate that veto-active cells function in vivo and are capable of preventing allograft rejection. Thus, donor-cell-mediated veto activity is the most likely explanation for the well-known graft tolerizing effect of pretransplant donor blood transfusions in kidney graft recipients. A prerequisite for a veto-active environment in vivo is the establishment of lymphoid microchimerism, in which veto-active donor and recipient cells mutually downregulate potential alloaggression. 相似文献
56.
57.
SB Christensen A Guider CJ Forster JG Gleason PE Bender JM Karpinski WE DeWolf MS Barnette DC Underwood DE Griswold LB Cieslinski M Burman S Bochnowicz RR Osborn CD Manning M Grous LM Hillegas JO Bartus MD Ryan DS Eggleston RC Haltiwanger TJ Torphy 《Canadian Metallurgical Quarterly》1998,41(6):821-835
Evaluation of a variety of PDE4 inhibitors in a series of cellular and in vivo assays suggested a strategy to improve the therapeutic index of PDE4 inhibitors by increasing their selectivity for the ability to inhibit PDE4 catalytic activity versus the ability to compete for high affinity [3H]rolipram-binding sites in the central nervous system. Use of this strategy led ultimately to the identification of cis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxyl ic acid (1, SB 207499, Ariflo), a potent second-generation inhibitor of PDE4 with a decreased potential for side effects versus the archetypic first generation inhibitor, (R)-rolipram. 相似文献
58.
SB Gelvin 《Canadian Metallurgical Quarterly》1998,16(11):1009-1010
59.
The in vivo labelling of 5-hydroxytryptamine (5-HT)1A receptors in the mouse brain was studied with the novel selective 5-HT1A receptor antagonist, NAD-299 ((R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran- 5-carboxamide hydrogen (2R,3R)-tartrate monohydrate). 3H-NAD-299 was injected in a tail vein and the radioactivity in various brain regions was determined. More than 90% of the radioactivity in hippocampus, 15 min after the injection, was intact NAD-299. At this time the amount of 3H-NAD-299 was highest in hippocampus followed by frontal cortex, mesencephalon, hypothalamus, striatum and cerebellum. The specific accumulation of radioactivity (after subtracting cerebellum values) in frontal cortex and hippocampus was maximal 10 to 30 min after the injection and had almost disappeared after 2 h. Saturation kinetics derived Bmax (pmol/g wet weight tissue) values of 19.6+/-2.0 in frontal cortex and 38.0+/-3.5 in hippocampus. The apparent Kd values expressed in nmol/kg 3H-NAD-299 injected, were 12.3+/-2.2 in frontal cortex and 20.3+/-3.1 in hippocampus. The 5-HT1A receptor antagonist, WAY-100,635 competitively inhibited the specific accumulation of 3H-NAD-299 and was about equipotent with unlabelled NAD-299 with ED50 values of 20-30 nmol/kg s.c. These compounds were about 10 times more potent than the 5-HT1A receptor antagonists, p-MPPI and NDL-249 and 100 times more potent than (S)-UH-301. 5-HT1A receptor agonists, e.g. 8-OH-DPAT and flesinoxan and partial agonists, e.g. pindolol, buspirone and ipsapirone had low potency in this in vivo assay. Spiperone and methiothepin inhibited the 3H-NAD-299 accumulation at 10 micromol/kg s.c. The alpha1-adrenoceptor antagonist, prazosin at 2 micromol/kg s.c. increased significantly the specific accumulation of 3H-NAD-299. Pretreatment of the mice with the non-selective, irreversible receptor antagonist, EEDQ produced a dose related long-lasting decrease in the accumulation of 3H-NAD-299. It is concluded that NAD-299 is a very suitable ligand for studies of 5-HT1A receptors in the brain in vivo. 相似文献
60.
SB Shustov VKh Khavinson TS Shutak BV Romashevski? 《Canadian Metallurgical Quarterly》1998,76(9):45-48
Epithelamine made in Russia (Samson, St. Petersburg) was tried for effects on carbohydrate metabolism and cardiovascular system in 33 patients with non-insulin-dependent diabetes mellitus (NIDDM). Adjuvant use of epithelamine in combined treatment of NIDDM promoted a stable compensation of carbohydrate metabolism, lowering of glycosylated hemoglobin, immunoreactive insulin. There was also a moderate hypotensive effect and improvement of left ventricular diastolic function. 相似文献