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It is fitting that the 100th anniversary of the Handbook of Experimental Pharmacology celebrates not only its founding but also the founding of experimental pharmacology as both had their beginnings in Germany. Founded in 1919 by Arthur Heffter (1859-1925) as the "Handbuch der Experimentellen Pharmakologie" and renamed to its current title in 1937, the Handbook has continued to capture the emergence and developments of experimental pharmacology since the initial systematic work of Rudolf Buchheim and his student Oswald Schmiedeberg. Heffter, the first Chairman of the German Society of Pharmacology, was also responsible for isolating mescaline as the active psychedelic component from the peyote cactus, thereby initiating a series of studies along with an Institute that, much like the Handbook and the discipline of pharmacology, continues to discover and disseminate new findings to this day. These early endeavors to establish pharmacology as a viable and valuable contributor to the medical sciences met with considerable resistance and challenges. However, the persistence and dedication of these early pharmacologists placed pharmacology on a firm foundation from which to spread this discipline globally, leading ultimately to our current understanding of the principles of drug action and with an impact likely unanticipated by these founding scientists. Summarizing the beginnings of these efforts and their early spread to other countries provides an appropriate context in which to document the many contributions pharmacological research has made over the past 100 years and provide an opportunity to anticipate expectations around its future developments.

Paradoxical pharmacology is a term first suggested by Richard Bond to refer to intriguing observations that chronic use of some drug types can have the opposite biological effect(s) to those seen following acute administration of the same drug. A good example of 'paradoxical pharmacology' is the research Richard has pioneered showing that whereas acute administration of β-blockers is contraindicated in the treatment of asthma, chronic use of certain β-blockers can have therapeutic benefit. It would appear that those β-blockers that can act as inverse agonists at the β2 receptor particularly show this paradoxical effect and the findings of Richard's research not only challenge the dogma of the treatment of asthma but also challenge many of the pharmacological principles of ligand/receptor interactions established by Sir James Black and others. In this paper, I discuss Richard's efforts to evaluate the chronic effects of β-blockers in the airways and how this research caught the imagination of Sir James Black., (Copyright © 2011. Published by Elsevier Ltd.)

Abstract: The manifestation of platelet ‘satallitism’ around neutrophils in whole blood is a long acknowledged phenomenon [1]. Circulating platelet–neutrophil complexes (PNC) occur in a diverse range of inflammatory disorders and infections that affect numerous organs of the body. Animal models have revealed that the formation of PNC is required for the recruitment of neutrophils to inflamed tissue, since platelets ‘prime’ neutrophils for efficient adhesion to vascular endothelium via the up-regulation of integrins and enhanced responsiveness to chemokines (Fig. 1). Perhaps surprisingly, the surface contact between platelets and neutrophils additionally enhances other neutrophil functions, such as chemotaxis that is required for migration into tissues, trans-cellular production of eicosanoids, phagocytosis and trapping of pathogens, increased respiratory burst leading to the production of reactive oxygen species (ROS), and modulation of neutrophil apoptosis (Fig. 1). Platelet P-selectin appears to have a particular role in enhancing the majority of these activities, and the influence of platelet P-selectin is not therefore confined to the initial rolling events in the process of neutrophil extravasation. [Copyright &y& Elsevier]

Phosphodiesterases are a diverse family of enzymes that hydrolyse cyclic nucleotides and thus play a key role in regulating intracellular levels of the second messengers cAMP and cGMP, and hence cell function. Theophylline and papaverine have historically been used therapeutically and are known to be weak inhibitors of PDE, but to what extent this contributed toward their clinical efficacy was poorly defined. However, the discovery of 11 isoenzyme families and our increased understanding of their function at the cell and molecular level provides an impetus for the development of isoenzyme selective inhibitors for the treatment of various diseases. This review focuses on the development of PDE3 inhibitors for congestive heart failure, PDE4 inhibitors for inflammatory airways disease and most successfully, PDE5 inhibitors for erectile dysfunctionBritish Journal of Pharmacology (2006) 147, S252–S257. doi:10.1038/sj.bjp.0706495 [ABSTRACT FROM AUTHOR]

Proteinase-activated receptors (PARs) are novel G-protein-coupled receptors activated by serine and other proteinases to induce changes in cellular function. There is extensive evidence that PARs are expressed in the airways in a variety of cell types that are relevant to inflammatory lung diseases, and that activation of these receptors might be linked to significant pathological changes. Thus, PARs are exciting new targets in lung disease research. However, much of the data to date has come from in vitro studies using limited pharmacological tools, and considerably more needs to be known about the functions of this family of receptors in the lung before their potential as drug targets can be established. [Copyright &y& Elsevier]

Presents information on a study about United Kingdom universities that are offering Bachelor of Sciences (BSc) pharmacology courses. Course content, laboratory-practical content and project or dissertation requirements; Issues that was considered in conducting the study; Discussion of the result.

Hypersensitivity of the `cough receptors'' is one of the primary causes of uncontrollable and nonproductive cough. These receptors are therefore the logical targets in developing antitussive therapeutics. The articles in this section focus primarily on the types of lung afferents mediating the cough reflexes and the mechanisms involved in regulating the activity and sensitivity of these afferents. Several major issues have been discussed in these presentations, including the pharmacologic, physiologic and neurochemical characteristics of the cough receptors; the effect of phenotypic switch of the rapidly adapting receptors (RARs) during chronic airway infection; the interaction between RARs and C-fiber afferents both at the receptor level and in the centrally mediated reflex pathway; and the cellular mechanisms and ion channel species involved in the hypersensitivity of the cough receptors. A number of important questions have emerged from these investigations. Answers to these questions should further advance our understanding of the peripheral mechanisms of cough reflexes. [Copyright &y& Elsevier]

Background The dual PDE3/4 inhibitor RPL 554 causes bronchodilation in patients with asthma or COPD and synergistically interacts with muscarinic receptor antagonists in relaxing human isolated bronchi in acute experimental settings. In the present study we investigated the long-lasting interaction between RPL554 and glycopyrronium by testing these drugs for their ability to relax both medium and small human isolated bronchi. Methods The relaxant effect and duration of action of RPL554 and glycopyrronium, alone, or in combination, were studied on the contractile tone induced by electrical field stimulation (EFS) or carbachol in medium and small human isolated bronchi. Relaxation was expressed as percentage of maximal response and synergy analyzed by Bliss Independence theory. Results Low concentrations of RPL554 and glycopyrronium induced maximal relaxation of medium bronchi at 160 ± 20 min and 50 ± 10 min, respectively, an effect detectable for at least 4 h. Maximal synergy was observed at ≃2 hrs (−71.4 ± 5.1%), and the combination extended the relaxation to at least 6 hrs, when the contractile tone was −41.2 ± 8.5% of the control responses. The combination induced the greatest effectiveness for EFS at 3 Hz and low-to-middle concentrations also produced significant synergism on small airways (21.1 ± 4.0%,P < 0.05), compared with the additive response. The combination induced lumen area enhancement of 69.1 ± 2.4% (P < 0.05), compared with the additive response (51.0 ± 5.4%). Conclusions RPL554 and glycopyrronium demonstrated a synergistic interaction in relaxing both human medium and small isolated bronchi, in terms of peak relaxation and an extended duration of action, suggesting that this combination may have a beneficial role in the treatment of asthma or COPD. [ABSTRACT FROM AUTHOR]

Long-acting muscarinic receptor antagonists (LAMAs) and long-acting β 2 -adrenoceptor agonists (LABAs) cause airway smooth muscle (ASM) relaxation via different signal transduction pathways, but there are limited data concerning the interaction between these two drug classes on human bronchi. The aim of this study was to investigate the potential synergistic interaction between aclidinium bromide and formoterol fumarate on the relaxation of human ASM. We evaluated the influence of aclidinium bromide and formoterol fumarate on the contractile response induced by acetylcholine or electrical field stimulation (EFS) on human isolated airways (segmental bronchi and bronchioles). We analyzed the potential synergistic interaction between the compounds when administered in combination by using Bliss independence (BI) theory. Both aclidinium bromide and formoterol fumarate completely relaxed segmental bronchi pre-contracted with acetylcholine ( E max : 97.5±2.6% and 96.4±1.1%; pEC 50 8.5±0.1 and 8.8±0.1; respectively). Formoterol fumarate, but not aclidinium bromide, abolished the contraction induced by acetylcholine in bronchioles ( E max : 68.1±4.5% and 99.0±5.6%; pEC 50 7.9±0.3 and 8.4±0.3; respectively). The BI analysis indicated synergistic interaction at low concentrations in segmental bronchi (+18.4±2.7%; P <0.05 versus expected effect) and from low to high concentrations in bronchioles (+19.7±0.9%; P <0.05 versus expected effect). Low concentrations of both drugs produced a synergistic relaxant interaction on isolated bronchi stimulated with EFS that was sustained for 6 h post-treatment (+55.1±9.4%; P <0.05 versus expected effect). These results suggest that combining aclidinium bromide plus formoterol fumarate provides synergistic benefit on ASM relaxation of both medium and small human airways, which may have major implications for the use of this combination in the clinic. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) and type 2 diabetes mellitus (T2DM) often coexist. The mechanistic links between these two diseases are complex, multifactorial, and not entirely understood, but they can influence the approach to treatment. Understanding whether COPD comes first followed by T2DM or vice versa, or whether the two diseases develop simultaneously due to common underlying mechanisms, is important for the development of novel therapeutic approaches to these two important diseases. In this review, we discuss the potential links between COPD and T2DM and pharmacological approaches that might target these links. [ABSTRACT FROM AUTHOR]

Aims Bacterial lipopolysaccharide (LPS) can induce bronchial hyperresponsiveness (BHR), but the underlying mechanisms remain to be determined. Here, the possible contribution of sensory nerves to LPS-induced BHR was examined in human isolated bronchi to pharmacologically identify the mechanisms underlying this phenomenon. Main methods Human isolated bronchial tone was induced by electrical field stimulation (EFS). The responses of airways to LPS, with or without capsaicin desensitization or thiorphan treatment were studied and the transient receptor potential vanilloid type 1 (TRPV1) expression was assessed. We performed similar experiments in the presence of a TRPV1 or a neurokinin (NK) 2 receptor antagonist using SB366791 and GR159897, respectively. Key findings LPS increased (≃ 2.3-fold, P < 0.001) the contraction induced by EFS, compared to control tissues. Acute administration of capsaicin enhanced (≃ 2.3-fold, P < 0.001) the EFS-mediated contraction, but did not potentiate the effect of LPS. Thiorphan increased (≃ 1.3-fold, P < 0.05) the contractile response of LPS treated tissues and, at lower frequencies, it enhanced (≃ 1.7-fold, P < 0.001) the capsaicin-induced contraction. In capsaicin-desensitized bronchi, LPS did not modify ( P > 0.05) the EFS contractile response, nor after treatment with thiorphan. Capsaicin desensitization reduced (≃ 0.4-fold, P < 0.001) the LPS-induced BHR. SB366791 and GR159897 prevented the LPS-induced BHR and the release of NKA. LPS increased (+ 85.3 ± 9.5%, P < 0.01) the surface membrane expression of TRPV1 in parasympathetic ganglia. Significance Our results demonstrate the involvement of capsaicin-sensitive sensory nerves and neutral endopeptidases in LPS-induced BHR of the human bronchi, associated with an upregulation of TRPV1 and release of NKA. [ABSTRACT FROM AUTHOR]

Cough is an indispensable defensive reflex. Although generally beneficial, cough is also a common symptom of diseases such as asthma, chronic obstructive pulmonary disease (COPD) and lung cancer. Cough remains a major unmet medical need and, although the centrally acting opioids have remained the antitussive drug of choice for decades, such opioids possess many unwanted side-effects. However, new research into the behaviour of airway sensory nerves has provided greater insight into the mechanisms of cough and new avenues for the discovery of novel non-opioid antitussive drugs. In this article, the pathophysiological mechanisms of cough and the implications of this research for the development of novel antitussive drugs will be discussed. A poster depicting the pharmacology of cough is available online and in print as to this article. [Copyright &y& Elsevier]