Asthma inhibition

Inhaled corticosteroids are the preferred long-term control therapy for persistent asthma in all patients because of their potency and consistent effectiveness they are also the only therapy shown to reduce the risk of death from asthma. Comparative doses are included in Table 80-3. Most patients with moderate disease can be controlled with twice-daily dosing some products have once-daily dosing indications. Patients with more severe disease require multiple daily dosing. Because the inflammatory response of asthma inhibits steroid receptor binding, patients should be started on higher and more frequent doses and then tapered down once control has been achieved. The response to inhaled corticosteroids is delayed symptoms improve in most patients within the first 1 to 2 weeks and reach maximum improvement in 4 to 8 weeks. Maximum improvement in FEVj and PEF rates may require 3 to 6 weeks. 

One of the goals of synthetic medicinal chemistry is to design potent inilibitors of clinically important proteases. Elastase inhibitors may be useful for treatment of emphysema, pancreatitis, and arthritis,a/b while inhibitors of the angiotensinogen-converting enzyme or of renin (Box 22-D) can help control blood pressure. Inhibition of thrombin, factor Xa, or other blood clotting factors (Fig. 12-17) may prevent blood clots and inhibition of the cytosolic tryptase may provide a new treatment for asthma. Inhibition of the cysteine protease cathepsin K may help combat osteoporosis and inhibition of cysteine proteases of corona viruses may fight the common cold. Cysteine proteases of schistosomes are also targets for protease inhibitors.c... 

Juergens, U. R., Stober, M., Schmidt-Schilling, L., Kleuver, T., Vetter, H. 1998c. Antiin ammatory effects of eucalyptol (1,8-cineole) in bronchial asthma Inhibition of arachidonic acid metabolism in human blood monocytes ex vivo. Eur. J. Med. Res. 3 407-412. 

Most of the drugs such as epinephrine and albuterol used to treat asthma attacks are bronchodilators—substances that expand the bronchial passages Newer drugs are designed to either inhibit the enzyme 5 lipoxygenase which acts on arachidomc acid m the first stage of leukotriene biosynthesis or to block leukotriene receptors... 

Theophylline s predominant mode of action appears to be bronchocHlation. However, it has also been shown that prophylactic acHriinistration of theophylline provides some protection from asthma attacks and suppresses the late-phase response (67,68). Some researchers beHeve that at therapeutic semm concentrations theophylline may inhibit the development of airway inflammation (69). There are conflicting reports on the effect of theophylline on allergen-induced bronchial hyperresponsiveness some clinical stucHes report a reduction in hyper-responsiveness, others do not (69,70). Theophylline clearly does not reverse the general bronchial hyperresponsiveness over the course of long-term therapy (71). Because of the relationship between... 

The action of epinephrine and related agents forms the basis of therapeutic control of smooth muscle contraction. Breathing disorders, including asthma and various allergies, can result from excessive contraction of bronchial smooth muscle tissue. Treatment with epinephrine, whether by tablets or aerosol inhalation, inhibits MLCK and relaxes bronchial muscle tissue. More specific bronchodilators, such as albuterol (see figure), act more selec-... 

Allergy. Figure 3 Leukotriene LT receptor antagonists inhibit the response of target cells to leukotrienes and relieve symptoms of allergic asthma bronchiale. 

Aspirin sensitive asthma, affecting about 10% of all asthmatics, is a nonallergic response to aspirin and other agents that inhibit cyclooxygenase-1. Mechanistically, the most likely reasons are lack of bronchoprotective prostaglandin E2 and shunting of arachidonic acid into the leukotriene pathway. 

Triggering of asthma attacks in asthmatics. This side effect is a pseudo-allergic reaction where COX-inhibition increases the availability of substrates for lipoxygenase, which are converted to broncho-constrictive leukotriens... 

The term refers to a distinct clinical syndrome characterized by aggressive and continuous inflammatory disease of the airways with chronic eosinophilic rhinosinus-itis, asthma and often nasal polyposis [6-8]. Aspirin and other NSAIDs that inhibit COX-1 exacerbate the condition, precipitating violent asthmatics attacks. This is a hallmark of the syndrome. The prevalence of aspirin hypersensitivity in the general population ranges from 0.6 to 2.5%, but is much more frequent in adult asthmatic subjects where it reaches 10-15%, although it is often underdiagnosed. 

A non-allergic mechanism imderlying precipitation of asthmatic attacks by aspirin in hypersensitive patients was proposed over 30 years ago [4]. It was founded on pharmacological inhibition of COX of arachidonic acid and explained a cross-reactivity between different NSAIDs varying in chemical structure. This COX theory was confirmed by several studies [11] and was further refined following discovery of the second COX isoenzyme - COX-2. At least two COX isoenzymes, COX-1 and COX-2, are coded by separate genes. Their role in inflammation, asthma and anaphylaxis has been reviewed previously [12]. 

Once diagnosed, patients with AlA should avoid aspirin and any other NSAIDs strongly inhibiting COX-1 their education is of utmost importance. They should receive a list of contraindicated and well-tolerated analgesics (table 2). Even topical administration (intravascular or by iontophoresis) of a NSAID may cause an asthma attack and should be avoided. 

Szczeklik A, Gryglewski RJ, Czerniawska-Mysik G Relationship of inhibition of prostaglandin biosynthesis by analgesics to asthma attacks in aspirin-sensitive patients. Br Med J 1975 1 67-69. 

The neuropeptide Y (NPY) belongs to a family of peptides that includes peptide YY and pancreatic polypeptide, and it is associated with several diseases such as asthma, immune system disorders, inflammatory diseases, anxiety, depression and diabetes mellitus. NPY is found in the central and peripheral nervous system, and its biological functions are mediated by interactions with five receptor sub-types, i.e. Yl, Y2, Y4, Y5 and Y6. Several studies indicate that the feeding behavior is influenced by interactions between NPY and Yl and Y5. Deswal and Roy used Cerius descriptors and genetic function approximation QSAR to investigate the structural determinants for the inhibition potency of 24 compounds with the general structure 4 for the NPY Y5 receptor [31]. The best QSAR (H = 0.720,... 

Other therapeutic uses of cannabinoid agonists have been reported. The potential of cannabinoids as a treatment for asthma is supported experimentally. A CBi agonist, (i )-methanandamide (21), inhibited nerve growth factor (NGF)-induced airway hyperresponsiveness in vivo [251]. The antipruritic effect of cannabinoids has been reported, the action being mediated by both CBi and CB2 pathways [252]. Treatment with cannabis extract improved urinary tract symptoms of multiple sclerosis patients significantly in an open-label pilot study [253]. 

Leukotriene modifiers either inhibit 5-lipoxygenase (zileuton) or competitively antagonize the effects of leukotriene D4 (montelukast and zafirlukast). These agents improve FEV, and decrease asthma symptoms, rescue drug use, and exacerbations due to asthma. Although these agents offer the convenience of oral therapy for asthma, they are significantly less effective than low doses of inhaled corticosteroids.2,33... 

---