REVIEW ARTICLE

Drugs 42 (2): 174-204, 1991 0012-6667/91/0008-0174/$15.50/0 © Adis International Limited. All rights reserved. DRU1047

PAF A Review of its Effects, Antagonists and Possible Future Clinical Implications (Part 11)1 Matyas Koltai, David Hosford, Philippe Guinot, Andre Esanu and Pierre Braquet Institut Henri Beaufour, Le Plessis Robinson, France

Contents 175 175 177

178 179

179 180 181

182 182 182 182 183 183 183 184 185 185 186 186

186 187 187 187

187 188 188 188 189

2.2 Effect of PAF Antagonists on the Central Nervous System (CNS) 2.2.1 Brain Function 2.2.2 Cerebral Ischaemia 2.2.3 Immune Encephalomyelitis 2.3 PAF Antagonists in Airway Hypersensitivity 2.3.1 In Vivo Studies 2.3.2 In Vitro Studies 2.3.3 Conclusion 2.4 PAF in Graft Rejection and Other Immune Responses 2.4.1 Graft Protection 2.4.2 Immune and Cytotoxic Processes 2.5 PAF and PAF Antagonists in Inflammation 2.5.1 Inflammatory Skin Disorders 2.6 Effect of PAF and PAF Antagonists in the Gastrointestinal Tract 2.6.1 Gastrointestinal Ulceration 2.6.2 Intestinal Ischaemia 2.6.3 Bowel Necrosis 2.6.4 Experimental Pancreatitis 2.6.5 Liver 2.7 PAF and PAF Antagonists in Kidney Pathology 2.7.1 Cellular and Haemodynamic Changes 2.7.2 Kidney Injury 2.7.3 Renal Immune Injury 2.8 Effect of PAF and PAF Antagonists on the Reproductive System 2.8.1 Ovulation and Preimplantation 2.8.2 Pregnancy and Embryonic Tissue 2.8.3 Antifertility Effect of PAF Antagonists 3. Clinical Studies 3.1 Reactivity of Human Subjects to PAF

I Part I of this article appeared in the previous issue of the Journal.

Platelet Activating Factor and PAF Antagonists

189 189 190

175

3.2 Clinical Studies on WEB 2086 (Apafant) 3.3 Clinical Studies on Ginkgolides 4. Conclusion

2.2 Effect of PAF Antagonists on the Central Nervous System (CNS) In ancient China, extracts from the leaves of the Ginkgo biloba tree were used to increase cerebral circulation. This practice was adopted by modem medicine, and several natural extracts [e.g. a standardised preparation of Tanakan' (IPSEN-Beaufour)], are marketed in various countries. Intensive research has been devoted to determine the pharmacological principle responsible for the effect of these extracts on the CNS. Now it seems likely that, at least in part, ginkgolides carry the beneficial, antiischaemic effect of the extract. Parallel with this research, the effect of various synthetic plateletactivating factor (PAF) antagonists on brain function has also been studied. 2.2.1 Brain Function The presence of various PAF homologues and analogues in a lipid extract of bovine brain has been demonstrated. The cerebral synthesis of PAF was evaluated by standard separation techniques, and correlation of the bioactivity with the acetylation state of the 2-position of the molecule (Kumar et al. 1988). The low basal level of PAF was greatly increased by intraperitoneal injection of chemoconvulsant drugs, such as picrotoxin and bicuculline, or electroconvulsion (Birkle et al. 1988). When 32P-labelled nerve endings (synaptosomes) were challenged with synthetic PAF, accelerated turnover of polyphosphoinositides and an increased Na+jCa++ exchange were observed. PAF infusion in isolated perfused rat brain increased blood-brain barrier permeability. These observations have pointed to the multiple pathophysiological role of PAF in the brain. PAF production by cultured rat cerebellar granule cells was identified and detected both in the cells and the incubation medium, indicating PAF release from cultured neurons (Yue et al. I 990d).

Since A23187 had only a mild stimulatory effect, the conclusion was drawn that neuronal-generated PAF might be synthesised mainly through a de novo pathway. Accordingly, Francescangeli and Goracci (1989) observed that rat brain synthesised PAF de novo from l-alkyl-2-acetyl-sn-glycerol and COPcholine by a 'OTT-insensitive' phosphocholine transferase, a Mg++ -dependent microsomal enzyme inhibited by Ca++. PAF has been implicated as a critical mediator in neuronal cell damage (Frerichs & Feuerstein 1990), since it increased free [Ca++]j levels in cells of the clones NG 108-15 and PCI2 (Kornecki & Ehrlich 1988). The increase was dependent on [Ca++]e and inhibited by the antagonistic PAF analogue CV-3988 and Ca++-influx blockers, such as prenylamine and diltiazem. These results suggest that PAF plays a physiological role in neuronal development and a pathophysiological role in degeneration occurring when neurons are exposed to circulatory changes as a result of trauma and stroke. PAF Receptors in the Brain PAF receptors are present together with PGE2 and leukotriene (LT) C4 binding sites in the brain (Dray et al. 1989). The occupancy with ginkgolide B of PAF binding sites in gerbil brain may be responsible for its anti-ischaemic effect (Marcheselli et al. 1990). Picomolar concentrations of PAF evoked inositol phosphate formation in primary astrocyte cultures (Murphy & Welk 1989, 1990). Lyso-PAF and down-regulation of PAF receptors with phorbol myristate acetate (PMA) abolished this accumulation. The responsiveness of astrocytes to PAF was not additive with arachidonic acid. These results provide evidence for traumainduced activation of astrocytes in the CNS. Hypothalamic Hormone Release In correlation with the presence of specific PAF receptors in hypothalamic membranes, ginkgolide B, L-652,731 and kadsurenone inhibited the in vi-

176

tro secretion of gonadotrophin-releasing hormone (GnRH) [luteinising hormone-releasing hormone (LHRH)] and somatostatin from rat median eminence, and stimulated corticotrophin releasing factor (CRF) and (j-endorphin secretion (Junier et al. 1988; Rougeot et al. 1990). These authors put forward the hypothesis that there are two populations ofPAF receptors in the rat hypothalamus, in contrast to platelets, which possess only one type of PAF binding site. PAF injected intravenously in rats significantly stimulated pituitary adrenocorticotrophic hormone (ACTH) and adrenal corticosterone secretion, while intraperitoneal administration of ginkgolide B prevented these changes (Bernardini et al. 1989). In explanted rat hypothalami, PAF-induced stimulation of immunoreactive CRF secretion showed a bell-shaped dose-response curve, and was inhibited by alprazolam and ginkgolide B. Indomethacin, eicosatetraenoic acid and verapamil also inhibited this PAF response, suggesting a mediation via Ca++ influx and PLA2 activation. These results support the view that PAF is an activator of the hypothalamic-pituitary-adrenal axis. In dispersed rat anterior pituitary cells in vitro, PAF induced a dose-dependent, rapid stimulation of prolactin release, and the response was blocked by dopamine agonists, L-652,731 and SRI 63-072 (Camoratto & Grandison 1989). a-Melanocytestimulating hormone (a-MSH) derives from proopiomelanocortin (PMOC) having the potential to generate ACTH and (j-endorphin from the anterior hypothalamus and septum, as well as lipotrophins «(j- and 'Y-LPH) and me1anotrophins (a-, (j- and 1'MSH) from the dorsolateral region of the rat hypothalamus. PMOC-derived peptide and corticosterone levels were inhibited by 5-day intravenous minipump infusion of PAF (Blasquez et al. 1990). Peroral treatment with ginkgolide B reversed this inhibitory effect. These data provide evidence that P AF and P AF antagonists can interfere with the endocrine system, and their effect may vary according to the route of application. Recent results may further facilitate understanding the molecular mechanisms by which PAF contributes to long term phenotypic changes in the

Drugs 42 (2) 1991

CNS (Squinto et al. 1989). PAF elicited a rapid and transient activation of the proto-oncogenes c-fos and c-jun in SH-SY5Y neuroblastoma cells, but only to a minor extent in Molt-4 T-Iymphocytes. This effect was inhibited by ginkgolide B, suggesting the involvement of specific PAF receptors. PAF treatment was able to activate gene expression through an AP-l element, therefore genomic transactivation might occur in target genes containing this transcription sequence. Eye and Ear Evidence has been accumulated that PAF and PAF antagonists can influence several functional parameters in the eye. PAF dose-dependently depleted the goblet cell population associated with conjunctival epithelium (Woodward et al. 1989). In addition, PAF increased and CV-6209 abolished conjunctival microvascular permeability, and PAFinduced leucocyte emigration was small or absent. High doses oflyso-PAF also increased conjunctival vascular permeability, suggesting a weak stimulation of PAF receptors or a sufficient conversion of lyso-PAF to biologically active PAF. PAF is involved in the corneal alkali bum-induced inflammatory response of the anterior segment of the rabbit eye (Bazan et al. 1987). The release of prostaglandins (PGs) and hydroxytetraenoic acids (HETE) from [14C]arachidonic acid injected into the anterior chamber was inhibited by topically applied ginkgolide B, whereas the increased protein concentration in the aqueous humour remained unaffected. Ginkgolide B also inhibited leucocyte infiltration and corneal oedema in immune complex keratitis (Domingo et al. 1990). Receptor binding studies in the iris and ciliary body showed high and low affinity PAF binding sites. Local application of PAF to the rabbit eye dose-dependently increased intraocular pressure (Verbey et al. 1989). Ginkgolide B abolished the hypertensive phase, and decreased protein and PGE2 content in the aqueous humour induced by laser irradiation, while indomethacin had no effect. These results suggest a mediator role for PAF in ocular inflammation. Thierry et al. (1989) demonstrated saturable,

Platelet Activating Factor and PAF Antagonists

specific, time-dependent and reversible binding of [3H]PAF to rat retinal membrane preparations. Scatchard analysis revealed binding affinity comparable with PAF receptors occurring in platelets, neutrophils, lung tissue and brain. PAF-induced disturbances in the electroretinogram may be mediated via these receptors (Bussolino et al. 1989b). In the chick retina, acetylcholine and dopamine stimulated PAF production, while other neurotransmitters were ineffective. Doly et al. (1990) found that lithium, used at concentrations that corresponded to therapeutically active doses, significantly decreased the amplitude of the electroretinogram, an effect that was abolished by cholera toxin and partially inhibited by ginkgolide B. These results support the hypothesis that PAF may influence retinal function via involvement of a G protein. Minute doses of PAF influenced inner ear endolymphatic potential. This effect was blocked by ginkgolide Band BM-13,177, a TXA2 receptor antagonist (Ernst et al. 1989a,b). Furosemide (frusemide)-induced changes of cochlear potential were also weakened by PAF antagonists and thromboxane (TX) A2 synthetase inhibitors (Ernst et al. 1989c). PAF antagonists may be useful either alone or in combination with other drugs in the clinical management of acute and chronic ocular inflammatory and allergic disorders, in the early phase of glaucoma and perhaps against retinal ischaemic injury. Our present knowledge is not sufficient to outline the potential therapeutic usefulness of these drugs in audiological disorders. 2.2.2 Cerebral Ischaemia

Effect of P AF on Cerebral Vessels Cerebral circulation is a distinct area in vascular pathophysiology, since the response of pial arterioles differs from that of peripheral resistant vessels. Armstead et al. (1988) studied pial arterioles through a closed cranial window in chloralose-anaesthetised piglets: PAF, norepinephrine (noradrenaline), and U 46619, a purported TXA2 receptor agonist, dose-dependently decreased pial arteriolar diameter. Topical and intravenous

177

administration of U66985, a putative PAF antagonist, selectively reduced PAF responses, but responses to norepinephrine and U46619 remained unchanged. PAF did not increase prostaglandin and leukotriene levels in the cortical subarachnoidal fluid. Thus, PAF is a potent cerebral vasoconstrictor, representing a mechanism independent of cyclooxygenase and lipoxygenase products. PAF also contracted isolated feline basilar arteries and human pial arteries (Uski & Reinstrup 1990), while in PGF2a-precontracted vessels it induced relaxation which was independent of eicosanoid release. A decreased sensitivity of platelets to PAF in migraine patients during headache-free intervals was also observed (Herman et al. 1989). Effect of Ginkgolide Band BN 50739 on Cerebral Ischaemia Although endogenous PAF does not modulate blood flow and metabolism in the normal rat brain (Kochanek et al. 1990), PAF has been implicated as an important mediator of cerebral ischaemic tissue injury. The role of PAF and ginkgolide B in cerebral ischaemia and related disorders has recently been reviewed (Braquet et al. 1989d; Panetta et al. 1989). A mediator role for PAF in spinal cord injury in rabbits has also been suggested (Lindsberg et al. 1990). Previous observations indicated that ginkgolide B prevented ischaemia/reperfusion-induced brain injury in gerbils (Panetta et al. 1987), and PAF receptor blockade enhanced early neuronal recovery after multifocal brain ischaemia in dogs (Kochanek et al. 1987). Our studies showed that ginkgolides significantly decreased stroke index, respiratory control ratio in isolated brain mitochondria and ischaemia-induced water and Na+ gain and K+ loss from brain tissue (Spinnewyn et al. 1987). Among various ginkgolides, ginkgolide B was the most effective (fig. 8). Kochanek et al. (1990) recently found that both ginkgolide B and WEB 2086 suppressed the formation of post-traumatic cerebral oedema, and ginkgolide B also reduced postischaemic hippocampal neuronal damage in rats subjected to 10minute forebrain ischaemia (Oberpichler et al. 1990).

Drugs 42 (2) 1991

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8. Correlation between PAF antagonistic activity ([3H]PAF binding assay in rabbit platelet membrane preparation) and the change in respiratory control ratio (RCR) [in mitochondria isolated after 10 minutes' cerebral ischaemia induced by the ligation of the common carotid arteries followed by 4 hours' recirculation] in Mongolian gerbils [from Spinnewyn et al. (1987) with permission]. Fig.

Evidence for the possible therapeutic potential of PAF antagonists in the management of cerebral ischaemia has been provided by recent studies with BN 50739 in anaesthetised rats. BN 50739 attenuated focal brain oedema, severe cortical microcirculatory failure, blood-brain barrier disruption and neuronal death in the cortex and the CA-l hippocampal region induced by a neodymium : yttrium-aluminium garnet laser technique (Frerichs et al. 1990). BN 50739 dose-dependently reduced the total number of the peripheral type benzodiazepine binding sites in the hippocampus increased by occlusion of the common carotid artery in gerbils and middle cerebral artery in mice (fig. 9), and inhibited oedema formation, Na+ gain and K+ loss after cerebral embolisation induced by intracarotid microsphere perfusion in rats (fig. 10; Duverger et al. 1990). BN 50726, a new hetrazepine type PAF antagonist, has recently been reported to protect gerbil brain against global ischaemia (Braquet et al. 1990). Both ginkgolide Band BN 50739 improved cerebral metabolism and induced recovery of auditory evoked potentials dur-

2.2.3 Immune Encephalomyelitis Intradermal injection of an encephalogenic adjuvant, composed of spinal cord homogenate or myelin basic protein mixed with an equal volume of Freund's complete adjuvant, induces experimental allergic encephalomyelitis in the rat representing an animal model of multiple sclerosis: In rats developing encephalomyelitis, intravenous PAF given on the fifth day increased the severity of the disease (Howat et al. 1989). Animals treated with ginkgolide B did not develop encephalomyelitis to any great extent. These results implicate PAF in the aetiology of this multiple sclerosis model. 200 a; :::>

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2.3 PAF Antagonists in Airway Hypersensitivity Heightened airway reactivity is a major characteristic of asthma. Inflammation as a consequence of the immediate hypersensitivity reaction also plays an important role in chronic asthma (Barnes 1989). Several mediators, including PAF, have been implicated in the pathomechanism of airway hyperresponsiveness (Larsen 1989). More recently, increasing attention has been paid to the late asthmatic response, because its treatment is still unsolved and only glucocorticoids offer alleviation. The role ofPAF in the pathogenesis of asthma and the significance of platelets and eosinophils in bronchial hyperresponsivness have recently been reviewed (Mencia-Huerta et al. 1990; Page 1988). 2.3.1 In Vivo Studies Guinea-pigs, passively sensitised with mouse ascitic fluid containing dinitrophenol-specific IgE antibodies and challenged with dinitrophenol coupled to bovine serum albumin, showed broncho-

constriction that was maximal 5 hours after challenge, and uninfluenced by mepyramine, FPL 55712 or ginkgoJide B alone (Desquand et al. 1989). However, pretreatment with the 3 drugs in combination reduced bronchoconstriction. This model mimics human bronchial asthma in terms ofbronchoconstriction and pharmacological sensitivity. Bronchoconstrictor responses to PAF were analysed in anaesthetised guinea-pigs (lwama et al. 1988) and cats (Underwood & Kadowitz 1989). Intravenous PAF dose-dependently increased lung resistance and decreased dynamic compliance and systemic arterial pressure. Sodium meclofenamate markedly reduced these parameters, with the exception of the blood pressure response, as did SG 29,548, a TX receptor blocking agent. U46619, a TX mimetic drug, and arachidonic acid mimicked these changes, while CV-3988 blocked all responses with the exception of that produced by U46619. These results show that, although airway and vasodepressor responses to PAF in the cat are mediated by different mechanisms, a similar PAFsensitive receptor is involved.

180

PAF produces bronchoconstriction, leucopenia and thrombocytopenia when injected intravenously into anaesthetised guinea-pigs. Ginkgolide B and BN 52111 or BN 52115 - 2 dioxolan compounds with PAF antagonistic properties - inhibited increased airway resistance and thrombocytopenia (Pons et al. 1989b). Higher doses ofBN 52111 partially antagonised the decrease in the number of circulating leucocytes, but the other two compounds had no effect. The dioxolan derivatives were more potent than ginkgolide B in reducing PAF-induced bronchopulmonary alterations, while ginkgolide B induced a more marked reduction of TXB2 generation. The effects of ginkgolide Band cyclosporin A, either alone or in combination, on PAF- and antigen-induced bronchoconstriction were studied in passively sensitised guinea-pigs (Touvay et al. 1989). Although a single administration of cyclosporin A alone had no effect on PAF-induced bronchoconstriction, a marked inhibition was found when it was combined with an inactive dose of ginkgolide B. This effect was associated with PAFinduced alterations in the number ofleucocytes and platelets. These results strengthen the hypothesis that PAF and the immune system are involved in the regulation of bronchopulmonary reactions. In anaesthetised guinea-pigs, PAF produced bronchial hyperresponsiveness to intravenous acetylcholine (Dixon et al. 1989). Pretreatment of guinea-pigs with propranolol or indomethacin elicited hyperreactivity to intravenous histamine. PAF-induced hyperresponsiveness was significantly attenuated by ginkgolide B, CV-3988 or WEB 2086, while these drugs had no effect on propranolol- and indomethacin-induced bronchial hyperresponsiveness. Therefore, the latter responses did not seem to involve PAF as mediator. SDZ 64-412 reduced airway hypersensitivity but not the increase of eosinophil cell count in the bronchoalveolar lavage fluid induced by histamine (Havill et al. 1990). WEB 2086, ketotifen and methylprednisolone also had a prophylactic effect against increased bronchial responses. The role of booster injection on ability of PAF antagonists to block antigen-induced bronchocon-

Drugs 42 (2) 1991

striction in ovalbumin-sensitised guinea-pigs was recently investigated (Desquand et al. 1990). Irrespective of the titres of circulating immunoglobulins at various times after booster injection, WEB 2086 and ginkgolide B were inactive against antigen-induced bronchoconstriction. However, when tried in guinea-pigs not subjected to booster injection, they inhibited bronchoconstriction induced by intratracheal installation of antigen or ovalbumin-induced contractions of lung strips. The booster injection may account for the loss of efficacy of PAF antagonists as an inflammatory challenge interfering with the pharmacological modulation of the bronchopulmonary and secretory effects of PAF in the lung. 2.3.2 In Vitro Studies In isolated rat and guinea-pig tracheal segments, PAF induces contraction and does not cause downregulation of ,8-adrenoceptors (Chand et al. 1988). In addition, PAF-contracted tracheal segments lost their ability to relax in response to isoprenaline (isoproterenol). In an in situ canine tracheal preparation, when infused into the tracheal arteries PAF dose-dependently augmented the smooth muscle tone induced by parasympathetic stimulation (Bethel et al. 1989). Regional application of PAF did not render the lung more sensitive to vagus nerve stimulation, suggesting a role for locally released secondary mediators. Tracheal smooth muscle strips, excised from guinea-pigs challenged in vivo with PAF for 7 days, exhibited increased sensitivity of smooth muscle to histamine but not to acetylcholine (Inoue & Kannan 1989). Cimetidine and indomethacin potentiated histamine-induced contractions both in control animals and in PAF-treated animals, while WEB 2086 inhibited PAF- and histamine-induced contractile responses (Johnson et al. 1990). These results suggest a synergistic interaction between histamine and PAF in smooth muscle hyperreactivity. Various LTD4 antagonists enhanced the effect of L-652,731 in ovalbumin- and arachidonic acidchallenged sensitised guinea-pig tracheal strips (Burka et al. 1989). When the effluent of perfused

Platelet Activating Factor and PAF Antagonists

lungs was superfused over tracheal, bronchial and lung parenchymal strips, the intra-arterial injection of PAF caused a release of spasmogens which contracted all tissues. Indomethacin inhibited these responses, however treatment with indomethacin of the assay tissues did not (Jancar et al. 1988). Pretreatment of the lungs with indomethacin or aspirin did not suppress PAF-induced spasmogen release but inhibited the release of cyclooxygenase products. The lipoxygenase inhibitor NDGA or L655,240 blocked the release of spasmogens from the perfused lungs. PAF response was completely abolished by ginkgolide B but remained uninfluenced by FPL 55712. It appears likely that PAF induces LTB4 release, which then further generates cyclooxygenase products. Indomethacin, ozagrel (OKY-046) - a TXA2 synthase inhibitor - and L655,240 or SKF-88046 - two TXA2 receptor antagonists - failed to inhibit PAF-induced contraction of guinea-pig parenchymal strips, while NDGA and BW775c were inhibitory, suggesting a major role for lipoxygenase products (Jancar et al. 1989b). In lungs isolated from actively sensitised guineapigs, antagonists related structurally to PAF (such as Ro 19-3704, Ro 19-1400 and CV 6209) as well as agents structurally unrelated to PAF (like ginkgolide B and WEB 2086) inhibited PAF-induced bronchoconstriction in normal tissue, but failed to influence that induced by PAF in actively sensitised animals (Pretolani et al. 1989). Ro 19-3704 and Ro 19-1400, at concentrations which abrogated the effects of PAF in the lungs of nonimmunised animals, inhibited bronchoconstriction, release of histamine and leukotriene-like material evoked by PAF injected intra-arterially into lungs of sensitised animals, while CV-6209 failed to block PAF responses. All antagonists suppressed oedema formation induced either by ovalbumin or PAF. On the other hand, PAF- and active immunisation-induced bronchoconstriction, mediator release and eosinophil content in the bronchoalveolar lavage fluid were all reduced by I-week treatment with nedocromil sodium (Pretolani et al. 1990). These results indicate that different mechanisms and the interaction of various mediators are involved in allergic bronchconstriction and in-

181

flammatory response, and suggest that sensitisation markedly modifies PAF responses in the lung. In guinea-pig parenchymal lung strips the effects of LTD4, acetylcholine, histamine and KCl coadministered with PAF were studied by Yaghi et al. (1989). There was no significant alteration in acetylcholine- and KCl-induced responses or in the PAF-induced inhibition of histamine response; however, PAF markedly and concentration-dependently decreased LTD4-induced contractions. Ginkgolide B, cyclooxygenase and lipoxygenase inhibitors interfered with PAF-induced attenuation of LTD4 contractions, suggesting a role of secondary TXA2 generation. In histamine-contracted guinea-pig tracheal preparations, PAF induced PGE2 production and relaxation (Brunelleschi et al. 1989). WEB 2086 inhibited both responses, while ginkgolide B markedly decreased relaxation, but completely abolished PGE2 release. More recently, human airways in culture were used to study the pathophysiology of pulmonary allergic reactions (Goswami et al. 1989). Ro 193704 and LY 171,883, a specific LTD4 receptor antagonist, inhibited PAF-stimulated respiratory glucoconjugate release, while indomethacin had no effect. Interestingly, PAF response was augmented by atropine, suggesting that cholinergic mechanisms are not involved in the effect of PAF. In guinea-pig and human lung preparations, [3H]WEB 2086-labelled specific PAF receptors proved to be an excellent model for studying the role of PAF in airway hyperreactivity (Dent et al. 1989b). Recently Salari and Wong (1990) demonstrated that cultured human lung epithelial cells synthesised PAF in response to PMA challenge, suggesting that these cells might participate in inflammatory lung diseases. 2.3.3 Conclusion It may be concluded that bronchial hyperres-

ponsiveness due to immediate type hypersensitivity can be carefully divided into several subtypes with differing pharmacological sensitivity, thus explaining the diverse clinical features and therapeutic interventions in bronchial asthma. PAF appears to be a modulator rather than a mediator in allergic

182

airway hyperreactivity, ~nd the therapeutic effectiveness of PAF antagonists may be restricted to the delayed bronchoconstriction and inflammatory response. Extensive and careful pharmacological analysis points to remarkable differences between species, our understanding of which is rather limited. At present, research on various PAF antagonists may be useful for differentiating subtypes of hypersensitivity reactions in the lung. 2.4 PAF in Graft Rejection and Other Immune Responses 2.4.1 Graft Protection The role of PAF in organ transplant rejection has recently been reviewed (Foegh 1988). Eicosanoids and PAF can modulate the immune response in vitro and in vivo. Prostaglandins seem to attenuate, while TXA2, leukotrienes and PAF potentiate the cell-mediated immune response. In addition, these compounds have nonimmunological effects that may modify oedema formation and decreased blood flow associated with the rejection process. An attempt was recently made to prolong organ preservation by applying ginkgolide B in traditionally used solution: a significantly lengthened pulmonary function was seen, compared to controls (Foegh et al. 1990). Furthermore, ginkgolide B was administered to lung transplant donors and recipients. This method can facilitate lung transplantation in clinical conditions even where there are long physical distances between donor and recipient. 2.4.2 Immune and Cytotoxic Processes Cyclosporin A dose-dependently inhibited lymphocyte proliferation and interleukin (IL)-1 and IL-2 production by rat spleen cells (Pignol et al. 1990a,b). Ginkgolide Band BN 52063 potentiated the effect of submaximal cyclosporin A doses. These alterations could be reproduced ex vivo after 4 days' treatment of rats with BN 52063. This finding is promising for the use of PAF antagonists in association with cyclosporin A to prevent graft rejection. Studies are in progress to determine whether PAF antagonists could decrease cyclosporin A-in-

Drugs 42 (2) 1991

duced nephrotoxicity without altering its immunosuppressive effect. Using 51Cr release as a measure of cytotoxicity Mandi et al. (1989) showed that ginkgolide B significantly reduced human natural killer activity against K 562 target cells. Preincubation of target cells with ginkgolide B induced a higher reduction of cytotoxicity than that of effector cells. Moreover, the increase in cytotoxicity induced by interferon was less marked when ginkgolide B was added in the incubation medium. The natural killer activity of the platelet-depleted large granular lymphocyte-enriched effector cell population was inhibited in a similar manner. The effect of BN 52111 and WEB 2086 was comparable to that of ginkgolide B, indicating that PAF binding sites are responsible for the phenomenon. The cytotoxic action of synthetic PAF was effectively suppresssed by ginkgolide B, providing indirect evidence for the involvement of PAF in natural killer activity. More recently, BN 50730, a novel PAF antagonist with a hetrazepine framework, has been reported to have potential therapeutic value in diverse pathological conditions, particularly against various allergic responses (Braquet et al. 1990). 2.5 PAF and PAF Antagonists in Inflammation The possible mediator role for PAF in acute and chronic inflammatory reactions has become a subject of considerable interest. PAF induced rat paw oedema which was suppressed by LY 171883, an LTD4 inhibitor, suggesting a role for lipoxygenase products in this inflammatory response (Silva et al. 1988). Repeated local PAF injections induced an autodesensitisation which was unaffected by adrenalectomy. In the mouse, PAF induced an early inflammatory response either when injected in the paw or the pleural cavity, while carrageenin produced a delayed reaction (Henriques et al. 1990). WEB 2170 inhibited these responses dose-dependently, while WEB 2086 was without effect, pointing to different receptor sites for PAF at the inflammatory site. Ginkgolide B injected intraperitoneally in the

Platelet Activating Factor and PAF Antagonists

rat inhibited pleural exudation and cell migration induced by zymosan (Martins et al. 1989). PAF given intrapleurally twice daily produced a selective and progressive desensitisation. In desensitised animals, both exudation and cell infiltration induced by zymosan were blocked whereas the serotonin response remained unchanged. PMA-induced rat pleurisy was also shown to involve PAF (Oh-ishi et al. 1989). Antigen challenge increased PGE2, TXA2 and LTB4 contents in the peritoneal inflammatory exudate induced by Arthus reaction (Jancar et al. 1989b). Indomethacin inhibited PGE2 and TXA2 release and increased LTB4 formation, while ginkgolide B suppressed LTB4 production and increased PGE2 release without influencing TXB2, suggesting that zymosan-induced pleurisy and Arthus reaction involve PAF release. A cooperation between PAF and TNF in superoxide anion generation by PMNL in vitro and antigen-induced arthritis in rabbits in vivo was recently described (Maestre et al. 1990). Femoral head cartilage implanted into the subcutaneous tissue of male Wistar rats showed constant glycosaminoglycan loss which remained uninfluenced by minute doses ofPAF infused by a minipump and ginkgolide B administered orally twice daily as a long term treatment (Howat et al. 1990). However, when cartilage was cultured in a medium that contained PAF and IL-l, the glycosaminoglycan loss was increased. This synergism between PAF and IL-l suggests a possible interaction between these mediators in arthropathies. The peritoneal fluid of patients who developed peritonitis after serial peritoneal dialysis contained PAF, providing evidence for the mediator role of PAF in inflammation (Montrucchio et al. I 989b). 2.5.11njlammatory Skin Disorders· In allergic patients, pollen injection released PAF and precursors to the sterile skin chambers overlying 'blister base' sites (Michel et al. 1988). This response was inhibited by ginkgolide Band L652,731. Based on measurements of plasma exudation in the skin, the effect of PAF appeared to be limited to the superficial microvasculature underlying the surface of skin window chambers

183

(Humphrey 1990). Cultured human skin keratinocytes (but not fibroblasts) activated by PAF accumulated the inositol phosphates DG and PGE2, while precursors and lyso-PAF had no such effect (Fisher et al. 1989a). Hellewell and Williams (1989) found that SRI 63-675 and CV-3988, 2 structurally related antagonists ofPAF, partially inhibited oedema formation induced by intradermal injection of PAF plus PGE2 in the rabbit skin. Structurally unrelated PAF antagonists, such as 48740 RP, ginkgolide B, WEB 2086, L-659,989, kadsurenone and its synthetic derivatives markedly inhibited only PAF response. This finding draws attention to the need for a careful selection of antagonists when the role of PAF in the inflammatory response is studied. Ginkgolide B inhibited dithranol (anthralin)-induced dermatitis (Kemeny et al. 1989, 1990), and BN 52063 suppressed contact dermatitis in mice (Lavaud et al. 1990). PAF potentiated endotoxininduced IL-l release from cultured guinea-pig keratinocytes (Pignol et al. 1990), while ginkgolide B inhibited the release of IL-l by UV-irradiated human epidermis cells (Csato et al. 1990). In conclusion, PAF is an important inflammatory mediator which may interact with other mediators like cytokines, thereby resulting in an autocatalytic augmentation of the inflammatory response. PAF antagonists, being able to interrupt this vicious circle, may be included in the therapeutical strategy of various inflammatory diseases. Their use, either alone or in combination with other anti-inflammatory drugs, also seems reasonable in a great variety of pathological conditions related to inflammation. 2.6 Effect of PAF and PAF Antagonists in the Gastrointestinal Tract 2.6.1 Gastrointestinal Ulceration Microcirculation plays an important role in the maintenance offunctional integrity of the gastrointestinal mucosa (Esplugues & Whittle, 1989; Wallace 1990; Whittle 1989). Changes in blood flow by local release of vasoactive or cytotoxic mediators, including oxygen-derived free radicals, eicosanoids

184

and PAF, have been implicated in the pathogenesis of various forms of peptic ulceration and erosive gastritis. Damage of microvessels and vascular endothelium is an initial event in the development of such lesions. Intravenous infusion of PAF induced hypotension and gastric mucosal injury related to congestion, elevation of thiobarbituric acid reactants and oxygen-derived free radicals (Binnaka et al. 1989). PAF-induced gastric ulceration was accompanied by a reduction in the number of circulating PMNLs and an increased adherence of PMNLs to microvascular endothelium (Kubes et al. 1990), while the role of oxygen free radicals was emphasised by the inhibition induced by superoxide dismutase plus catalase (Yoshida et al. 1989). Increased acetylhydrolase activity in rats carrying water-immersion stress-induced gastric ulcers suggested an increased conversion of Iyso-PAF to PAF (Fujimura et al. 1989). CV-3988 inhibited distinct bleeding and the increase in mucosal vascular permeability induced by acid in perfused stomach of anaesthetised rats (Hatakeyama et al. 1989). The involvement ofPAF receptors in Cl- secretion which follows a circadian rhythm has also been demonstrated (Hanglow et al. 1989). Ginkgolide Band BN 52063 markedly inhibited gastrointestinal ulceration induced by PAF and endotoxin in rats, while ginkgolides and triazolam partially reduced restraint-stress-induced gastric damage in young female but not male rats (Braquet et al. 1988). Partial protection was also seen in rats with ethanol-induced gastric damage. In contrast to atropine and ranitidine, ginkgolide B affected neither gastric hypersecretion in pylorus-ligated rats nor aspirin-induced gastric ulceration. In a further study, ginkgolide B was more effective against PAFinduced gastric lesions than in reducing endotoxininduced gastrointestinal damage (Etienne et al. 1989b). More recently, BN 50727, a new hetrazepine type PAF antagonist, has been reported to exert prominent gastroprotective properties (Braquet et al. 1990). L-652,731 inhibited an endotoxin-induced increase of intragastric pressure (Esplugues & Whittle 1989), but tetrodotoxin did not influence the rise

Drugs 42 (2) 1991

of intragastric pressure induced by the TXA2 mimetic U46619 (Esplugues et al. 1989). LTC4 and PAF, which affect gastric microcirculation, caused mild gastric mucosal injury and greatly augmented lesions produced by other irritants such as absolute ethanol, taurocholate, aspirin or stress (Konturek et al. 1989). These lesions accompanied by LTC4 generation were further increased by PAF (Dembinska-Kiec et al. 1989). Ginkgolide B abolished PAF-induced gastric lesions and reduced LTC4 generation when PAF and ethanol were given together. PAF amplified oxidative stress during reperfusion of ischaemic stomach (Droy-Lefaix et al. 1988). Eliakim et al. (1988) demonstrated that sulfasalazine and prednisolone, used for the treatment of ulcerative colitis, enhanced PAF production. Pretreatment with dexamethasone attenuated endotoxin-induced haemoconcentration, hypotension and gastroduodenal damage (Ibbotson & Wallace 1989a,b), and significantly reduced PAF synthesis in the lung but had no effect on the endotoxin-induced increase in PAF release and vascular permeability in gastrointestinal tissues. The conclusion can be drawn that dexamethasoneinduced protection may be related to the inhibition of PAF release from the lung, and PAF released from the gastrointestinal tissue probably contributes little to the systemic disturbances induced by endotoxic shock. PAF given parenterally induces severe gastric mucosal damage. Since PAF and PAF-metabolising enzymes are present in the brain, Cucala et al. (1989) studied rat gastric acid secretion and gross mucosal integrity in response to intracerebroventricular PAF and compared its effect with that induced by thyrotrophin-releasing hormone (TRH), a known central gastric secretagogue. Centrally applied TRH and intravenous pentagastrin increased gastric acid output, while intracerebroventricular PAF decreased acid output and reduced pentagastrin-stimulated gastric acid secretion. TRH and PAF induced different morphological changes in the stomach. It appears likely, therefore, that a central gastric secretion modulatory system exists through which PAF initiates gastroprotective effects.

Platelet Activating Factor and PAF Antagonists

2.6.2 Intestinal Ischaemia Mesenteral artery occlusion and reperfusion released PAF in anaesthetised dogs (Filep et aI. 1989). Ginkgolide B did not influence the myeloperoxidase activity, but decreased malondialdehyde formation, mucosal permeability and N-acetyl-{:1-glucosaminidase release, indicating the activation of specific PAF receptors in ischaemia-induced intestinal mucosal damage (Otamiri & Tagesson 1989; Otamiri et al. 1989). CV-3988 significantly reduced gross and histological gastric damage, and the increased chemoluminescence activity of PMNL in the portal vein of rats subjected to haemorrhagic shock (lwai et al. 1989), suggesting that PAF-generated hypoxia stimulates oxygen free radical production which contributes to gastrointestinal injury.

2.6.3 Bowel Necrosis Several candidate mediators of acute inflammation, such as type-E prostaglandins, histamine and bradykinin are potent pro-diarrhoeal colonic secretagogues which increase serosal to mucosal transport of Cl- and passive water efflux. PAF increased transepithelial potential differences and short circuited currents in muscle-stripped rat colon (Buckley & Hoult 1989); lyso-PAF produced a much smaller but discernible effect. PAF displayed an effect when applied to the serosal surface, but remained ineffective after mucosal application. Inhibitor studies suggested that Cl- was the principal ion carrier but kadsurenone, CV-3988 and WEB 2086 did not block the response. Unlike bradykinin, PAF did not cause PGE2 release into the serosal bathing fluid, and its effect remained uninfluenced by piroxicam, mefenamic acid or flurbiprofen. This suggests that PAF has a powerful pro-diarrhoeal secretory action which is not mediated by PAF receptors and does not seem to be dependent on prostanoid generation. Rats treated with PAF or endotoxin develop ischaemic bowel necrosis associated with shock (Sun & Hsueh 1988). Morphological changes in TNFinduced bowel lesions were indistinguishable from those caused by PAF; TNF induced PAF produc-

185

tion in bowel tissue, and the effects of TNF and endotoxin on PAF production were additive. Furthermore, TNF and endotoxin were synergistic in inducing bowel necrosis, and TNF-induced bowel necrosis was due to PAF release, since SRI 63-119 offered a protective effect (Hsueh & Sun 1989). Pretreatment with allopurinol or superoxide dismutase plus catalase markedly improved the lesions induced by PAF injected into the mesenteric vasculature of the rat, indicating that intestinal damage was mainly due to the release of oxygen free radicals (Cueva & Hsueh 1988). Allopurinol ameliorated small bowel lesions, showing that the major source of oxygen free radicals was xanthine oxidase. Superoxide dismutase/catalase did not alter hypotension induced by PAF but improved haemoconcentration and leucopenia. The mediator role of PAF in intestinal inflammation and ulceration has been further investigated (Wallace 1988, 1990; Wallace et al. 1989a). Ginkgolide B, WEB 2086 and WEB 2170 accelerated healing of chronic colitis. Long term treatment with ginkgolide B or mesalazine (5-aminosalicylic acid) given intracolonically did not affect colonic damage, although ginkgolide B reduced the incidence of adhesions and diarrhoea, while mesalazine did not (Wallace et al. 1989b). Using an in vitro superfusion system, the colon segments exised from normal rats were contracted by PAF, but noninflamed segments of ascending colon isolated from rats subjected to colitis 2 weeks before did not respond to PAF. These results are contradictory to the concept that PAF plays a role in the acute inflammatory response in this model, but emphasise the importance of PAF in the prolongation of inflammation and ulceration. The contractility changes in ascending colon may occur as a consequence of inflammation.

2.6.4 Experimental Pancreatitis A single injection ofPAF into the superior pancreaticoduodenal artery of rabbits induced dosedependent morphological alterations such as oedema, necrosis and PMNL infiltration in the pancreatic tissue and increased serum amylase activ-

186

ity, both characteristic of acute pancreatitis (Emanuelli et al. 1989). CV-3988 and atropine antagonised the effect of PAF, pointing to a potential role for cholinergic mechanisms in PAF-induced pancreatic alterations. The preventive effect of ginkgolide B on the formation of oxygen free radicals in cerulein-induced acute pancreatitis in rats also suggests a therapeutic value for PAF antagonists in this disease (Dabrowski et al. 1990).

2.6.5 Liver Parenchymal cells (hepatocytes) are the sites at which the principal metabolic functions of the liver are located. In the perfused liver, vasoconstriction and glycogenolysis induced by zymosan, PAF and arachidonic acid were inhibited by indomethacin and bromophenacyl bromide, an inhibitor ofPLA2 (Altin & Bygrave 1988). Since cultured Kupffer and endothelial cells, but not hepatocytes, produced eicosanoids, and eicosanoids (especially prostaglandins) induced similar pattern of responses when added directly to the perfused liver, nonparenchymal cells seem to be responsible for the mediation of these responses. PAF rapidly reduced the number of cell surface receptors in isolated rat Kupffer cells to a new steady-state concentration (Chao et al. 1989a). When receptor synthesis was inhibited by cycloheximide in the absence ofPAF, the half-life of the surface PAF receptors was about 4 hours, suggesting that these receptors are not recycled and their loss from the plasma membrane is accelerated by PAF binding. Ginkgolide B or U66985 alone had no effect on the number of surface PAF receptors, but PAF antagonists caused a concentration-dependent inhibition ofPAF-induced receptor downregulation. This reversible process was prevented by cycloheximide, suggesting that the restored PAF receptor is newly synthesised rather than recycled. A23187 stimulated PAF synthesis and release in cultured rat Kupffer cells (Chao et al. 1989b). PAF release appeared to be an important cellular signal which facilitated communication between hepatic sinusoidal and parenchymal cells. PAF production

Drugs 42 (2) 1991

in stimulated reticuloendothelial cells was responsible for hepatic glycogenolysis. PAF-stimulated PGI2, PGE2 and PGF2a production was inhibited by L-659,989, kadsurenone, L-652,731 and ginkgolide B (Levine 1988). Ibuprofen abolished prostaglandin release but did not affect glycogenolysis (Lapointe & Olson 1989); thus, in contrast to previous observations, the 2 responses do not appear to be causally related. Prior exposure of the cells to PAF or teleocidin and aplysiatoxin (2 TPA-type tumour promoters) or mezerein (a second stage tumour promoter known to activate Ca++/phospholipid-dependent protein kinase C), all inhibited PAF-induced responses, indicating a homologous and heterologous desensitisation. In [3H]inositollabelled Kupffer cells, SRI 63-675 inhibited the PAF-induced increase of labelled inositol phosphate production (Fisher et al. 1989b). Concomitantly, PAF elevated cytosolic free Ca++ concentrations in a single Kupffer cell loaded with fura2; thus interactions between PAF and Kupffer cells may result in haemodynamic and metabolic responses. In bile duct-ligated conscious cirrhotic rats, intravenous gink~olide B reduced portal pressure, lowered the cardiac index, and exhibited a higher systemic vascular resistance and lower portal tributary blood flow (Sekiyama et al. 1990), showing that PAF might be one of the mediators responsible for the hyperdynamic circulation in cirrhosis. L-652,731 and CV-3988 reduced PAF-induced rapid ascites formation, systemic hypotension, haemoconcentration, and the development of acute erosions in the gastrointestinal mucosa (Guarner et al. 1989). These experiments draw attention to the mediator role of PAF in a great variety of gastrointestinal pathophysiological disorders, supporting the view of a possible clinical application of PAF antagonists in gastric and intestinal ulceration, intestinal ischaemia, and chronic bowel and liver diseases. Under these conditions these drugs may have benefit as anti-inflammatory and tissue-protective agents. The antiprotease activity of ginkgolide B underlines its probable usefulness in acute and chronic pancreatitis.

Platelet Activating Factor and PAF Antagonists

2.7 PAF and PAF Antagonists in Kidney Pathology 2.7.1 Cellular and Haemodynamic Changes PAF production induced by angiotensin II in cultured mesangial cells indicates a possible role for the phospholipid mediator in angiotensin IIinduced progression of renal glomerular disease (Neuwirth et al. 1989). Continuous infusion or bolus injection ofPAF in anaesthetised dogs markedly reduced renal plasma flow, glomerular filtration, and urinary Na+ excretion in parallel with systemic hypotension (Hebert et al. 1989). L655,240 - a TXA2-PG endoperoxide antagonist failed to prevent the decrease of renal plasma flow and filtration rate, but attenuated PAF-induced diminution of urinary Na+ excretion. In isolated rat kidney, PAF produced a potent and reproducible vasodilator effect which appeared to be dependent on the albumin content in the perfusion fluid (Gerkens 1990). Further experiments will better clarify the effect of PAF on kidney function. 2.7.2 Kidney Injury PAF produced by various cells and organs may be involved in the mechanism of proteinuria and other nephropathies. In anaesthetised rats ginkgolide Band alprazolam given after 30-minute occlusion of the left renal artery induced an immediate increase in urine flow, glomerular filtration and Na+ excretion (Lopez-Farre et al. 1990; Plante et al. 1989). Decreased renal blood flow, glomerular filtration rate and urine flow rate induced by endotoxin infusion in anaesthetised male rats were significantly improved by ginkgolide B and SRI 63675 (Tolins et al. 1989). 2.7.3 Renal Immune Injury Ginkgolide B dose-dependently reduced the release of anaphylactic mediators in perfused guineapig kidney (Rossoni et al. 1990), and markedly decreased PAF-induced IL-l and TNF production (Gomez-Chiarri et al. 1990). Release of histamine and lipid mediators during renal anaphylaxis was blocked by ginkgolide B (Berti et al. 1990). Ca-

187

mussi et al. (1990) have analysed the significance of PAF/cytokine interaction in renal pathology. Cyclosporin A has been used in kidney transplantation as an immunosuppressant, but its nephrotoxicity remains a relevant clinical problem. Ginkgolide B significantly decreased planar cell surface area and a glomerular cross-sectional area in cultured rat mesangial cells and isolated rat glomeruli challenged by PAF or cyclosporin A, indicating that cyclosporin A-induced kidney dysfunction may be due to PAF release (Lamas et al. 1990). Micropuncture studies in Munich-Wistar rats showed that ginkgolide B blunted the deleterious effects of cyclosporin A on superficial nephrons, while the total renal function remained uninfluenced (Pavao dos Santos et al. 1989). Taken together, the evidence suggests that PAF appears to playa mediator role in immunological kidney damage, graft rejection, cyclosporin A-induced immunosuppression, and presumably in renal ischaemia, suggesting that PAF antagonists may offer protection against these disorders. 2.8 Effect of PAF and PAF Antagonists on the Reproductive System More recently, increasing attention has been paid to the role of PAF in mammalian reproduction. The results of this research have been summarised in a recent review (Page & Abbott 1989). 2.B.1 Ovulation and Preimplantation Follicle rupture during ovulation is associated with inflammation-like changes (Harper 1989). Ginkgolide B inhibited follicle rupture, hormonestimulated increase of ovarian collagenolysis and vascular permeability in rats whose ovulation was stimulated by human chorionic gonadotrophin (Abigosum et al. 1989). Simultaneous PAF administration reversed this effect. At 2-hour sampling intervals during the ovulatory process in gonadotrophin-primed Wistar rats, the ovaries contained PAF levels lower than normal (Espey et al. 1989). The ovarian lipid extract also contained PAF inhibitor(s) that comigrated with PAF whose levels were also decreased in response to gonadotrophin.

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PAF levels in the uterus were elevated by progesterone and PGE2 (Alecozay et al. 1990; Harper 1989). These results suggested that PAF antagonists might interfere with sperm function, ovulation and implantation, however, more recent results showed a failure of PAF antagonists to inhibit implantation in mice (Milligan & Finn 1990). CV3988 inhibited the in vitro stimulatory effect ofPAF in mouse oocytes, indicating the involvement of specific PAF receptors in the fertilisation process (Minhas et al. 1989). 2.B.2 Pregnancy and Embryonic Tissue Mouse embryos produced soluble PAF possessing properties similar to authentic PAF (Collier et al. 1988; O'Neill et al. 1989a,b). SRI 63-441, SRI 63-412, WEB 2086 and ginkgolide B reduced PAF release from embryos challenged by PLA2. Kodama et al. (1989) reported successful isolation of PAF in mouse embryos, while Ryan et al. (1989) found that in vitro production of PAF could influence embryonic metabolism, as indicated by increased production of C02 from the carbon-l position ofiactate. PAF induced in vitro fertilisation, assessed by a positive J3-human chorionic gonadotrophin per oocyte retrieval. The increase in the number of positive pregnancy tests suggested a PAF-mediated support of pre-embryonic development. Rat embryos produced cyclooxygenase arachidonate metabolites with the rank order of 6keto-PGFla > PGF2a = TXB2, while no lipoxygenase products were detected (Geissler et al. 1989). Early postimplantation rat embryos also produced PAF. These results demonstrate an increased lipid metabolism and suggest a role for various lipid mediators including PAF in the initiation and maintenance of pregnancy. These early pregnancy signals were demonstrated in all domestic animals (Hansel & Hickey 1989). PAF injected into the left uterine horn induced a dose-dependent decidua-like reaction in the pseudopregnant rat (Acker et al. 1989). Ginkgolide B inhibited the effect of PAF on decidua-like reaction, indicating the involvement of specific PAF receptor sites which were then characterised in purified uterine membranes from pregnant rabbits;

Drugs 42 (2) 1991

relative potencies of PAF and its antagonists in displacing [3H]PAF were: Iyso-PAF > CV-3988 > PAF > U66985 > A 02405 > ginkgolide B > U 66982 (Kudolo & Harper 1989). Kudolo and Harper (1991) described the presence of unique PAF receptor subtypes in the uterus of pregnant rabbits using specific antagonists and PAF analogues, and emphasised the importance of species specificity of receptor binding. PAF, in addition to eicosanoids, has been suggested to initiate parturition at term in uncomplicated pregnancies. Recently, a several-fold increase in the PAF concentration of amniotic fluid from complicated pregnancies was demonstrated (Hoffman et al. 1990), suggesting that P AF may be a contributing factor associated with premature labour. 2.B.3 Antifertility Effect of PAF Antagonists CV-3988, U66985 and SRI 63-441, all structural analogues ofPAF, inhibited fertilisation in vitro and in vivo in rabbits when added to the ejaculate before insemination (Spinks et al. 1990). Antagonists, not being structural analogues of PAF, were ineffective. SRI 63-441 given intravenously prior to ovulation had no effect on fertilisation, but when it was instilled into the vagina immediately before insemination, a significantly reduced fertilisation rate was achieved. It is concluded that PAF antagonists can directly influence the sperm membrane rather than antagonise the effect ofPAF. PAF increased whereas WEB 2086 decreased in vitro fertilisation rate (Kuzan et al. 1990). Using videomicroscopy, synthetic PAF resulted in a statistically significant increase in the motility of human spermatozoa, while Iyso-PAF had no such effect (Harper et al. 1989; Ricker et al. 1989). These results suggest that treatment of spermatozoa with PAF in severely asthenozoospermic males may be of therapeutic value. This recent progress in reproduction biology obviously emphasises the significance of PAF, and suggests that some carefully selected PAF antagonists may have significance as local contraceptives and therapeutic interventions in premature labour.

Platelet Activating Factor and PAF Antagonists

3. Clinical Studies Apart from the abundance of experimental studies, relatively few papers as yet have been published on the clinical pharmacology of PAF antagonists. Publications are currently available only on ginkgolides and WEB 2086 (Apafant). 3.1 Reactivity of Human Subjects to PAF In human volunteers PAF has been proven to be a potent bronchoconstrictor (Cuss et al. 1986; Roubin et al. 1987): acute bronchoconstriction was reversed within an hour without the appearance of a late response. In contrast to animal studies demonstrating increased nonspecific airway hypersensitivity (Christman et al. 1987; Robertson et al. 1988), inhaled PAF failed to induce airway hyperresponsiveness to methacholine in human subjects (Hopp et al. 1989; Lai et al. 1990). On the other hand, 6 hours after PAF challenge a microvascular leakage and a cellular infiltration occurred in the bronchoalveolar lavage fluid (Evans et al. 1988). In parallel with an alveolar neutrophil infiltration, blood neutrophil counts fell; a rebound neutrophilia then ensued (Wardlaw et al. 1990). PAF-induced hyperresponsiveness was accompanied by in vitro neutrophil and eosinophil activation and chemotaxis (Brunjzeel et al. 1986; Wardlaw et al. 1986). In humans, a dose-related acute weal and flare response was elicited by intradermal administration of PAF, providing a useful test system for the evaluation of PAF antagonists in clinical patients (Archer et al. 1984; Henocq & Vargaftig 1986). Ex vivo, PAF-induced platelet aggregation is a convenient and useful test for evaluating the effects and pharmacokinetics ofPAF antagonists in clinical patients. 3.2 Clinical Studies on WEB 2086 (Apafant) WEB 2086 dose-dependently inhibited ex vivo platelet aggregation induced by epinephrine, ADP, collagen or PAF in intravenous and inhalative single rising dose tolerance trials in human volun-

189

teers (Adamus et al. 1989a). The safety, tolerability and pharmacological activity were examined in 2 double-blind placebo-controlled within-subject crossover studies (Adamus et al. 1989b). Treatment with WEB 2086 abolished the adverse haemodynamic changes induced by PAF (Adamus et al. 1990). No clinically significant drug-related effects on vital and laboratory. parameters or obvious drug-dependent adverse reactions were observed. Using PAF-induced ex vivo platelet aggregation a clinical trial, carried out in single oral, oral multiple-dose and inhalation administrations, indicated a rapid oral absorption of apafant, plus linear pharmacokinetics for the mean plasma concentrations, approximately 60% binding to plasma proteins, a mean renal clearance of 192 ml/min (11.5 L/h), and no accumulation in tissues of volunteers with normal kidney function (Brecht et al. 1991). The efficacy of this drug as a new therapeutic principal in specific diseases, however, can only be demonstrated conclusively in the context of future clinical studies. 3.3 Clinical Studies on Ginkgolides Ginkgolides, especially BN 52063 (a standardised mixture of ginkgolide A, Band C) and ginkgolide B, have also undergone clinical trials. BN 52063 was the first drug shown to be a potent PAF antagonist in humans, by Guinot et al. (1987). In a randomised, double-blind, crossover study performed in 8 atopic asthmatic patients, 3 days' treatment with BN 52063 significantly antagonised early asthmatic response to nebulised allergen. The drug also showed a tendency to inhibit residual bronchial hyperreactivity assessed by acetylcholine provocation 6 hours after antigen challenge. No side effects were reported during active treatment. These results were confirmed in single- and multiple-dose studies in normal volunteers and atopic patients using 2-week treatment with BN 52063 (Guinot et al. 1988b) and ginkgolide B (Braquet et al. 1987c). As a preventive agent against allergic bronchoconstriction and dermal responses, the effect of BN 52063 was clinically evaluated in normal volun-

190

teers challenged by nebulised PAF (Roberts et al. 1988a) and allergic patients subjected to aerosolised antigen (Roberts et al. 1988b). Randomised, coded BN 52063 and identical placebo capsules were given to the subjects in a double-blind fashion, and the data obtained indicated that BN 52063 is an active and relatively selective PAF antagonist in humans. However, in contrast to the skin where weal and flare reactions were inhibited by approximately 50% in both normal and atopic subjects, the bronchoconstriction induced by either PAF and methacholine inhalation in normal volunteers or allergen challenge in atopic patients was only partially affected. The effects of peroral and nebulised BN 52063 on the response to isocapnic hyperventilation with dry cold air and exercise were assessed in a study using both a single dose and short term treatment in 10 patients with exercise-induced asthma (Wilkens et al. 1990). Peroral treatment did not result in a reduction of bronchoconstriction during both challenges, but inhibited PAF-induced ex vivo platelet aggregation. Inhalation of BN 52063 did not influence bronchoconstriction and platelet aggregation. On the third day of peroral treatment there was no effect on the exercise-induced initial bronchoconstriction, but the prolonged reduction in peak expiratory flow rates was attenuated. Accordingly, there was also a decrease in plasma concentrations of fl-thromboglobulin and platelet factor 4 elevated by exercise-induced platelet secretion. In addition, administered orally in a dose of240 mgfday for 4 weeks - in 5 different clinical centres in France each including 16 patients - BN 52063 caused a significant improvement in daily expiratory peak flow variations in patients with mild to moderate asthma compared to the placebo-treated groups (Bon voisin & Guinot 1990; Guinot et al. 1988a). Taken together, these data suggest that, because of the complex pathomechanism of bronchial asthma, the effect of BN 52063 varies according to the challenge applied and the aetiology of the disease, and most likely only the late bronchoconstrictor responses are alleviated. Therefore, BN 52063 may be an effective antiasthma drug per-

Drugs 42 (2) 1991

haps in combination with other bronchodilator agents. BN 52063 given in single oral doses of 80 and 120mg inhibited the acute weal and flare reactions induced by subcutaneously injected PAF in 5 healthy volunteers entered in a single-blind crossover trial (Guinot et al. 1986), as well as in 6 normal subjects in a double-blind, placebo-controlled, crossover study (Chung et al. 1987; Duchier et al. 1990). Both doses blocked PAF-induced ex vivo platelet aggregation in a platelet-rich plasma, but did not affect ADP-induced aggregation. A case of a clinically manifested systemic mastocytosis, inducing erythema of the face and trunk with recurrent facial flushing, conjunctivitis, palpitation, dizziness, abdominal pain, diarrhoea, nausea and severe hypotensive attacks was successfully treated with BN 52063 120mg peroral doses given twice daily for 3 weeks (Guinot et al. I 988c). Weal and flare reaction elicited by intradermal PAF injection in 12 atopic patients was antagonised by 120mg oral BN 52063 (Markley et al. 1990). Histologically, the reaction was characterised by neutrophil and eosinophil recruitment at the site of injection which, however, remained uninfluenced by the drug. In a randomised double-blind clinical study performed in 18 healthy male volunteers with oral administration of 80 and 240 mgjday for 14 days, BN 52063 significantly decreased the CD4+jCD8+ T cell ratio, marginally depressed phytohaemagglutinin-induced lymphocyte proliferation in a doseand time-dependent manner, but had no effect on neutrophil phagocytosis, lymphokine production, and natural killer activity (Charpentier et al. 1990). This study also proved that BN 52063 was well tolerated. Clinical studies are currently being performed to evaluate the effectiveness ofBN 52063 and ginkgolide B in septic shock, cerebral ischaemia, renal transplantation and burn injury using the strategy of the pathophysiological experience summarised in this review. A list of PAF antagonists that have recently undergone clinical trials is shown in table II.

Platelet Activating Factor and PAF Antagonists

191

Table II. PAF antagonists under development (from Pharmaprojects, Richmond, Surrey, England, 1990)

Drugs

Originator

Indications

Clinical trial status

Apafant (WEB 2086)

Boehringer Ingelheim (Germany)

Phase II

WEB 2170

Boehringer Ingelheim (Germany)

BN 50726 BN 50730 BN 52021 (BN 52063) Ginkgolide B

IPSEN-Beaufour (France) IPSEN-Beaufour (France) IPSEN-Beaufour (France)

L-680573 (MK-287)

Merck & Co. (USA)

RP 55778 RP 59227

Rh6ne-Poulenc (France) Rh6ne-Poulenc (France)

Sch 37370

Schering Plough (USA)

Y-24180

Yoshitomi (Japan)

Antiasthmatic, antiallergic, antithrombotic Antithrombotic, hypertensive, antiasthmatic, antiallergic Antiasthmatic, antiallergic Antiasthmatic, antiallergic Cardiovascular, antiasthmatic, antiallergic, vulnerary, haemostatic Antiasthmatic, antiallergic, antithrombotic Cardiovascular Antiasthmatic, antiallergic, protease inhibitor Antihistamine systemic, antiasthmatic, antiallergic, antithrombotic Antiasthmatic, antiallergic

4. Conclusion In the last 2 years considerable progress has been achieved in PAF research. An enormous mass of information has become available on the effects of PAF and specific PAF receptor antagonists in a great variety of cells and organs indicating that, similarly to eicosanoids, PAF plays an important mediator or modulator role in various pathophysiological events. Careful pathophysiological and pharmacological analyses performed with PAF antagonists in immediate airway hypersensitivity responses have led to a better understanding of the mechanisms working in bronchial asthma. After great early expectations, these results may have been disappointing as to the possible clinical application of PAF antagonists in asthma; however, after a careful re-evaluation of our knowledge a much better specification of their therapeutic indication now seems possible. This has been exemplified by the thus far few clinical trials (section 3) on ginkgolide Band BN 52063 showing that these safe drugs, perhaps in combination with other antiasthma agents, can be applied in the treatment of the human bronchial asthma.

Phase I Phase I Phase I Phase III

Phase I Phase I Phase I Phase I

Phase I

In contrast to previous research activities devoted predominantly to inflammation, allergic states (such as immediate and delayed hypersensitivity reaction) and immune complex diseases and haemostasis, increasing attention has been paid in the last 2 years to the involvement of PAF in circulatory disorders, such as ischaemic states in the brain, heart and gastrointestinal tract. A great deal of evidence has been provided suggesting a role for PAF in various shock conditions as well. Therefore, it is clear now that natural and synthetic PAF antagonists are candidates for the clinical treatment and prevention of stroke, myocardial infarction, gastrointestinal ulceration and various pathological conditions related to peripheral circulatory failure. The indication that PAF might be involved in atherogenesis is remarkable in this respect, although this finding needs further elucidation. Recognition of the role of PAF in reproductive physiology is remarkable and might be an initial step in the rapid development of new, harmless contraceptive drugs or devices. Studies on physiological feedback mechanisms involved in the regulation of hormone release in the brain are of great interest. These results em-

Drugs 42 (2) 1991

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phasise the significance of cell membrane processes, particularly the release of PAF, as an important signal molecule for troph hormone secretion. These mechanisms may also be active at the peripheral level, triggering opposite effects in hormone secretion, thus suggesting highly sensitive mechanisms through which PAF can modulate feedback control of hormonal homeostasis. This is underlined by observations indicating that Cl- secretion in the rat exhibits diurnal variations similar to the well known circadian rhythm in corticoid secretion, pointing to the complexity of the physiological and pathophysiological entity of PAf and PAF antagonists. Studies on the relationship between the framework and PAF receptor antagonist properties have led to several definitive conclusions which might be useful for future studies to develop increasingly effective drugs with PAF antagonistic effects. In this respect, particular attention should be paid to the diversity of PAF receptors in different organs of various species. Better specification of these binding sites by well defined biochemical methods may result in even more specific antagonists and a more specific therapeutic approach to various diseases. This process may lead to the solution of the greatest problem in the research of PAF antagonists, notably a better specification of the therapeutic indication for a particular drug in the clinical management of a well determined pathological condition or disease. Such activity may accelerate the introduction of PAF antagonists to the treatment of human diseases. The basic concept of the molecular mode of action of PAF has been confirmed by recent studies. In this context, the effect of PAF antagonists on cellular Ca++ metabolism and Na+ /H+ exchange deserve particular attention and may be the most important in the prevention and treatment of various ischaemic states. The difference between the mode of action of PAF antagonists and slow Ca++ channel blockers should be taken into consideration and better specified in the near future. The recognition of the modulatory role for PAF in cellto-cell interaction and the concept of PAF/cytokine interaction as a basic mechanism of cellular

injury will shed more light on the significance of PAF in various pathophysiological disorders, and will facilitate the therapeutic application of PAF antagonists in ischaemic states and shock conditions.

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H (Eds) Pharmacology of cerebral ischemia, Wissenschaftliche Velagsgesellschaft, in press, 1990 Eliakim R, Karmeli F, Razin E, Rachmilewicz D. Role of plateletactivating factor in ulcerative colitis: enhanced production during active disease and inhibition by sulfasalazine and prednisolone. Gastroenterology 95: 1167-1172, 1988 Elstad MR, Stafforini DM, McIntyre TM, Prescott SM, Zimmerman G. Platelet-activating factor acetylhydrolase increases during macrophage differentiation. Journal of Biological Chemistry 264: 8467-8470, 1989 Emanuelli G, Montrucchio G, Gaia E, Dughera L, Corvetti G, et al. Experimental acute pancreatitis induced by platelet-activating factor in rabbits. American Journal of Pathology 134: 315-326, 1989 Ernst A, Syka J, Mest HJ. Arachidonate metabolites change furosemide-induced cochlear potentials. Hearing Research 40: 3944, 1989b Ernst A, Syka J, Riedel A, Mest HJ. The effect of PAF in the cochlea of guinea-pigs. Prostaglandins 38: 523-525, 1989a Ernst A, Syka J, Riedel A, Mest HJ. Local effects of PAF in guineapig inner ear. Journal of Lipid Mediators I: 297-301, 1989c Espey LL, Tanaka N, Woodward DS, Harper MJ, Okamura H. Decrease in ovarian platelet-activating factor during ovulation in the gonadotropin-primed immature rat. Biology of Reproduction 41: 104-110, 1989 Esplugues JV, Whittle BJ. Mechanisms contributing to gastric motility changes induced by PAF-acether and endotoxin in rats. American Journal of Physiology 256: G275-0282, 1989 Esplugues JV, Whittle BJ, Moncada S. Local opioid-sensitive afferent sensory neurones in the modulation of gastric damage induced by PAF. British Journal of Pharmacology 97: 579-585, 1989 Etienne A, Hecquet F, Guilmard C, Soulard C, Braquet P. Inhibition of rat endotoxin-induced lethality by BN 52021 and BN 52063, compounds with PAF-acether antagonistic effect and protease-inhibitory activity. International Journal of Tissue Reactions 9: 19-26, 1987 Etienne A, Soulard C, Thonier F, Braquet P. Modulation of eosinophil recruitment in the rat by the platelet-activating factor (PAF) antagonist, BN 52021, the somatostatin analog, BIM 23014, and by cyclosporin A. Prostaglandins 37: 345-357, 1989a Etienne A, Thonier F, Braquet P. Protective effect of the PAFantagonist BN 52021 on several models of gastro-intestinal mucosal damage in rats. International Journal of Tissue Reactions II: 59-64, 1989b Evans TW, Chung KF, Rogers DF, Barnes PJ. Effect of a PAF antagonist, WEB 2086, on airway microvascular leakage in the guinea-pig and platelet aggregation in man. British Journal of Pharmacology 34: 164-168, 1988 Fauler J, Sielhorst G, Frolich Jc. Platelet-activating factor induces the production of leukotrienes by human monocytes. Biochimia et Biophysica Acta 1013: 80-85, 1989 Feliste R, Perret B, Braquet P, Chap H. Protective effect of BN 52021, a specific antagonist of platelet-activating factor (PAFacether) against diet-induced cholesteryl ester deposition in rabbit aorta. Atherosclerosis 78: 151-158, 1989 Felix SB, Steger A, Baumann G, Busch R, Ochsenfeld G, et al. Platelet-activating factor-induced coronary constriction in the isolated perfused guinea-pig heart and antagonistic effects of the PAF antagonist WEB 2086. Journal of Lipid Mediators 2: 9-20, 1990 Filep J, Herman F, Braquet P, Mozes T. Increased levels of platelet-activating factor in blood following intestinal ischemia in

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the dog. Biochemical and Biophysical Research Communications 158: 353-359, 1989 Fisher GJ, Talwar HS, Ryder NS, Voorhees JJ. Differential activation of human skin cells by platelet-activating factor: stimulation of phosphoinositide turnover and arachidonic acid mobilization in keratinocytes but not in fibroblasts. Biochemical and Biophysical Research Communications 163: 1344-1350, 1989a Fisher RA, Sharma RV, Bhalla RC. Platelet-activating factor increases inositol phosphate production and cytosolic free Ca2+ concentrations in cultured rat Kupffer cells. FEBS Letters 251: 22-26, 1989b Fitzgerald MF, Parente L, Whittle BJ. Release of PAF-acether and eicosanoids from guinea-pig alveolar macrophages by FMLP: effect of cyclooxygenase and lipoxygenase inhibition. European Journal of Pharmacology 164: 539-546, 1989 Fletcher JR, DiSimone AG, Earnest M. Platelet activating factor receptor antagonist improves survival and attenuates eicosanoid release in severe endotoxemia. Annals of Surgery 211: 312-316, 1990 Floch A, Bousseau A, Hetier E, F1oc'h, F, 80st PE, et al. RP 55778, a PAF receptor antagonist, prevents and reverses LPSinduced hemoconcentration and TNF release. Journal of Lipid Mediators I: 349-360, 1989 Flores NA, Sheridan DJ. Electrophysiological and arrhythmogenic effects of platelet activating factor during normal perfusion, myocardial ischaemia and reperfusion in the guineapig. British Journal of Pharmacology 101: 734-738, 1990 Foegh ML. Eicosanoids and platelet-activating factor mechanisms in organ rejection. Transplantation Proceedings 20: 12601263, 1988 Foegh ML, Conte JV, Jacobsson J, Ramwell PW. Organ preservation and BN 52021. In Braquet P (Ed.) Ginkgolides: chemistry, biology, pharma!=Ology and clinical perspectives, Vol. 2, pp. 719-723, JR Prous, Barcelona, 1990 Fontaliran F, Guillon JM, Koltai M, Braquet P. Reduction of infarct size by Ginkgolide B (BN 52021) in coronary artery ligated rats. In Braquet P (Ed.) Ginkgolides: chemistry, biology, pharmacology and clinical perspectives, Vol. 2, pp. 405411, JR Prous, Barcelona, 1990 Francescangeli E, Goracci G. The de novo biosynthesis of platelet-activating factor in rat brain. Biochemical and Biophysical Research Communications 16: 107-112, 1989 Frerichs KU, Feuerstein GZ. Platelet-activating factor: key mediator in neuroinjury. Cerebrovascular and Brain Metabolism Reviews 2: 148-160, 1990 Frerichs KU, Lindsberg PJ, Hallenbeck JM, Feuerstein G. Platelet-activating factor and progressive brain damage following focal brain injury. Journal of Neurosurgery 73: 223-233, 1990 Gay JC. Priming of neutrophil oxidative responses by plateletactivating factor. Journal of Lipid Mediators 2: SI61-S175, 1990 Geissler FT, Kuzan FB, Faustman EM, Henderson Jr WR. Lipid mediator production by post-implantation rat embryos in vitro. Prostaglandins 38: 145-155, 1989 Gerkens JF. Inhibition of vasoconstriction by platelet-activating factor in the in situ blood perfused rat mesentery. Clinical and Experimental Pharmacology and Physiology 16: 161-167, 1989 Gerkens JF. Reproducible vasodilatation by platelet-activating factor in blood- and Krebs-perfused rat kidneys is albumindependent. European Journal of Pharmacology 177: 119-126, 1990 Gilboe DD, Kintner D, Fitzpatrick JH, Emoto E, Esanu A, et al. Recovery of postischemic brain metabolism and function following treatment with a free radical scavanger and platelet-

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activating factor antagonists. Journal of Neurochemistry 56: 111-119,1991 GilfiJlan AM, Wiggan GA, Hope WC, Patel BJ, Welton AF. Ro 19-3704 directly inhibits immunoglobulin E-dependent mediator release by a mechanism independent of its platelet-activating factor antagonist properties. European Journal of Pharmacology 176: 255-262, 1990 Gomez-Cambronero J, Durstin M, Molski TF, Naccache PH, Shaafi RI. Calcium is necessary for the platelet-activating factor release in human neutrophils stimulated by physiological stimuli: role of G-proteins. Journal of Biological Chemistry 264: 12699-12704, 1989 Gomez-Chiarri M, Egido J, Gomez C, Bricio T, Lerma JL, et al. Production of PAF and cytokines by glomerular ceJls of rats with nephrotic syndrome. Effect of the PAF receptor antagonist BN 52021. In Braquet P (Ed.) Ginkgolides: chemistry, biology, pharmacology and clinical perspectives, Vol. 2, pp. 581-589, JR Prous, Barcelona, 1990 Goswami SK, Ohashi M, Stathas P, Marom ZM. Platelet-activating factor stimulates secretion of respiratory glycoconjugate from human airways in culture. Journal of AJlergy and Clinical Immunology 84: 726-734, 1989 Guarner F, WaJlace JL, MacNaughton WK, Ibbotson GC, et al. Endotoxin-induced ascites formation in the rat: partial mediation by platelet-activating factor. Hepatology 10: 788-794, 1989 Guinot P, BambriJla C, Duchier J, Braquet P, Bonvoisin B, et al. Effect of BN 52063, a specific PAF-acether antagonist, on bronchial provocation test to aJlergens in asthmatic patients: a preliminary study. Prostaglandins 34: 723-731,1987 Guinot P, BambriJla C, Duchier J, Taytard A, Summerhayes C. The clinical effects of BN 62063, a specific PAF-acether antagonist. In Braquet P (Ed.) Ginkgolides: chemistry, biology, pharmacology and clinical perspectives, Vol. I, pp. 345-354, JR Prous, Barcelona, 1988a Guinot P, Braquet P, Duchier J, Cournot A. Inhibition of PAFacether induced weal and flare reaction in man by a specific PAF antagonist. Prostaglandins 32: 160-163, 1986 Guinot P, Summerhayes C, Berdah L, Duchier J, Revillaud RJ. Treatment of adult systemic mastocytosis with a PAF-acether antagonist BN 52063. Lancet 2: 114, 1988b Guinot P, Summerhayes C, Bonvoisin B. PAF and aJlergic diseases in human: clinical evidence for the role ofPAF in airway hypersensitivity and asthma and the effects of BN 52063, a specific PAF-acether antagonist. In Braquet P (Ed.) New trends in lipid mediators research, Vol. 2, pp. 118-127, Karger, Basel, 1988c Hanglow AC, Bienenstock J, Perdue MH. Effects of platelet-activating factor on ion transport in isolated rat jejunum. American Journal of Physiology 257: G845-G850, 1989 Hansel W, Hickey GL. Early pregnancy signals in domestic animals. Annals of the New York Academy of Sciences 541: 472484, 1988 Harper MJ. Platelet-activating factor: a paracrine factor in preimplantation stages of reproduction? Biology of Reproduction 40: 907-913, 1989 Harper MJK, Woodard DS, Norris CJ. Spermicidal effect of antagonists of platelet-activating factor. Fertility and Sterility 51: 890-895, 1989 Havill AM, Van Valen RG, Handley DA. Prevention of nonspecific airway hyperreactivity after allergen chaJlenge in guineapigs by PAF receptor antagonist SDZ 64-412. British Journal of Pharmacology 99: 396-400, 1990 Hayashi H, Kudo I, Kato I, Nozawa R, Nojima S, et al. A novel

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bioaction ofPAF: induction of microbicidal activity in guineapig bone marrow ceJls. Lipids 23: 1119-1124, 1988 Hebert RL, Sirois P, Plante GE. Inhibition of platelet-activating factor induced renal hemodynamic and tubular dysfunctions with L-655-240, a new thromboxane-prostaglandin endoperoxide antagonist. Candian Journal of Physiology and Pharmacology 67: 304-308, 1989 HeJlegouarch A, Auguet M, Guillon JM, Baranes J, Pirotzky E, et al. Lack of effect of atrial natriuretic factor on the tone induced in rat portal vein by platelet-activating factor. European Journal of Pharmacology 145: 245-248, 1988 HeJleweJl PG, Williams TJ. Antagonism ofPAF-induced oedema formation in rabbit skin: a comparison of different antagonists. British Journal ofPharrnacology 97: 171-180, 1989 Henocq E, Vargaftig BB. Accumulation of eosinophils in response to intracutaneous PAF-acether and aJlergens in man. Lancet I: 1378-1379, 1986 Henriques MG, Weg VB, Martins MA, Silva PM, Fernandes PD, et al. Differential inhibition by two hetrazepine PAF antagonists of acute inflammation in the mouse. British Journal of Pharmacology 99: 164-168, 1990 Herman F, Magyar K, Kovacs K, Filep J. Decreased sensitivity of platelets to platelet-activating factor in migraine patients during the headache-free interval. Correspondence. Thrombosis and Haemostasis 62: 818, 1989 Heuer H, Letts G, Meade CJ. Tumor necrosis factor (TNF) and endotoxin prime effects of PAF in vivo. Journal of Lipid Mediators 2: SI01-SI08, 1990 Heymans F, Steiner E, Jouquey S, Godfoid JJ. PAF receptor. 2. Quantitative hydrophobic contribution on the agonist's etheroxid chain. Journal of Lipid Mediators I: 303-312, 1989 Hirafuji M, Maeyama K, Watanabe T, Ogura Y. Transient increase of cytosolic free calcium in cultured human vascular endothelial ceJls by platele't-activating factor. Biochemical and Biophysical Research Communications 154: 910-917, 1988 Hoffman DR, Romero R, Johnston JM. Detection of plateletactivating factor in amniotic fluid of complicated pregnancies. American Journal of Obstetrics and Gynecology 162: 525-528, 1990 Hofmann B, Meisgeier U, Ostermann G, Kl6cking HP, Hoffmann A, et al. Effect of BN 52021 on PAF-induced release of tissue-type plasminogen activator. In Braquet P (Ed.) Ginkgolides: chemistry, biology, pharmacology and clinical perspectives, Vol. 2, pp. 291-303, JR Prous, Barcelona, 1990 Hopp RJ, Bewtra AK, Agrawal DK, Townley RG. Effect of platelet-activating factor inhalation on nonspecific bronchial reactivity in man. Chest 96: 1070-1072, 1989 Hosford D, Braquet P. Potential role for platelet activating factor in shock and ischaemia. Journal of Critical Care 5: 1-22, 1990b Hosford D, Braquet P. Antagonists of platelet-activating factor: chemistry, pharmacology and clinical applications. In Ellis G P & West GB (Eds) Progress in medicinal chemistry, Vol. 27, pp. 325-380, 1990a Hosford D, Mencia-Huerta JM, Page C, Braquet P. Natural antagonists of platelet-activating factor. Phytotherapy Research 2: 1-24, 1988 Howat DW, Chand N, Braquet P, Willoughby DA. An investigation into the possible involvement of platelet-activating factor in experimental allergic encephalomyelitis in rats. Agents and Actions 27: 473-476, 1989 Howat D, Desa F, Chander C, Moore A, Willoughby DA. The synergism between PAF and interleukin-I on cartilage breakdown. Journal of Lipid Mediators 2: SI43-SI49, 1990 Hsueh W, Sun XM. Tumor necrosis factor-induced bowel necro-

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sis: the role of platelet-activating factor. Advances in Prostaglandin, Thromboxane and Leukotriene Research 19: 363-366, 1989 Humphrey DM. Inflammatory exudates in skin windows induced by I-O-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine. American Journal of Pathology 136: 467-477,1990 Hunyadi J, Judak R, Kenderessy AS, Braquet P, Dobozy A. Enhancing effect of whole-body ultraviolet light irradiation on Candida albicans activity of human polymorphonuclear leukocytes. Dermatologische Monatsschrift 175: 326-332, 1989 Ibbotson GC, Wallace JL. Inhibitory effects of dexamethasone in endotoxic shock and its relation to PAF-acether synthesis in the gastrointestinal tract and lung. Journal of Lipid Mediators I: 273-282, 1989a Ibbotson GC, Wallace JL. Beneficial effects of prostaglandin E2 in endotoxic shock are unrelated to effects on PAF-acether synthesis. Prostaglandins 37: 237-250, 1989b Inoue T, Kannan RS. Platelet-activating factor-induced functional changes in the guinea-pig trachea in vitro. Respiratory Physiology 77: 157-171, 1989 Iwai A, Itoh M, Yokoyama Y, Yasue N, Miyamoto T, et al. Role of PAF in ischemia-reperfusion injury in the rat stomach. Scandinavian Journal of Gastroenterology 162 (Suppl.): 63-66, 1989 Iwama T, Shikada K, Tanaka S. Pharmacological modulation of platelet-activating factor (PAF)-induced bronchoconstriction and hypertension in anaesthetized guinea-pigs. Journal of Pharmacy and Pharmacology 40: 544-547, 1988 Jancar S, Braquet P, Sirois P. Release of eicosanoids in rat peritoneal cavity during the Arthus reaction: effect of the PAFantagonist BN 52021 and indomethacin. InternationalJournal ofImmunopharmacology II: 129-132, 1989a Jancar S, Theriault P, Lauziere M, Braquet P, Sirois P. PAF-induced release of spasmogens from guinea-pig lungs. British Journal of Pharmacology 96: 153-162, 1989b Jancar S, Theriault P, Procenccal B, Cloutier S, Sirois P. Mechanisms of action of platelet-activating factor on guinea-pig lung parenchyma strips. Canadian Journal of Physiology and Pharmacology 66: 1187-1191, 1988 Janero DR, Burghardt C. Production of platelet-activating factor by the injured heart muscle cell (cardiomyocyte). Research Communications in Chemical Pathology and Pharmacology 67: 201-218, 1990 Johnson PR, Armour CL, Black JL. The action of platelet activating factor and its antagonism by WEB 2086 on human isolated airways. European Respiratory Journal 3: 55-60, 1990 Joseph R, Welch KM. Granulocytes, platelet-activating factor and myocardial injury (correspondence). Circulation 79: 140-141; 1989 Jouve R, Puddu PE, Langlet F, Lanti M, Guillen Jc. Anti-arrhythmic effects of BN 52021 after circumflex coronary artery occlusion-reperfusion in dogs: analysis of 87 experiments using the proportional hazards cox's model. In Braquet P (Ed.) Ginkgolides: chemistry, biology, pharmacology and clinical perspectives. Vol. 2, pp. 437-448, JR Prous, Barcelona, 1990 Junier MP, Tiberghien C, Rougeot C, Faveur V, Dray F. Inhibitory effect of platelet-activating factor (PAF) on luteinizing hormone-releasing hormone and somotastatin release from rat median eminence in vitro correlated with the characterization of specific PAF receptor sites in rat hypothalamus. Endocrinology 123: 72-80, 1988 Karasawa A, Rochester JA, Lefer AM. Beneficial actions of BN 50739, a new PAF receptor antagonist, in murine traumatic

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shock. Methods and Findings in Experimental and Clinical Pharmacology 12: 231-237, 1990 Kawaguchi H, Sawa H, Izuka K, Yasuda H. Platelet-activating factor stimulated angiotensin converting enzyme activity. Journal of Hypertension 8: 173-177, 1990 Kemeny L, Csato M, Dobozy A. Pharmacological studies on dithranol-induced irritative dermatitis in mice. Archives of Dermatological Research 281: 362-365, 1989 Kemeny L, Csato M, Braquet P, Dobozy A. Effect of BN 52021, a platelet activating factor antagonist, on dithranol-induced inflammation. British Journal of Dermatology 122: 539-544, 1990 Kochanek PM, Dutka AJ, Kumaroo KK, Hallenbeck JM. Platelet-activating factor receptor blockade enhances early neuronal recovery after multifocal brain ischemia in dogs. Life Sciences 41: 2639-2644, 1987 Kochanek PM, Nemoto EM, Schoettle R. Cerebrovascular effects of platelet-activating factor receptor antagonism in the rat: effects on normal cerebral blood flow and posttraumatic edema. In Braquet P (Ed.) Ginkgolides: chemistry, biology, pharmacology and clinical perspectives, Vol. 2, pp. 619-628, JR Prous, Barcelona, 1990 Kochanek PM, Melick JA, Schoettle RJ, Magargee MJ, Evans RW, et al. Endogenous platelet activating factor does not modulate blood flow and metabolism in normal rat brain. Stroke 21: 459-462, 1990 Kodama H, Muto H, Maki M. Isolation and identification of embryo-derived platelet-activating factor in mice. Nippon Sanka Fujinka Gakkai Zasshi 41: 899-906, 1989 Koenderman L, Brujnzeel PL. Increased sensitivity of the chemoattractant-induced chemiluminescence in eosinophils isolated from atopic individuals. Immunology 67: 534-536, 1989 Koltai M, Tosaki A, Guillon JM, Hosford D, Braquet P. PAFantagonists as potential therapeutic agents in cardiac anaphylaxis and myocardial ischemia. Cardiovascular Drug Reviews 7: 177-198, 1989a Koltai M, Tosaki A, Hosford D, Braquet P. BN 52021, a PAF receptor antagonist, protects isolated working rat hearts against arrhythmias induced by ischemia but not reperfusion. European Journal of Pharmacology 164: 293-302, 1989b Koltai M, Tosaki A, Hosford D, Esanu A, Braquet P. Effect of BN 50739, a new PAF antagonist on ischaemia-induced ventricular arrhythmias in isolated working rat hearts. Cardiovascular Research, in press, 1991 Konturek SJ, Brzozowski T, Drozdowicz D, Garlicki J, Beck G. Role ofleukotrienes and platelet-activating factor in acute gastric mucosal lesions in rats. European Journal of Pharmacology 164: 285-292, 1989 Kornecki E, Ehrlich YH. Neuroregulatory and neuropathological actions of the ether-phospholipid platelet-activating factor. Science 240: 92-94, 1988 Korth R, Hirafuji M, Keraly CL, Delautier D, Bidault J, et al. Interaction of the PAF antagonist WEB 2086 and its hetrazepine analogues with human platelets and endothelial cells. British Journal of Pharmacology 98: 653-661,1989 Klocking HP, Markwardt F, Hoffmann A. Release of tissue plasminogen activator by platelet-activating factor. Thrombosis Research 38: 413-416, 1986 Kroegel C, Pleass R. Yukawa T, Chung KF, Westwick J, et al. Characterization of platelet-activating factor-induced elevation of cytosolic free calcium concentration in eosinophils. FEBS Letters 243: 41-46, 1989a Kroegel C, Yukawa T, Westwick J. Barnes PJ. Evidence for two platelet-activating factor receptors on eosinophils: dissociation between PAF-induced intracellular calcium mobilization, de-

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granulation and superoxides anion generation in eosinophils. Biochemical and Biophysical Research Communications 162: 511-521, I 989b Kubes P, Suzuki M, Granger DN. Platelet-activating factor-induced microvascular dysfunction: role of adherent leukocytes. American Journal of Physiology 258: GI58-GI63, 1990 Kudolo GB, Harper MJK. Characterization of platelet-activating factor binding sites on the uterine membranes from pregnant rabbits. Biology of Reproduction 41: 587-603, 1989 Kudolo GB, Harper MJK. Molecular heterogeneity of plateletactivating factor (PAF) receptors in rabbit endometrial membranes: autoradiographic and biochemical evidence. Biology of Reproduction, in press, 1991 Kumar R, Harvey SA, Kester M, Hanahan DJ, Olson MS, et al. Production and effects of platelet-activating factor in the rat brain. Biochimia et Biophysica Acta 963: 375-383, 1988 Kuzan FB, Geissler Fr, Henderson Jr WR. Role of spermatozoal platelet-activating factor in fertilization. Prostaglandins 39: 6174, 1990 Lagente V, Fortes ZB, Garcia-Leme J. Effect of BN 52021 on PAF-induced changes of the mesenteric microvasculature. In Braquet P (Ed.) Ginkgolides: chemistry, biology, pharmacology and clinical perspectives, Vol. 2, pp. 267-273, JR Prous, Barcelona, 1990 Lai CK, Jenkins JR. Polosa R, Holgate ST. Inhaled PAF fails to induce airway hyperresponsiveness to methacholine in normal human subjects. Journal of Applied Physiology 68: 919-926, 1990 Lamas S, Olivera A, Lopez-Novoa JM, Lopez-Farre A, Hernando L, et al. Effect of BN 52021 on cyclosporine-induced glomerular function impairment. In Braquet P (Ed.) Ginkgolides: chemistry, biology, pharmacology and clinical perspectives, Vol, 2, pp. 547-559, JR Prous, Barcelona, 1990 Lang C, Dobrescu C. Attenuation of burn-induced changes in hemodynamics and glucose metabolism by the PAF antagonist SRI 63-675. European Journal of Pharmacology 156: 207-214, 1988 Lapointe DS, Olson MS. Platelet-activating factor-stimulated hepatic glycogenolysis is not mediated through cyclooxygenasederived metabolites of arachidonic acid. Journal of Biological Chemistry 264: 12130-12133, 1989 Larsen GL. New concepts in the pathogenesis of asthma. Clinical Immunology and Immunopathology 53: 107-118, 1989 Laurindo FR, Goldstein RE, Davenport NJ, Ezra D, Feuerstein GZ. Mechanisms of hypotension produced by platelet-activating factor. Journal of Applied Physiology 66: 2681-2690, 1989 Lavaud P, Mathieu J, Bienvenu P, Braquet M, Gerasimo JF, et al. Modulation ofleucocyte activation in the early phase of the rabbit burn injury. Burns 14: 15-20, 1988 Lavaud P, Rodrigue F, Carre C, Touvay C, Mencia-Huerta JM, et al. Effect of the platelet-activating factor antagonist, BN 52063, on contact dermatitis in the mouse. In Braquet P (Ed.) Ginkgolides: chemistry, biology, pharmacology and clinical perspectives, Vol. 2, pp. 787-795, JR Prous, Barcelona, 1990 Lefer AM. Platelet-activating factor (PAF) and its role in cardiac injury. Progress in Clinical and Biological Research 301: 5360, 1989 Lellouch-Tubiana A, Lefort J, Simon MT, Pfister A, Vargaftig BB. Eosinophil recruitment into guinea-pig lungs after PAFacether and allergen administration. American Review of Respiratory Diseases 137: 948-954, 1988 Levi R, Genovese A, Pinckard RN. Alkyl chain homologs of platelet-activating factor and their effects on the mammalian

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heart. Biochemical and Biophysical Research Communications 161: 1341-1347, 1989 Levine L. Platelet-activating factor stimulates arachidonic acid metabolism in rat liver cells (C-9 cell line) by a receptor-mediated mechanism. Molecular Pharmacology 34: 793-799, 1988 Lewis MS, Whatley RE, Cain P, McIntyre TM, Prescott SM, et al. Hydrogen peroxide stimulates the synthesis of platelet-activating factor by endothelium and induces endothelial celldependent neutrophil adhesion. Journal of Clinical Investigation 82: 2045-2055, 1988 Lindsberg PJ, Jacobs TP, Paakkari lA, Hallenbeck JM, Feuerstein G. Effect of systemic platelet-activating factor (PAF) on the rdbbit spinal cord microcirculation. Journal of Lipid Mediators 2: 41-58, 1990 Lopez-Farre A, Bernabeu F, Gomez-Garre D, Ramon y Cajal S, Braquet P, et al. Platelet-activating factor antagonists treatment protects against postischemic acute renal failure in rats. Journal of Pharmacology and Experimental Therapeutics 253: 328-333, 1990 Maestre C, Zarco P, Gomez-Guerrero C, Gonzales E, HerreroBeaumont G, et al. Cooperation between tumor necrosis factor (TNF) and platelet activating factor (PAF) in the inflammatory response. Journal of Lipid Mediators 2: SI51-S159, 1990 Man RYK, Hu W, Kinnaird AAA. Coronary response to plateletactivating factor in the perfused rat heart. Journal of Lipid Mediators 2: 75-83, 1990 Mandi Y, Farkas G, Koltai M, Beladi I, Mencia-Huerta JM, et al. The effect of the platelet-activating factor antagonist, BN 52021, on human natural killer cell-mediated cytotoxicity. Immunology 67: 370-374, 1989 Marcheselli VL, Rossowska MJ, Domingo MT, Braquet P, Bazan NG. Distinct platelet-activating factor binding sites in synaptic endings and in intracellular membranes of rat cerebral cortex. Journal of Biological Ghemistry 265: 9140-9145, 1990 Markey AC, Barker JNWN, Archer CB, Guinot P, Lee TH, et al. Platelet activating factor-induced clinical and histological responses in atopic skin and their modification by the platelet activating factor antagonist BN 52063. Journal of the American Academy of Dermatology 23: 263-268, 1990 Marquis 0, Robaut C, Cavero I. Evidence for the existence and ionic modulation of platelet-activating factor receptors mediating degranulatory responses in human polymorphonuclear leukocytes. Journal of Pharmacology and Experimental Therapeutics 250: 293-300, 1989 Martins MA, Silva PM, Faria-Neto HC, Bozza PT, Dias PM, et al. Pharmacological modulation of PAF-induced rat pleurisy and its role in inflammation by zymosan. British Journal of Pharmacology 96: 363-371, 1989 Maruyama M, Farber NE, Vercellotti GM, Jacob HS, Gross GJ. Evidence for the role of platelet activating factor in the pathogenesis of irreversible but not reversible myocardial injury after reperfusion in dogs. American Heart Journal 120: 510-520,1990 Masugi F, Sakaguchi K, Saeki S, Imaoka M, Ogihara T. Dietary salt, blood pressure and circulating levels of l-O-hexadecyl-2acetyl-sn-glycero-3-phosphocholine in patients with essential hypertension. Journal of Lipid Mediators 1: 341-348,1989 McColl SH, Krump E, McDonald PP, Braquet M, Naccache PH, et al. Granulocyte-macrophage colony-stimulating factor enhances the synthesis of leukotriene B4 by human neutrophils in response to PAF-acether. Journal of Lipid Mediators 2: SII9S128, 1990 McCormack 00, Barnes PG, Evans TW. Evidence against a role for platelet-activating factor in hypoxic pulmonary vasoconstriction in the rat. Clinical Sciences 77: 439-443, 1989

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Mencia-Huerta JM, Hosford D, Braquet P. Acute and long-term pulmonary effects of platelet-activating factor. Clinical and Experimental Allergy 19: 125-132, 1990 Meng HP, Kutryk MJ, Pierce NG. Effect of platelet-activating factor (PAF) on sodium calcium exchange in cardiac sarcolemmal vesicles. Molecular and Cellular Biochemistry 92: 45-51, 1990 Michel L, Denizot Y, Thomas Y, Benveniste J, Dubertret L. Release of PAF-acether and precursors during allergic cutaneous reactions. Lancet 2: 404, 1988 Mickelson JK, Simpson PJ, Lucchesi BR. Myocardial dysfunction and coronary vasoconstriction induced by platelet-activating factor in the post-infarcted rabbit isolated heart. Journal of Molecular and Cellular Cardiology 20: 547-561, 1988 Milligan SR, Finn CA. Failure of platelet-activating factor (PAFacether) to induce decidualization in mice and failure of antagonists of PAF to inhibit implantation. Journal of Reproduction and Fertility 88: 105-112, 1990 Minhas BS, Kumar R, Ricker DD, Roudebush WE, Dodson MG, et al. Effects of platelet activating factor on mouse oocyte fertilization in vitro. American Journal of Obstetrics and Gynecology 161: 1714-1717, 1989 Mock BH, English D. Granulocyte-macrophage colony-stimulating factor enhances exudation of neutrophils to sites of inflammatory challenge in vivo. Journal of Lipid Mediators 2: S137S141, 1990 Montrucchio G, Alloatti G, Mariano F, De Paulis R, Cavalli PL, et al. Role of platelet-activating factor in the reperfusion injury of rabbit ischemic heart. American Journal of Pathology 137: 71-83, 1990 Montrucchio G, Alloatti G, Tetta C, De Luca R, Saunders RN, et al. Release of platelet-activating factor from ischemic-reperfused rabbit heart. American Journal of Physiology 25: HI236-HI246, 1989a Montrucchio G, Mariano F, Cavalli PL, Viglino G, -Emanuelli G, et al. Platelet-activating factor is produced during infectious peritonitis in CAPD patients. Kidney International 36: 10291036, 1989b Moon 00, Van der Zee H, Weston LK, Gudewicz PW, Fenton JW, et al. Platelet modulation of neutrophil superoxide anion production. Thrombosis and Haemostasis 63: 91-96, 1990 Moqbel R, Cromwell 0, Kay AB. The effect of nedocromil sodium on human eosinophil activation. Drugs 37 (Suppl. I): 1922, 1989 Moqbel R, Macdonald AJ, Cromwell 0, Kay AB. Release ofleukotriene C4 (LTC4) from human eosinophils following adherence to IgE- and IgG-coated schistosomula of Schistosoma mansoni. Immunology 69: 435-442, 1990 Morita E, Schroder JM, Christophers E. Chemotactic responsiveness of eosinophils isolated from patients with inflammatory skin diseases. Journal of Dermatology 16: 348-351, 1989 Morris DD, Moore IN. Equine peritoneal macrophage production of thromboxane and prostacyclin in response to plateletactivating factor and its receptor antagonist SRI 63-441. Circulatory Shock 28: 149-158, 1989 Morrison WJ, Shukla SD. Antagonism of platelet-activating factor receptor binding and stimulated phosphoinositide-specific phospholipase C in rabbit platelets. Journal of Pharmacology and Experimental Therapeutics 250: 831-835, 1989 Mozes T, Braquet P, Filep J. Platelet-activating factor: an endogenous mediator of mesenteric ischemia-reperfusion-induced shock. American Journal of Physiology 257: R872-R877, 1989

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Murphy S, Welk S. Arachidonic acid evokes inositol phospholipid hydrolysis in astrocytes. FEBS-Letters 257: 68-70, 1989 Murphy S, Welk S. Hydrolysis of phosphoinositides in astrocytes by platelet-activating factor. European Journal of Pharmacology 188: 399-401, 1990 Myers AK, Robey JW, Price RM. Relationships between tumour necrosis factor, eicosanoids and platelet-activating factor as mediators of endotoxin-induced shock in mice. British Journal of Pharmacology 99: 499-502, 1990 Neuwirth R, Satriano JA, DeCandido S, Clay K, Schlondorff D. Angiotensin II causes formation of platelet-activating factor in cultured rat mesangial cells. Circulation Research 64: 11241129,1989 Ng DS, Wong K. Platelet-activating factor (PAF) stimulates phosphatidylinositol hydrolysis in human peripheral blood mononuclear leukocytes. Research Communications in Chemical Pathology and Pharmacology 66: 219-231, 1989 Nijkamp FP, van Heuven-Nolsen D. The PAF antagonist BN 52021 inhibits endotoxin-induced hyperreactivity to histamine in guinea-pig airways but not in coronary vessels. In Braquet P (Ed.) Ginkgolides: chemistry, biology, pharmacology and clinical perspectives, Vol. 2, pp. 197-206, JR Prous, Barcelona, 1990 Northover AM. Effects ofPAF and PAF antagonists on the shape of venous endothelial cells in vitro. Agents and Actions 28: 142-148, 1989 Northover AM. Modification by some antagonists of the shape changes on venous endothelial cells in response to inflammatory agents in vitro. Agents and Actions 29: 184-188, 1990 Oberpichler H, Sauer D, Rossberg C, Mennel HD, Krieglstein J. PAF antagonist ginkgolide B reduces postischemic neuronal damage in rat brain hippocampus. Journal of Cerebral Blood Flow and Metabolism 10: 133-135, 1990 O'Donnel SR, Barnett CJK. pAz values for antagonists of platelet-activating factor on aggregation of rabbit platelets. British Journal of Pharmacology 94: 437-442, 1988 O'F1aherty JT, Redman JF, Jacobson DP. Mechanisms involved in the bidirectional effects of protein kinase C activators on neutrophil responses to leukotriene B4. Journal of Immunology 144: 1909-1913, 1990 Ohar JA, Pyle JA, Waller KS, Hyers TM, Webster RO, et al. American Review of Respiratory Diseases 141: 104-110, 1990 Oh-ishi S, Hayashi I, Hayashi M, Yamaki K, Utsunomiya I. Pharmacological demonstration of inflammatory mediators using experimental inflammatory models: rat pleurisy induced by carrageenin and phorbol myristate acetate. Dermatologica 179 (Suppl. I): 68-71, 1989 O'Neill C, Collier M, Ryan JP, Spinks NR. Embryo-derived platelet-activating factor. Journal of Reproduction and Fertility 37 (Suppl.): 19-27, 1989a O'Neill C, Ryan JP, Collier M, Saunders DM, Ammit AJ, et al. Supplementation of in vitro fertilization culture medium with platelet activating factor. Lancet 2: 769-772, 1989b Orozco C, Cock I, Perkins AV, Clarke FM. Platelet-activating factor and serum components from oestrus mice co-operate to mimick the activity of 'early pregnancy factor' in the rosette inhibition assay. Journal of Reproduction and Fertility 88: 447457, 1990 Ostermann G, Lans A, Holtz H, Ruhling K, Winkler L, et al. The degradation of platelet-activating factor in serum and its dis.. criminative value in atherosclerotic patients. Thrombosis Research 52: 529-548, 1988 Otamiri T, Tagesson C. Role of phospholipase Az and oxygenated free radicals in mucosal damage after small intestinal ischemia

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and reperfusion. American Journal of Surgery 157: 562-565, 1989 Otamiri T, Lindahl M, Tagesson C. Phospholipase A2 inhibition prevents mucosal damage associated with small intestinal ischaemia in rats. Gut 29: 489-494, 1988 Page CPo The role of platelet activating factor in asthma. Journal of Allergy and Clinical Immunology 81: 144-150, 1988 Page CP, Abbott A. PAF: new antagonists, new roles in disease and a major role in reproductive biology. Trends in Pharmacological Sciences 10: 255-257, 1989 Page CP, Coyle AJ. The interaction between PAF, platelets and eosinophils in bronchial asthma. European Respiratory Journal 2 (Suppl.): 483-487, 1989 Panetta T, Marcheselli VL, Braquet P, Spinnewyn B, Bazan NG. Effects of a platelet-activating factor antagonist (BN 52021) on free fatty acids, diacylglycerols, polyphospho-inositides and blood flow in the gerbil brain: inhibition of ischemia-reperfusion induced cerebral injury. Biochemical and Biophysical Research Communications 149: 580-587, 1987 Panetta T, Marcheselli VL, Braquet P, Bazan NG. Arachidonic acid metabolism and cerebral blood flow in the normal, ischemic, and reperfused gerbil brain: inhibition of ischemiareperfusion-induced cerebral injury by a platelet-activating factor antagonist (BN 52021). Annals of the New York Academy of Sciences 559: 340-351, 1989 Parnham MJ, Bittner C, Lambrecht G. Antagonism of plateletactivating factor induced chemiluminescence in guinea-pig peritoneal macrophages in differing states of activation. British Journal of Pharmacology 98: 574-580, 1989 Paubert-Braquet M, Hosford D, Klotz P, Guilbaud J, Braquet P. Tumor necrosis factor primes PAF-induced superoxide production by human neutrophils: possible involvement ofG proteins. Journal of Lipid Mediators 2: SI-SI4, 1990 Paul-Eugene N, Dugas B, Picquot S, Lagente V, Mencia-Huerta JM, et al. Influence of interleukin-4 on the FCERII/CD23 expression of human monocytes. Journal of Lipid Mediators 2: 95-101, 1990 Pavao dos Santos OF, Boim MA, Bregman R, Draibe SA, Barros EJ, et al. Effect of platelet-activating factor antagonist on cyclosporine nephrotoxicity. Glomerular hemodynamics evaluation. Transplantation 47: 592-595, 1989 Pignol B, Henane S, Chaumeron S, Mencia-Huerta JM, Braquet P. Modulation of the priming effects of platelet-activating factor on the release of interleukin-I from lipopolysaccharidestimulated rat spleen macrophages. Journal of Lipid Mediators 2: S93-SI00, 1990a Pignol B, Henane S, Sorlin B, Rola-Pleszczynski M, Mencia-Huerta JM, et al. Effect oflong-term treatment with platelet-activating factor on IL-I and IL-2 production by rat spleen cells. Journal of Immunology 145: 980-984, 1990b Pignol B, Lonchampt MO, Chabrier PE, Mencia-Huerta JM, Braquet P. Platelet-activating factor potentiates interleukin-I/epidermal cell-derived thymocyte-activating factor release by guinea-pig keratinocytes stimulated with lipopolysaccharide. Journal of Lipid Mediators 2: S83-S91, 1990c Plante GE, Sirois P, Braquet P. Platelet-activating factor antagonism with BN 52021 protects the kidney against acute ischemic injury. Prostaglandins, Leukotrienes and Essential Fatty Acids 34: 53-60, 1989 Pons L, Droy-Lefay MT, Braquet P, Bueno L. Involvement of platelet-activating factor (PAF) in endotoxin-induced intestinal motor disturbances in rats. Life Sciences 45: 533-541, 1989a Pons F, Touvay C, Lejeune V, Carre C, Vilain B, et al. Action

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of platelet-activating factor (PAF) antagonists on the bronchopulmonary effects of PAF in the guinea-pig. Journal of Lipid Mediators I: 329-340, 1989b Popper H, Knipping G, Czarnetski BM, Steiner R, Helleis G, et al. Activation and release of enzymes and major basic protein from guinea-pig eosinophil granulocytes induced by different inflammatory stimuli and other substances: histochemical, biochemical, electron microscopic study. Inflammation 13: 147162, 1989 Poubelle P, Rola-Pleszczynski M. PAF enhances the production of tumor necrosis factor alpha by human monocytes: partial antagonism by BN 52021. In Braquet P (Ed.) Ginkgolides: chemistry, biology, pharmacology and clinical perspectives, Vol. 2, pp. 695-705, JR Prous, Barcelona, 1990 Pretolani M, Lefort J, Vargaftig BB. Limited interference of specific PAF antagonists with hyperresponsiveness to PAF itself of lungs from actively sensitized guinea-pigs. British Journal of Pharmacology 97: 433-442, 1989 Pretolani M, Lefort J, Silva P, Malanchere E, Dumarey C, et al. Protection by nedocromil sodium of active immunization-induced bronchopulmonary alterations in the guinea pig. American Review of Respiratory Diseases 141: 1259-1265, 1990 Rabier M, Damon M, Chanez P, Mencia-Huerta JM, BouSQuet J, et al. Platelet-activating factor, neutrophil chemotaxis and ginkgolides. In Braquet P (Ed.) Ginkgolides: chemistry, biology, pharmacology and clinical perspectives, Vol. 2, pp. 105115, JR Prous, Barcelona, 1990 Rabinovici R, Rudolph AS, Yue TL, Feuerstein G. Biological response to liposome-encapsulated hemoglobin (LEH) are improved by a PAF antagonist. Circulatory Shock 31: 431-445, I 990a Rabinovici R, Yue TL, Farhat M, Smith III EF, Esser KM, et al. Platelet-activating factor (PAF) and tumor necrosis factor (TNF) interactions in endotoxeQlic shock: studies with BN 50739, a novel PAF antagonist. Journal of Pharmacology and Experimental Therapeutics 255: 256-263, 1990b Redl H, Vogl C, Bahrami S, Schiesser A, Paul E, et al. Effect of PAF antagonist BN 52021 in an ovine endotoxin shock. Journal of Lipid Mediators 2: S 195-S20 I, 1990 Reinhold SL, Zimmerman GA, Prescott SM, Mcintyre TM. Phospholipid remodeling in human neutrophils: parallel activation of a deacylation/reacylation cycle and platelet-activating factor synthesis. Journal of Biological Chemistry 264: 2165221659, 1989 Ricker DD, Minhas BS, Kumar R, Robertson JL, Dodson MG. The effects of platelet-activating factor on the motility of human spermatozoa. Fertility and Sterility 52: 655-658, 1989 Rivero A, Gomez-Guerrero C, Egido J, Braquet M, Gonzales E. Effect of BN 52021 on the superoxide anion release by human neutrophils and monocytes induced by tumor necrosis factor and gamma interferon. In Braquet P (Ed.) Ginkgolides: chemistry, biology, pharmacology and clinical perspectives, Vol. 2, pp. 65-73, JR Prous, Barcelona, 1990 Roberts NM, McCusker P, Chung KF, Barnes PJ. Effect ofa PAF antagonist, BN 52063, on PAF-induced bronchoconstriction in normal subjects. British Journal of Clinical Pharmacology 26: 65-72, 1988a Roberts NM, Page CP, Chung KF, Barnes PJ. Effect of a PAF antagonist, BN 52063, on antigen-indueed, acute and late onset cutaneous responses in atopic subjects. Journal of Allergy and Clinical Immunology 82: 236-241, 1988b Robertson DG, Coyle AJ, Rhoden KJ, Grandordy BM, Page CP, et al. The effect of platelet-activating factor on histamine and

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muscarinic receptor function in guinea pig airways. American Review of Respiratory Diseases 137: 1317-1322, 1988 Rola-Pleszczynski M. Priming of human monocytes with PAF augments their production of tumor necrosis factor. Journal of Lipid Mediators 2: S77-S82, 1990 Rose JK, Debs RA, Philip R, Ruis NM, Valone FH. Selective activation of human monocytes by platelet activating factor analog 1-0-hexadecyl-2-0-methyl-sn-glycero-3-phosphorylcholine. Journal ofimmunology 144: 3513-3517, 1990 Rossoni G, Berti F, Buschi A, Braquet P. The ginkgolide BN 52021 antagonizes the immune release of histamine and other lipid mediators from guinea-pig isolated kidney. In Braquet P (Ed.) Ginkgolides: chemistry, biology, pharmacology and clinical perspectives, Vol. 2, pp. 521-529, JR Prous, Barcelona, 1990 Rougeot C, Junier MP, Minary P, Weidenfeld J, Braquet P, et al. Intracerebroventricular injection of platelet-activating factor induces secretion of adrenocorticotropin, {j-endorphin and corticosterone in conscious rats: a possible link between the immune and nervous system. Neuroendocrinology 51: 267-275, 1990 Rubin AE, Smith U, Patterson R. The bronchoconstrictor properties of platelet-activating factor in humans. American Review of Respiratory Diseases 136: 1145-1151, 1987 Ryan JP, Spinks NR, O'Neill C, Ammit AJ, Wales RG. Plateletactivating factor (PAF) production by mouse embryos in vitro and its effects on embryonic metabolism. Journal of Celhllar Biochemistry 40: 387-395, 1989 Sagach VF, Dmitrieva AV, Braquet P. Influence of BN 52021 on cardiac and hemodynamic changes during the development of post-ischemic shock reaction. In Braquet P (Ed.) Ginkgolides: chemistry, biology, pharmacology and clinical perspectives. Vol. 2, pp. 341-352, JR Prous, Barcelona, 1990 Salari H, Wong A. Generation of platelet activating factor (PAF) by human lung endothelial cell line. European Journal of Pharmacology 175: 253-259, 1990 Salem P, Deryckx S, Dulioust A, Vivier E, Denizot Y, et al. Immunoregulatory functions of paf-acether. IV. Enhancement of IL-l production by muramyl dipeptide-stimulated monocytes. Journal of Immunology 144: 1338-1344, 1990 Sanjar S, Aoki S, Boubekeur K, Burrows L, Colditz I, et al. Inhibition of PAF-induced eosinophil accumulation in pulmonary airways of guinea-pigs by anti-asthma drugs. Japanese Journal of Pharmacology 51: 167-172, 1989 Sanjar S, Aoki S, Boubekeur K, Chapman ID, Smith MA, et al. Eosinophil accumulation in pulmonary airways of guinea-pigs induced by exposure to an aerosol of platelet-activating factor: effect of anti-asthma drugs. British Journal of Pharmacology 99: 267-272, 1990 Satoh K, Imaizumi T, Kawamura Y, Yoshida H, Takamatsu M, et al. Increased activity of the platelet-activating factor acetylhydrolase in plasma low density lipoprotein from patients with essential hypertension. Prostaglandins 37: 673-682, 1989 Schaer GL, Hursey TL, McAlister K, Campbell D, Manabat N, et al. Platelet activating factor is an important mediator of myocardial reperfusion injury. Abstract. American College of Cardiology 17: 228A, 1991 Schattner M, Parini A, Fouque F, Vargaftig BB. Touqui L. Selective inhibition of adrenaline-induced human platelet aggregation by the structurally related PAF antagonist Ro 19-3704. British Journal of Pharmacology 96: 759-766, 1989 Sekiyama T, Gaudin C, Roulot D, Lebrec D, Braquet P, et al. Evidence for platelet-activating factor as a mediator for hyperdynamic circulation in conscious cirrhotic rats. In Braquet P (Ed.) Ginkgolides: chemistry, biology, pharmacology and

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clinical perspectives, Vol. 2, pp. 321-329, JR Prous, Barcelona, 1990 Selak MA, Smith JB. Platelet-activating factor-induced calcium mobilization in human platelets and neutrophils: effects of PAFacether antagonists. Journal of Lipid Mediators I: 152-167, 1989 Shukla SD, Morrison WJ, Dhar A. Desensitization of plateletactivating factor-stimulated protein phosphorylation in platelets. Molecular Pharmacology 35: 409-413, 1989 Silberstein DJ, Owen WF, Gasson JC, DiPersico JF, Golde DW, et al. Enhancement of human eosinophil cytotoxicity and leukotriene synthesis by biosynthetic (recombinant) granulocytemacrophage colony stimulating factor. Journal ofImmunology 137: 3290-3294, 1986 Silva PM, Martins MA, Castro-Faria-Neto HC, Cordeiro RS, Vargaftig BB. Adrenalectomy exacerbates paw edema without interfering with desensitization induced by PAF-acether in rats. Brazilian Journal of Medicine and Biological Research 21: 855858, 1988 Sipka S, Dinya Z, Koltai M, Braquet P, Bojan F, et al. Inhibition of neutrophil capillary migration by platelet-activating factor. In Braquet P (Ed.) Ginkgolides: chemistry, biology, pharmacology and clinical perspectives. Vol. 2, pp. 96-103, JR Prous, Barcelona, 1990 Siren AL, Feuerstein G. Effects ofPAF and BN 52021 on cardiac function and regional blood flow in conscious rats. American Journal of Physiology 257: H25-H32, 1989 Sirois MG, Jancar S, Braquet P, Plante GE, Sirois P. PAF increases vascular permeability in selected tissues: effect of BN 52021 and L-655,240. Prostaglandins 36: 631-644, 1988 Sirois MG, Plante GE, Braquet P, Sirois P. Tumor necrosis factor primes the effects of platelet activating factor on rat vascular permeability. Journal of Lipid Mediators 2: S 109-SII7, 1990 Soloviev AI, Braquet P. The role of PAF-acether in the mechanisms of isolated coronary arteries spasm under hypoxia and its inhibition by BN 52021. In Braquet P (Ed.) Ginkgolides: chemistry, biology, pharmacology and clinical perspectives, Vol. 2, pp. 353-367, JR Prous, Barcelona, 1990 Spinks NR, Ryan JP, O'Neill C. Antagonists of embryo-derived platelet-activating factor act by inhibiting the ability of the mouse embryo to implant. Journal of Reproduction and Fertility 88: 241-248, 1990 Spinnewyn B, Blavet N, Clostre F, Bazan NG, Braquet P. Involvement of platelet-activating factor (PAF) in cerebral postischemic phase in Mongolian gerbils. Prostaglandins 34: 337340, 1987 Squinto SP, Block AL, Braquet P, Bazan NG. Platelet-activating factor stimulated a fox/jun/ AP-I transcriptional signaling system in human neuroblastoma cells. Journal of Neuroscience Research 24: 558-566, 1989 Stahl GL, Craft DV, Lento PH, Lefer AM. Detection of plateletactivating factor during traumatic shock. Circulatory Shock 26: 237-244, 1988 Stahl GL, Terashita ZI, Lefer AM. Role of platelet-activating factor in propagation of cardiac damage during myocardial ischemia. Journal of Pharmacology and Experimental Therapeutics 244: 898-904, 1988 Stanton AWB, Izumi T, Antoniw JW, Piper PJ. Platelet-activating factor (PAF) antagonist, WEB 2086, protects against PAFinduced hypotension in Macaca fascicularis. British Journal of Pharmacology 97: 643-646, 1989 Stewart AG. CV 6209 is a non-competitive antagonist of plateletactivating factor receptors on guinea-pig resident peritoneal macrophages. Clinical and Experimental Pharmacology and Physiology 16: 813-820, 1989

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Stewart AG, Dubbin PN, Harris T, Dusting GJ. Platelet activating factor may act as a second messenger in the release oficosanoids and superoxide anions from leukocytes and endothelial cells. Proceedings of the National Academy of Sciences USA 87: 3215-3219, 1990 Stewart AG, Dusting GJ. Characterization of receptors for platelet-activating factor on platelets, polymorphonuclear leukocytes and macrophages. British Journal of Pharmacology 94: 1225-1233, 1988 Stewart AG, Phillips WA. Intracellular platelet-activating factor regulates eicQsanoid generation in guinea-pig resident peritoneal macrophages. British Journal of Phrmacology 98: 141-148, 1989 Sturm MJ, Strophair JM, Kendrew PJ, Vandongen R, Beilin U, et at. Whole blood aggregation and plasma Iyso-PAF related to smoking and atherosclerosis. Clinical and Experimental Pharmacology and Physiology 16: 597-605, 1989 Sun XM, Hsueh W. Bowel necrosis induced by tumor necrosis factor in rats is mediated by platelet-activating factor. Journal of Clinical Investigation 81: 1328-1331, 1988 Tahraoui L, Floch A, Mondot S, Cavero I. High affinity specific binding sites for tritiated platelet-activating factor in canine platelet membranes: counterparts of platelet-activating factor receptors mediating platelet aggregation. Molecular Pharmacology 34: 145-151, 1988 Tahraoui L, Floch A, Cavero I. Functional validation of plateletactivating factor receptor sites characterized biochemically by a specific and reproducible (lH)platelet-activating factor binding in human platelets. Journal of Pharmacology and Experimental Therapeutics 252: 1221-1227, 1990 Thierry A, Doly M, Braquet P, Cluzel J, Meyniel G. Presence of specific platelet-activating factor binding sites in the rat retina. European Journal of Pharmacology 163: 97-\01, 1989 Thorn R. Structural stability and morphogenesis (trans. Fowler DH), Benjamin-Addison Wesley, New York, 1975 Tolins JP, Vercellotti GM, Wilkowske M, Jacob HS, Raij L. Role of platelet-activating factor in endotoxemic acute renal failure in the male rat. Journal of Laboratory and Clinical Medicine 113: 316-324, 1989 Tool AT, Verhoeven AJ, Roos D, Koenderman L. Platelet-activating factor (PAF) acts as an intercellular messenger in the changes of cytosolic free Ca2+ in human neutrophils induced by opsonized particles. FEBS Letters 259: 209-212, 1989 Tosaki A, Koltai M, Braquet P, Szekeres L. Possible involvement of platelet activating factor in anaphylaxis of passively sensitized, isolated guinea pig hearts. Cardiovascular Research 23: 715-722, 1989 Touvay C, Vilain B, Lejeune V, Mencia-Huerta JM, Braquet P. Effect of cyclosporin A and platelet-activating factor (PAF) antagonist, BN 52021, on PAF, and antigen-induced bronchoconstriction in the guinea-pig. Biochemical and Biophysical Research Communications 163: 118-123, 1989 Travers JB, Li Q, Kniss DA. Fertel RH. Identification of functional platelet-activating factor receptors in Raji Iymphoblasts. Journal of Immunology 143: 3708-3713,1989 Travers JB, Sprecher H, Fertel RH. The metabolism of plateletactivating factor in human T-Iymphocytes. Biochimia et Biophysica Acta \042: 193-197, 1990 Ukena D, Krogel C, Dent G, Yukawa T, Sybrecht G, et at. PAFreceptors on eosinophils: identification with a novel ligand, (3H)WEB 2086. Biochemical Pharmacology 38: 1702-1705, 1989 Underwood DC, Kadowitz PJ. Analysis of bronchoconstrictor responses to platelet-activating factor in the cat. Journal of Applied Physiology 67: 377-382, 1989

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Uski TK, Reinstrup P. Actions of platelet-activating factor on isolated feline and human cerebral arteries. Journal of Cerebral Blood Flow and Metabolism \0: 428-431, 1990 Vallance SJ, Downes CP, Cragoe EJ, Whetton AD. Granulocytemacrophage colony-stimulating factor can stimulate macrophage proliferation via persistence activation of N+/H+ antiport activation. Biochemical Journal 265: 359-364, 1990 Vallari DS, Austinhirst R, Snyder F. Development of specific functionally active receptors for p1atelet-activating factor in HI.,. 60 cells following granulocytic differentiation. Journal of Biological Chemistry 265: 4261-4265, 1990 Valone FH. Identification of platelet-activating factor receptors in PS88D murine macrophages. Journal of Immunology 140: 2389-2394, 1988 Valone FH, Epstein LB. Biphasic platelet-activating factor (PAF) synthesis by human monocytentimulated with interleukin 1b (IL 1,6) and tumor necrosis factor (TNF). FASEB Journal 2: 878, 1988 Vargaftig BB, Braquet P. PAF-acether today: relevance for acute experimental anaphylaxis. British Medical Bulletin 43: 312-335, 1987 Verbey NL, Van Delft JL, Van Haeringen NJ, Braquet P. Plateletactivating factor and laser trauma of the iris. Investigative Ophthalmology and Visual Sciences 30: 1 \0 1-11 03, 1989 Vercellotti GM, Mo1dow CF, Wickham Jacob HS. Endothelial cell platelet-activating factor primes neutrophil responses: amplification of endothelial activation by neutrophil products. Journal of Lipid Mediators 2: S23-S30, 1990 Vercellotti GM, Wickham NW, Gustafson KS, Yin HQ, Herbert M, et aI. Thrombin-treated endothelium primes neutrophil functions: inhibition by platelet-activating factor receptor antagonists. Journal of Leukocyte Biology 45: 483-490, 1989 Vercellotti GM, Yin HG, Gustafson KS, Nelson RD, Jacob HS. Platelet-activating factor primes neutrophil responses to agonist role in promoting neutrophil-mediated endothelial damage. Blood 71: 1100-1107, 1988 Viossat I, Chapelat M, Chabrier PE, Braquet P. Effects of platelet activation factor (PAF) and its receptor antagonist BN 52021 on isolated perfused guinea-pig heart. Prostaglandins, Leukotrienes and Essential Fatty Acids 38: 189-194, 1989 Vornovitskii EG, Ignateva VB, Gollash M, Kulikov VI, Lipatkina LI. Cardiodepressive effect of platelet activating factor. Bulletin of Experimental Biology and Medicine \07: 27-30, 1989a Vornovitskii EG, Ignateva VB, Gollash M, Kulikov VI, Kuznetsova n, et at. Interactions of PAF and its antagonists in the guinea pig atrial myocardium. Bulletin of Experimental Biology and Medicine \08: 137-139, 1989b Wahler GM, Coyle DE, Sperelakis N. Effects of platelet-activating factor on single potassium channel currents in guinea pig ventricular myocytes. Molecular and Cellular Biochemistry 93: 6976, 1990 Wainwright CL, Parratt JR, Bigaud M. The effects of PAF antagonists on arrhythmias and platelets during acute myocardial ischaemia and reperfusion. European Heart Journal \0: 235243, 1989 Wallace JL. Release of platelet-activating factor (PAF) and accelerated healing induced by a PAF antagonist in an animal model of chronic colitis. Canadian Journal of Physiology and Pharmacology 66: 422-425, 1988 Wallace JL. Lipid mediators in gastric ulcer. American Journal of Physiology 258: GI -G 11, 1990 Wallace JL, Braquet P, Ibbotson GC, MacNaughton WK, Cirino C. Assessment of the role of platelet-activating factor in an

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animal model ofinflammatory bowel disease. Journal of Lipid Mediators 1: 13-23, 1989a Wallace JL, MacNaughton WI

PAF. A review of its effects, antagonists and possible future clinical implications (Part II).

REVIEW ARTICLE Drugs 42 (2): 174-204, 1991 0012-6667/91/0008-0174/$15.50/0 © Adis International Limited. All rights reserved. DRU1047 PAF A Review o...
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