Disease relevance of 2-(1-quinolyl)ethoxy-[[(2R,5S)-5-(stearylcarbamoyloxymethyl)tetrahydrofuran-2-yl]methoxy]phosphinic acid

• Although all of the treatments significantly reduced the severity of anterior uveitis, SRI 63-441 plus indomethacin was the most effective, indomethacin and naproxen were intermediately effective, and SRI 63-441 was the least effective [1].
• Young male Sprague-Dawley rats were anesthetized with pentobarbital and divided into six experimental groups: 1) control, 2) LPS alone (2 mg/kg), 3) hypoxia alone (5% O2), 4) LPS+hypoxia, 5) WEB 2086 (PAF antagonist)+LPS+hypoxia, and 6) SRI 63-441 (PAF antagonist)+LPS+hypoxia [2].
• Effects of platelet-activating factor antagonist SRI 63-441 on endotoxemia in sheep [3].
• A similar reduction in the number of implantation sites was achieved with 20 micrograms SRI 63-441/30 g body weight/day [4].
• SRI 63-441 reduced the hypotension response in the rat, where the ED50 values for inhibition of MAP were 0.16 mg/kg i.v. and 0.19 mg/kg i.v. for the recovery period [5].

High impact information on 2-(1-quinolyl)ethoxy-[[(2R,5S)-5-(stearylcarbamoyloxymethyl)tetrahydrofuran-2-yl]methoxy]phosphinic acid

• We tested the effect of PAF receptor antagonists, CV 3988 and SRI 63-441, on endotoxin-induced hemodynamic changes and lung vascular injury [6].
• Pretreatment with SRI 63-441 prevented the depressed hypoxic pulmonary vasoconstriction after low dose (2 mg/kg) endotoxin [6].
• Inhibition of PAF by SRI 63-441 alone, at the dosage and schedule used in these experiments, did not significantly prolong xenograft survival or function [7].
• Four separate PAF receptor antagonists, CV-3988, CV-6209, SRI-63-441, and SRI-63-675 drastically reduced the PAF-stimulated protein phosphorylation [8].
• Concordant mouse-to-rat cardiac xenografts are also relatively resistant to prolongation of graft survival following treatment with SRI 63-441 alone or in combination with CsA or FK506 [9].

Chemical compound and disease context of 2-(1-quinolyl)ethoxy-[[(2R,5S)-5-(stearylcarbamoyloxymethyl)tetrahydrofuran-2-yl]methoxy]phosphinic acid

• However, although WEB 2086 was as effective as SRI 63-441 in reducing PAF-induced platelet aggregation, ex vivo, it did not significantly reduce IL-1 beta/TNF alpha-induced uveitis [10].

Biological context of 2-(1-quinolyl)ethoxy-[[(2R,5S)-5-(stearylcarbamoyloxymethyl)tetrahydrofuran-2-yl]methoxy]phosphinic acid

• The ED50 value for SRI 63-441 inhibition of hemoconcentration in the dog was 0.18 mg kg-1 i.v. In the primate model of PAF-induced hemoconcentration, controls responded to 3.5 micrograms kg-1 i.v. PAF with a 30 +/- 6% increase in hematocrit [11].
• We believe that these results demonstrate that the use of the SRI 63-441 to specifically interfere with the function of PAF has the effect of prolonging graft survival in those systems in which performed antibody and/or complement activation are important components of the hyperacute reaction [9].
• PAF-induced [Ca++]i mobilization was inhibited by several structurally unrelated PAF antagonists such as BN 50739, WEB 2086, SRI 63-441 and BN 52021, in a dose-dependent manner with IC50 values of 4.8, 6.9, 809 and 98500 nM, respectively [12].
• The negative inotropic effect of PAF was, however, antagonized by drugs known to inhibit PAF-induced platelet aggregation: the order of relative potency was SRI 63-441 greater than CV-3988 greater than alprazolam greater than or equal to triazolam; i.e., the same order in which these compounds antagonize the effects of PAF on platelets [13].
• We assessed the ability of the PAF antagonist SRI 63-441 to inhibit ocular vascular permeability induced by the intravenous injection of endotoxin or anterior chamber paracentesis [14].

Anatomical context of 2-(1-quinolyl)ethoxy-[[(2R,5S)-5-(stearylcarbamoyloxymethyl)tetrahydrofuran-2-yl]methoxy]phosphinic acid

• The cleavage rate and morphology of embryos cultured from the 2-cell to blastocyst stage in media containing SRI 63-441 or iloprost (10 micrograms/ml) were normal, precluding a gross toxic effect [4].
• The ED50 for inhibition of MAP by SRI 63-441 was 0.20 mg/kg i.v. Following injection of tritium-labeled SRI 63-441, 56.8 +/- 2.4% of the dose was recovered in the urine and 43.2 +/- 8.9% in the feces in the rats while in dogs 38.7 +/- 5.6% and 60.9 +/- 23.5% of the dose was excreted in the urine and feces, respectively [5].
• Treatment with a platelet-activating factor receptor antagonist, SRI 63-441, inhibited interleukin 1-induced increases in vascular permeability and leukocyte infiltration in the rabbit eye following the intravitreal injection of human interleukin 1-alpha [15].
• This TxB2 increase was not prevented by prior treatment of macrophages with SRI 63-441 [16].
• Effects of platelet-activating factor antagonist SRI 63-441 on endotoxin-induced changes in rat mesenteric microcirculation [17].

Associations of 2-(1-quinolyl)ethoxy-[[(2R,5S)-5-(stearylcarbamoyloxymethyl)tetrahydrofuran-2-yl]methoxy]phosphinic acid with other chemical compounds

• In the ACI to sensitized BN cardiac allograft model, the use of SRI 63-441 alone, or in combination with CsA, FK506, or prostaglandin E2 (PGE2), does not prolong graft survival [9].
• The SRI 63-441 and SRI 63-675 inhibited PLC totally with an IC50 value of 0.78 and 1.27 microM, respectively [18].
• In addition, SRI 63-441 potentiated angiotensin II- and hypoxia-induced vasoconstrictions [19].
• FSK-mediated vasodilation was not mimicked by 1,9-dideoxy-FSK, which is biologically inactive on AC but alters K+ channels identically to FSK, nor was it attenuated by the platelet-activating factor antagonist SRI 63-441 or the cyclooxygenase inhibitor indomethacin [20].
• We conclude that SRI 63-441 is a less specific PAF receptor antagonist in vivo compared with WEB 2086 and that cyclooxygenase products, but not PAF, contribute significantly to the cardiopulmonary responses induced by exogenously infused TNF-alpha in pigs [21].

Gene context of 2-(1-quinolyl)ethoxy-[[(2R,5S)-5-(stearylcarbamoyloxymethyl)tetrahydrofuran-2-yl]methoxy]phosphinic acid

• Furthermore, pretreatment of the rats with two different PAF receptor-antagonists, WEB 2086 (10 mg/kg IP) and SRI 63-441 (10 mg/kg IP), failed to block LPS-induced (1 mg/kg) increase in lung MPO [22].
• A PAF receptor antagonist, SRI 63-441, blocked the increased complement receptor expression in a dose-dependent manner with maximal inhibition of 80-95% at 5 x 10(-6) M [23].
• We investigated whether platelet-activating factor (PAF) mediates endotoxin-induced systemic and pulmonary vascular derangements by studying the effects of a selective PAF receptor antagonist, SRI 63-441, during endotoxemia in sheep [3].
• The specificity of this effect was demonstrated by its inhibition by the specific PAF-receptor antagonist, SRI 63-441 [24].
• In the 24-hour RR/UW group, donor pretreatment with SRI 63-441 (20 mg/kg, intravenously) and recipient treatment with SOD (15 mg/kg, intravenously) or SOD + catalase (15 mg/kg and 5000 units/kg, intravenously) produced a 3-week survival comparable to preservation in UW followed by RR alone [25].

Analytical, diagnostic and therapeutic context of 2-(1-quinolyl)ethoxy-[[(2R,5S)-5-(stearylcarbamoyloxymethyl)tetrahydrofuran-2-yl]methoxy]phosphinic acid

• To evaluate the role of platelet-activating factor on intestinal perfusion and injury, two platelet-activating factor antagonists, SRI 63-441 and WEB 2086, were injected 10 minutes before the hypoxic exposure [26].
• Our results demonstrate that inhibition of PAF function by SRI 63-441 has a variable effect on the survival of cardiac allografts in presensitized rat recipients [9].
• Using the primates in a cross-over design, the ED50 of SRI 63-441 was 0.11 mg kg-1 i.v. At this ED50 value, the ratio of nmol kg-1 PAF used versus nmol kg-1 antagonist is approximately 1:25 [11].
• In a splenectomized mouse bioassay 6 micrograms alprazolam inhibited, for 3 h, the thrombocytopenia induced by 0.1 micrograms PAF; 4 micrograms iloprost and 0.5 microgram SRI 63-441 were effective for 6 and 12h respectively [4].
• The first experiment used reciprocal embryo transfers, in which blastocysts from mice treated with PAF antagonist (SRI 63-441) or saline (controls), from Days 1 to 4 of pregnancy, were transferred to Day-3 pseudo-pregnant recipients which were also treated with SRI 63-441 or saline on Days 1-4 of pregnancy [27].

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