MXPA98001165A - Method and composition for the treatment of the - Google Patents

Abstract

The present invention relates: A method for treating a patient suffering from asthma induced by an antigen, who has been excited with this antigen, or providing a chronic treatment to an asthma patient to reduce hyper-sensitivity of the respiratory tract , this method comprises the intra-bronchial administration to the patient of a pharmaceutical composition containing in each dose approximately 0.05 to 1.0 mg of ultra-low molecular weight heparins (ULMWH), which have a mean molecular weight of 3,000 daltons or less, per kilogram of the patient's body weight. The pharmaceutical compositions for inhalation, used in the novel method of treatment, are also provist

Description

METHOD AND COMPOSITION FOR THE TREATMENT OF ASTHMA This application incorporates the material included in Disclosure Document No. 377066, filed at the Office of Patents and Trademarks on June 23, 1995. The invention relates to methods and compositions for preventing and eliminating the symptoms and manifestations of asthma. Chronic asthma can be considered as a predominantly 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 individuals. Persistent inflammation is responsible for bronchial hyperresponsiveness or hypersensitivity of the respiratory tract. Mucosal edema and obstruction due to mucus and hypersecretion may be present; The pulmonary parenchyma is normal. The narrowing of the airways can be reversed spontaneously or by means of therapy. Type I (immediate) immune responses can play an important role in the development of asthma in children and many adults; However, when the onset of the disease occurs in adulthood, allergic factors can be difficult to identify. Exposure to dry and cold air, exercise and other aggravating factors can also cause asthma.

The most common symptoms of asthma are shortness of breath and narrowing of the chest; panting, dyspnea and cough may also be prominent. Reduced pulmonary function typical of obstructive rather than restrictive airway disease is usually observed. Asymptomatic periods often alternate with paroxysms. Of the known triggers of asthma, allergens and exercise have received the most attention. Both are powerful stimuli that occur naturally, exercise is a potential factor in the daily life of each asthmatic, while allergens only affect some people with asthma. However, more is known about the effects of the antigen. The general goals of drug therapy for asthma are the prevention of bronchospasm and the control for prolonged periods of bronchial hyperreactivity. Because it is usually not possible for any patient or physician to predict when bronchospasm may occur, patients with almost all episodic attacks and / or all weather season attacks may require continuous therapy. Beta agonists are useful as bronchodilator agents; they stimulate the beta2-adrenergic receptors, increase the intracellular cAMP and can inhibit the release of the mediators of the mastoid cells. Other useful drugs include theophylline and related xanthine, which produce bronchodilation through unknown mechanisms; the bis-chroma, which prevent the release of mediating substances and block respiratory neuronal reflexes, and corticosteroids, which primarily decrease inflammation and edema. Anticholinergic drugs can relieve bronchospasm by blocking parasympathetic cholinergic impulses at the receptor level. Antihistamines occasionally prevent or cancel out allergic asthmatic episodes, particularly in children, but they will not only be partially effective in asthma, because histamine is only one of many mediators. The modalities of current drugs used for the treatment of allergy-induced asthma have a number of drawbacks. In general, conventional agents have a relatively short duration of action and may be, partially or totally, ineffective when administered after the excitation of the antigen occurs. Also, due to the serious adverse effects associated with the use of agents, such as beta2-adrenergic agonists and corticosteroids, the therapeutic safety margin with such agents is relatively narrow and patients who use them should be carefully monitored. Bronchial hyperreactivity (or airway hypersensitivity) is a hallmark of asthma and is closely related to the fundamental inflammation of the airways. The worst of asthma and inflammation of the respiratory tract is associated with the increase in bronchial hyperreactivity, which can be induced by both 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 decreased regulation of beta2-receptors, can worsen bronchial hyperreactivity. At present, corticosteroids are the only effective agents available, which decrease 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 research continues for safe and effective agents that reduce bronchial hyperreactivity.

It has been discovered in several past years that heparin, administered intrabronchially, can be an effective inhibitor of bronchospasm and bronchoconstriction and, consequently, is of value in the prophylaxis of asthma (see, for example, Ahmed et al., New Eng. J. Med., 329: 90-95, 1993; Ahmed, Resp. Drucr 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 to 5,000 daltons, effectively prevent antigen-induced bronchoconstriction; these low molecular weight heparins also exhibit considerably less anticoagulant activity than commercial heparin, a convenient property when these agents are used in the treatment of asthma (see Ashkin et al., Am. Rev. Resp. Dis., 1993 Intl Conf. Abstracts, pp. A660 While various heparins have been found useful as prophylactic agents when administered prior to excitation with the antigen, however, they have been described in the prior art as non-effective, when administered after excitation with the antigen, in modifying the bronchoconstrictor response and the airways hypersensitivity (Ahmed et al., J. Appl. Physiol., 76: 893-901, 1994).

It is an object of the present invention to provide a method and compositions for the treatment of antigen induced asthma and bronchial hyperreactivity, which do not possess the drawbacks of the prior art. It is a further object of the present invention to provide a method and compositions for the treatment of asthma, which are effective in preventing and eliminating the manifestations of an asthmatic episode. 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 hyperresponsiveness, and even when administered after excitation of the antigen to the patient. In complying with these objects and others, which will become apparent below, the invention resides in a method of treating a patient suffering from antigen induced asthma, through intrabronchial administration to the patient of a pharmaceutical composition comprising approximately from 0.05 to 1.0 mg of ultra-low molecular weight heparins per kilogram of the body body of the patient in each dose. The administration of these heparins can be on an acute basis following the excitation of the antigen or on a chronic basis to suppress bronchial hyperreactivity. The ultra-low molecular weight heparins used in the present invention have average molecular weights of less than 3,000 daltons and may exhibit a low level of anticoagulant activity or substantially no anticoagulant activity at all. Also novel inhalant compositions are provided in the form of a liquid or powder nebulizer or aerosol compositions containing suitable concentrations of ultra-low molecular weight heparins. Figure 1 is a bar graph illustrating the effect of previous treatment with heparin (CY222), ultra-low molecular weight, inhaled, at various dose levels in acute bronchoconstriction induced with antigen in an allergic sheep. The data are shown as the average antigen induced ± change in SE% in the SRjj, without and after the previous treatment with the CY222. SRL = specific resistance of the lung + = significantly different from the control of the antigen (P <.05). Figure 2 is a bar graph illustrating the effect of pretreatment with heparin (CY216), of low molecular weight, inhaled, in acute bronchoconstriction induced with antigen in an allergic sheep. The data are shown as the mean induced with antigen ± change in SE% in the SRL, without and after the previous treatment with CY216. Figure 3 is a bar graph illustrating the effect of pretreatment with heparin (Fragmin), of medium molecular weight, inhaled in the bronchoconstriction induced with antigen in an allergic sheep. The data are shown as the average antigen-induced ± SE change% in the SRL, without and after treatment with Fragmin. Figure 4 is a bar graph illustrating the effect of pretreatment with heparin (CY222), ultra-low molecular weight, inhaled in airway hypersensitivity induced with antigen, in an allergic sheep. The data are shown as the average after the antigen ± SE% of PD4, as a percentage of the baseline, without and after previous treatment with CY222. PD4 = cumulative provocation dose of carbachol, which increases the SRL to 400% above the baseline + = significantly different from the antigen alone (P <.05). Figure 5 is a bar graph illustrating the effect of pretreatment with heparin, (CY216) of low molecular weight, inhaled, in airway hypersensitivity induced with antigen in an allergic sheep. The data are shown as the average after the antigen ± SE of PD4, as the percentage of the baseline, without and after previous treatment with CY216. Figure 6 is a bar graph illustrating the effect of pretreatment with heparin (Fragmin), medium molecular weight, inhaled, in airway hypersensitivity induced by antigen in an allergic sheep. The data are shown as the average after the antigen ± SE of PD4, as the percentage of the baseline, without and after the previous treatment with Fragmin. Figure 7 is a graph illustrating the comparative protective effects of inhaled CY222, CY216 and Fragmin on the acute bronchoconstrictor response (ABR), induced with antigen, in an allergic sheep. The data are shown as the average after the antigen ± SE% protection of the ABR induced with antigen. The horizontal thick bars represent the ID50 + = significantly different from the Fragmin (P <.05) * = significantly different from the CY216 (P <.05) Figure 8 is a graph illustrating the comparative protective effects of inhaled CY222, CY216 and Fragmin on airway hypersensitivity (AHR) induced with antigen, in an allergic sheep. The data are shown as the average after antigen ± SE% protection of the changes induced with antigen in the PD4. Figure 9 is a bar graph illustrating the effect of CY222 on airway hypersensitivity induced with antigen, with CY222 being administered as an aerosol, immediately after excitation with the antigen. + = significantly different from the baseline (P <.05) Figure 10 is a bar graph illustrating the effect of commercial heparin on airway hypersensitivity induced with antigen, with commercial heparin being administered as a spray immediately after excitation with the antigen. Figure 11 is a bar graph illustrating the effest of Fragmin in airway hypersensitivity induced with antigen with Fragmin being administered as an aerosol immediately after excitation with the antigen. Heparin, a sulfonated ucopolysaccharide, was synthesized in mastoid cells as a proteoglycan and is abundant particularly in the lungs of several animals. Heparin is not a specific compound of a fixed molecular weight, but is actually a heterogeneous mixture of sulfonated polysaccharide chains, composed of repeated units of D-glucosamine and any of the L-iduronic or D-glucuronic acids. The average molecular weight of heparin isolated from animal tissues varies from approximately 6,000 to 30,000 daltons. Pharmacologically, heparin is primarily known as an anticoagulant. This activity results from the ability of heparin to bind to some residues of antithrombin III (AT-III), which accelerates the neutralization by AT-III of activated coagulation factors and prevents the conversion of protro bina to thrombin . Larger amounts of heparin can inactivate thrombin and early coagulation factors, preventing the conversion of fibrinogen to fibrin. The anticoagulant activity of heparin is related to the molecular weight of its polysaccharide fragments; low molecular weight components or fragments (eg, fragments having a molecular weight of less than 6,000 daltons) have moderated the low effects of antithrombin and hemorrhages. Similarly, low molecular weight heparins, isolated from animal tissue, have reduced anticoagulant properties, because they consist primarily of smaller fragments or molecular weight fractions.

Commercial heparin, which is generally derived from the lung of the beef or intestinal mucosa of the pig, has an average molecular weight of about 15,000 to 17,500 daltons. Heparin has been shown to act as a specific blocker of IP3 receptors, and inhibits IP3 mediated by calcium release. We have previously suggested that heparin can block IP3 receptors in mastoid cells and, therefore, interfere with signal transduction and can modulate mastoid cell degranulation and mediator release. In vivo and in vitro studies support this concept and have shown that inhaled heparin can attenuate allergic bronchoconstriction in sheep, prevent asthma induced by exercise, as well as inhibit the release of histamine from mastoid cells induced by the IgE Heparin inhaled in doses up to 1,000 units / kg, has been found to have no effect on the partial time of thromboplastin (PTT), thus suggesting a "non-anticoagulant" effect. Low molecular weight heparins (average molecular weight of approximately 4,500 daltons), which has reduced APTT activity, have been reported to be effective in animal studies in preventing acute broncho-constrictor (ABR) response induced with antigens, and bronchial hyperreactivity, also referred to as bronchoconstrictive hypersensitivity (AHR). However, as discussed 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 improving AHR subsequent to antigen excitation in the subjects of proof. These heparins apparently provide only a preventive, prophylactic effect, but not of value in treating an asthmatic episode caused by the antigen. It has now been discovered, surprisingly, that ultra-low molecular weight heparin fractions (ULMWH) are not only effective inhibitors of airway anaphylaxis, but are also highly effective in reducing SHR, even when administered after of the excitation of the antigen. Chronic regular use of ULMWH should also reduce AHR and, therefore, ULMWH can be used for chronic asthma therapy, when it is caused by specific (ie antigenic) or non-specific factors. Accordingly, the present invention is a method for treating a patient suffering from asthma induced with antigen, who has been excited with an antigen that causes asthma, which comprises the intrabronchial administration to the patient of a pharmaceutical composition containing approximately 0.05 to 1.0 mg of one or more fractions of the ULMWH per kilogram of body weight of the patient, in each dose of the composition, and preferably of about 0.075 to 0.75 mg / kg per dose. For purposes of this application, ULMWH can be defined as fractions of heparin having an average molecular weight of 3,000 daltons or less. The ULMWH having an average molecular weight of 2,500 daltons or less may be even more effective when used in the method of the invention. Each fraction of the ULMWH may comprise disaccharides, trisaccharides, tetrasaccharides and / or pentaaccharides, as well as molecules of greater chain length. According to the invention, a patient suffering from asthma induced with antigen, who has inhaled, ingested or otherwise contacted an antigen (ie, has been "excited" with an antigen) of a known type causes asthmatic episodes in that patient, when or not the patient already exhibited symptoms of ABR and / or AHR, was promptly administered by inhalation with a dose of a pharmaceutical composition containing one or more fractions of the ULMWH, cumulatively present in the concentration ranges described above. Additional doses can be administered immediately, as needed, until the patient returns or maintains the normal resistance levels of the air flow. The invention also comprises the chronic administration of ULMWH to patients with asthma, to reduce and suppress AHR. "Chronic administration", as used herein, refers to the administration of the compositions containing the ULMWH, at least once a day, for at least ten consecutive days. Chronic administration of a composition containing about 0.05 to 1.0 mg / kg per dose and preferably about 0.075 to 0.75 mg / kg per dose can be continued indefinitely to deliver a therapy that suppresses AHR, at least comparable to corticosteroids, but substantially without side effects. Despite the known activity of heparins N-desulfated in other biological systems, for example as inhibitors of cell growth, it has been found that the ULMWH fractions that are active and can be used in the present invention for the treatment of asthmatic patients, are all N-sulfated; N-desulfated fractions are not effective. The ULMWH inhalant compositions used in the present invention may comprise liquid or powder compositions containing the ULMWH and are suitable for nebulization and intrabronchial use, or aerosol compositions administered by means of determined doses distributed in an aerosol unit. . Suitable liquid compositions comprise the ULMWH in a pharmaceutically acceptable inhalant aqueous solvent, for example an isotonic saline solution or bacteriostatic water. The solutions are administered by means of a nebulized spray pump or dispenser, actuated by tightening, or by any other conventional means, to cause or enable the required quantity of the liquid composition to be inhaled into the patient's lungs. Suitable powder compositions include, by way of illustration, powdered preparations of heparin intermixed completely with lactose or other inert powders acceptable for intrabronchial administration. The powder compositions can be administered by means of an aerosol dispenser or enclosed in a rupturable capsule, which can be inserted by the patient in a device that perforates the capsule and blows the powder in a stable current suitable for inhalation. Aerosol formulations for use in the present method will typically include fluorinated alkane propellants, surfactants and co-solvents, and may be filled into aluminum containers or other conventional aerosol containers, which are then sealed by a suitable metering valve and pressurized with the propellant. The total concentration of fractions of the ULMWH in any vehicle suitable for use in accordance with the present invention must be sufficiently high to supply the required dose of approximately 0.05 to 1.0 mg of the ULMWH / kg. Thus, for example, if a nebulizer delivers 4 ml of solution per dose, the concentration of the ULMWH in the solution, in the case of a patient weighing 75 kg, should be approximately 1.0 to 20.0 mg / ml. As those skilled in the pharmaceutical arts will appreciate, many conventional methods and apparatuses are available to deliver precisely dosed doses of intrabronchial drugs and to regulate the amount of desired dose, according to the weight of the patient and the severity of the patient's condition. . Also, there are many vehicles, recognized in the art, liquid, powder and aerosol, suitable for the intrabronchial compositions of the ULMWH of the present invention. The invention is not limited to any particular inert carrier, solvent, carrier or excipient and is not restricted to any particular method or apparatus or intrabronchial administration. The ULMWH compositions described herein provide a highly effective treatment for antigen-induced asthma, even after excitation with the antigen has occurred. To demonstrate the unexpected superiority of the ULMWH fractions, compared to the higher molecular weight heparins in treating antigen-induced asthma, after excitation of the antigen, experiments were conducted comparing the effects of different types of heparins in allergic sheep, both before and after the excitation of the antigen. Detailed descriptions of these experiments and the results obtained are indicated in the following examples, as in the figures shown in the drawings. The following examples, while illustrating the method of the invention and demonstrating the efficacy thereof, do not attempt to indicate specific materials, procedures or dose regimens, which should be used exclusively for the purpose of practicing the invention.

EXAMPLE I Administration of Heparin Before the Excitation of Antigens Methods Resistance to Pulmonary Airflow Ten and six allergic sheep, with only acute bronchoconstrictor response, previously documented, to the antigen Asear is suum, were used for all studies. The sheep were intubated with a fist-type nasotracheal tube and the resistance (Rj) to the pulmonary air flow was measured by the esophageal balloon catheter technique, while the thoracic gas volume was measured by the body plethysmography. The data are expressed as the specific (SRL defined as RL by the volume of the thoracic gas (V ^ g).) Sensitivity of the Respiratory Tracts To assess the sensitivity of the respiratory tract, cumulative dose-response curves were made to inhaled cabbage, measuring the SRL before and after the inhalation of the regulated saline solution and after each administration of 10 breaths with increased concentrations of carbachol (0.25, 0.5, 1.0, 2.0 and 4.0% weight / volume of solution). Respiratory measures were measured by determining the cumulative provocation dose (PD4) of carbachol (in units of respiration) that increased the SR to 400% above the baseline.A breath unit is defined as a respiration of a 1% carbachol solution. Fractions of Heparin: In the experiment comparing the effectiveness of various heparin materials administered to the allergic sheep prior to excitation of the antigen, a UL MWH (CY222, Sanofi, Paris, France), a low molecular weight heparin (CY216, Sanofi) and a medium molecular weight heparin (Fragmin, Kabivitrum Stockholm, Sweden) were used. The molecular weight and the other characteristics of these heparin fractions are indicated in Table I. TABLE 1 MOLECULAR WEIGHT AND CHARACTERISTICS OF THE FRACTIONS OF HEPARIN CY222 CY216 FRAGMIN (ULMWH, (LMWH) (MMWH) Molecular Weight 2355 d 4270 d 6400 d Anti-Xa Activity 70 IU / mg 112 IU / mg 158 IU / mg Anti-IIa activity 12 U: I / mg 29 U: I: / mg APTT 28 IU / mg 45 IU / mg 58 IU / mg Anti-Xa / APTT ratio 2.5 2.5 2.72% GAG content 70% 60% 65%% chain ULMW 88% 27% 11% (mol weight <2500 d) As indicated in the table, the ULMWH used in this experiment not only has a molecular weight well below 3,000, but also about 88% of the heparin chains included in this fraction have molecular weights below 2,500.

Experimental Protocol Respiratory Tract Studies Each sensitivity of the respiratory tract (PD4) of the baseline of the animal was determined, and then on different experimental days the sheep underwent excitation of the respiratory tract with the Ascaris suum antigen. L SR was measured, before and immediately after the excitation and then every hour until 2 hours when the SRL returned to the baseline. After arousal, PD4 was measured. The protocol was repeated at least 14 days later, after the previous treatment with CY222, CY216 and Fragmin aerolized, at doses of 0.31, 0.62, 1.25, 2.5 and 5.0 mg / kg. Data Analysis: Data are expressed as (a) average ± SE% change of SRL; (b) PD as% of the baseline; (c)% protection of the acute response of the bronchoconstrictor (ABR) and (d)% protection of the airways hypersensitivity (AHR).

SR | _ after excitation - SR? _ Baseline x 100 (a) SR | _ (% change) = SR | _ baseline PD4 after excitation x 100 (b) PD4 (% of baseline) = PD4 of baseline Control? SRL% - LMWHF? SRL% x 100 (c) ABR Protection% = Control? SRL% LMWHF PD4 - CONTROL ANTIGEN PD4 X 100 (D) AHR protection% = PD4 baseline - PD4 control antigen The comparative effects of the pretreatment with the test materials in the ABR and AHR are indicated in Tables 2-6 and are illustrated graphically in Figures 1 to 8. The data show that the previous treatment with the aerolized CY222, CY216 and Fragmin , attenuated with the acute bronchoconstrictor response, induced by antigen in a dose-dependent manner; the doses for the minimum effects were 0.62 mg / kg, 1.25 mg / kg and 2.5 mg / kg, respectively. The previous treatment with aerolyzed CY222, CY216 and Fragmin, attenuated the AHR induced with the antigen in a dose-dependent manner, the minimum effective doses were 0.62 mg / kg, 1.25 mg / kg and 5.0 mg / kg, respectively. The analysis of the drug comparison revealed that the protective effects were inversely related to the molecular weight of the heparin fractions. The ULMW fraction, CY222, was the most potent agent, as shown by the significant inhibition of bronchoconstriction induced by antigen and AHR at a dose of 0.6 mg / kg, while CY216 and Fragmin were not effective at this dose. The mean values of the ID50 group of CY222, CY216 and Fragmin against allergic bronchoconstriction were 0.5, 1.3 and 1.8 mg / kg, respectively. The average group values of the ID50 of CY222, CY216 and Fragmin against the AHR were 0.51, 2.5 and 4.7 mg / kg.

TABLE 2 EFFECT OF PREVIOUS TREATMENT WITH CY222 ON ANTIGEN-INDUCED BRONCOCONSTRICTION CONTROL OF ANTIGEN CY222 Dose Post-Line Line Post- Post- (mq / kg) Base Excitation Base CY222 Excitation 0. 31 1.15 3.27 * 1.17 1.08 2.66 * (n = 7) (0.04) (0.33) (0.05) (0.06) (0.35) 0. 62 1.15 3.27 * 1.15 1.21 1.65+ (n = 7) (0.04) (0.33) (0.05) (0.06) (0.06) 1. 25 1.16 3.43 * 1.08 1.17 1.71+ (n = 6) (0.04) (0.32) (0.06) (0.05) (0.19) 2. 5 1.13 3.31 * 1.04 1.06 1.33+ (n = 6) (0.04) (0.39) (0.05) (0.10) (0.09) . 0 1.13 3.31 * 1.16 1.12 1.56+ (n = 6) (0.04 (0.39) (0.05) (0.02) (0.12) The data are shown as mean ± SE SRL (thickened lung resistensia), without and after previous treatment with increasing doses of the inhaled CY222.

* Significantly different from the baseline (P <0.05) + Significantly significant antigen control (P <0.05) TABLE 3 EFFECT OF PREVIOUS TREATMENT WITH CY216 IN ANTIGEN-INDUCED BRONCOCONSTRICTION CONTROL OF THE ANTIGEN CY216 Dose Post-Line Line Post- Post- (mg / kg) Base Excitation Base CY216 Excitation 0. 31 0.92 2.64 * 1.12 1.08 3.21 * (n = 7) (0.04) (0.23) (0.07) (0.04) (0.09) 0. 62 0.92 2.64 * 1.04 1.07 2.54 * (n = 7) (0.04) (0.23) (0.06) (0.03) (0.31) 1. 25 1.12 3.24 * 1.04 1.20 2.03 + (n = 8) (0.04) (0.29) (0.07) (0.13) (0.36) 2. 5 1.14 3.36 * 1.05 1.04 1.76+ (n = 5) (0.05) (0.48) (0.07) (0.11) (0.32) . 0 1.09 3.35 * 1.09 1.18 1.75+ (n = 6) (0.04) (0.14) (0.03) (0.08) (0.20) The data are shown as mean ± SE SRL (thickened lung resistensia), without and after the previous treatment are doses of the inhaled CY216.

* Differently significant of the baseline (P <0.05) + Differently significant antigen control (P <0.05) TABLE 4 EFFECT OF TREATMENT WITH FRAGMIN IN THE INDUCED BRONCOCONSTRICTION BY ANTIGEN CONTROL OF ANTIGEN FRAGMIN Dosage Post-Line Line Post- Post- (mq / kg) Base Excitation Base FRAGMIN Excitation 1. 25 1.04 3.37 * 1.11 1.07 2.71 * (n = 7) (0.06) (0.32) (0.05) (0.08) (0.42) 2. 5 0.96 3.19 * 1.07 1.16 1.56+ (n = 6) (0.04) (0.30) (0.08) (0.12) (0.25) . 0 1.00 3.39 * 0.98 0.98 1.47+ (n = 7) (0.01 = (0.39) (0.03) (0.03) (0.21) The data are shown as mean ± SE SRL (thickened lung resistensia), without and after the previous treatment they are doses of the inhaled Fragmin.

* Differentially significant of the baseline (P <0.05) + Differently significant antigen control (P <0.05) TABLE 5 EFFECT OF PREVIOUS TREATMENT WITH CY222. CY216 AND FRAGMIN INHALED. IN HYPERSENSITIVITY OF RESPIRATORY ROUTES INDUCED WITH ANTIGEN The data are shown as the average ± SE of carbacol PD4 in units of respiration, for the baseline and after the antigen, without (control) and after the previous treatment (drug) with several fractions of heparin. PD4 = carbacol cumulative provocation dose which increased the SR | _ to 400% above the baseline. A breath unit is equivalent to a 1 mg / ml breath of carbachol. * Significantly different from baseline (P <0.05) + Significantly different from antigen control (P <0.05) TABLE 6 COMPARISON OF THE PROTECTIVE EFFECTS OF THE CY222 INHALED (ULTRA-LOW MOLECULAR WEIGHT); LA CY 216 (LOW MOLECULAR WEIGHT) AND FRAGMIN (MEDIUM MOLECULAR WEIGHT) IN THE INDUCED BRONCHONSTRICTION WITH ANTIGEN AND THE HYPERSENSITIVITY OF THE ROADS RESPIRATORY The data shows how the average ± SE% protection in each dose, the average DI50 of the calculated group (dose of inhibition that causes 50% protection) is also shown for each group. / Significant protection (P < 0.05) + Significantly different from Fragmin (P <0.05) * Significantly different from CY216 (P <0.05) EXAMPLE II Administration of Heparins Following the Antiane Exsysation The same experimental protocol was followed as in Example 1, exsept that: (a) the three heparin materials administered to the test animals were CY222, a somersial heparin (weight molecular weight of approximately 15,000 daltons) and the Fragmin and (b) the heparins were administered to the animals as an aerosol, immediately after excitation by the antigen. The data tested is indicated in Table 7 and illustrated graphically in Figures 9 to 11.

TABLE 7 COMPARATIVE EFFECTS OF INHALED COMMERCIAL HEPARIN (8 mg / kg), THE FRACTION OF MEDIUM MOLECULAR WEIGHT HEPARIN (FRAGMIN, 5 mg / kg) AND THE FRACTION OF ULTRA-LOW MOLECULAR WEIGHT HEPARIN (CY222, 0.6 mg / kg) IN THE HYPERSENSITIVITY OF THE RESPIRATORY ROUTES, INDUCED BY ANTIGEN Baseline Post- Post- Antigen Antigen (Control) (Heparin) Heparin 18.9 ± 2.1 10.5 ± 0.2 * 8.9 ± 2.2 * Fragmin 22.7 ± 3.2 13.3 ± 2.0 * 9.5 ± 2.6 * CY222 20.4 ± 1.7 11.7 ± 2.1 * 25.1 ± 1.1 * The data are shown as the mean ± SE PD400 of sarbasol in units of respiration (one unit of respiration is equivalent to a respiration of 1 mg / ml of sarbasol). All the agents were nebulized immediately "after" the exsitiation is the antigen. * Significantly different from baseline (p <0.05) + Significantly different from antigen control (p <0.05). Only the CY222 offered significant protection.

As indicated by Table 7 and Figures 9-11, the inhaled CY222, administered after exsysation by the antigen, substantially modified the AHR after the antigen. This efesto was not observed in somersial heparin or Fragmin, in which there was no improvement in the AHR of the administration after the exsisation of these heparins. Thus, methods and sompositions have been provided that achieve the various objects of the invention and that adapt well to comply with the sondisiones of pristine use. As several modalities of the previous invention are possible and as several sambios can be done in these modalities, previously indicated, it will be assumed that all the material, here, will be interpreted as illustrative and not in a limiting sense. What is claimed as novel and what is desired to be protected by a patent is stated in the following claims.

Claims (34)

1. CLAIMS 1. A method to treat a patient suffering from antigen-induced asthma, which has been excited is an antigen that induces asthma, this method involves intrabronchial administration to the patient of a pharmacological somatosis who are approximately 0.05 to 1.0 mg of ultra-low molecular weight heparins (ULMWH) per kilogram of surrogate weight of the sada dose in the past, these ULMWH have an average weight of 3,000 daltons or less.
2. 2. One method of agreement is claim 1, in which the ULMWH have an average weight of 2,500 daltons or less.
3. 3. One method of agreement is claim 1, in which the somposission is approximately 0.075 to 0.75 mg of the ULMWH per kilogram per dose.
4. 4. One method of agreement is claim 1, in which the somposision contains approximately 1.0 to 20.0 mg of the ULMWH per ml of the somposision.
5. 5. One method, I agree, is claim 1, in which the ULMWH substantially do not have anticoagulant activity.
6. 6. One method, I agree is the reivindisasión 1, in which the ULMWH somenar disastaridos, trisasáridos, tetrasasáridos or pentasasáridos.
7. 7. One method, I agree, is claim 1, in which the somposission results in a dissolution of the ULMWHs in a windy inhaling vehicle, which can be achieved pharmaceutically.
8. 8. One method of agreement is claim 7, in which the vehicle is an isotonic saline solution or basteriostátisa water.
9. 9. One method of agreement is the vindication 7, in which the somposission is administered by means of a pump or a nebulizer that is astivated when tightened.
10. 10. One method of agreement is claim 7, in which the somposision also includes an aerosol propellant and is administered by means of an inhaler at a given aerosol dose.
11. 11. One method, I agree, is claim 1, in which the somposisance of a powder preparation of the intermixed ULMWH is an inert powder, assumable for intrabronchial administration.
12. 12. One method, I agree is the vindication 11, in which the inert dust is the wasteful.
13. 13. One method of agreement is the claim 11, in which the deposition is administered by means of an aerosol dispenser.
14. 14. A method, according to claim 11, wherein the somposisance is administered from a ruptured sachet.
15. 15. A method to treat a patient who suffers from asthma, by the redussion and suppression of the hypersensitivity of the respiratory tract, this method involves intrabronchial administration, on a srónisa basis, to a patient, of a pharmaceutic somposision containing approximately 0.05 at 1.0 mg of ultra-low molecular weight heparins (ULMWH) per kilogram of body weight of the sada-dose inlet, these ULMWH have an average weight of 3,000 daltons or less.
16. 16. One method of agreement is the vindication 15, in which the ULMWH have an average weight of 2,500 daltons or less.
17. 17. One method of agreement is the vindication 15, in which the somposition contains approximately 0.075 to 0.75 mg of the ULMWH per kilogram per dose.
18. 18. One method of agreement is the claim 15, in which the somposission is approximately 1.0 to 20.0 mg of the ULMWH per ml of the deposition.
19. 19. A method, according to claim 15, wherein the ULMWH substantially does not have anti-coagulative activity.
20. 20. One method of agreement is the vindication 15, in which the ULMWH somersates disascaridos, trisacharides, tetrasasáridos or pentasasáridos.
21. 21. A pharmaceutic pharmacy for the treatment of a patient suffering from asthma induced by antigen, this somposisance comprises approximately 0.05 to 1.0 mg of the ULMWH per kilogram of the weight of the pasture in a single dose, in a pharmaceutically acceptable inhalant vehicle, these ULMWH they have an average weight of 3,000 daltons or less.
22. 22. A somposision, of agreement is the reivindisasión 21, in which the ULMWH have an average molecular weight of 2,500 daltons or less.
23. 23. A composition, of agreement are the reivindisasión 21, sual somprende approximately 0.075 to 0.75 mg of the ULMWH per kilogram per dose.
24. 24. A somposission, according to claim 21, the sual contains approximately 1.0 to 20.0 mg of the ULMWH per ml of the composition.
25. 25. A composition, according to claim 21, where the ULMWH substansially have no antisoagulant astividad.
26. 26. A somposission, of agreement is the reivindisasión 21, in which sada ULMWH somersates disascaridos, tri-saccharides, tetrasacáridos or pentasasáridos.
27. 27. A somposision, of agreement is the reivindisasión 21, the sual somprende a solusión of the ULMWH in an inhabitant vehileulo asuoso, aseptable farmaséutisamente.
28. 28. A somposission, of agreement is the vindication 27, in which the vehicle is an isotonic saline solution or basteriostátisa water.
29. 29. A somposision, of agreement are the vindication 27, the suals adesüada for the administration by means of a pump or a nebulizer that is assiona when tightened.
30. 30. A somposission, of agreement is the claim 27, which also includes an aerosol propellant and is added to the administration by means of an inhaler of a certain dose of aerosol.
31. 31. A somposision, of agreement is the vindication 27, the sual somprende a preparasión in dust of the intermixed ULMWH are an inert powder, aseptable for intrabronchial administration.
32. 32. A somposision, of agreement are the vindication 3 ^, in which the inert dust is the wasteful.
33. 33. A somposision, of agreement is the reivindisasión 31, the sual is administered by means of an aerosol dispenser.
34. 34. A composition, of agreement are the reivindisasión 31, the sual is administered from a sapsula that can be broken.