MXPA00000992A - Method and compositions for treating late phase allergic reactions and inflammatory diseases - Google Patents

Abstract

A method of treating a mammalian patient suffering from or prone to a condition characterized by late phase allergic reactions, airway hyperresponsiveness or inflammatory reactions, e.g., asthma, allergic rhinitis, allergic dermatitis, allergic conjunctivitis, inflammatory bowel disease or rheumatoid arthritis, comprising the administration to the patient of an oral, parenteral, intrabronchial, topical, intranasal or intraocular pharmaceutical composition containing in each dose about 0.005 to about 1.0 mg per kilogram of patient body weight of ultra-low molecular weight heparins (ULMWH) or other sulfated polysaccharides having average molecular weights of about 1,000-3,000 daltons. Suitable inhalant and other pharmaceutical compositions for use in the novel treatment method are also disclosed.

Description

METHOD AND COMPOSITIONS FOR THE TREATMENT OF ALLERGIC REACTIONS IN THE LATE PHASE AND INFLAMMATORY DISEASES BACKGROUND OF THE INVENTION 1. Field of the invention The invention relates to methods and compositions for preventing and reversing the symptoms and manifestations of late-stage allergic reactions and inflammatory diseases. 2. Description of the Prior Art Chronic asthma can be considered primarily an inflammatory disease with associated bronchospasm. The degree of reactivity and narrowing of the bronchi in response to stimuli is greater in asthmatic individuals than in normal ones. Persistent inflammation is sensitive to bronchial hyperreactivity or airway tenderness (HSVR). Edema of the mucosa, obturation and hypersecretion of mucus may be present; The pulmonary parenchyma is normal. The narrowing of the airways can be reversed spontaneously or with therapy. Immune responses of type 1 (immediate) may play an important role in the development of asthma in children and many adults. However, when the onset of the disease occurs in adulthood, it can be difficult to identify allergic factors. Exposure to cold and dry air, exercise and other aggravating factors can also trigger asthma. The general objectives of asthma drug therapy are the prevention of bronchospasm and long-term control of bronchial hyperreactivity. Because it is usually not possible for a patient or physician to predict when bronchospasm may occur, patients with almost the most episodic and / or completely temporary attacks may require ongoing therapy. Beta agonists are useful as bronchodilator agents; they stimulate beta2 adrenergic receptors, increase in intracellular aAMP and can inhibit the release of astrocyte mediators. Other useful drugs include theophylline and xanthine-related drugs, which produce bronchodilation through unknown mechanisms; bischromone, cromolyn, which prevents the release of mediating substances and blocks respiratory neuronal reflexes; and corticosteroids, which mainly decrease inflammation and edema. Anticholinergic drugs can relieve bronchospasm by blocking sympathetic cholinergic impulses at the receptor level. Antihistamines occasionally prevent or interrupt 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 the treatment of allergy-induced asthma present some disadvantages. In general, conventional agents have a relatively short duration of action and may be partially or totally ineffective when administered after the antigen challenge occurs. In addition, due to the serious adverse effects associated with the use of agents such as beta-adrenergic agonists and corticosteroids, the therapeutic safety margin with these agents is relatively narrow and the patients who use them must be carefully monitored. Bronchial hyperresponsiveness (or HSVR) is a hallmark of asthma and is closely related to the underlying airway inf ation. The worsening of asthma and inflammation of the respiratory tract is associated with the increase in bronchial hyperreactivity, which can be induced by antigenic and non-antigenic stimuli. Beta2-adrenergic agonists are potent agents for the treatment of bronchospasm, but have no effect on airway inflammation or bronchial hyperreactivity. In fact, the chronic use of beta2-adrenergic agents alone, causing down-regulation of beta2 receptors, can worsen bronchial hyperreactivity. In the present, corticosteroids are the only effective agents available that decrease bronchial hyperreactivity. Although inhaled corticosteroids are relatively safe in adult patients with asthma, these agents have a high toxicity in children, including adrenal suppression and reduced bone density and growth. Thus, the search continues for safer and more effective agents that reduce bronchial hyperresponsiveness. Allergic copr asthma patients, after a challenge by exhaling with the specific antigen, present at least two characteristics of different bronchial responses. Most individuals develop an acute bronchoconstrictor response only, which resolves spontaneously within 1-3 hours. These people are called "acute responders." However, a smaller number of individuals develop an early and a delayed response. These individuals are called "double responders." In double 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 double responders are of clinical importance, due to their association corL-prolonged airway hyperreactivity or hypersensitivity (HSVR), worsening of symptoms and the generally worse form of clinical asthma, requiring aggressive therapy. Pharmacological studies in allergic animals have shown that not only the bronchoconstrictor response but also the influx of inflammatory cells and the mediator release pattern in double responders is very different from acute responders. While histamine is the most likely bronchoconstrictor mediator during the acute phase, the activated products of the lipoxygenase pathway (ie, leukotrienes) may be the primary mediator involved in the late phase reaction. However, mast cells have a central role in allergic responses of the airways mediated by IgE, and cromolyn sodium (a stabilizer of the mast cell membrane, theoretically should avoid bronchoconstrictive responses in both "acute" and "double" responders The heterogeneity of mast cell subtypes may play a significant role in divergent responses and may depend on differences in signal transduction (the second messenger system.) For some years it has been discovered that heparin administered intrabronchially may to be an effective inhibitor of bronchospasm and bronchoconstriction and consequently of value in the prophylaxis of asthma (see, for example, Ahmed et al., New Eng. J. Med., 329: 90-95, 1993; Ahmed, Resp. Drug. Deliv., IV: 55-63, 1994). It has further been discovered that low molecular weight heparins, for example, heparins with an average molecular weight of 4,000-5,000 daltons, effectively prevent antigen-induced bronchoconstriction; these low molecular weight heparins also have considerably lower anticoagulant activity compared to commercial heparin, a desirable property when these agents are used in the treatment of asthma (see Ash in et al., Am. Rev. Resp. Dis., 1993 Intl. Conf. Abstracts, page A660). However, commercial and low-weight heparins are not effective in suppressing HSVR when administered after the patient has been exposed to the antigen. In patent application serial No. 08 / 516,786 we discovered that ultra low molecular weight heparins (HPMUB) having an average molecular weight of less than about 3,000 daltons are effective in suppressing HSVR in acute asthmatic responders, even when they are administered after the patient has been challenged with the antigen. However, experimental and clinical studies have shown that while inhaled commercial heparin can also attenuate antigen-induced bronchoconstriction, early phase in acute responders (although not after challenge with antigen) is ineffective in the treatment of responders. double. Hence, there was still considerable doubt after our previous work with HPMUB as to whether these substances would show efficacy in the treatment of double or late responders as it does in acute responders. The current, conventional therapeutic modalities for asthmatic patients who are acute responders are generally a more aggressive and prolonged version of therapies practiced in acute responders, described in the above. However, these therapies are not particularly effective in the suppression of HSVR, ~~ as previously noted, and, as a result of their generally short duration of action, they can not avoid the late phase reaction and the HSVR observed in responders. double. However, it should be noted that the airways are simply a prototype of organs or tissues affected by late phase reactions (RFT). It has been established in the medical literature that late phase bronchoconstriction and ARH observed in double-responding asthmatic patients is not an isolated phenomenon limited to asthmatic or even pulmonary conditions. These are cutaneous, nasal, ocular and systemic manifestations of RFT in addition to the pulmonary manifestations. These allergic RFT phenomena are considered closely interrelated from the point of view of immunological mechanisms. See, Lemanske and Kaliner, "Late Phase Allergic Reactions," published in Allergies, Principies and Practice (Mosby Yearbook, Inc., 4th ed., 1997). According to the most recent understanding of the mechanisms of the RFT it seems that clinical diseases (whether of the skin, lung, nose, eyes and other organs) that involve allergic mechanisms have a histological inflammatory component that follows the allergic reaction or immediate hypersensitivity that occurs in the challenge with the antigen. This sequence of responses seems to be connected to the mediators of the mast cells and is propagated by other cells resident within the target organs or by cells recruited at the sites of mast cells or basophilic granulation. Corticosteroids that have been shown to be valuable in the management of different allergic diseases and asthma can be beneficial because of their ability to attenuate this inflammatory process. In addition, there are extrapulmonary diseases where the 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 that may be of short duration or which, like spheroidal and non-steroidal anti-inflammatory drugs, can frequently cause adverse systemic or gastrointestinal reactions. Improved pharmaceutical treatments for late-stage allergic reactions and inflammatory diseases are necessary.

SUMMARY OF THE INVENTION It is an object of this invention to provide more effective and safe methods and compositions for the treatment of conditions characterized by late phase allergic reactions or inflammatory reactions. Another object of the present invention is to provide a method and compositions for the treatment of asthma in late phase, induced by antigen and bronchial hyperreactivity that does not present the disadvantages of the prior art. Another object of the present invention is to provide a method and compositions for the treatment of asthmatic double responders that are effective in the prevention and regression of late-stage asthma manifestations. Yet another object of the present invention is to provide a method and compositions as described above that are highly effective in decreasing specific and non-specific bronchial hyperreactivity, and even when administered after challenge with antigen to the patient.

In accordance with these objectives and others that will be apparent hereinafter, the invention is a method of treating a mammalian patient having a condition characterized by late-stage allergic reactions, including, for example, pulmonary, nasal RFT, cutaneous, ocular and systemic or characterized by inflammatory reactions, through intrabronchial, oral, topical, parenteral, intranasal or intraocular administration to the patient of a pharmaceutical composition and containing from approximately 0.005 to __ approximately 1.0 mg of molecular weight heparins ultralow (HPMUB) per kilogram of patient's body weight in each dose. The administration of these heparins can be on an acute basis such as after challenge with antigen or on a chronic basis to suppress inflammatory reactions such as bronchial hyperreactivity in patients with asthma. HPMUBs effective in the method of the invention have average molecular weights of about 1,000 to about 3,000 daltons and may have a low level of anticoagulant activity or virtually no anticoagulant activity. The novel pharmaceutical compositions are also provided including, for example, inhalant (intrabronchial) compositions in the form of nebulizers or liquid aerosol compositions __ or powder containing the appropriate concentrations of these HPMUB; BRIEF DESCRIPTION OF THE DRAWINGS FIGURE 1 is a graph illustrating the "effects of antigen challenge on two groups of allergic sheep, one composed of acute responders and the other of double responders." The data for each group are shown as the average change ±% DE induced by antigen peii ~ REp (lung specific resistance), shown before (baseline) _, immediately after (PA) and up to 8 hours after the antigen. + = Significantly different from the baseline (P <0.05 ) * = significantly different from double responders (P <0.05) FIGURES 2A and 2B consist of two graphs illustrating the differential effects of commercial inhaled heparin on antigen-induced bronchoconstriction in two groups of allergic sheep, one composed of acute responders (n = 8) and the other of double responders (n = 13). + = significantly different from the baseline (P <0.05) * = significantly different from the control (P < 0.05). FIGURE 3 is a graph illustrating the effect of pretreatment with inhaled Frag in® (average molecular weight 5,030 daltons) at 5.0 mg / kg on antigen-induced bronchoconstriction in double-responder allergic sheep. The data are shown as the average REp (in cm H0 / L / sec) in a group of animals exposed to the antigen, first without drug treatment and again several days after the pretreatment with Fragmin. FIGURE 4 is a bar graph illustrating the effect of pretreatment with inhaled Fragmin® at 5.0 mg / kg on HSVR in allergic sheep. The data are shown as the mean ± SD DP4ocr in baseline exhalation units and 24 hours after challenge with the antigen in a group of animals exposed to the antigen, first without drug treatment and again several days after pretreatment with Fragmin . DP400 - cumulative cumulative dose of carbachol, increasing the REp to 400% over the baseline. + = significantly different from the baseline (P <; 0.05) FIGURE 5 is a graph illustrating the effect of previous treatment with inhaled CY-216 (average molecular weight 4,270 daltons) at 1.25 mg / kg on antigen-induced bronchoconstriction in double responder allergic sheep. The data are shown as the mean ± SD change induced by antigen in REp in a group of animals exposed to the antigen, first without drug treatment and again a few days after the previous treatment with CY-216. FIGURE 6 is a bar graph illustrating the effect of pre-treatment with inhaled CY-216 at 1.25 mg / kg on HSVR in allergic sheep. The data are shown as mean ± SD DP400 in exhalation units in the baseline line and 24 hours after challenge with antigen in a group of animals exposed to the antigen, first without drug treatment and again several days after the previous treatment with CY -216. + = Significantly different from the baseline (P <0.05) FIGURE 7 is a graph illustrating the effect of previous treatment with inhaled HPMUB CY-222 (average molecular weight 2,355 daltons) at 1.0 mg / kg in bronchoconstriction Antigen-induced in double-responder allergic sheep The data are shown as the average change ±% DE induced by antigen in REP in a group of animals exposed to the antigen, first without drug treatment and again a few days after the previous treatment with CY -222. * = Significantly different from the control _ (P <0.05) FIGURE 8 is "a bar graph illustrating the effect of previous treatment with CY-2 22 inhaled at 1.0 mg / kg in HSVR in allergic sheep. The data are shown as mean ± SD DP400 in "exhalation units in the baseline and 24 hours after challenge with antigen in a group of animals exposed to the antigen, first without drug treatment and again a few days after the previous treatment with CY -222. + = Significantly different from baseline (P <0.05) FIGURE 9 is "a graph illustrating the effect of post-challenge treatment with inhaled CY-222 antigen at 1.0 mg / kg on antigen-induced bronchoconstriction in double responder allergic sheep. The data are shown as the average change ±% DE induced by antigen in REP, shown before, immediately after (time zero) and up to 8 hours after the antigen, in a group of animals exposed to the antigen, first without treatment with medication and another a few days later when CY-222 was administered immediately after the subsequent measurement of the REP antigen (arrow). * = significantly different from the control (P <0.05) FIGURE 10 is a bar graph that "illustrates the effect of post challenge treatment with antigen (arrow in FIGURE 9) with CY-222 inhaled at 1.0 mg / kg over HSVR in allergic sheep The data are shown as the average ± DE DP400 in units of exhalation in the baseline and 24 hours after challenge with antigen in a group of animals exposed to the antigen, first without drug treatment and again some days after when CY-222 was administered immediately after challenge with antigen. = = significantly different from baseline (P <0.05) FIGURE 11 is a graph illustrating the effect of previous treatment with inhaled HPMUB FRU-70 (average molecular weight 2,500 daltons) at 1.0 mg / kg in antigen-induced bronchoconstriction in double-responder allergic sheep.The data are shown as the mean change ±% DE induced by antigen in REp in a group of animals exposed to the antigen, first without treatment with medication and again a few days after the previous treatment with FRU-70. * = significantly different from control (P <0.05) FIGURE 12 is a bar graph illustrating the effect of pre-treatment with inhaled FRU-70 at 1.0 mg / kg on HSVR in allergic sheep. The data are shown as the mean ± SD DP400 in exhalation units in the baseline and 24 hours after challenge with the antigen in a group of animals exposed to the antigen, first without drug treatment and again a few days after the previous treatment with antigen. FRU-70.

+ = Significantly different from the baseline (P <0.05) FIGURE 13 is a graph illustrating the = effect of post-challenge treatment with antigen with inhaled FRU-70 at 0.5 mg / kg on antigen-induced bronchoconstriction in allergic sheep double responders.a The data are shown as the average ±% DE induced antigen change in REP, shown before, immediately after (time zero) and up to 8 hours after the antigen, in a group of animals exposed to the antigen, first without treatment with medication and again some days later when the FRU-70 was administered immediately after the measurement-after the REp antigen (arrow). * = significantly different from the control (P <0.05) FIGURE 14 is a bar graph illustrating the effect of post antigen challenge treatment (arrow in FIGURE 13) with FRU-70 inhaled at 0.5 mg / kg in HSVR in allergic sheep. The data are shown as the mean ± SD DP400 in exhalation units in the baseline and 24 hours after challenge with antigen in a group of animals exposed to the antigen, first without drug treatment and again a few days later when FRU-70 was administered immediately after challenge with antigen. + = Significantly different from the baseline (P <0.05) FIGURE 15 is a graph illustrating the effect of post challenge treatment with antigen with an inhaled hexasaccharide mixture (average molecular weight 1,930 daltons) at 0.5 mg / kg in Induced bronchoconstriction pox antigen in double responder allergic sheep. The data are shown as the average change ±% SD induced by antigen in REp, shown before, immediately after (time zero) and up to 8 hours after the antigen, in a group of animals exposed to the antigen, first without drug treatment and again a few days later when the mixture of hexasaccharides was administered immediately after the subsequent measurement of the REp antigen (arrow). * = significantly different from the control (P <0.05) FIGURE 16 is a bar graph illustrating the effect of post challenge treatment with antigen (arrow in FIGURE 15) with inhaled hexasarcharide mixture at 0.5 mg / kg in HSVR in allergic sheep. The data are shown as the mean ± SD T) p4"oo in units of exhalation in the baseline and 24 hours after challenge with antigen in a group of animals exposed to the antigen, first without drug treatment and some - days later when the mixture of hexasaccharides was administered immediately after challenge with the antigen.

+ = Significantly different from the baseline (P <0.05) FIGURE 17 is a graph illustrating the effect of post-challenge treatment with purified, inhaled hexasaccharide antigen (average molecular weight 1,998 daltons) at 0.062 mg / kg in Bronchoconstriction induced by the antigen in double-responder allergic sheep. The data are shown as the average change ±% SD induced by the antigen in REP, shown before, immediately after (time zero) and up to 8 hours after the antigen in a group of animals exposed to the antigen, first without drug treatment and again a few days later when the hexasaccharide was administered immediately after the subsequent measurement of the REp antigen (arrow). * = significantly different from the control (P <0.05) FIGURE 18 is a bar graph illustrating the effect of post-challenge antigen treatment (arrow in FIGURE 17) with purified hexasaccharides, inhaled at 0.062 mg / kg "in HSVR in allergic sheep The data are shown as the mean ± SD DP400 in exhalation units in the baseline and 24 hours after challenge with the antigen first, without drug treatment and again a few days later when the hexasaccharide was administered immediately after of the challenge with antigen. + = significantly different from the baseline (P <; 0.05) FIGURE 19 is a graph illustrating the effect of post-challenge antigen treatment with purified, inhaled tetrasaccharide (average molecular weight 1,290 daltons) at 0.062 mg / kg on antigen-induced bronchoconstriction in double responder allergic sheep. The data are shown as the average change ±% DE induced by antigen in REp, shown before, immediately after (time zero) and up to 8 hours after the antigen, in a group of animals exposed to the antigen, first without drug treatment and again a few days later when the tetrasaccharide was administered immediately after the subsequent measurement of the REp antigen (arrow). * = significantly different from control (P <0.05) FIGURE 20 is a bar graph illustrating the effect of post-challenge treatment with antigen (arrow in FIGURE 19) with purified tetrasaccharide, inhaled at 0.062 mg / kg in HSVR in allergic sheep. The data are shown as the mean ± SD DP400 in exhalation units in the baseline and 24 hours after challenge with antigen first, without drug treatment and again a few days later when the tetrasaccharide was administered immediately after the antigen challenge. + = significantly different from the baseline (P <0.05) FIGURE 21 is a graph illustrating the effect of post challenge treatment with inhaled octasaccharide antigen (average molecular weight 2,480 daltons) at 0.25 mg / kg induced bronchoconstriction by antigen in double responder allergic sheep. The data are shown as the average change ±% DE induced by antigen in REp, shown before, immediately after (time zero) and up to 8 hours after the antigen, in a group of animals exposed to the antigen, first without drug treatment and again a few days later when the octasaccharide mixture was administered immediately after the subsequent measurement of the REp antigen (arrow). * = significantly different from the control (P <0.05) FIGURE 22 is a bar graph illustrating the effect of post challenge treatment with antigen (arrow in FIGURE Al) with octasaccharide, inhaled at 0.25 mg / kg in HSVR in allergic sheep. The data are shown as the mean ± SD DP400 in exhalation units in the baseline and 24 hours after challenge with antigen first, without drug treatment and again a few days later when the octasaccharide was administered immediately after challenge with antigen. + = significantly different from the baseline (P <0.05) FIGURE 23 is a graphical graph illustrating the effect of previous treatment with inhaled disaccharide (average molecular weight 660 daltons) at 1.0 mg / kg on antigen-induced bronchoconstriction in allergic sheep double responders. The data are shown as the average change ±% DE induced by antigen in REp, shown before, immediately after (time zero) and up to 8 hours after the antigen, in a group of animals exposed to the antigen, first without drug treatment and again a few days after the previous treatment with the disaccharide. FIGURE 24 is a graph illustrating the "effect of pre-treatment with orally administered purified hexasaccharide (average molecular weight 1,998 daltons) at 2.0 mg / kg on antigen-induced bronchoconstriction in a double responder allergic sheep." The data are shown as average change ±% DE induced by antigen in REp in a single sheep exposed to the antigen, first without drug treatment and again some days after the previous treatment with hexasaccharide FIGURE 25 is a bar chart illustrating the effect of previous treatment with purified hexasaccharide, orally administered at 2.0 mg / kg in HSVR in an allergic sheep The data are shown as mean ± SD DP400 in exhalation units at baseline and 24 hours after challenge with antigen in a single exposed sheep to the antigen, first without treatment with medication and again some days after the previous treatment with hexasaccharide. A graph illustrating the effect of previous treatment with purified hexasaccharide, administered intravenously (average molecular weight 1,998 daltons) at 0.25 mg / kg on antigen-induced bronchoconstriction in. a double responder allergic sheep. The data "are shown as the average change ±% DE induced by antigen in REP in a single sheep exposed to the antigen, first without drug treatment and again a few days after the previous co-hexasaccharide treatment." FIGURE 27 is a bar graph which illustrates indeed the previous treatment with purified hexasaccharides, administered intravenously at 0.25 mg / kg on HSVR in allergic sheep.The data are shown as mean ± SD DP400 in exhalation units in the baseline and 24 hours after the challenge with the antigen in a single sheep exposed to the antigen, first without drug treatment and again a few days after the previous hexasaccharide treatment.

FIGURE 28 is a "bar graph illustrating the comparative activity in prevention of the influx of eosinophils induced by antigen in the bronchoalveolar lavage fluid of three groups of mice administered, respectively, with purified, inhaled, oral and intraperitoneal hexasaccharide.

DETAILED DESCRIPTION OF THE INVENTION The present invention pertains, in general, to a method of treating mammalian patients that exhibit or are prone to the development of disease conditions characterized by late phase allergic reactions and / or by inflammatory reactions, as well as the compositions Novel pharmaceuticals containing ultra low molecular weight heparins that are suitable for use in the practice of the method. Heparin, a sulfated mucopolysaccharide, is synthesized in mast cells as a proteoglycan and is particularly abundant in the lungs of various animals. The heparin is not a specific compound of fixed molecular weight but is actually a heterogeneous mixture of variably sulfated polysaccharide chains composed of repeating units of D-glucosein and L-iduronic or D-glucuronic acid. The average molecular weight of heparin isolated from animal tissues is in the range of about 6, 000 to approximately 30,000 daltons. From the pharmacological point of view, heparin is known primarily as an anticoagulant. This activity results from the ability of heparin to bind to some of the residues of antithrombin III (AT-III), accelerating the neutralization by AT-III of the activated coagulation factors and the prevention of the conversion of prothrombin to thrombin. Larger amounts of heparin can inactivate thrombin and early coagulation factors by preventing the conversion of fibrinogen to fibrin.

The hemorrhagic activity of heparin is related to the molecular weight of its polysaccharide fragments; low molecular weight components or fragments (e.g., fragments having a molecular weight of less than 6,000 daltons) have moderate to low antithrombin and hemorrhagic effects. In the same way, low molecular weight heparins isolated from animal tissue generally have reduced hemorrhagic properties compared to commercial heparin but may still have significant anticoagulant activity. Commercial heparin, which is usually obtained from the beef lung or intestinal mucosa of pigs, has an average molecular weight of approximately 15,000-17,500 daltons. It has been shown that heparin acts as a specific blocker of IP3 receptors and inhibits the release of calcium mediated by IP3. we have previously suggested that heparin can block IP3 receptors in mast cells and thus interfering with signal transduction can modulate the degranulation of mast cells and release the mediator. In vivo and in vitro studies support this concept and have shown that inhaled heparin can attenuate allergic bronchoconstriction in sheep, prevent exercise-induced asthma, as well as inhibit anti-IgE-induced mast cell histamine release. Heparin inhaled in doses of up to 1,000 units / kg has been shown to have no effect on partial thromboplastin time (TTP), thus suggesting a "non-anticoagulant" effect. It has also been reported that low molecular weight heparins (average molecular weight of 4,500 daltons), which have reduced ATTP activity, were effective in animal studies avoiding the antigen-induced bronchoconstrictor response (RBA) and bronchial hyperresponsiveness, also known co or hypersensitivity of the respiratory tract (HSVR). However, as described and illustrated in more detail below, neither commercial heparin nor medium or low molecular weight heparins, even those with very low anticoagulant activity, are effective in reducing HSVR after challenge with antigen in test animals. .

These heparins apparently only provide a prophylactic, preventive effect, but they are not of value in the treatment of asthmatic episodes triggered by the antigen. It has been discovered and reported in the patent application No. 08 / 517,786 that ultra-low molecular weight heparin fractions (HPMUB) are not only effective inhibitors of airway anaphylaxis, but are highly effective in reducing HSVR even when administered after challenge with the antigen. Chronic, regular use of HPMUB can also reduce HSVR, and "HPMUBs can therefore be used for chronic asthma therapy, whether caused by specific (ie, antigenic) or non-specific factors. , and described the test data demonstrating the efficacy of HPMUB in the treatment of early stage asthma in acute responders, not in the treatment of "double responders" who experience early and late phase bronchoconstriction and prolonged HSVR. , based on our previous studies, it had not been possible to predict that HPMUB, either administered before or after challenge with antigen, would be effective in the inhibition of bronchoconstriction (in early and late phase) and of HSVR in double responders. This lack of prediction is evident from the fact that commercial heparin and heparins of medium or low molecular weight (p. that molecular> 3,000) inhibit HSVR in acute responders when administered before challenge with the antigen, but have no significant effect on the suppression of the late phase reaction and the HSVR observed in the double responders. After conducting other controlled studies with HPMUB, we discovered, surprisingly, that heparin fractions having average molecular weights of about 1,000 to about 3,000 are effective, when inhaled by double responders before or even after challenge with the antigen, in the suppression of bronchoconstriction in early and late phase and HSVR. Even more surprisingly, we have found that oral and intravenous (or other parenteral) administration of HPMUBs before challenge with the antigen effectively inhibits bronchoconstriction and HSVR in double responders. Accordingly, the present invention is, in one aspect, in a method of treating a mammalian patient who is a double responder and has late phase asthma, induced by the antigen, consisting of intrabronchial administration to the patient, before or after of the challenge with the antigen, of a pharmaceutical composition containing about 0.005 to about 1.0 mg of one or more effective HPMUB fractions per kilogram of the patient's body weight in each dose of the composition, and preferably from about 0.075 to about 0.75 mg / kg per dose. For the purposes of this application, "effective HPMUB" can be defined as fractions of heparin having an average molecular weight of approximately 1,000-3,000 daltons. HPMUB having an average molecular weight of about .1,000-2,500 daltons are particularly effective when used in the method of the invention. Each HPMUB fraction may consist of tetrasaccharides, pentasaccha- ridides, hexasaccharides, septasaccharides, octasaccharides and decasaccharides as well as larger chain length molecules. The fractions of the HPMUB used in the invention are oligomers of sulphated saccharide units which may have, for example, the following genexal structural formula: Despite the known activity of N-desulfated heparins in other biological systems, for example as inhibitors of cell growth, it has been found that the saccharide units in the HPMUB fractions that are effective for the purposes of the present invention are N -sulphated; N-desulfated fractions are ineffective. Although the sulfated polysaccharides which are used in the method and compositions of the invention are generally known herein as ultra low molecular weight heparins, i.e., ultra low molecular weight fractions obtained from heparin in its natural state (or synthetic versions thereof). HPMUB), the invention may also comprise the use of sulfated polysaccharides obtained from heparin sulfate, dermatan sulfate, chondroitin sulfate, pentosana polysulfate and / or other glycosaminoglycans and mucopolysaccharides. The target sulphated polyscarcharide fractions must, however, have an average molecular weight of about 1,000-3,000,000 daltons. The pharmaceutically acceptable salts of the effective HPMUBs or any of the other sulfated polysaccharides mentioned in the above may also be used, for example, the sodium, calcium or potassium salts. In accordance with this first aspect of the invention, a human or other mammalian patient who is a double responder who has inhaled, ingested or otherwise come into contact with an antigen (ie, has been "challenged" with an antigen) of a type known for prorocar asthmatic episodes in this patient, or a patient who may be exposed at a future time to a challenge with an antigen, is administered by exhalation of at least one dose of a pharmaceutical composition containing one or more cumulatively effective HPMUBs present in the concentrations described above. Additional doses may subsequently be administered as necessary after challenge with the antigen until the patient regains or maintains their normal levels of resistance in the airways. The invention also comprises, in a second aspect, the chronic administration of effective HPMUB to patients with dual-responding asthma to reduce and suppress HSVR in early and late phase. "Chronic administration", as used herein, refers to the administration of pharmaceutical compositions containing HPMUB effective at least once a day for at least 10 consecutive days. Chronic administration of a composition containing from about 0.005-1.0 mg / kg: per dose and, preferably, about 0.0075-0.75"mg / kg per dose, may be continued indefinitely to provide HSVR suppression therapy at least comparable to corticosteroids but substantially - without the adverse effects The inhalation (intrabronchial) compositions of HPMUB used in the present invention to treat late phase asthma and other pulmonary conditions may comprise liquid or powder compositions containing effective fractions of HPMUB and suitable for nebulization and intrabronchial use, or aerosol compositions administered by a metered dose dispensing aerosol unit Suitable liquid compositions comprise, for example, HPMUBs effective in an aqueous, pharmaceutically acceptable inhalant solvent, eg, isotonic saline or bacteriostatic water. they are administered by me provided with a pump or spray dispenser ~ nebulized by compression or by any other conventional means to allow the necessary amount of dose of the liquid composition to be inhaled into the lungs of the mammalian patient. Suitable powder compositions include, as an illustration, powdered preparations of heparin perfectly mixed with lactose or other inert powders acceptable for intrabronchial administration. The powder compositions can be administered by an aerosol dispenser or contained in a rupturable capsule which can be inserted into the patient's mammal in a device that pierces the capsule and blows the powder out in a continuous stream suitable for exhalation . Aerosol formulations for use in the present method will usually include alkano-fluorinated propellants, surfactants and co-solvents and can be filled in aluminum or other conventional aerosol containers that are then closed by a suitable metering valve and pressurized with propellant, producing a metered dose inhaler (MDI). The total concentration of effective HPMUBs in any propellant vehicle suitable for use in a pressurized aerosol dispenser, such as an IDM, should be sufficiently high to provide a dose of approximately 0.005-0.1 mg (5-100 μg) of the HPMUB effective per kilogram of body weight of the patient per administration. Thus, for example, if an IDM delivers approximately 895 μl of the propellant vehicle containing the medicament by activation, the concentration of the HPMUB "effective in the vehicle in the case of a mammalian patient weighing 75 kg would be approximately 0.0045-0.088 mg / μl (4.5-88 μg / μl) supplying 0.375 to 7.5 mg (375-7,500 μg) of HPMUB by activation, if it is desired to deliver the total dose with a single activation If a dose with two activations is desired, the concentration interval The corresponding concentration would be approximately 0.0022-0.044 mg / μl (2.2-44 μg / μl), providing 0.188 to 3.75 mg (188-3,750 μg) of HPMUB per activation.The total concentration of the effective HPMUB in any liquid nebulizer solution should be sufficiently high to provide a dose of approximately 0.05-1.0 mg (50-1000 μg) of effective HPMUB per kilogram of patient body weight per administration, for example, if the nebulizer After 5 ml of solution per activation, the concentration of effective HPMUB in the case of a mammalian patient weighing 75 kg should be approximately 0.75-15.0 mg / ml. In another aspect of the invention, compositions containing effective HPMUBs are administered orally or parenterally (for example IV or IM) to mammalian patients suffering from late phase asthma induced by antigen, ie, they are double responders, before of the patient's exposure to challenge by the antigen. Oral or parenteral compositions contain about 0.005 to about 1.0 mg of effective HPMUBs per kg of patient's body weight in each dose. Oral or parenteral compositions can be administered up to 8 hours (but preferably no more than 4 hours) before challenge with the antigen and are effective in reducing early and late phase bronchoconstriction and suppression of HSVR.

As those skilled in the pharmaceutical art will appreciate, many of the conventional methods and apparatuses are available for the administration of precisely measured doses in intrabronchial medicaments and for controlling the amount of dose desired according to the weight of the patient and the severity of the condition. of the same. In addition, there are multiple liquid, powder and aerosol vehicles recognized in the art suitable for the intrabronchial HPMUB compositions of the present invention, and multiple pharmaceutically acceptable oral and parenteral vehicles that can be employed for oral and parenteral compositions containing HPMUB. The invention is not limited to any of the vehicles, solvents, particular inert carrier excipients or dosage forms and is not limited to any of the particular methods or apparatus of intrabronchial administration. The pharmaceutical compositions can also be dosage forms containing the effective HPMUB as active ingredients in any of the pharmaceutically acceptable oral, injectable or IV dosing vehicles or in topical or intraocular vehicles. Each dosage form includes approximately 0.005-1.0 mg / kg of the patient's average body weight of the effective HPMUB (one or a combination of HPMUB) and the inert pharmaceutically acceptable ingredients, eg, excipients, vehicles, fillers , binders, disintegrants, solvents, solubilizing agents, sweeteners, conventional coloring agents and other inactive ingredients that are regularly included in the pharmaceutical dosage forms for oral administration. Suitable oral dosage forms include tablets, capsules, caplets, gelatin capsules, pills, liquid solutions, suspensions or elixirs, powders, dragees, micronized particles or systems for osmotic delivery. Injectable and IV dosage forms include isotonic saline solutions or dextrose solutions containing suitable buffers and preservatives. Many of the suitable dosage forms and vehicles, and lists of ingredients inactive for these, are well known in the art and are set forth in the common texts such as Remigton's Pharmaceutical Sciences, 17th edition (1985). The HPMUB compositions described herein provide highly effective treatment for early and late phase antigen-induced asthma even after it has occurred in challenge of the antigen, as well as for other conditions characterized by late phase allergic reactions. To demonstrate the unexpected superiority of effective HPMUB compared to higher molecular weight heparins in the treatment of asthmatic double responders, experiments were conducted comparing the effects of different types of heparin on double responder allergic sheep, before and after challenge with the antigen . Detailed descriptions of these experiments and the results obtained are mentioned in the following examples, as well as in the graphs shown in the drawings.

The following examples, while illustrating the methods and compositions of the invention and demonstrating the efficacy thereof, are not intended to establish specific compositions, materials, procedures or dosage regimens that should be used exclusively to practice the invention.

EXAMPLE 1 Administration of inhaled HPMUB to allergic sheep, double responders Methods Resistance of the pulmonary airways: _ ^ Allergic sheep with double bronchoconstrictor response, previously documented to the antigen Ascaris suum were used for all studies. The sheep were intubated with a nasotracheal balloon tube and the pulmonary airflow resistance (Ri) was measured by the esophageal balloon catheter technique, while the volume of thoracic gas was measured by body plethysmography. The data were expressed as specific RL (REP, defined as the RL times of thoracic gas volume (Vtg)).

Respiratory tract sensitivity: _ __ To assess airway sensitivity, cumulative dose-response curves were performed for inhaled cholcol [sic] by measuring REP before and after exhalation of buffered saline and after each administration of 10 inhalations of increasing concentrations of carbacol (0.25, 0.5, 1.0, 2.0 and 4.0% weight / volume of solution). Airway sensitivity was measured by determining the cumulative challenge dose (DP400) of carbachol (in exhalation units) that increased the REp to 400% over the baseline. An exhalation unit was defined as an exhalation of 1% carbachol solution.

Heparin fractions: _ _ _ _ In the studies reported here, different heparin materials were administered to the double responder allergic sheep before and / or after challenge with the antigen. Some of these heparins were fractions of HPMUB of average molecular weight between 1,000 and 3,000 daltons, some were of higher average molecular weight and one was of lower molecular weight. The heparin fractions tested are set forth in Table 1 below.

TABLE 1 FRACTIONS OF HEPARINE AND ITS MOLECULAR PESOS A mixture of anticoagulant octasaccharides. A mixture of octasaccharides not anticoagulant. Octasaccharide obtained from commercial porcine heparin, containing mainly tetrasaccharide, hexasaccharide, octasaccharide and decasaccharide fractions. 4 Obtained from the mixture of hexasaccharides by column chromatography, in gel, contains fractions of approximately 70% octasaccharide and 30% decasaccharides. Obtained from the mixture of hexasaccharides by gel column chromatography. Obtained from the hexasaccharide mixture by gel column chromatography. 7 The disacapdo was trisulfated but had a molecular weight so low that it could not be considered an HPMUB fraction with properties similar to heparin.

Experimental protocol __ __ Studies of the expiratory pathways _ _ ___ The sensitivity (DP400) of the airways in the baseline of each animal was determined, and then in different experimental routes the sheep underwent airway challenge with the antigen Ascaris suum. The REP_ was measured before and immediately after the challenge, and then every hour for 8 hours. The DP400 after the challenge was measured 24 hours after challenge with the antigen when HSVR occurred. The protocol was repeated at least 14 days later, but each animal was administered with a dose of one of the fractions of the test heparin approximately 30 minutes before the challenge with the antigen or immediately after the REp measurement after the challenge.

Analysis of the data The data were expressed as: (a) REp (% change) = subsequent REP _the challenge - REp of baseline x 100 / REp of the baseline (b) DP4oo (in exhalation units) Results FIGURE 1 illustrates differential reactions to challenge with the antigen of two groups of allergic sheep, one composed of acute responders and the other of double responders. The REp of the acute responders returned to the levels approximately of the baseline after about 3 hours after the antigen and remained there. However, in the double responders there is a peak of the late phase in the REP approximately 6 hours with - levels remaining significantly above the baseline through the 8 hour endpoint of the study. It is this second peak of the late phase that characterizes double responders. FIGURES 2A and 2B depict the effects of pre-challenge treatment with commercial heparin inhaled on ERP in acute responders (FIGURE 2A) and in double responders (FIGURE 2B). Although the REp of the acute responders remained at the levels close to the baseline even after the challenge with the antigen, the REp of the early phase and of the late phase in the double responders was not alleviated by the previous treatment with heparin, even in double responders has been administered up to 2,000 units per kilogram. FIGURES 3-6 illustrate the lack of efficacy of low molecular weight heparin fractions, Fragmin and CY-213, in the modification of bronchoconstriction or HSVR in double responders when administered before the challenge with the antigen. FIGURES 7-10 show that pretreatment and post-challenge treatment with the inhaled HPMUB CY-222 antigen (average molecular weight 2355 d, within the range of effective HPMUBs according to the invention) were more effective - in significantly modifying the antigen-induced bronchoconstriction in the early and late phase and the HSVR in double responders. FIGURES 11-14 illustrate the efficacy of pretreatment and post challenge treatment with the antigen with the HPMUB FRU-70 (molecular weight averaged "25OH d) in the treatment of early and late phase asthma.

FIGURES 15-22 demonstrate the efficacy of different fractions of the effective HPMUB, even when administered after challenge with the antigen, in the significant reduction of bronchoconstriction and HSVR in double responders. "" "FIGURE 23 shows the fraction of disaccharides, having an average molecular weight of only about 660 d (substantially below the weight range necessary for effective HPMUB fractions) was ineffective in the modification of antigen-induced bronchoconstriction in the double-responder allergic sheep. data are "shown in FIGURES 7-14 and 17-22 the dosage of the effective HPMUB administered to the allergic sheep was the lowest effective dose (determined by the tests in dose ranges) for each fraction of HPMUB. It will be noted that the different HPMUB had minimal variation in the effective dose levels in the treatment of double responders. The minimum effective dose was approximately 1.0 mg / kg for CY-222 and for FRU-70 administered before challenge with the antigen, but approximately 0.5 mg / kg for FRU-70 administered after challenge with the antigen and for the mixture of hexasaccharides inhaled The purified tetrasaccharide, having the lowest average molecular weight of any of the effective HPMUBs tested, had a minimal effective dose when administered after the 0.062 mg / kg antigen, such as the purified hexasaccharide. These data suggest that purified fractions having an average weight close to the lower limit of approximately 1000 d may be the most effective HPMUB, at least in the treatment of double responders. The optimal domain and / or structural sequence for the antiallergic and / or antiinflammatory activity observed seems to be the tetrasaccharide.

EXAMPLE 2 Administration of oral HPMUB to double responder allergic sheep The procedure of Example 1, in terms of test animals and evaluation methods, was followed in the present experiment. A double responder allergic sheep was orally administered with 2 mg / kg of purified hexasaccharide (average molecular weight 1998 daltons) 90 minutes before challenge with the Ascaris Suum antigen. The effects of pretreatment with the hexasaccharide on the REP from the baseline (time of administration of the i.e. xasaccharide) through 8 hours after challenge with the antigen are reflected in FIGURE 24. A. Also shown in FIGURE 24 for For purposes of comparison, there is a percentage change in REp in the same double responder sheep (in an experiment conducted a few days before) challenged with the antigen but without previous treatment with HPMUB. Shown in FIGURE 25 are the respective DP400 values measured at the baseline and after the antigen when the sheep was challenged with the antigen previously treated with hexasaccharide and without previous treatment (control).

EXAMPLE 3 Administration of intravenous HPMUBs to double responder allergic sheep The procedure of Example 2 was followed with another double responder allergic sheep, except that 0.25 mg / kg of purified hexasaccharide was administered intravenously one hour before challenge with the antigen in a experiment, while the antigen was administered without previous treatment in the second experiment (control). The change in the percentage in the REp for the experiments with pre-treatment and control are shown in FIGURE 26 and the DP400 values for the experiments in the baseline and after the antigen are shown in FIGURE 27.

EXAMPLE 4 Prevention of eosinophil influx induced by antigen in mice In four groups of sensitized laboratory mice (n = 3 in each group), bronchoalveolar lavage was performed 24 hours after challenge with the antigen to determine the eosinophil influx values in each group. Mice were treated with aerosolized saline (placebo) or purified hexasaccharide administered by the following routes and in the following dosage amounts, respectively: inhaled aerosol, oral (100 μg) and intraperitoneal (40 μg). The percentage of inhibition of the eosinophil influx in each treatment group was determined by comparing the level of this influx measured in the bronchoalveolar lavage fluid after the administration of the hexasaccharide with the saline group. The average values of percent inhibition for the three treatment groups of mice are shown in FIGURE 28. Mice receiving inhaled and oral hexasaccharide showed a 40-50% reduction in eosinophil influx whereas mice receiving Intraperitoneal hexasaccharide showed approximately a 20% reduction in such influx. The mice (n = 3) were placed in a chamber containing 10 mg of hexasaccharide in 9 ml of water for injection, bacteriostatic, which was pulverized. The mice were allowed to inhale the aerosol for approximately 30 minutes. The differential effects of commercial heparin observed in acute and double responders (as shown in FIGURES 2A and 2B) could indicate the relationship of the different signaling pathways during airway anaphylaxis. This could suggest that during the immunologically mediated mastocyte reaction in the respiratory tract, IP3 is the mainly active pathway in "acute responders" while pathways other than IP3 (eg, diacylglycerol / protein kinase C or other pathways). ) may be operands in "double responders". The late phase response and HSVR are associated with marked inflammation in the airways. Pathological studies of the airway mucosa and bronchoalveolar lavage (BAL) have shown an influx of eosinophils, neutrophils and T lymphocytes activated during this phase. Increased levels of inflammatory mediators derived from eosinophils in plasma and BAL, including the eosinophilic cationic protein and the main basic protein, have been observed during the late phase reaction. The overregulation of TH-type cytokines (IL4 and IL5) after challenge with the allergen has also been observed during the late phase. Thus, the cellular inflammatory response, in combination with the released proinflammatory mediators (for example leukotrienes, PAF, eosinophilic proteins, etc.) and locally produced cytokines in the bronchial mucosa, play a central role in late-stage allergic inflammation and bronchoconstriction The HSVR and thus, the inflammation of the respiratory tract can be modified by preventing the release of the mastomediator by "antiallergic agents" (for example cromolyn sodium) or by the action of "anti-inflammatory" agents such as glucocorticosteroids. The "antiallergic" agents are only effective as prophylactic agents and can prevent mediator and HSVR release. Because these agents do not possess anti-inflammatory activity, they are generally ineffective when administered after exposure to the antigen. Conversely, "anti-inflammatory" agents may attenuate HSVR after antigen and airway inflammation, either before or after exposure to the antigen. Our data suggest that the actions of HPMUB are analogous to the "anti-inflammatory actions of glucocorticosteroids." Since effective HPMUBs can modify HSVR even when administered after challenge with the antigen, they should also be useful in the treatment of the non-asthmatic conditions associated with HSVR, eg, chronic bronchitis, emphysema, and cystic fibrosis, Furthermore, in view of our findings related to the efficacy of certain HPMUBs in the inhibition of asthmatic RFT in a way that resembles the effects Anti-inflammatories of corticosteroids, effective HPMUB should also be useful in the treatment of the following conditions by the following routes of administration: 1. Delayed-phase reactions and inflammatory response in extrapulmonary sites: (a) allergic rhinitis (b) allergic dermatitis ( c) allergic conjunctivitis 2. Extrapulmonary diseases where the inflammatory response Tory plays a major role: (i) inflammatory bowel disease (ii) rheumatoid arthritis and other vascular diseases of collagen (iii) glomerulonephritis (iv) inflammatory skin diseases (v) sarcoidosis. - 3. Routes of administration (i) intrabronchial (ii) intranasal (iii) intraocular (iv) topical (v) oral (vi) parenteral (IM or IV) However, it should be emphasized that the invention is not limited or restricted in no sense to any of the physiological or biochemical mechanisms, real or theoretical, but comprises the methods of treatment of the conditions characterized by late-stage allergic reactions, or the treatment of double-responding mammalian patients, and the compositions for use in these methods described in the previous, regardless of the real mechanisms of action involved. In this way it has been shown that the methods and compositions that achieve the different objectives of the invention and that adapt well to meet the conditions of practical use have been provided. As it is possible to make different possible embodiments of the previous invention, and as different changes could be made in the modalities set forth above, it should be understood that all aspects described herein should be construed as illustrative and not in a limiting sense. What is claimed as new and desired to be protected by the Patent titles is established in the following clauses.

Claims (60)

1. A method of treating a mammalian patient suffering from or prone to suffering characterized by late-stage allergic reactions, airway hypersensitivity or inflammatory reactions, the method comprising administering to the patient a pharmaceutical composition containing from about 0.005 to about 1.0. mg of ultralow molecular weight heparins (HPMUB) per kilogram of body weight - of the patient in each dose, the HPMUBs having an average molecular weight of from about 1,000 to about 3,000.

2. The method according to claim 1, wherein the HPMUB have an average molecular weight of from about 1000 to about 2500 daltons.

3. The method according to claim 1, wherein the HPMUB comprise heparin fractions selected from the group consisting of tetrasaccharides, pentasaccharides, hexasaccharides, septasaccharides, octasaccharides and decasaccharides and the pharmaceutically acceptable salts thereof.

4. The method according to claim 1, wherein the HPMUBs are N-sulfated.

The method according to claim 1, wherein the composition contains about 0.075 to about 075 mg of the HPMUB per kilogram per dose.

6. The method according to claim 1, wherein the HPMUBs have practically no anticoagulant activity.

The method according to claim 1, wherein the composition is administered orally, parenterally, topically, intrabronchially, intranasally or intraocularly.

The method according to claim 7, wherein the parenteral administration is intramuscular intravenous cr.

The method according to claim 1, wherein the condition is characterized by late-stage allergic reactions selected from the group consisting of late-phase pulmonary reactions, delayed-phase nasal reactions, delayed-phase skin reactions, ocular reactions in late phase and systemic reactions in late phase.

10. The method according to claim 9, wherein late phase reactions are late phase pulmonary reactions.

11. The method according to claim 10, wherein the condition is late stage asthma.

The method according to claim 1, wherein the condition is a non-asthmatic condition characterized by hypersensitivity of the respiratory tract.

The method according to claim 12, wherein the condition is selected from the group consisting of chronic bronchitis, emphysema and cystic fibrosis.

The method according to claim 1, wherein the condition is characterized by inflammatory reactions.

The method according to claim 1, wherein the condition is selected from the group consisting of allergic rhinitis, allergic dermatitis, allergic conjunctivitis, inflammatory bowel disease, rheumatoid arthritis, vascular collagen diseases, glomerulonephritis, inflammatory diseases of the skin and sarcoidosis.

16. The method according to claim 1, wherein the composition consists of a solution or suspension of HPMUB in an aqueous, pharmaceutically acceptable, liquid inhalant vehicle.

17. The method according to claim 16, wherein the vehicle is isotonic saline or bacteriostatic water.

18. The method according to claim 16, wherein the composition is administered by means of a compression-driven pump or nebulizer.

19. The method according to claim 16, wherein a sufficient amount of the composition is administered to the patient to provide a dose of approximately 0.05-1.0 mg / kg of the UML H.

20. The method according to claim 16, in where the composition contains about 0.75-15.0 mg / ml of 1 to HPMUB.

21. The method according to claim 1, wherein the composition is the aerosol composition containing an aerosol propellant.

22. The method according to claim 21, wherein the composition is dosed through an inhaler for metered doses.

23. The method according to claim 21, wherein a sufficient amount of the composition is administered to the patient to provide a dose of about 0.005-0.1 mg / kg of HPMUB- ^ _

24. The method according to claim 21 , wherein the composition contains approximately 2.2-88 μg / μl of the HPMUB.

25. The method according to claim 1, wherein the composition contains a powder preparation of the HPMUB intermixed with an inert powder acceptable for intrabronchial administration.

26. The method according to claim 25, wherein the inert powder is lactose.

27. The method according to claim 25, wherein the composition is administered by an aerosol dispenser.

28. The method according to claim 25, wherein the composition is administered by a capsule that can be broken.

29. The method according to claim 1, wherein the composition is administered to the patient prior to challenge with the antigen inducing the allergic reaction.

30. The method according to claim 1, wherein the composition is administered to the patient after challenge with the antigen inducing the allergic reaction.

31. A pharmaceutical composition for the treatment of a mammalian patient suffering from or prone to a condition characterized by late-stage allergic reactions, airway hypersensitivity or inflammatory reactions, the composition contains about 0.005 to about 1.0 mg of HPMUB per kilogram of the patient's body weight in each dose in a pharmaceutically acceptable inhalant, oral, parenteral, topical, intranasal or intraocular vehicle, the HPMUB having an average molecular weight of from about 1000 to about 3000 daltons.

32. The composition according to claim 31, wherein the HPMUB have an average molecular weight of from about 1000 to about 2500 daltons.

The composition according to claim 31, wherein the HPMUB comprise heparin fractions selected from the group consisting of tetrasaccharides, pentasaccharides, hexasaccharides, septasaccharides, octasaccharides and decasaccharides and the pharmaceutically acceptable salts thereof.

34. The composition according to claim 31, wherein the HPMUB are N-sulfated.

35. The composition according to claim 31 which contains about 0.075 to about 0.75 of the HPMUB per kilogram per dose.

36. The liquid or fluid composition according to claim 31 which contains about 1.0 to about 20.0 mg of the HPMUBs per Xl of the composition.

37. The composition according to claim 31, wherein the HPMUB have virtually no anticoagulant activity.

38. The composition according to claim 31 comprising a solution of the HPMUB in an aqueous, pharmaceutically acceptable inhalant vehicle.

39. The composition according to claim 38, wherein the carrier is isotonic saline or bacteriostatic water.

40. The composition according to claim 38 which is suitable for administration by means of a compression-driven pump or nebulizer.

41. The composition according to claim 38 which further includes an aerosol propellant and is suitable for administration by a metered aerosol dose inhaler.

42. The composition according to claim 31 which contains a powder preparation of the HPMUB intermixed with an inert powder acceptable for intrabronchial administration.

43. The composition according to claim 42, wherein the inert powder is lactose.

44. The composition according to claim 42 which is administered by an aerosol dispenser.

45. The composition according to claim 42 which is administered from a capsule that can be broken.

46. The composition according to claim 31 which contains a pharmaceutically acceptable oral vehicle.

47. The composition according to claim 46 which is an oral dosage form selected from the group consisting of tablets, capsules, caplets, gelatin capsules, pills, liquid solutions, suspensions or elixirs, powders, dragees, micronized particles and osmotic delivery systems.

48. The composition according to claim 47 further comprising excipients, carriers, fillers, binders, disintegrants, solvents, solubilizing agents, sweeteners or coloring agents.

49. The composition according to claim 331 which contains a pharmaceutically acceptable parenteral vehicle.

50. The composition according to claim 49, wherein the vehicle consists of an isotonic saline solution or a dextrose solution.

51. The composition according to claim 49 which is suitable for intravenous administration.

52. The composition according to claim 49 which is suitable for intramuscular administration.

53. The composition according to claim 31 which contains a pharmaceutically acceptable topical carrier.

54. The composition according to claim 31 which contains a pharmaceutically acceptable intranasal vehicle.

55. The composition according to claim 31 which contains a pharmaceutically acceptable intraocular vehicle.

56. A method of treating a mammalian patient suffering from or prone to a condition characterized by late-stage allergic reactions, airway hypersensitivity or inflammatory reactions, the method is the administration to the patient of a pharmaceutical composition containing about 0.005 to about 1.0 mg of sulfated polysaccharides per kilogram of the patient's body weight in each dose, the sulfated polysaccharides having an average molecular weight of about 1000 to about 3000 daltons.

57. The method according to claim 56, wherein the sulphated polysaccharides are obtained from glycosaminoglycans or mucopolysaccharides.

58. The method according to claim 57, wherein the sulfated polysaccharides are obtained from heparin, heparan sulfate, dermatan sulfate, chondroitin sulfate or pentosana polysulfate.

59. The method according to claim 56, wherein the sulfated polysaccharides comprise tetrasaccharides, pentasaccharides, hexasaccharides, septasaccharides, octasaccharides and decasaccharides and the pharmaceutically acceptable salts thereof.

60. The method according to claim 59, wherein the sulfated polysaccharides comprise the tetrasaccharides.