Sansom J E, Brooks J, Burton J L, Archer C B
Department of Dermatology, University of Bristol, UK.
Clin Exp Dermatol. 1996 Jan;21(1):33-7.
Previous studies show that oral antihistamines affect the weal and flare response to intradermal injections of the inflammatory mediators platelet-activating factor (PAF) and bradykinin (BK). The aim of this study was to compare the effects of terfenadine (an H1-antagonist) and cimetidine (an H2-antagonist) on weal and flare responses to PAF and BK in healthy non-atopic human volunteers. The effects of doxepin on PAF responses were investigated, as there is evidence that doxepin may have direct anti-PAF effects in addition to its known antihistaminic actions. Terfenadine significantly reduced weal and flare responses to PAF (mean reduction 53 and 73%, respectively) and flare responses to BK (mean reduction 78%) but had no effect on weal responses to BK. Doxepin significantly reduced both weal and flare responses to PAF (mean reduction 43 and 68%, respectively, at higher doses of PAF). Cimetidine had no effect on weal or flare responses to PAF or BK. These findings suggest that the flare response to intradermal BK is mediated via histamine release while the weal response is not. The effects of the various antagonists of PAF-induced responses suggest that its effects too may be mediated via histamine, the similarity of the effects of terfenadine and doxepin on these responses indicating that the effects of doxepin may be due to its known antihistamine activity rather than to any specific PAF-antagonistic properties. Platelet-activating factor (PAF) is a phospholipid which is released from a wide range of cell types and also from vascular endothelium. PAF is formed by the conversion of ether-linked phospholipids initially to the biologically inactive lyso-PAF and then by acetylation to PAF. Intradermal injection of PAF in human skin causes vasodilatation and increased vascular permeability, producing a weal and flare response with accompanying pruritus. Bradykinin (BK) is a vasoactive polypeptide formed by the action of enzymes known as kallikreins on inactive precursors called kininogens. Its effects include an increase in blood flow and vascular permeability and stimulation of the release of prostaglandins and histamine. On intradermal injection in human skin it causes a weal and flare response with associated pain rather than pruritus. Previous studies have suggested that the weal and flare response to PAF may be mediated in part by histamine release. Given that BK is known to cause histamine release it appears possible that the responses to both compounds may be modified by conventional antihistamines. Experiments based on this premise have found that antihistamines have a pronounced effect on the flare response to PAF but a less marked effect on weal responses. The weal response to BK was unaffected by systemic antihistamines but studies have produced conflicting results with regard to effects on the flare response. The aim of this study was to compare the effects of terfenadine (an H1-antagonist) and cimetidine (an H2-antagonist) on PAF- and BK-induced weal and flare responses in healthy, non-atopic human volunteers. Based on the treatment of cold urticaria it has been suggested that doxepin, which has known H1- and H2-antagonistic effects, may in addition show specific anti-PAF activity. We compared the effects of doxepin on PAF-induced intradermal responses with those of terfenadine and cimetidine in this study.
以往研究表明，口服抗组胺药会影响皮内注射炎症介质血小板活化因子（PAF）和缓激肽（BK）后的风团及潮红反应。本研究旨在比较特非那定（一种H1拮抗剂）和西咪替丁（一种H2拮抗剂）对健康非特应性人类志愿者PAF和BK所致风团及潮红反应的影响。鉴于有证据表明多塞平除了具有已知的抗组胺作用外，可能还具有直接的抗PAF作用，因此对多塞平对PAF反应的影响进行了研究。特非那定显著降低了对PAF的风团及潮红反应（平均降低分别为53%和73%）以及对BK的潮红反应（平均降低78%），但对BK的风团反应无影响。多塞平显著降低了对PAF的风团及潮红反应（在较高剂量PAF时，平均降低分别为43%和68%）。西咪替丁对PAF或BK的风团或潮红反应均无影响。这些发现表明，皮内注射BK后的潮红反应是通过组胺释放介导的，而风团反应则不是。PAF诱导反应的各种拮抗剂的作用表明，其作用也可能通过组胺介导，特非那定和多塞平对这些反应的作用相似，表明多塞平的作用可能是由于其已知的抗组胺活性，而非任何特定的PAF拮抗特性。血小板活化因子（PAF）是一种磷脂，可从多种细胞类型以及血管内皮中释放。PAF是由醚键连接的磷脂先转化为生物活性不高的溶血PAF，然后通过乙酰化转化为PAF而形成的。在人体皮肤内注射PAF会导致血管扩张和血管通透性增加，产生风团及潮红反应并伴有瘙痒。缓激肽（BK）是一种血管活性多肽，由称为激肽释放酶的酶作用于称为激肽原的无活性前体而形成。其作用包括增加血流量和血管通透性以及刺激前列腺素和组胺的释放。在人体皮肤内注射时，它会引起风团及潮红反应并伴有疼痛而非瘙痒。以往研究表明，对PAF的风团及潮红反应可能部分由组胺释放介导。鉴于已知BK会引起组胺释放，似乎这两种化合物的反应都可能被传统抗组胺药改变。基于这一前提的实验发现，抗组胺药对PAF的潮红反应有显著影响，但对风团反应的影响较小。全身性抗组胺药对BK的风团反应无影响，但关于对潮红反应的影响研究结果相互矛盾。本研究的目的是比较特非那定（一种H1拮抗剂）和西咪替丁（一种H2拮抗剂）对健康非特应性人类志愿者PAF和BK诱导的风团及潮红反应的影响。基于对寒冷性荨麻疹的治疗，有人提出具有已知H1和H2拮抗作用的多塞平可能还具有特定的抗PAF活性。在本研究中，我们比较了多塞平与特非那定和西咪替丁对PAF诱导的皮内反应的影响。
