Novel targets and regulatory ordeal by QT interval

Abstract

Platelet-activating factor (PAF), also known as PAF-acether and AGEPC (acetyl-glyceryl-ether-phosphorylcholine), is a lipid-derived biological messenger active at subnanomolar concentrations [1]. ‘PAF’ is something of a misnomer as it acts on a variety of cells, not only on platelets, with possible roles in allergy and inflammation as well as haemostasis/ thrombosis. PAF is made from acyl-PAF in a two-step process summarized in Figure 1: a highlyregulated cytosolic enzyme phospholipase A2 (PLA2) acts on acyl-PAF to produce lyso-PAF, which is then acetylated to give PAF. PLA2 simultaneously liberates free arachidonic acid from the 2-position of glycerol in cell membranes initiating the production of eicosanoids (prostaglandins, leukotrienes, and lipoxins) in parallel with PAF. PAF is inactivated by deacetylation which regenerates the inactive lyso-PAF precursor. PAF is produced by activated inflammatory cells and acts via specific G-protein-coupled PAF-receptors. Injected subcutaneously it produces many of the signs and symptoms of inflammation, including vasodilatation and redness, increased vascular permeability and wheal formation, and, at higher concentrations, hyperalgesia. It is a potent chemotaxin for neutrophils and monocytes, and recruits eosinophils into the bronchial mucosa in the late phase of asthma. It can itself activate PLA2, reinforcing eicosanoid synthesis by positive feedback. It has spasmogenic effects on both bronchial and ileal smooth muscle and stimulates arachidonate turnover and TXA2 generation by platelets, producing shape change and releasing platelet granule contents. The PAF pathway (of biosynthesis, receptors, and downstream transduction events) is thus an attractive therapeutic target, but it is not yet clear whether inhibiting it will prove therapeutically advantageous in thrombotic or inflammatory diseases.There was great excitement following the discovery of PAF (by Jacques Benveniste, a French immunologist) in the early 1970s, but sadly no drugs have really made it to market. However, the anti-inflammatory actions of the glucocorticoids may partly be caused by inhibition of PAF synthesis [2], so we should not give up hope. Competitive antagonists of PAF and/or specific inhibitors of lyso-PAF acetyltransferase could well be useful anti-inflammatory and/or anti-asthmatic drugs. The PAF antagonist lexipafant is effective in a rat model of acute pancreatitis [3], but several small human studies have been negative or inconclusive. Icatibant, an antagonist at bradykinin B2 receptors, was also effective in animal models of pancreatitis but not in the human disease.It has since been licensed in Europe for use in hereditary angiooedema in patients with C1-esterase deficiency, exemplifying how difficult it can be to find the optimum match between an inhibitor or antagonist of a mediator and disease target: one of many challenges for translational medicine [4]. The same message is provided by a complement inhibitor, eculizumab, also recently licensed in Europe for the rare and previously almost completely untreatable disease paroxysmal nocturnal haemoglobinuria – see articles in our new drugs’ mechanisms feature [5, 6]. Rupatidine is a combined H1 and PAF antagonist [7], licensed in several parts of the world for treating allergic rhinitis and for chronic urticaria, but it is not clear what (if anything) its action on PAF receptors adds to its therapeutic efficacy over and above its antihistamine action [8].The withdrawal from the market of another less-sedating antihistamine, terfenadine, ushered in the modern era of regulatory concern over cardiac safety of non-cardiac drugs. Astemizole, also a less-sedating antihistamine, had similar effects and was also withdrawn, raising the spectre of a drug-class effect. This has not proved to be the case: many non-cardiac drugs with quite different primary pharmacology have been implicated [9] and several antihistamines British Journal of Clinical Pharmacology DOI:10.1111/j.1365-2125.2010.03657.x