Allergic rhinitis: meaningful and less meaningful combination treatments including reminiscences.

Allergic rhinitis (AR) results from a complex allergen-driven mucosal inflammation in the nasal cavity. Current guideline-based therapy for allergic rhinitis include oral and nasal antihistamines, topical and systemic glucocorticoids, decongestants, antimuscarinic agents, mast cell stabilizing drugs, leukotriene-receptor antagonists, and others. In spite of guideline recommendations, most patients are using multiple therapies in an attempt to achieve symptom control. Therefore, more effective therapies for the management of AR are clearly required. Recently, a novel fixed dose combination containing azelastine and fluticasone propionate has successfully been introduced. At present, it represents the only meaningful topical drug combination. Perhaps, it will be followed by others.

Soft drugs for future treatment of chronic obstructive pulmonary disease (COPD).

COPD is a major cause of chronic morbidity and mortality worldwide. Current treatment is aimed at symptomatic relief. In contrast to bronchial asthma, glucocorticoid treatment strategies have proved disappointing. Consequently, there is a need to develop more effective therapeutic strategies to replace present treatment. Advances in understanding the pathogenesis of COPD have the potential for identifying new therapeutic targets. Additionally, forgotten old compounds might undergo a revival by means of novel pharmaceutical technology.

Current animal models of bronchial asthma.

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.

Can corticosteroids be beaten in future asthma therapy?

Despite the enormous therapeutic advance, there is a general trend towards increasing morbidity and mortality due to asthma, which suggests that there is a need for new and improved treatments. The past decade was determined by the so-called "new biology" that identified and cloned almost all receptors and ion channels. This scientific revolution should lead to a more rapid identification of novel targets for major diseases and processes like high throughput screening and combinatorial chemistry should have improved and fastened the development of new drugs. Interestingly, exactly the opposite has happened. With the exception of leukotriene receptor antagonists and some monoclonal antibodies, no new developments have been introduced into asthma therapy during the last decade. The most promising approach is still to find drugs like corticosteroids with multiple functions. However, there is no evidence at the very moment that corticosteroids can be beaten in the next ten years. Therefore, our task is to improve the corticosteroids and make therapy with them even safer. The so-called soft-steroids such as loteprednol and etiprednol belong to the future promising therapeutically effective and safe treatments of allergic disorders.

Possibilities in improvement of glucocorticoid treatments in asthma with special reference to loteprednol etabonate.

Allergic conditions contribute significantly to the burden of chronic disease in the industrialized world. The increasing prevalence has lead research into the discovery and development of various new therapeutic strategies. Despite considerable efforts of the pharmaceutical industry, the leukotriene antagonists were the only new class of asthma treatments to be licensed in the past 30 years. Topical glucocorticoids (GCs) are the most potent and effective therapy for treating allergic diseases. However, their use is limited by diverse undesired effects. Changes in pharmacokinetic parameters of GCs may be an interesting and promising approach to improve efficacy and safety of inhaled GCs. Loteprednol etabonate has been developed on the basis of the retrometabolic drug design. In animal studies, it has been demonstrated to have long-lasting anti-allergic (anti-asthmatic) effects without influencing the hypothalamic-pituitary axis (HPA). This soft steroid is now in phase III of the clinical development. Recently, loteprednol has been proven to be effective in the management of allergic rhinitis (400 microg once daily). No suppression of HPA was observed at clinically effective and higher doses. In conclusion, loteprednol as the first representative of soft steroids elicits marked anti-inflammatory effects, but has no impact on endocrine responses. It may represent a promising new therapy in the treatment of allergic rhinitis and asthma.

Asthma therapy in the new millennium.

Bronchial asthma is one of the most common chronic diseases in modern society and yet, despite the availability of highly effective drugs, there is increasing evidence to suggest that its incidence is increasing. It is a general health problem in several industrialised countries and will remain one for the next decades. With regard to asthma pathogenesis, our understanding has increased tremendously over the last two decades. Therefore, the potential for specific targeted and constructed therapies has become evident. Monoclonal antibodies to IgE, soluble receptors or antibodies to certain cytokines such as IL-4 and IL-5 are being investigated as possible treatments for asthma. Besides the already known receptor antagonists, new compounds directed to novel receptor types (e.g. cytokine, adenosine, adhesion molecules, etc.) are now under development. New targets in the cytosol will come into focus. Preliminary studies of selective phosphodiesterase (PDE) inhibitors in asthmatic patients have been encouraging. It is also very likely that the use of glucocorticoids cannot be excluded from therapy. However, we should generate new glucocorticoids with less side-effects, probably by using the so-called retrometabolic drug design. The first representative of this new steroid class, loteprednol is already approved for the therapy of certain allergic disorders. Because asthma is a disease of many different gene polymorphisms, gene therapy seems to be of low success at present. Alternatively, antisense oligonucleotides could be used. Future developments may also include strategies targeting the remodeling of structural elements of the airways. Today's intensive search for new treatments should ensure a greater diversity of therapeutic possibilities for the management of asthma in the next millennium.

Drug therapy in asthma bronchiale in the new millennium.

Asthma bronchiale represents a major health issue in industrialized countries and will likely remain so for decades. The drug treatment of asthma demonstrates certain peculiarities: revolutionary new drug introductions happen almost each quarter century. With improved understanding of asthma pathogenesis and drug metabolism, the potential for specific targeted and constructed therapies has become evident. Monoclonal antibodies to IgE and certain cytokines such IL-4 and IL-5 are being investigated as possible treatments for asthma. Similarly, preliminary studies of selective phosphodiesterase inhibitors in asthmatic patients have been encouraging. Other potential therapies include for example inhibitors of cytokine synthesis, promoters of Th2-Th1 switch, adenosine receptor agonists or antagonists, etc.. A new way is represented by a modified retrometabolic drug design resulting in so-called soft drugs. The first representative of this new drug class is loteprednol etabote (LE), a non-fluorinated glucocorticoid approved for the allergic ophthalmological indications and now in clinical trial for the treatment of allergic airway diseases. Today's intensive search for new treatments should ensure a greater diversity of therapeutic possibilities for the management of asthma in the new millennium.

Therapy of bronchial asthma with adenosine receptor agonists or antagonists.

Adenosine is an endogenous nucleoside that is released under pathological conditions and interacts with four G-protein-coupled receptor subtypes. These receptors are widely distributed throughout the body. They are involved in many central and peripheral processes, including immunological and inflammatory responses. In inflammatory and asthmatic conditions, the extracellular concentration of adenosine increases in the airway tissue. It enhances mast cell degranulation and bronchoconstriction, but may also inhibit eosinophil or lymphocyte function or modulate reactive oxygen species generation in neutrophils. Despite a large number of studies clearly indicating the effects of adenosine in vitro, many aspects of the mechanisms involved in the adenosine-mediated responses are still unclear, and our knowledge is limited in understanding the complex multifactorial interactions occurring in the whole body. The discovery of adenosine receptor compounds acting with increasing selectivity will bring new approaches to the use of adenosine receptor agonists and antagonists and may clarify some of the current uncertainties. On the basis of our present knowledge, the development of adenosine A(2A)- or (A3)-receptor agonists as antiinflammatory agents or A(2B)-receptor antagonists as inhibitors of mast cell degranulation for the treatment of asthma holds promise.

Animal models of chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD), which encompasses both chronic bronchitis and emphysema, is one of the most common respiratory conditions of adults in the developed world. Despite the high prevalence and enormous cost to healthcare and society, COPD has received scant attention in comparison to other respiratory conditions such as asthma and lung cancer. It is often thought of as a self-inflicted disease. But not all people who smoke develop COPD and not all patients with COPD are smokers. The causes of COPD are different. Its pathogenesis is complex. There are very few effective treatments. Therefore, there is an urgent need to improve present therapy by drugs with new modes of actions. In contrast to many human diseases, chronic bronchitis and emphysema occur seldom in the animal world. Therefore, we have to mimic some characteristic features of these diseases in animals. For this reason, a wide variety of animal models have been developed and are employed in the search for new chemical entities for the treatment of COPD. In the present paper, the experimental models of COPD are critically reviewed.

Animal models of allergic rhinitis.

Actively sensitized Brown Norway rats and guinea pig are useful species for studying drug effects on symptoms of experimental rhinitis. Even if not all symptoms of human rhinitis can be induced and detected in the same animal species, the predictablity of methods generally used is well acceptable. In the present review, advantages and disadvantages of experimental methods of rhinitis will be discussed.

Animal models of bronchial asthma.

Due to the continuous increase in prevalence and morbidity in asthma, there is an urgent need to improve present therapy by drugs with new modes of actions. In contrast to many human diseases, allergic asthma does not occur in the animal world. Therefore, we have to mimic some characteristic feature of asthma in animals. For this reason, a wide variety of animal models have been developed and are employed in the search for new chemical entities for asthma therapy. In the present paper, the experimental models of the most characteristic asthma symptoms are critically reviewed.

Loteprednol etabonate: a soft steroid for the treatment of allergic diseases of the airways.

There are several approaches for developing new antiallergic/antiasthmatic agents. One of them is the improvement of an existing class of effective drug classes. Due to some undesired effects of intranasal or inhaled corticosteroids, there is a need for better tolerated corticosteroids. Loteprednol etabonate belongs to the so-called class of soft steroids because it is metabolized by a one-step reaction (hydrolysis) without using the cytochrome P450 monooxygenase system. In in vitro investigations using human cells, loteprednol inhibited the release of proinflammatory cytokines (e.g., TNF-alpha, GM-CSF, IL-4, IL-5) according to its relative binding potency to the glucocorticoid receptor. In in vivo animal studies, loteprednol effectively inhibited allergically induced vascular leakage in the nasal cavity of actively sensitized Brown Norway rats and rhinorrhea in actively sensitized domestic pigs following nasal challenge. In several models of allergic asthma, it was clearly demonstrated that loteprednol was able to suppress the allergically induced late phase eosinophilia in mice, rats and guinea pigs. After intrapulmonary administration of loteprednol, only a slight, statistically nonsignificant reduction in thymus weight was observed in a dose range far less than the therapeutically relevant doses. Its therapeutic ratio is clearly superior to those of beclomethasone and budesonide. Loteprednol is a safe steroid with an extremely wide range between therapeutic and side effect inducing doses. Its elimination profile, its pronounced binding to plasma protein and erythrocytes and the low oral bioavailability makes this drug highly suitable for nasal or pulmonary use.

New N-(pyridin-4-yl)-(indol-3-yl)acetamides and propanamides as antiallergic agents.

A series of new N-(pyridin-4-yl)-(indol-3-yl)alkylamides 44-84 has been prepared in the search of novel antiallergic compounds. Synthesis of the desired ethyl (2-methyindol-3-yl)acetates 1-4 was achieved by indolization under Fischer conditions; Japp-Klingemann method followed by 2-decarboxylation afforded the ethyl (indol-3-yl)alkanoates 17-25. Amidification was successfully carried out by condensation of the corresponding acids or their N-aryl(methyl) derivatives with 4-aminopyridine promoted by 2-chloro-1-methylpyridinium iodide. Efforts to improve the antiallergic potency of the title series by variation of the indole substituents (R1, R2, R) and the length of the alkanoic chain (n = 1, 2, 3) led to the selection of N-(pyridin-4-yl)-[1-(4-fluorobenzyl)indol-3-yl]acetamide 45, out of 41 compounds. This amide was 406-fold more potent than astemizole in the ovalbumin-induced histamine release assay, using guinea pig peritoneal mast cells, with an IC50 = 0.016 microM. Its inhibitory activity in IL-4 production test from Th-2 cells was identical to that of the reference histamine antagonist (IC50 = 8.0 microM) and twice higher in IL-5 assay: IC50 = 1.5 and 3.3 microM, respectively. In vivo antiallergic activity evaluation confirmed efficiency of 45 in sensitized guinea pig late phase eosinophilia inhibition, after parenteral and oral administration at 5 and 30 mg/kg, respectively. Its efficiency in inhibition of microvascular permeability was assessed in two rhinitis models; ovalbumin and capsaicin-induced rhinorrhea could be prevented after topical application of submicromolar concentrations of 45 (IC50 = 0.25 and 0.30 microM); and it also exerted significant inhibitory effect in the first test after iv and oral administration, with ID50 = 0.005 and 0.46 mg/kg.

Effects of a selective PDE4 inhibitor, D-22888, on human airways and eosinophils in vitro and late phase allergic pulmonary eosinophilia in guinea pigs.

The actions of a novel selective inhibitor of type 4 cyclic nucleotide phosphodiesterase (PDE4), D-22888, on human airway smooth muscle tone and human eosinophil respiratory burst in vitro and bronchoalveolar eosinophilia in allergen-challenged sensitized guinea pigs in vivo were assessed. D-22888 was a selective inhibitor of PDE4, exhibiting an IC50 against human neutrophil PDE4 of 0.15 microM, compared to IC 50 values of 4.4 microM and 1.1 microM for human platelet PDE3 and PDE5, respectively. D-22888 relaxed inherent tone in human bronchial rings in a concentration-dependent manner with an IC50 of 5.0 microM (geometric mean, 95% ci 3.0-8.4 microM) and also caused a concentration-dependent inhibition of opsonized zymosan-induced superoxide anion generation by human eosinophils with an IC50 of 3.1 microM (1.0-9.2 microM). Treatment of actively sensitized guinea pigs with single oral doses of D-22888 2 h before or 4 h after challenge reduced bronchoalveolar lavage (BAL) eosinophil numbers, 24 h after aerosol allergen challenge, by 48% and 73% at 10 mg/kg and 30 mg/kg, respectively, 2 h pre-challenge and 68% at 30 mg/kg 4 h post-challenge. Chronic twice-daily oral dosing with D-22888 for three days caused inhibition of 24 h post-challenge BAL eosinophilia, amounting to 88% at 30 mg/kg. These in vivo actions were comparable with those achieved with other selective PDE4 inhibitors and with the corticosteroid, dexamethasone. We conclude that D-22888 exerts actions on airway smooth muscle and eosinophil recruitment and activation that suggest that D-22888 may be a promising new drug for use in the treatment of allergic obstructive airways>> diseases such as bronchial asthma.

1,5-Disubstituted indazol-3-ols with anti-inflammatory activity.

A series of new indazol-3-ol derivatives was synthesized. Some of these compounds exhibit interesting anti-inflammatory activities in various models of inflammation. 5-Methoxy-1-[quinoline-2-yl-methoxy)-benzyl]-1H-indazol-3-ol (27) strongly inhibits the oxidation of arachidonic acid to 5-hydroperoxyeicosatetraenoic acid catalyzed by 5-lipoxygenase (IC50 = 44 nM). 27 also inhibits the contraction of sensitized guinea pig tracheal segments (IC50 = 2.9 microM). In guinea pigs treated with 27 (1 mg/kg i.p.) 2 h before antigen provocation, there was a marked inhibition (47%) of the antigen-induced airway eosinophilia. After topical application of 1 microgram/ear 27 inhibits the arachidonic acid induced mouse ear edema (41%).

The real gordian knot: racemic mixtures versus pure enantiomers.

Many drugs exist as asymmetric three-dimensional (chiral) molecules and will therefore have several stereoisomers. There are often pharmacodynamic, pharmacokinetic and/or toxicological differences between enantiomers. The choice between developing a racemate or single enantiomers depends on therapeutic advances and developmental costs involved. Regarding the target environment for drug intervention, even if natural physiological mediators are achiral, their receptors may demonstrate a preference for the (-)- or (+)-enantiomer of agonists or antagonists. It is also obvious that the majority of enzymes and channels are stereospecific, at least to a variable extent. From a pharmacokinetics point of view, chirality can have an influence on drug absorption, distribution, metabolism and elimination. With a few exceptions, toxicological differences between isomers of known drugs are less dramatic than thought to be and only seldom substantiate the necessity of a racemic switch. The pharmaceutical industry is currently very interested in the so-called "racemic switch." Before proceeding to a racemic switch it is necessary to determine if 1) it is chemically feasible to produce a single enantiomer; 2) a clinical advantage is obtainable through a racemic switch; and 3) a marketing advantage is obtainable. The real goal of a racemic switch should be the rational development of compounds that are profitable for the company and--first of all--beneficial for the patient.

Quantification of rigidity and tremor activity in rats by using a new device and its validation by different classes of drugs.

Subjective techniques employed for measuring skeletal muscle tone and tremor, leading symptoms of several diseases, have certain limitations. Objective methods are usually more sensitive and accurate. The equipment developed by the authors allows the objective and rapid measurement of experimentally induced rigidity and tremor in the same small laboratory animal (rat). The present method considerably reduces the number of animals needed to investigate the activity of drugs, especially when compounds should be screened. Due to the greater sensitivity of the equipment, doses of reserpine and oxotremorine which do not cause any postural, autonomic or parasympathetic symptoms can be used to induce muscular rigidity and tremor. Therefore, not only the number of animals but also their stress can be reduced. It was possible to differentiate the oxotremorine-induced tremor from the spontaneous motor activity and to determine qualitative differences in tremor caused by antitremor agents. A number of clinically effective muscle relaxants and antiparkinsonian drugs were examined in this model in order to determine its utility.

Experimental studies on acute and chronic action of azelastine on nasal mucosa in guinea pigs, rats and dogs.

Azelastine (CAS 37932-96-0) nasal spray (Allergodil, Rhinolast, Astelin) was investigated in acute experiments in guinea pigs and after a 26-week local application period with daily repeated administration for effects on ciliary beat activity (acute experiments) and morphology of nasal mucosa. The commercially available spray did not inhibit ciliary beat activity in guinea pigs nor did it cause any inflammatory or atrophic changes after 26-week daily local application on nasal mucosa in rats and dogs.