1. Field of the Invention
The invention relates to methods and compositions for preventing and reversing the symptoms and manifestations of late phase allergic reactions and inflammatory diseases.
2. Description of the Prior Art
Chronic asthma can be considered to be predominantly an inflammatory disease with associated bronchospasm. The degree of reactivity and narrowing of the bronchi in response to stimuli is greater in asthmatics than in normal individuals. Persistent inflammation is responsible for the bronchial hyperreactivity or airway hyperresponsiveness (AHR). Mucosal edema, mucus plugging and hypersecretion may be present; pulmonary parenchyma is normal. Airway narrowing may reverse spontaneously or with therapy. Type 1 (immediate) immune responses may play an important role in the development of asthma in children and many adults; however, when onset of disease occurs in adulthood, allergic factors may be difficult to identify. Exposure to cold dry air, exercise and other aggravating factors also may trigger asthma.
The general goals of drug therapy for asthma are prevention of bronchospasm and long-term control of bronchial hyperreactivity. Because it is usually not possible for either patient or physician to predict when bronchospasm may occur, patients with all but the most episodic and/or entirely seasonal attacks may require continuous therapy.
Beta agonists are useful as bronchodilator agents; they stimulate beta.sub.2 -adrenergic receptors, increase intracellular cAMP, and may inhibit the release of mast cell mediators. Other useful drugs include theophylline and related xanthine drugs, which produce bronchodilation through unknown mechanisms; the biscromone, cromolyn, which prevents the release of mediator substances and blocks respiratory neuronal reflexes; and corticosteroids, which primarily decrease inflammation and edema. Anticholinergic drugs may relieve bronchospasm by blocking parasympathetic cholinergic impulses at the receptor level. Antihistamines occasionally prevent or abort allergic asthmatic episodes, particularly in children, but they can only be partially effective in asthma because histamine is only one of many mediators.
The current drug modalities used for treatment of allergy-induced asthma suffer from a number of drawbacks. In general, the conventional agents have a relatively short duration of action and may be partially or wholly ineffective when administered after antigen challenge occurs. Moreover, because of serious adverse effects associated with the use of agents such as beta.sub.2 -adrenergic agonists and corticosteroids, the therapeutic margin of safety with such agents is relatively narrow and patients using them must be carefully monitored.
Bronchial hyperreactivity (or AHR) is a hallmark of asthma and is closely related to underlying airway inflammation. Worsening of asthma and airway inflammation is associated with increase in bronchial hyperreactivity, which can be induced by both antigenic and non-antigenic stimuli. Beta.sub.2 -adrenergic agonists are potent agents for the treatment of bronchospasm, but have no effect on airway inflammation or bronchial hyperreactivity. In fact, chronic use of beta.sub.2 -adrenergic agents alone, by causing down regulation of beta.sub.2 -receptors, may worsen bronchial hyperreactivity. At present, corticosteroids are the only effective agents available which diminish bronchial hyperreactivity. Although inhaled corticosteroids are relatively safe in adult patients with asthma, these agents have tremendous toxicity in children, including adrenal suppression and reduced bone density and growth. Thus, the search for safer and effective agents which diminish bronchial hyperreactivity continues.
Patients with allergic asthma, following an inhalation challenge with the specific antigen exhibit at least two different patterns of bronchial responses. The majority of subjects develop an acute bronchoconstrictor response only, which resolves spontaneously within 1-3 hours; these subjects are termed "acute responders". A smaller number of subjects, however, develop both an early and a late response. These subjects are termed "dual responders". In dual responders, the acute response, which resolves spontaneously, is followed 4-12 hours later by a secondary increase in airway resistance ("late phase response"). Late responses and thus dual responders are of clinical importance, because of their association with prolonged airway hyperreactivity or hyperresponsiveness (AHR), worsening of symptoms and generally worse form of clinical asthma, requiring aggressive therapy.
Pharmacological studies in allergic animals have demonstrated that not only the bronchoconstrictor response but also the inflammatory cell influx and the mediator release pattern in dual responders is quite different from acute responders. Whereas histamine is the likely bronchoconstrictor mediator during acute phase, activated products of the lipoxygenase pathway (i.e., leukotrienes) may be the major mediator involved in late phase reaction. Mast cells, however, have a central role in IgE-mediated allergic airway responses, and cromolyn sodium (a mast-cell membrane stabilizer), theoretically should prevent bronchoconstrictor responses in both "acute" and "dual" responders. Heterogeneity of mast cell subtypes may play a significant role in divergent responses and it may be dependent upon differences in signal transduction (second messenger system).
It has been discovered in the past several years that heparin administered intrabronchially can be an effective inhibitor of bronchospasm and bronchoconstriction and is consequently of value in the prophylaxis of asthma (see, e.g., Ahmed et al., New Eng. J. Med., 329:90-95,1993; Ahmed, Resp. Drug Deliv., IV:55-63, 1994). It has been discovered further that low molecular weight heparins, e.g., heparins with an average molecular weight of 4,000-5,000 daltons, effectively prevent antigen-induced bronchoconstriction; these low molecular weight heparins also exhibit considerably less anticoagulant activity than commercial heparin, a desirable property when these agents are used in the treatment of asthma (see Ashkin et al., Am. Rev. Resp. Dis., 1993 Intl. Conf. Abstracts, p. A660). Both commercial and low-weight heparins are not effective, however, in suppressing AHR when administered after the patient has been exposed to antigen.
In parent application Ser. No. 08/516,786 we disclosed that ultra-low molecular weight heparins (ULMWH) having an average molecular weight less than about 3,000 daltons are effective in suppressing AHR in acute asthmatic responders, even when administered after the patient has been challenged with antigen. However, experimental and clinical studies have shown that while inhaled commercial heparin can also attenuate early phase antigen-induced bronchoconstriction in acute responders (though not after antigen challenge) it is ineffective in the treatment of dual responders. Hence, there was still considerable doubt after our earlier work with ULMWH as to whether these substances would show efficacy in the treatment of dual or late responders as they do in acute responders.
The current, conventional therapeutic modalities for asthmatic patients who are dual responders are generally a more aggressive and time-prolonged version of the therapies practiced on acute responders, described above. However, these therapies are not particularly effective in suppressing AHR, as noted previously, and, as a result of their generally short duration of action, cannot prevent the late phase reaction and AHR observed in dual responders.
It should be noted, however, that the airways are merely a prototype of organs or tissues affected by late phase reactions (LPR's). It has been established in the medical literature that the late phase bronchoconstriction and AHR observed in dual responder asthmatic patients is not an isolated phenomenon restricted to asthmatic or even pulmonary conditions. There are cutaneous, nasal, ocular and systemic manifestations of LPR's in addition to the pulmonary ones. These allergic LPR phenomena are considered closely interrelated from the point of view of immunologic mechanisms. See Lemanske and Kaliner, "Late Phase Allergic Reactions", published in Allergies. Principles and Practice (Mosby Yearbook, Inc., 4th ed. 1997). According to the latest understanding of LPR mechanisms it appears that the clinical diseases (whether of the skin, lung, nose, eye or other organs) recognized to involve allergic mechanisms have a histologic inflammatory component which follows the immediate allergic or hypersensitivity reaction that occurs on antigen challenge. This sequence of response appears to be connected to mast cell mediators and propagated by other resident cells within target organs or by cells recruited into the sites of mast cell or basophilic degranulation. Corticosteroids which have proven valuable in the management of various allergic diseases and asthma may be beneficial because of their ability to attenuate this inflammatory process.
Furthermore, there are extra-pulmonary diseases where inflammatory response plays a major role, for example, inflammatory bowel disease, rheumatoid arthritis, glomerulonephritis and inflammatory skin disease. These conditions are also often treated with anti-inflammatory agents which may be of short duration or which, like steroidal and non-steroidal anti-inflammatory drugs, may frequently cause adverse systemic or gastrointestinal reactions.
Improved pharmaceutical treatments for late phase allergic reactions and inflammatory diseases are required.