Clive P. Page

Outcomes for COPD pharmacological trials: from lung function to biomarkers

The American Thoracic Society/European Respiratory Society jointly created a Task Force on “Outcomes for COPD pharmacological trials: from lung function to biomarkers” to inform the chronic obstructive pulmonary disease research community about the possible use and limitations of current outcomes and markers when evaluating the impact of a pharmacological therapy. Based on their review of the published literature, the following document has been prepared with individual sections that address specific outcomes and markers, and a final section that summarises their recommendations.

The future challenges facing the development of new antimicrobial drugs

The emergence of resistance to antibacterial agents is a pressing concern for human health. New drugs to combat this problem are therefore in great demand, but as past experience indicates, the time for resistance to new drugs to develop is often short. Conventionally, antibacterial drugs have been developed on the basis of their ability to inhibit bacterial multiplication, and this remains at the core of most approaches to discover new antibacterial drugs. Here, we focus primarily on an alternative novel strategy for antibacterial drug development that could potentially alleviate the current situation of drug resistance — targeting non-multiplying latent bacteria, which prolong the duration of antimicrobial chemotherapy and so might increase the rate of development of resistance.

Anti-inflammatory effects of low-dose oral theophylline in atopic asthma

Theophylline, in addition to its bronchodilator effect, may attenuate inflammation in asthma. We did a double-blind placebo-controlled study of the effect of oral theophylline on the inflammatory response of the bronchial mucosa to inhalation of allergen in 19 atopic asthmatic subjects. Bronchoscopy and bronchial biopsy were done 24 hours after allergen inhalation before and after six weeks of treatment with oral slow-release theophylline, 200 mg 12 hourly. The mean serum concentration was 36.6 mumol/L, which is below the currently-accepted therapeutic range. After treatment with theophylline there was a significant reduction in the number of EG2-positive activated eosinophils (5.9 before and 2.1 after treatment, Wilcoxon signed rank p < 0.05) and total eosinophils (16.7 before and 7.6 after treatment, p < 0.05) beneath the epithelial basement membrane. We conclude that low-dose oral theophylline attenuates airway inflammatory response to allergen inhalation in atopic asthma.

Pharmacology and Therapeutics of Bronchodilators

Bronchodilators are central in the treatment of of airways disorders. They are the mainstay of the current management of chronic obstructive pulmonary disease (COPD) and are critical in the symptomatic management of asthma, although controversies around the use of these drugs remain. Bronchodilators work through their direct relaxation effect on airway smooth muscle cells. at present, three major classes of bronchodilators, β2-adrenoceptor (AR) agonists, muscarinic receptor antagonists, and xanthines are available and can be used individually or in combination. The use of the inhaled route is currently preferred to minimize systemic effects. Fast- and short-acting agents are best used for rescue of symptoms, whereas long-acting agents are best used for maintenance therapy. It has proven difficult to discover novel classes of bronchodilator drugs, although potential new targets are emerging. Consequently, the logical approach has been to improve the existing bronchodilators, although several novel broncholytic classes are under development. An important step in simplifying asthma and COPD management and improving adherence with prescribed therapy is to reduce the dose frequency to the minimum necessary to maintain disease control. Therefore, the incorporation of once-daily dose administration is an important strategy to improve adherence. Several once-daily β2-AR agonists or ultra-long-acting β2-AR-agonists (LABAs), such as indacaterol, olodaterol, and vilanterol, are already in the market or under development for the treatment of COPD and asthma, but current recommendations suggest the use of LABAs only in combination with an inhaled corticosteroid. In addition, some new potentially long-acting antimuscarinic agents, such as glycopyrronium bromide (NVA-237), aclidinium bromide, and umeclidinium bromide (GSK573719), are under development, as well as combinations of several classes of long-acting bronchodilator drugs, in an attempt to simplify treatment regimens as much as possible. This review will describe the pharmacology and therapeutics of old, new, and emerging classes of bronchodilator.

Heparin in inflammation: potential therapeutic applications beyond anticoagulation.

In this chapter we have described anti-inflammatory functions of heparin distinct from its traditional anticoagulant activity. We have presented in vivo data showing heparins beneficial effects in various preclinical models of inflammatory disease as well as discussed some clinical studies showing that the anti-inflammatory activities of heparin may translate into therapeutic uses. In vivo models that use low-anticoagulant heparins indicate that the anticoagulant activity can be distinguished from heparins anti-inflammatory properties. In certain cases such as hypovolemic shock, the efficacy of a low-anticoagulant heparin derivative (GM1892) exceeds heparin. Data also suggest that nonconventional delivery of heparin, specifically via inhalation, has therapeutic potential in improving drug pharmacokinetics (as determined by measuring blood coagulation parameters) and in reducing the persistent concerns of systemic hemorrhagic complications. Results from larger clinical trials with heparin and LMW heparins are eagerly anticipated and will allow us to assess our predictions on the effectiveness of this drug class to treat a variety of human inflammatory diseases.

Platelet-activating factor as a mediator of allergic disease

Many different mediators have been implicated in allergic responses and allergic diseases.14 It is becoming increasingly apparent that no single mediator can account for allergic diseases, such as asthma, rhinitis, eczema, or anaphylaxis, and that the clinical manifestation depends on a complex interaction of mediators that are released from a variety of cells. Although previous research concentrated on the mast cell as the key cell in allergic reactions, it now appears likely that other inflammatory cells, such as macrophages, eosinophils , neutrophils, platelets, and lymphocytes, may also contribute to the inflammatory response. The recognition that cells, other than mast cells, such as eosinophils,5 platelets,6 and macrophages,7 may be activated by IgE-dependent mechanisms has focused attention on these other cells as sources of mediators. Histamine,8 prostaglandinsg and leukotrienes3 have been previously proposed as playing a role in mediating allergic responses. Another mediator that is receiving increasing attention is PAF, a highly potent inflammatory mediator formed, like prostaglandins and leukotrienes, by the action of phospholipase A, on membrane phospholipids. The purpose of this article is to review the various effecs of PAF that may be relevant to allergic diseases and to speculate on its possible involvement in allergy. With the introduction of specific PAF antagonists during the next few years, the role of this inflammatory mediator will be clarified. had previously been demonstrated in the rabbit that platelets provided the major source of histamine among the blood elements,” but it was not known whether histamine release during allergen challenge represented a direct or indirect consequence of the recognition of allergen by antibody. Histamine release in sensitized rabbits undergoing antigen challenge was demonstrated to be the consequence of IgE-dependent activation of basophils that, in turn, released a soluble product capable of eliciting platelet activation.““S ‘* This product was termed PAF and was subsequently demonstrated to be a phospholipid.‘3 The chemical structure was then identified in 1979 by three independent groups as 1-o-alkyl-2-acetyl-sn-glyceryl-3phosphorylcholine (Fig. 1). 14-16 This phospholipid has been variously referred to as PAF-acether,14 acetyl glyceryl ether phosphorylcholine,‘5 or antihypertensive polar renomedullary lipid.16 The original nomenclature (PAF) will be used throughout this article, although it is now apparent that PAF has many other actions in addition to activation of platelets.

Therapeutic uses of heparin beyond its traditional role as an anticoagulant

A number of physiological effects have been ascribed to heparin since its discovery almost 80 years ago, many of which are independent from its first-described and best- characterized activity as an anticoagulant. Heparin and heparan sulphate are believed to possess many biological activities that include the ability to modulate embryonic development, neurite outgrowth, tissue homeostasis, wound healing, metastasis, cell differentation, cell proliferation and inflammation. In this review, David Tyrell, Stephen Kilfeather and Clive Page examine some of the activities of heparin (and heparin derivatives) beyond its effects as an anticoagulant, and discuss the therapeutic potential of this old, but certainly not antiquated, drug.

β2-Agonist Therapy in Lung Disease

β2-Agonists are effective bronchodilators due primarily to their ability to relax airway smooth muscle (ASM). They exert their effects via their binding to the active site of β2-adrenoceptors on ASM, which triggers a signaling cascade that results in a number of events, all of which contribute to relaxation of ASM. There are some differences between β2-agonists. Traditional inhaled short-acting β2-agonists albuterol, fenoterol, and terbutaline provide rapid as-needed symptom relief and short-term prophylactic protection against bronchoconstriction induced by exercise or other stimuli. The twice-daily β2-agonists formoterol and salmeterol represent important advances. Their effective bronchodilating properties and long-term improvement in lung function offer considerable clinical benefits to patients. More recently, a newer β2-agonist (indacaterol) with a longer pharmacodynamic half-life has been discovered, with the hopes of achieving once-daily dosing. In general, β2-agonists have an acceptable safety profile, although there is still controversy as to whether long-acting β2-agonists may increase the risk of asthma mortality. In any case, they can induce adverse effects, such as increased heart rate, palpitations, transient decrease in PaO2, and tremor. Desensitization of β2-adrenoceptors that occurs during the first few days of regular use of β2-agonist treatment may account for the commonly observed resolution of the majority of these adverse events after the first few doses. Nevertheless, it can also induce tolerance to bronchoprotective effects of β2-agonists and has the potential to reduce bronchodilator sensitivity to them. Some novel once-daily β2-agonists (olodaterol, vilanterol, abediterol) are under development, mainly in combination with an inhaled corticosteroid or a long-acting antimuscarinic agent.

The effect of the selective PAF antagonist BN 52021 on PAF- and antigen-induced bronchial hyper-reactivity and eosinophil accumulation.

Sensitised guinea-pigs were exposed to an aerosol of ovalbumin (100-500 micrograms/ml) and normal animals were exposed to an aerosol of platelet activating factor (PAF) (250-1000 micrograms/ml). Twenty-four hours later, bronchial reactivity was assessed by measurement of air overflow in response to i.v. histamine or acetylcholine using the Konsett-Rossler technique. Additionally, bronchoalveolar lavage was performed by washing the lungs with 10 ml of 0.9% saline and differential counts obtained to assess the ability of PAF and antigen to elicit pulmonary inflammatory cell recruitment. Both PAF and antigen exposure produced a dose-related increase in bronchial reactivity, while treatment with the vehicle (either 0.25% bovine serum albumin or 0.9% saline) had no effect on airway responsiveness. Furthermore, both PAF and antigen exposure produced a selective accumulation of eosinophils into the airways. There was no significant change in the number of neutrophils, macrophages or lymphocytes. The selective PAF antagonist BN52021 inhibited both the development of bronchial hyper-reactivity and the eosinophil influx into the airways induced by PAF or antigen exposure. These observations suggest that PAF has a central role to play in the antigen induced eosinophil accumulation and subsequent bronchial hyper-reactivity.

The role of nitric oxide as an endogenous regulator of platelet and neutrophil activation within the pulmonary circulation of the rabbit.

1 Intravenous (i.v.) administration of adenosine diphosphate (ADP), platelet activating factor (PAF) and thrombin induced a dose‐related accumulation of 111indium‐labelled platelets within the thoracic region of anaesthetized rabbits. 2 I.v. administration of the inhibitor of NO biosynthesis, l‐NG‐nitro arginine methyl ester (l‐NAME; 10 mg kg−1) significantly potentiated the peak platelet accumulation induced by ADP, PAF and thrombin. Additionally l‐NAME prolonged the disaggregation of platelets in comparison to d‐NAME (10 mg kg−1). Such changes were reversible by the administration of l‐arginine (900 mg kg−1). 3 I.v. administration of PAF induced a small accumulation of 111indium‐labelled neutrophils within the pulmonary circulation which could be greatly potentiated by pretreatment of the animals with l‐NAME. In contrast, thrombin administration did not cause significant accumulation of 11indium‐labelled erythrocytes in the pulmonary circulation of anaesthetized rabbits. 4 Intracarotid (i.c.) administration of thrombin induced a marked accumulation of radiolabelled platelets within the cranial vasculature which was not potentiated by the prior administration of l‐NAME (at either 10 mg kg−1 or 100 mg kg−1). 5 These results suggest that endogenous NO may regulate platelet and polymorphonuclear leukocyte activation within the pulmonary but not the cerebral circulation of rabbits.