Current Pharmaceutical Design - Volume 12, Issue 25, 2006

Asthma bronchiale, affecting 155 millions people worldwide, has emerged as a major public health problem worldwide over the past 20 years. Although data indicate that current asthma therapies led to limited decreases in death rates, it continues to be a significant health care problem. As we head into the 21st century doctors have a vast arsenal of drugs and treatments at their disposal allowing asthmatics to lead normal fulfilled lives. Can we improve asthma therapy available at present? Indeed, despite a large number of drugs available to clinicians, up to 15% of patients suffer from uncontrollable disease symptoms, increasing the demand for novel therapies that possess new modes of action. Despite considerable efforts by the pharmaceutical industry, it has been difficult to develop novel therapeutic agents; the leukotrien modifiers are the only new class of asthma treatments that has been approved. Fortunately, omelizumab (an anti-IgE) has very recently been introduced and appears to be effective and an addition to the currently available therapeutics. In addition, there are numerous therapies in clinical development that combat the inflammation found in asthma. This issue of “Current Pharmaceutical Design” contains the text of nine invited review articles. The selection of topics and authors was made with the intention to cover various areas of ongoing drug development efforts for asthma therapy. Asthma is not a natural disease in the animal kingdom. Debates come up from time to time whether mice can develop asthma or not. Therefore the variety of artificially established animal models is quite wide. Animal experimentation has been indispensable not only in establishing or verifying the safety and the effectiveness of a given drug candidate but animal models have been crucial in providing basic information about the physiological and pathological processes associated with the disease. Kurucz and Szelenyi [1] review the current state of the art of animal models used to investigate asthma. They analyse how these different models contributed to our understanding of the disease and how successfully they helped to recognize or to introduce new, more effective pharmacons that can be used for the treatment of asthma. Great variability in patient responses to current asthma therapy is observed in the clinic. Whereas, for example, a lot of patients respond well to steroid treatment, some patients are resistant to this kind of therapy. The review by Pahl et al. [2] deals with various aspects of genetic and genomic variability as one source for this observed variability. For many years phosphodiesterases (PDEs) attracted little attention in drug discovery efforts. However, the success of viagra and new generation PDE5 inhibitors reinforced interest in targeting other PDEs for chronic airway diseases. Meanwhile, PDE4 inhibitors such as roflumilast are close to market approval. Giembycz and Smith [3] review the literature of another phosphodiesterase isoenzyme (PDE7A) as a new drug candidate for asthma therapy. Folkerts and Nijkamp [4] will mainly deal with the possible therapeutic application of the NO concept. Such interventions might be targeted in various ways, e.g. by using selective reactive nitrogen- and oxygen-scavengers, selective NO donors and selective nitric oxide synthase inhibitors. The possible therapeutical opportunities are reviewed in this paper. Nitric oxide has already made it from the bench to the bedside, and it is likely that new developments in this area will drastically change respiratory medicine during the coming 5-10 years. Airway remodelling is one of the hallmarks of asthma pathogenesis. The article by Das et al. [5] will focus on this aspect. Since the pathological changes are thought to contribute to the clinical symptoms of the disease new targets may arise from these changes. It may be feasible to have therapeutics with disease modifying effects in chronic inflammatory diseases. Therefore, this raises the possibility of approaching asthma with the aim of developing disease modifying therapies. Inhaled corticosteroids still are the most effective treatment available for allergic airway diseases and are likely to remain the cornerstone of managing persistent asthma/allergic rhinitis in the foreseeable future. Bodor and Buchwald [6], with their article on the pharmacology of soft corticosteroids, highlight on a group of compounds showing better separation of local effects from systemic side effects. Soft corticosteroids are particularly well-suited for this purpose, and because of their promising airway activity. Asthma treatment guidelines advocate the use of long-acting β2-agonists (LABA) in addition to inhaled corticosteroids (ICS) in patients whose asthma is uncontrolled by ICS alone, thereby addressing two processes fundamental to asthma: bronchoconstriction and inflammation....

Human asthma is on the rise worldwide. The necessity to develop effective treatments against it requires an organized effort which covers every aspect of the disease from the pathological alterations via the genetic background to the use and development of active remedies. In these processes animal experiments have served an indispensable role. As asthma is not a natural disease in the animal kingdom the variety for artificially established animal models is quite wide. The possible selection ranges from the laboratory mouse to the horse, it includes ferret and sheep and even favorite pets such as cats and dogs. The large number of the models indicates that to some extent they might not be appropriate or it means that there is no generally accepted model of human asthma. Whatever the reason for this diversity animal models helped us to understand the detailed pathogenesis of some aspects of the disease, they helped us to develop compounds which are more active then previously used ones, and these models proved to us that human asthma is a unique, possibly species-specific disease the eradication of which requires a huge effort. This enormous task should include the collaboration of the clinical and basic research for the development of improved, advanced animal models, which in turn could strengthen our understanding about human asthma.

Patient response to asthma therapy is consistently observed to be heterogeneous. Pharmacogenomics is the study of inherited differences in interindividual drug disposition and effects, with the goal of selecting the optimal drug therapy and dosage for each patient. This review will cover selected examples of gene polymorphisms that influence the outcome of asthma therapy, and whole-genome expression studies using microarray technology that have shown tremendous potential for benefiting asthma pharmacogenomics. The utility of the mouse as an experimental system for pharmacogenomic discovery will also be discussed in the context of asthma therapy.

Over the last fifteen years there has been much excitement in the idea that targeting phosphodiesterase (PDE) 4 with small molecule inhibitors could lead to the discovery of novel, steroid-sparing compounds with utility in treating a multitude of diseases associated with chronic inflammation. However, dose-limiting side effects, of which nausea and vomiting are the most common are worrisome, have hampered their clinical development. Indeed, a fundamental obstacle that still is to be overcome by the pharmaceutical industry is to make compounds that dissociate beneficial from the adverse events. Unfortunately, both of these activities of PDE4 inhibitors represents an extension of their pharmacology and improving the therapeutic ratio has proved to be a major challenge. Several strategies have been considered, with some degree of success, but compounds with an optimal pharmacophore still have not been reported. An alternative approach to targeting PDE4 is to inhibit other cAMP PDE families that are also expressed in immune and pro-inflammatory cells in the hope that the beneficial activity can be retained at the expense of side effects. One such candidate is PDE7A. In this article we review the literature on PDE7A and explore the possibility that selective small molecule inhibitors of this enzyme family could provide a novel approach to alleviate the inflammation that is associated with many inflammatory diseases including asthma, chronic obstructive pulmonary disease, atopic dermatitis, psoriasis, lupus, rheumatoid arthritis and multiple sclerosis.

The discovery of the delicate role of endogenous nitric oxide in the homeostasis of various cellular functions and the dynamic behaviour of the airways, has led to a new, rapidly progressing area of physiological science, that has direct bearing for our understanding of multiple airway diseases. The potentially protective effects of nitric oxide include: neuromodulation by mediating inhibitory non-cholinergic nonadrenergic nerve activity; smooth muscle relaxation, attenuating airway hyperresponsiveness to bronchoconstrictor stimuli and immun-suppression. NO itself or SNO can be administerd directly to the airways, and the development of gene transfer therapy seems to become a realistic approach in the treatment of airway diseases. However, NO has also harmfull effects, especially when it interacts with other molecules. At present, there are novel opportunities to modulate nitric oxidesynthesis aimed to restore the balance between the protective and deleterious effects of nitric oxide. This is potentially beneficial in both airway and alveolar diseases. Such interventions might be targeted in various ways, e.g. by using selective reactive nitrogen- and oxygen- scavengers, selective NO donors and selective nitric oxide synthase inhibitors. The possible therapeutical opportunities are reviewed in this paper. Nitric oxide has already made it from the bench to the bedside, and it is likely that new developments in this area will drastically change respiratory medicine during the coming 5- 10 years.

Current asthma therapy is aimed at controlling disease symptoms. A subset of asthma patients remains symptomatic despite optimal therapy indicating that an unmet medical need exists for these patients. Innovative therapeutics are needed to treat the unmet need in asthma and biopharmaceutical approaches may provide an opportunity for identifying these agents. It is proposed that airway remodeling contributes to asthma symptoms and this feature of disease pathology may be a target for future therapies. The current review focuses on the contribution of one feature of airway remodeling, subepithelial fibrosis, towards disease and highlights some of the mechanisms that may contribute to this feature of airway remodeling. Further, some potential molecular targets are identified for consideration for therapeutic intervention.

Inhaled and intranasal corticosteroids (ICSs) still are the most effective treatment available for allergic airway diseases and are likely to remain the cornerstone of managing persistent asthma/allergic rhinitis in the foreseeable future. Even if the therapeutic index of this class increased significantly with the introduction of newer corticosteroids, and even if new therapeutic potentials are beginning to emerge with our increasing understanding of the mechanisms of asthma, chronic obstructive pulmonary disease, and rhinitis, corticosteroid development still remains a very important field for drug designers. After a brief review of issues related to the structure-activity relationships of glucocorticoids and the main determinants of their receptor-binding affinity at the glucocorticoid receptor, the main focus of the present article will be on the development of soft corticosteroids, as they are particularly well suited to separate local activity from systemic side effects, which still is an important issue for ICSs. Design consideration required in the search for safe and effective soft drugs on one hand, and safe and effective ICSs on the other hand, will be briefly discussed and illustrated with a number of cases, in particular, with that of loteprednol etabonate and etiprednol dicloacetate, soft corticosteroids that are being developed for a full spectrum of therapeutic applications including asthma and allergic rhinitis.

Asthma treatment guidelines advocate the use of long-acting β2-agonists (LABA) in addition to inhaled corticosteroids (ICS) in patients whose asthma is uncontrolled by ICS alone, thereby addressing two processes fundamental to asthma: bronchoconstriction and inflammation. Superior control - including a reduction in severe exacerbations - of asthma and COPD by ICS/LABA combination therapy has been demonstrated. Results from clinical studies suggest additive and potentially synergistic effects when the two agents are used in combination. No new safety-related issues have been identified with ICS/LABA compared with the monocomponents. The exact mechanisms for the enhanced efficacy of ICS/LABA combinations are under investigation but likely include drug interactions at the receptor level and interwoven signalling pathways, which may result in improved function of ®2- adrenoceptors and steroid receptors. Data from preclinical studies provide evidence of additive, compensatory, complementary and synergistic effects of ICS and LABA in the control of inflammation and airway and lung remodelling. These effects may contribute to the improved efficacy seen when treating asthma and COPD with ICS/LABA combinations in clinical studies. Two ICS/LABA combination products are available: budesonide/formoterol (Symbicort®) and salmeterol/fluticasone propionate (SeretideTM). An ICS/LABA combination in a single inhaler represent safe, effective and convenient treatment options for the management of patients with asthma and COPD. Clinical results also suggest that adjustable dosing with budesonide/formoterol provides better asthma control than fixed dosing. Further elucidation of the underlying mechanisms responsible for this superior disease control is needed.

The severity and incidence of asthma has dramatically increased in the developed nations over the last decades. Although the reason for this development is unknown, epidemiological studies and experimental data have lead to the suggestion that this phenomenon is associated with the decline of infectious diseases, which induce T helper 1 and/or T regulatory responses. Supporting this view are recent publications showing that animals can be protected from developing asthma by using different immune stimulatory strategies. One approach is based on vaccinations using live or killed bacteria or their components, CpG-ODNs or DNA vaccination, which all induce allergen-specific or unspecific Th1 responses. Th1 responses lead to the production of IFN-γ, IL-12, IL-18 and IL-23, thereby inhibiting Th2 responses and thus the development of asthma. A further strategy both for the prevention and therapy of asthma is the induction of Tr cells. Tr cells have also been shown to suppress allergic Th2 responses, however, in contrast to Th1 cells through a cell/cell contact mediated mechanism or by the secretion of the anti-inflammatory cytokines IL-10 and/or TGF-β. Furthermore, there is growing information on how to induce Tr cells both in animals and humans. Here we review the data showing that animals can be protected from developing asthma by immune stimulation leading to Th1 or Tr responses. Possible future human use and safety of the described strategies are also discussed.

There is considerable evidence that T-helper 2 (Th2) cells play a central role in the pathogenesis of allergic diseases such as bronchial asthma, hay fever or food allergy. The differentiation of naïve T cells into Th2 cells producing a specific pattern of cytokines is tightly controlled and regulated by transcription factors. Thus down-regulation of mRNAlevels of a single transcription factor leads to a “knock-down” of several mediators simultaneously, representing an advantage compared to earlier approaches involving down-regulation of one intercellular inflammatory mediator, which is unlikely to influence all pathophysiological aspects of the disease. We review the impact of specific and master transcription factors involved in Th2 cell commitment and evaluate approaches for the down-regulation of these proteins by degradation of their mRNA using nucleic-acid based technologies including antisense oligonucleotides, ribozymes, DNAzymes, decoys oligonucleotides and RNA interference.