Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q15004 (PAF)
 2,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A series of N-(heterocyclic alkyl)pyrido[2,1-b]quinazoline-8-carboxamides were evaluated for their ability to antagonize slow-reacting substance of anaphylaxis (SRS-A) induced contractions of guinea pig ilea and to inhibit thromboxane synthase in vitro. The results indicated that those pyrido[2,1-b]quinazoline-8-carboxamides bearing a branched-chain alkyl moiety in the 2-position and a four to six atom linear chain between a 3- or 4-substituted pyridine or a 1-substituted imidazole ring and the carboxamide nitrogen atom showed the best combination of potencies in the two assays. Several of these compounds were found to be orally active inhibitors of LTE4-induced bronchoconstriction in the guinea pig and LTE4-induced skin wheal formation in the rat. One of the most potent analogues, 2-(1-methyl-ethyl)-N-(1H-imidazol-1-ylbutyl)-11-oxo-11H-pyrido [2,1-b]quinazoline-8-carboxamide (36), was selected for extensive pharmacological investigation. It was found that this compound was not a specific inhibitor of LTE4-induced symptomatology, but exhibited more general activity by inhibiting bronchospasm in guinea pigs induced by LTC4, LTD4, PAF, and histamine and skin wheal formation in rats and guinea pigs induced by LTC4, LTD4, and PAF. In addition, 36 was orally active in the passive cutaneous anaphylaxis assay, suggesting that it also exhibits mediator release inhibitory activity. On the basis of the overall pharmacological profile of 36 and its closely related analogues, it was concluded that these compounds may be useful for the treatment of asthma.
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PMID:N-(heterocyclic alkyl)pyrido[2,1-b]quinazoline-8-carboxamides as orally active antiallergy agents. 287 17

The effects of ICI 185,282 (5(Z)-7-([ 2,4,5-cis]-4-O-hydroxyphenyl-2-trifluoromethyl-1, 3-dioxan-5-yl)heptenoic acid) have been studied on guinea-pig platelets and pulmonary smooth muscle in-vitro and in-vivo. When tested on guinea-pig lung parenchyma in-vitro. ICI 185,282 (1 x 10(-7) M) produced a significant shift in U-46619 response curves (concentration ratio of 13:3); the antagonist (1 x 10(-5) M) did not modify histamine responses. When tested on guinea-pig trachea in-vitro ICI 185,282 (1 x 10(-7) M) caused significant inhibition of U-46619 and PGD2 responses (concentration ratios of 8.3 and 14.1, respectively); the antagonist (1 x 10(-5) M proved less effective against contractions of PGF2 alpha, LTD4 and histamine (concentration ratios of 7.0, 1.5 and 1.6). When added to guinea-pig platelet rich plasma in-vitro, ICI 185,282 (x 10(-6), 1 x 10(-5) M) caused concentration-dependent parallel shifts to the right of U-46619 aggregation curves, yielding concentration ratios of 13.6 and 141.9, respectively. In-vitro, addition of ICI 185,282 (x 10(-5) M) to indomethacin-treated pulmonary smooth muscle did not modify resting tone, neither did it induce aggregation or swelling in platelet-rich plasma preparations. When administered orally to guinea-pigs ICI 185,282 (0.1, 0.5 mg kg-1) caused a significant inhibition of U-46619-induced platelet aggregation ex-vivo which persisted greater than or equal to 8 h. In-vivo, a single oral dose of ICI 185,282 (1 mg kg-1) inhibited bronchospasm induced by U-46619, PGD2, PGF2 alpha, arachidonic acid, LTD4 and PAF; responses to histamine were unaffected.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Studies in the guinea-pig with ICI 185,282: a thromboxane A2 receptor antagonist. 290 37

Interference between the ginkgolides BN-52020 and BN-52021 and the effects of PAF-acether on the cardiovascular and pulmonary functions of guinea-pigs has been studied. BN-52020 (ED50 = 1.1 mg/kg i.v.) and BN-52021 (ED50 = 0.78 mg/kg i.v.) inhibit bronchospasm, hypotension and concomitant generation of TXA2-like activity induced by PAF-acether in anaesthetized guinea-pigs. This protecting activity is specific against PAF-acether since the two ginkgolides do not affect bronchoconstriction, hypotension and TXA2-like activity in the circulating blood due to Histamine, Acetylcholine and LTC4. BN-52021 reduces in a concentration-dependent way the formation of TXB2 caused by PAF-acether in guinea-pig perfused lungs without interference with the effect of Histamine, LTC4 and Arachidonic acid on these tissues. Using actively sensitized (Ovalbumin) guinea-pigs BN-52020 (ED50 = 2.45 mg/kg i.v.) and BN-52021 (ED50 = 1.71 mg/kg i.v.) protect the animals from lethal immunological reaction suggesting that PAF-acether must play a role in the expression of anaphylactic bronchoconstriction and hypotension. The present results indicate that BN-52021 and in a lesser extent BN-52020, which are neither bronchodilators nor cyclooxygenase inhibitors, display a selective antagonistic activity against PAF-acether and may have potential therapeutical implication in asthma.
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PMID:Protection by two ginkgolides, BN-52020 and BN-52021, against guinea-pig lung anaphylaxis. 309 17

The bronchodilator properties of RU 42173, a new beta-adrenergic stimulant with an original structure, as a cyclic analogue of an arylethanolamine, have been evaluated on different in vitro and in vivo models and compared with those of salbutamol and isoprenaline. RU 42173 equipotently inhibited histamine-, acetylcholine-, and KCl-induced contractions in isolated guinea pig trachea or small bronchus and in isolated human bronchus. When administered to guinea pigs by the IV or aerosol route, RU 42173 dose-dependently inhibited bronchospasm induced by histamine, acetylcholine, and methacholine. It also inhibited PAF-induced bronchoconstriction and PAF-induced hyperreactivity to histamine. Moreover, RU 42173 had a rapid onset and prolonged duration of action. The potency of RU 42173 was similar to that of salbutamol.
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PMID:Bronchospasmolytic effects of RU 42173. 324 Sep 17

Platelet activating factor (PAF-acether) is a potential mediator of asthma and inflammation. Recently, the suggestion was made that inhibition of PAF-acether by disodium cromoglycate (DSCG) might be partly responsible for the effectiveness of DSCG in asthma. We have extended these studies and examined the effects of antiallergic and bronchodilator drugs on PAF-acether induced bronchospasm after i.v. administration in guinea pigs and in vitro platelet aggregation in rabbits. Neither DSCG nor Wy-41,195, a potent orally effective antiallergic, altered either of the PAF-acether responses. Furthermore, aerosolized ipratropium, promethazine, ketotifen and FPL 55712 failed to affect the PAF-acether-induced bronchospasm. The same drugs were also ineffective against platelet aggregation induced by PAF-acether. In contrast, aerosolized thiazinamium chloride inhibited the bronchospasm and also inhibited PAF-acether-induced platelet aggregation. Thiazinamium chloride possessed weak antiaggregatory effects against ADP and was without effect against arachidonic acid-induced platelet aggregation. Both lipoxygenase and cyclooxygenase products of arachidonic acid metabolism appear to be involved in PAF-acether bronchospasm since i.v. administered lipoxygenase inhibitors (phenidone, BW755c and NDGA) and indomethacin independently inhibited this in vivo response. However, these drugs failed to alter platelet aggregation to PAF-acether. Thiazinamium chloride may be capable of directly antagonizing the PAF-acether-induced platelet aggregatory response and, in addition, inhibiting the synthesis and/or effects of bronchoconstrictor amines and endogenously generated arachidonic acid metabolites.
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PMID:The effects of antiallergic and bronchodilator drugs on platelet-activating factor (PAF-acether) induced bronchospasm and platelet aggregation. 615 79

1. We have investigated the effects of RP 73401, a novel, potent and highly selective cyclic nucleotide phosphodiesterase (PDE) type IV inhibitor, in guinea-pig and rat models of bronchoconstriction and allergic inflammation. In some models, the effects of RP 73401 have been compared with those of the standard PDE type IV inhibitor, rolipram. 2. RP 73401 (0.4-400 micrograms kg-1, intratracheally (i.t.) on lactose) inhibited antigen-induced bronchospasm in previously sensitized conscious guinea-pigs (ID50: 7 +/- 1 micrograms kg-1) and in anaesthetized rats (ID50: 100 +/- 25 micrograms kg-1). Rolipram inhibited the antigen-induced bronchospasm in guinea-pigs with an ID50 of 5 +/- 1 micrograms kg-1. In guinea-pig bronchoalveolar lavage (BAL) fluid, total inflammatory cell and eosinophil numbers were reduced by RP 73401 (ID50s: 3.9 +/- 0.8 micrograms kg-1 and 3.2 +/- 0.7 micrograms kg-1, respectively). In the rat, inflammatory cell numbers are less affected. Only the highest dose of RP 73401 (400 micrograms kg-1) significantly inhibited eosinophil influx (41 +/- 16% inhibition). 3. RP 73401 (0.02-100 micrograms kg-1, i.v.) inhibited PAF-induced bronchial hyperreactivity to bombesin in the anaesthetized guinea-pig (ID50: 0.09 +/- 0.03 micrograms kg-1) and inhibited (0.4-40 micrograms kg-1, i.t.) histamine-induced airway microvascular leakage in the anaesthetized guinea-pig by approximately 60% at all doses. 4. RP 73401 relaxed guinea-pig isolated trachea under basal tone (EC50: 9 nM) and when precontracted with histamine (IC50: 2 nM), methacholine (IC50: 29 nM) or leukotriene D4 (LTD4, IC50: 4 nM). 5. RP 73401 (0.4-100 microg kg-1, i.t.) inhibited bronchospasm induced by histamine (ID.%: 34 +/- 6 microg kg-1), methacholine (ID50: 66 +/- 12 pg kg-1) and LTD4 (ID50: <4 microg kg-1) in the anaesthetized guinea pig.Against these same bronchoconstrictors, rolipram (i.t.) had ID5o values of 44 +/- 4, 72 +/- 18 and<4 pg kg- respectively. RP 73401 (4 and 40 pg kg-, i.t.) increased the magnitude and duration of bronchodilatation produced by salbutamol in the anaesthetized guinea-pig. At doses producing significant bronchodilatation, RP 73401 was without effect on heart rate or blood pressure in the anaesthetized guinea-pig. RP 73401 (0.01 -0.25 mg kg-1, i.v.) did not affect heart rate and produced only a small fall in blood pressure in the anaesthetized rat.6. These data demonstrate that RP 73401 and rolipram inhibit antigen- and mediator-induced bronchospasmin guinea-pigs with the same potency. Furthermore, RP 73401 administered directly into the airways, protects against allergic airway inflammation. These results indicate the importance of PDE IV in regulating smooth muscle and inflammatory cell activity. At doses suppressing the inflammatory response in the lung, RP 73401 had little effect in the cardiovascular system. RP 73401 may have a role as a bronchodilator and, more importantly, as a prophylactic anti-inflammatory agent in the treatment of asthma.
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PMID:Anti-inflammatory and bronchodilator properties of RP 73401, a novel and selective phosphodiesterase type IV inhibitor. 788

1. PF 10040 displaced [3H]-PAF from binding sites on rabbit platelets with an IC50 = 1.07 x 10(-5) M, which was approximately three orders of magnitude below that of a standard PAF antagonist WEB 2086 (IC50 = 4.23 x 10(-9) M). 2. PF 10040 at doses of 5 and 10 mg (direct intratracheal administration) had no effect on the acute bronchoconstriction induced by PAF in neonatally immunized rabbits (airway resistance RL or dynamic compliance Cdyn). However, the PAF-induced increase in airway responsiveness to inhaled histamine was significantly inhibited (RL and Cdyn) by both doses of PF 10040. 3. PF 10040 (5 and 10 mg) significantly inhibited the total pulmonary cell infiltration and neutrophil influx induced by PAF as assessed by bronchoalveolar lavage. PAF-induced eosinophil infiltration into the airways was significantly inhibited in rabbits that received only 10 mg PF 10040. 4. We suggest from the results of the present study that PF 10040 does not exert an inhibitory effect on PAF-induced airway responses solely via antagonism of the PAF receptor located on platelets, as PF 10040 significantly inhibited PAF-induced airway hyperresponsiveness in the absence of an effect on the acute bronchospasm induced by PAF. 5. We provide further evidence that pulmonary eosinophil infiltration and the development of airway hyperresponsiveness are not causally related events as the lower dose of PF 10040 (5 mg) significantly inhibited PAF-induced airway hyperresponsiveness yet was without effect on the eosinophil influx.
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PMID:Effect of PF 10040 on PAF-induced airway responses in neonatally immunized rabbits. 801 26

The anti-inflammatory, analgesic and antipyretic properties of the new non-steroidal anti-inflammatory agent, meloxicam, were investigated in a variety of animal models and compared with the properties of piroxicam, diclofenac, indomethacin and several other NSAIDs. With respect to the total effect of a single oral dose, the anti-exudative effect of meloxicam on carrageenan-induced oedema in the rat exceeded that of all the NSAIDs included in the comparison. Additionally, meloxicam showed the greatest potency of all the compounds examined with respect to adjuvant-induced arthritis in the rat, the granuloma pouch model and the cotton pellet test in the rat. Unlike indomethacin, in the carrageenan pleurisy model in the rat, meloxicam caused both a dose-dependent reduction in exudate volume and also inhibition of leucocyte migration. Meloxicam showed a strong and lasting effect on inflammatory pain in the rat. Like other NSAIDs, but unlike dipyrone, meloxicam had no effect in the hot plate and tail clamp tests, which are used to identify weak central analgesic effects. Unlike dipyrone and like indomethacin, meloxicam had no effect in a model of visceral distention pain. In common with other NSAIDs, meloxicam had no influence on the body temperature of normothermic rats in the anti-inflammatory dose range, but did reduce yeast-induced fever in the rat in a dose-dependent manner. Like piroxicam, meloxicam had a uricosuric effect on rats treated with oxonic acid. Low-dose meloxicam inhibited both bradykinin-induced and PAF-induced bronchospasm in the guinea-pig, but had no effect on acetylcholine-induced bronchospasm. Piroxicam had greater ulcerogenic effects in the rat stomach than meloxicam. The therapeutic range of meloxicam in the rat, with regard to inhibition of adjuvant arthritis, was several times greater than that of piroxicam, indomethacin, diclofenac and naproxen.
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PMID:Anti-inflammatory, analgesic, antipyretic and related properties of meloxicam, a new non-steroidal anti-inflammatory agent with favourable gastrointestinal tolerance. 856 18

A large series of experiments carried out in animals and humans suggest that histamine release is not involved in the leakage phenomenon induced by bradykinin (BK) challenge. These experiments comprise in vitro studies on skin and bronchial human mast cells and in vivo studies on guinea pig airways and human skin using mepyramine, chlorpheniramine and terfenadine as reference H1-anti-histamines. Nevertheless, it has been shown recently that the H1 antagonist cetirizine 10 mg p.o. markedly inhibits skin reactions induced by BK challenge (intradermal injection of 212 micrograms BK in 10 microL saline and prick test with a solution of 21.2 micrograms/microL). In a guinea pig model, this drug also inhibited the bronchospasm induced by increasing concentrations of BK given by iv route (0.25 to 2 micrograms/Kg) and aerosol (3 to 300 micrograms/Kg). This inhibition was similar to the one obtained with the specific BK antagonist HOE 140 (15 pM/Kg). New data in the literature suggest the existence of various pharmacological mediators possibly involved in the BK-induced reaction: neuromediators, nitric oxyde and PAF. They also suggest that this reaction presents itself as a well defined sequence of pharmacological events. Since we could show that there is no binding of cetirizine to a human recombinant B2 receptor in vitro, some hypotheses are raised in order to explain this unexpected inhibiting effect of cetirizine.
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PMID:[Skin reactions to bradykinin]. 885 Oct 34

Various mediators of inflammation have been suggested as being important in the pathogenesis of asthma. These include histamine, acetylcholine, bradykinin, adenosine, prostaglandins D2 and F2 alpha, thromboxane A2, leukotrienes, PAF and, more recently, various cytokines. Intervention in the action of these mediators is proposed to offer therapeutic benefit, and recent advances in drug therapy have centred on two main approaches. Specific and potent leukotriene antagonists and inhibitors of leukotriene biosynthesis have emerged, and their effects against allergen challenge, cold-air- and exercise-induced bronchospasm and aspirin-sensitive asthma have been evaluated. A small number of studies have also been conducted in clinical asthma, with both acute and long-term (up to 20 weeks) efficacy studies being reported. A considerable degree of inter-individual variation is seen in the degree of protection afforded by leukotriene intervention. The extent to which inhibiting one set of inflammatory mediators can be expected to attenuate the asthmatic response can be questioned. As yet, there is no way of distinguishing leukotriene-related asthma from other types. It is likely, however, that leukotriene intervention may be useful in some patients with specific forms of the disease; for example, aspirin-sensitive asthma. Leukotriene intervention is unlikely to replace inhaled corticosteroids in the treatment of asthma, and its position in the guidelines for the management of asthma remain unclear thus far.
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PMID:Anti-leukotriene intervention: is there adequate information for clinical use in asthma? 895 14


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