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

Until recently asthma was considered to be caused mainly by bronchospasm of the smooth airway musculature. Accordingly beta-adrenergic agonists were the drugs of choice. During the last decade, however it has become increasingly clear that ongoing chronic inflammation of the bronchial wall plays a prominent role in the disease process. During the early bronchoconstriction after allergen challenge, histamine is probably the most important mediator. The late reaction is characterized by an inflammatory infiltration of the bronchial wall, notably by eosinophils and lymphocytes. A complex interplay of mediators as leukotrienes, prostaglandins and PAF may lead to a chronic inflammation. Inflammatory changes are seen in bronchial biopsies and broncho-alveolar lavage fluid even of mild and asymptomatic asthmatic patients. Based on this new disease concept, antiinflammatory drugs have become the mainstay of therapy even in mild to moderate asthmatics. Beta-adrenergic agonists remain the most important drug for the relief of acute bronchospasm.
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PMID:[Pathophysiology of bronchial asthma]. 127 75

Anti-histamine and anti-PAF effects of epinastine were tested in rats, guinea pigs and rabbits. Epinastine showed a potent histamine H1-blocking effect, but the potency was slightly less than that of ketotifen in histamine-induced contraction of guinea pig ileum and histamine-induced cutaneous reactions in rats. In histamine-induced dye leakage into the nasal cavity tested in rats, the drug was slightly more potent than ketotifen and azelastine. Epinastine as well as ketotifen suppressed rabbit platelet aggregation induced by PAF at higher concentrations compared with WEB 2086, a specific PAF-antagonist. In the bronchospasm induced by PAF in guinea pigs, epinastine was more effective than ketotifen in inhibiting the bronchoconstriction, while it showed no remarkable effect on the hypotension induced by PAF. Epinastine caused a potent antagonistic effect on LTC4-induced contraction of isolated guinea pig trachea. In conclusion, the potent anti-histamine, anti-PAF and anti-LT effects of epinastine may significantly contribute to its antiallergic activity.
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PMID:Antiallergic effect of epinastine (WAL 801 CL) on immediate hypersensitivity reactions: (II). Antagonistic effect of epinastine on chemical mediators, mainly antihistaminic and anti-PAF effects. 135 Jul 91

According to recent literature, the "anti-allergy" properties of antihistamines are linked to their antagonistic ability on receptor H1. In the majority of experimental models the immediate allergic responses is followed by a late phase. Especially at the pulmonary level, the presence of a late response after an allergic provocation is considered to correlate with the severity of asthma. The reference anti-allergy drugs, such as the inhaled corticosteroids or the cromones, without anti H1 activity, inhibit this late pulmonary response. Azelastine, ketotifen and cetirizine, three substances that are antagonistic to the anti-H1 receptor reduce the late pulmonary response. In addition, these three substances have other "anti-allergy" characteristics. Azelastine inhibits production of superoxide by the pulmonary neutrophils and eosinophils after PAF provocation in animals. Cetirizine significantly inhibits eosinophil infiltration in the bronchoalveolar lavage liquid in asthmatics with a late allergic bronchospasm. The presence of anti-histaminic and anti-allergy characteristics on the same molecule may perhaps convey a supplementary therapeutic benefit in the treatment of allergic symptoms.
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PMID:Pharmacological treatment of allergies. 136 95

Asthma bronchiale (a.b.) is defined as paroxysmal or permanent, partly or completely reversible dyspnoea due to a bronchospasm resulting from pathological hyperreactivity of the bronchial system. In the pathogenesis participate allergic, immuno-infiltrative and genetic factors, irritating substances (environment) and infectious. The allergic constituent acts via sensitization and allergization of the mast cell, to its degranulation with release of mediators (histamine, serotonin, leukotrienes, thromboxane, PAF) with subsequent bronchoconstriction and production of viscous mucus. As to adrenergic factors, a block of beta-adrenergic receptors and reduced adrenal function is involved. As to non-adrenergic factors an increased sensitivity of the parasympathetic--vagus is involved which conditions bronchoconstriction and hyperkrinia. From the clinical aspect extrinsic (atopic) and intrinsic (cryptogenic) asthma bronchiale can be differentiated. The former is encountered more frequently in childhood and adolescence, in subjects with a positive family-history, high IgE and positive skin tests and a known allergen. The latter type of a.b. is found in adolescence, in subjects with a negative family-history, with eosinophilia; it is conditioned by infection (e.g. chronic bronchitis), strain, cold and takes a dangerous course (aspirin). As to the course, attacks of a.b. are involved with a symptom-free interval (extrinsic a.) easily controlled by treatment. Then there is the chronic form with a variable course and the necessity of permanent treatment. Status asthmaticus is in recent years with increasing frequency the cause of death and thus calls for maximal treatment. It is the third most serious form of a.b. Assessment of arterial blood gases is very important as a check of treatment as well as from the prognostic aspect (cross-over intubation). From the differential diagnostic aspect we must consider the asthmoid component in chronic bronchitis, pulmonary embolism, left-sided cardiac failure, tracheal or bronchial compression by an aortal aneurysm, tumour. The differential diagnosis is not always easy.
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PMID:[Bronchial asthma. Pathogenesis and clinical aspects]. 145 62

Ro 24-5913, (E)-4-[3-[2-(4-cyclobutyl-2- thiazolyl)ethenyl]phenylamino]-2,2-diethyl-4-oxobutanoic acid, has been identified as a chemically unique, potent and selective LTD4 antagonist. In vitro, Ro 24-5913 competes with [3H]LTD4 for its binding site on guinea pig lung membranes with an IC50 of 6.4 +/- 2.2 nM. In isolated guinea pig tracheal smooth muscle, Ro 24-5913 produces concentration-dependent rightward shifts of LTD4-induced contraction curves (pA2 value of 9.6 +/- 0.2). The slope of the Schild plot is not significantly different from 1, indicating that the antagonism is of a competitive nature. In the human bronchus, Ro 24-5913 is an effective antagonist of LTD4-induced contractions (pKB of 9.3 +/- 0.1). In vivo, Ro 24-5913 dose-dependently inhibits LTD4-induced bronchoconstriction in guinea pigs by the i.v. (ID50 0.13 mg/kg), oral (ID50 0.12 mg/kg) and aerosol (IC50 0.008%) routes of administration. This in vivo activity is specific as evidenced by the inability of Ro 24-5913 to inhibit bronchoconstriction induced by LTB4, PAF or histamine. In comparison with other LTD4 antagonists evaluated in this guinea pig model, Ro 24-5913 is markedly superior in terms of oral potency, bioavailability and oral duration of action. Ro 24-5913 also blocks allergic bronchospasm mediated by endogenously generated leukotrienes in guinea pigs; the potency and duration of action is nearly equivalent to that seen as an antagonist of bronchoconstrictions produced by exogenous LTD4. In summary, Ro 24-5913 is representative of a novel chemical class of LTD4 receptor antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pharmacologic actions of Ro 24-5913, a novel antagonist of leukotriene D4. 165 10

Thromboxane sensitive (TP)-receptors are widely distributed in the airways smooth muscle of various species. In man they mediate constrictor responses, not only to TxA2 but also to other prostanoids such as PGD2 and PGF2 alpha. The evidence for the involvement of these TP-receptors in human asthma is equivocal; however, the recent development of potent, selective TP-receptor blocking drugs such as GR32191 has provided the opportunity to answer this question. GR32191 (80mg p.o.) caused a marked inhibition of PGD2 but not methacholine-induced bronchospasm in asthmatic subjects, and also caused a modest reduction in allergen-induced bronchospasm. However, it had no inhibitory effect against the bronchoconstriction resulting from inhaled PAF or from exercise. Finally, GR32191 was tested in moderate to severe asthmatics for its ability to reduce symptom scores. At a dose of 40mg four times a day for three weeks, GR32191 had no effect upon morning or evening peak expiratory flow rates, on subjective symptom score, on bronchodilator usage or on occurrence of nocturnal dyspnoea. These results do not support a key role for prostanoids acting through TP-receptors in the aetiology of asthma.
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PMID:GR32191 and the role of thromboxane A2 in asthma--preclinical and clinical findings. 179 65

SDZ MKS 492 (R(+)-(8-[( 1-(3,4-Dimethoxyphenyl)-2-hydroxyethyl)amino]-3,7-dihydro-7-(2- methoxyethyl)-1,3-dimethyl-1H-purine-2,6-dione) relaxes airway smooth muscle in vitro and impairs, or reverses, spasm of guinea-pig airways in vivo. Effects on bronchospasm in the guinea-pig may additionally include actions on airway hyperreactivity, since SDZ MKS 492 can inhibit the development, or expression, of airway hyperreactivity due to infusion of PAF, (+/-)isoprenaline, endotoxin or injection of immune complexes. In addition to influencing airway tone, inhaled SDZ MKS 492 diminishes the pulmonary accumulation of macrophages, eosinophils and neutrophils that follows inhalation of allergen by actively sensitized guinea-pigs. SDZ MKS 492 offers the prospect of a monotherapy for asthma, combining bronchodilator and anti-inflammatory activities with prophylactic efficacy.
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PMID:SDZ MKS 492. 179 72

Various cells are associated with inflammatory events characteristic of atopic allergy and asthma. As well as T cells and eosinophils, mast cells, basophils, mononuclear phagocytes and platelets have all to be considered particularly as their mediators have potential for contributing directly to the features of bronchial asthma. Nevertheless, mast cell/T lymphocyte/eosinophil interactions may be of particular significance. For instance, the acute symptoms of allergy and asthma such as sneezing, bronchospasm and hives are believed to be largely the result of mediator release from mast cells whereas chronic symptoms (the result of allergic inflammation) can be explained on the basis of eosinophil-mediated tissue damage. Allergen is recognized directly by T cells. Specialized T cell subsets, possibly the Th2 equivalent, predominate in allergy and elaborate IL-4 (an essential co-factor for IgE production) and IL-5 which brings about terminal differentiation and activation of the eosinophil. Basic proteins derived from the crystalloid granule together with PAF and leukotrienes produce chronic wheeze, bronchial irritability, and might also be involved in permanent nasal blockage in chronic rhinitis. This general hypothesis is continually being tested. It is clearly important to identify precise molecular targets in allergy and asthma in order to construct therapeutic strategies.
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PMID:T lymphocytes and their products in atopic allergy and asthma. 193 73

In a previous report, it was shown that cultures of peripheral blood leukocytes, from allergic individuals, in the presence of antigen will produce bronchospasm inducing agents in the supernatants. In this study, the responsibility of several mediators was analyzed, i.e., histamine, IgE, prostaglandins E2 and F2 alpha and leukotrienes C4. The results failed to demonstrate a significant release of histamine. Measurable amount of IgE could be recovered from active supernatants. Following removal of IgE and IgE-antigen complexes, the immediate bronchospastic response disappeared without so many changes in the delayed response. PGE2 and PGF2 alpha could be demonstrated in the active supernatants, which could be blocked by indomethacin. No significant differences in the bronchial challenge could be demonstrated between the two samples. Samples contained significant amount of leucotrienes C4. Treatment of cultures with NDGA (cyclooxygenase inhibitor) blocked almost completely the bronchial response. Therefore, in this assay, IgE, IgE-antigen complexes and leukotrienes C4 seem to play a major role in the induction of bronchospasm in sensitized individuals. We are clearly aware that the mediators production in vitro may eventually reflect only part of the events taking place in vivo. Nevertheless, this model allows the analysis of several major mediators and eventually some of their interactions. The role of PAF is now under study.
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PMID:Bronchospasm induced in allergic patients by in vitro released mediators. II. Analysis of possible mechanisms. 244 88

The main feature in asthma is bronchial eosinophilic inflammation, induced, in genetically predisposed subjects, by known (aeroallergens, viral infection, occupational agents) and unknown agents. Inflammation critically increases bronchial responsiveness so that even rather mild stimuli (exercise, cold air, mist, allergens) are able to induce obstructive reactions. When preventive measures (specific immunotherapy, avoidance of inflammatory and precipitating factors) are inadequate, a pharmacological treatment is necessary. This should, in addition relieve bronchospasm, neutralize precipitating factors and reduce inflammation. In the first case bronchospasmolytic antireactive agents (beta 2-stimulants, antimuscarinic agents, theophyllines) should be used, whereas, in the second case, the first choice drugs are corticosteroids. Chromon derivatives can also be considered for both their antireactive and antiflogistic effects. It is impossible to elaborate rigid therapeutic schemes. Therapy must be individualized on the basis of symptoms, objective physical signs and functional data. Drugs, except theophylline (for which slow release oral formulations are preferred), should be preferably administered by inhalation. For patients who cannot properly master the use of metered dose inhalers, spacer devices or dry powder inhalers are indicated. Whereas mild asthmatic forms can be treated without corticosteroids, these are absolutely necessary when bronchospasmolytics and chromon derivatives, although appropriately used, do not provide a satisfactory control of the asthmatic syndrome. Many other drugs are now under study (antileukotrienes, anti-PAF, anti-5-lipoxygenase, anti-phospholipase A2), but the results published so far do not seem very promising. Anti-histamines, calcium antagonists, alpha-blocking drugs are justified only in some circumstances. The antireactive activity of loop diuretics is interesting, but its real therapeutic value is still to be assessed. Antibiotics are only needed in the (rare) cases of worsening of asthmatic symptoms due to infective sensitive agents.
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PMID:[Pharmacologic therapy of bronchial asthma]. 257 15


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