6,963 publications from this institution
"Bradykinin-Induced Airway Microvascular Leakage and Bronchoconstriction are Mediated via a Bradykinin B2 Receptor: Reply." American Review of Respiratory Disease, 144(1), pp. 238–239
Several neuropeptides have now been localized to nerves in human airways and have marked effects on airway smooth muscle tone, bronchial blood flow, microvascular leakage, and airway secretions. There is mounting evidence that they may act as neurotransmitters of nonadrenergic, noncholinergic nerves and may be co-transmitters of classic autonomic nerves. Vasoactive intestinal peptide and the related peptide histidine methionine are potent relaxants of human airways in vitro, yet their effects in vivo are disappointing because of problems in delivery. Sensory neuropeptides such as substance P, neurokinins A and B, and calcitonin gene-related peptide may be involved in neurogenic inflammatory reactions in asthma. Although there have been no clinical benefits from these discoveries, in the future the development of agents that interfere with or mimic neuropeptide effects may offer novel therapeutic approaches to airway diseases such as asthma.
The addition of an inhaled long-acting beta2-agonist (LABA) to an inhaled corticosteroid (ICS) gives optimal control of asthma in most patients and two fixed combination inhalers (salmeterol/fluticasone and formoterol/budesonide) are increasingly used as a convenient controller in patients with persistent asthma. There is a strong scientific rationale for the combination of these two drug classes. ICS suppress the chronic inflammation of asthma and reduce airway hyperresponsiveness and this is achieved at low doses in most patients. LABA act on different aspects of the pathophysiology of asthma. In addition to their bronchodilator action, LABA also inhibit mast cell mediator release, plasma exudation and may reduce sensory nerve activation. Thus these two classes of drug address complementary aspects of the pathophysiology of asthma that neither drug class is able to achieve alone. There are several positive interactions between LABA and ICS. Corticosteroids increase the expression of beta2-receptors by increasing gene transcription. Experimentally this protects against the loss of beta2-receptors in response to long-term exposure to beta2-agonists. While this is unlikely to be important in bronchodilator responses to beta2-agonists, in view of the large beta-receptor reserve, it is probably important in preventing loss of beta-agonist effects on the nonbronchodilator actions of LABA discussed earlier. beta2-Agonists may potentiate the molecular mechanism of corticosteroid actions, with increased nuclear localization of glucocorticoid receptors and additive or sometimes synergistic suppression of inflammatory mediator release. Thus LABA and ICS may optimize each others beneficial actions in the airways, but the low systemic effects of these drugs do not result in any increase in adverse effects. Long-acting beta2-agonists corticosteroid inhaler therapy is therefore a logical advance and results in effective control of asthma in the majority of patients without significant adverse effects. This simplified approach to long-term asthma therapy has a strong scientific rationale.
The invention of balloon angioplasty as a treatment of obstructive coronary disease by Andreas Gruntzig in 1977 was a huge leap forward in technology, and undoubtedly will always remain the first revolution in interventional cardiology. However, this technique was plagued by multiple problems including the risk of acute occlusion of the vessel due to extensive dissection requiring emergency bypass surgery 1 . While late luminal enlargement and vascular remodelling could occur, more often constrictive vascular remodelling was the case instead, with consequent restenosis. The advent of bare metal stenting and the landmark BENESTENT trial have established bare metal stenting as the second revolution in interventional cardiology 2 . This technology provided a solution to acute vessel occlusion by sealing the dissection flaps and preventing recoil. The rate of subacute occlusion was reduced to 1.5%, making emergency by-pass surgery a rare occurrence, truly a thing of the past. Restenosis rates were further reduced from 32% to 22% at seven months, but this was still high, and neointimal hyperplasia still occurred, necessitating repeat revascularisation. Since the vessel was now caged with metal, late luminal enlargement and advantageous vascular remodelling no longer occurred. Another problem, namely that of late stent thrombosis, was also first described 3 . To solve the issue of in-stent restenosis - after the failure of brachytherapy - drug eluting stents were introduced. Indeed, the followup of the first 45 patients implanted with the sirolimus eluting Bx velocity stent (Cordis, Johnson & Johnson, Warren, NJ, USA) had negligible neointimal hyperplasia. This was confirmed in the RAVEL study 4,5 . Drug eluting stents were thus dubbed the third revolution in interventional cardiology. Both large scale randomised trials and allcomer registries showed excellent results in terms of the need for repeat revascularisation. This technology brought closer the results of percutaneous coronary intervention to that of coronary bypass graft surgery. Serruys’ “rosy” prophecy came true 6 , however, it soon turned out that, as in all true “roses”, this one also has its thorns. The thorn of the first generation of drug eluting stents was an increased risk of late stent thrombosis. Registries of all comers treated with drug eluting stents showed late stent thrombosis rates of 0.53% per year, with a continued increase to 3% over four years 7,8 . In patients with complex multivessel disease (ARTS II), the rate of combined definite, probable and possible stent thrombosis was as high as 9.4% at five years, accounting for 32% of MACE events 9 . In addition, the pathology showed uncovered struts and inflammatory reaction in post-mortem specimens. Vasomotion testing showed abnormal vasoconstriction response to acetylcholine distal to the stent, suggesting that the structure and function of the endothelium remained abnormal 10 . All
No abstract is provided for this article.
No abstract is provided for this article.
"Neuropeptides in the Respiratory Tract: Part I." American Review of Respiratory Disease, 144(5), pp. 1187–1198
Drug-eluting stents (DES) have significantly reduced rates of restenosis; however, elution from their surface of cytotoxic and cytostatic drugs, together with the presence of non-erodable polymers, is associated with impaired endothelialization, allergic reactions, inflammation, and vascular dysfunction, factors which have all been implicated in the most prominent safety concern with DES today —stent thrombosis (ST).1–3 The development of newer DES with polymers that are either more biocompatible, biodegradable, or completely absent, together with completely biodegradable stents has been an important step forward to minimize the potential risk of ST. Despite this, however, the rapid restoration of a functional endothelium appears, in theory at least, to be one of the most intuitive ways of minimizing the risk of ST and excessive neointimal proliferation.4 Therefore, it comes as no surprise that soon after the discovery of endothelial progenitor cells (EPCs),5 a novel coronary stent, the Genous™ EPC capture stent (OrbusNeich, Florida, USA), was developed which had a proprietary coating that contained anti-human CD34 antibodies ( Figure 1 ). These antibodies were able to capture circulating EPCs, such that the EPC capture stent was considered a potential solution to many of the problems of coronary stenting. Figure 1 Schematic diagram illustrating the underlying principal behind the EPC capture stent. The CD-34 antigen on the EPC binds to the anti CD-34 antibody on the stent's surface to promote rapid endothelialisation. Six years on, and Beijk et al. 6 report the 1-year outcomes of the TRIAS HR study, the first randomized study comparing the Genous™ EPC stent with a conventional DES (the Taxus Liberte stent). This study adds to the paucity of data already available on the EPC stent, and disappointingly reaffirms the disparity between technological promise and real-life clinical results. Prior to the completion of 1-year follow-up this single-centre study was transformed into … *Corresponding author. Tel: +31 10 7035260, Fax: +31 10 4369154, Email: p.w.j.c.serruys{at}erasmusmc.nl
