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WO1993019734A1 - Procede et composition de traitement de l'asthme provoque par un antigene et par l'effort - Google Patents

Procede et composition de traitement de l'asthme provoque par un antigene et par l'effort Download PDF

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Publication number
WO1993019734A1
WO1993019734A1 PCT/US1993/002880 US9302880W WO9319734A1 WO 1993019734 A1 WO1993019734 A1 WO 1993019734A1 US 9302880 W US9302880 W US 9302880W WO 9319734 A1 WO9319734 A1 WO 9319734A1
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Prior art keywords
heparin
composition
induced
units
exercise
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Application number
PCT/US1993/002880
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English (en)
Inventor
Tahir Ahmed
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Baker Norton Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
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Publication of WO1993019734A1 publication Critical patent/WO1993019734A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters

Definitions

  • the invention relates to methods of preventing and reversing the symptoms and manifestations of asthma.
  • Chronic asthma can be considered to be predominantly an inflammatory disease with associated bronchospasm.
  • the degree of reactivity and narrowing of the bronchi in response to stimuli is greater in asthmatics than in normal individuals. Persistent inflammation is responsible for the bronchial hyperreactivity. Mucosal edema and mucus plugging and hypersecretion may be present; pulmonary parenchyma is normal. Airway narrowing may reverse spontaneously or with therapy.
  • Type 1 (immediate) immune responses may play an important role in the development of asthma in children and many adults; however, when onset of disease occurs in adulthood, allergic factors may be difficult to identify. Exposure to cold dry air, exercise and other aggravating factors also may trigger asthma.
  • Beta agonists are useful; they stimulate beta 2 - adrenergic receptors, increase intracellular cAMP, and inhibit the release of inflammatory mediators.
  • Other useful drugs include theophylline and related xanthine drugs, which produce bronchodilation through unknown mechanisms; the biscromone, cromolyn, which prevents the release of mediator substances and blocks respiratory neuronal reflexes, and corticosteroids, which primarily decrease inflammation and edema.
  • Anticholinergic drugs may relieve bronchospasm by blocking parasympathetic cholinergic impulses at the receptor level.
  • Antihistamines occasionally prevent or abort allergic asthmatic episodes. particularly in children, but they can only be partially effective in asthma because histamine is only one of many mediators.
  • Standard treatment for exercise-induced asthma includes the use of an inhalant.
  • Beta 2 -adrenergic agents administered 15 minutes before exercise provide some protection from broncho-constriction for up to four hours, and cromolyn sodium administered up to two hours prior to exercise may afford limited protection in some patients.
  • the current drug modalities used for treatment of allergy-induced and exercise-induced asthma suffer from a number of drawbacks.
  • the conventional agents have a relatively short duration of action and must be repeatedly administered for prophylaxis.
  • the therapeutic margin of safety with such agents is relatively narrow and patients using them must be carefully monitored.
  • the current treatment regimens are inadequate and often of only limited prophylactic value.
  • Still another object of the present invention is to provide a method and compositions as described above which are highly effective in preventing the onset of exercise-induced asthma.
  • Yet a further object of the present invention is to provide a method and compositions as described above which are safe, simple and relatively inexpensive.
  • the invention resides in a method of treating a patient suffering from antigen- induced or exercise-induced asthma through the intrabronchial administration to the patient of a pharmaceutical composition comprising from about 300 to about 2,000 units of heparin per kilogram of patient body weight in each dose, with about 1 to 4 doses administered daily.
  • Novel inhalant heparin compositions are also provided in the form of liquid or powdered nebulizer or aerosol compositions containing suitable concentrations of heparin.
  • FIG. 1 is a bar graph showing the effect of increasing doses of inhaled heparin on bronchoconstriction, with data given as mean ⁇ SE% increase SR L (specific lung resistance) .
  • FIG. 2 is a bar graph comparing the effects of benzyl alcohol, dextran sulfate and N-desulfated heparin on antigen-induced bronchoconstriction.
  • the open bars represent control data, while post-drug treatment data are shown in hatched bars.
  • FIG. 3 is a bar graph comparing the effects of inhaled heparin on bronchoconstriction responses induced by antigen, compound 48/80 and histamine.
  • FIG. 4 is a bar graph showing the time-dependent inhibition of antigen-induced bronchoconstriction by inhaled heparin (1,000 units/kg). Data are shown as mean ⁇ SE. Starred values are significantly different from control (p ⁇ 0.05) .
  • FIG. 5 includes four graphs showing the in vitro effects of heparin on antigen-induced tracheal smooth muscle contraction in sheep:
  • 5A - Shows the inhibition of antigen-induced contraction by increasing doses of heparin; the tension is plotted as a percent of the acetylcholine maximum reflected in 5C.
  • 5B Shows comparative inhibition by heparin (H) and nedocro il (NED) of antigen-induced tracheal muscle contraction.
  • 5D Shows failure of heparin and nedocromil to modify acetylcholine-tracheal muscle contraction as shown by EC 50 .
  • FIG. 6 includes bar graphs reflecting the effects of inhaled heparin (1,000 units/kg) on exercise-induced bronchoconstriction in 3 human subjects, with data shown as percent decrease in specific airway conductance (SG aw ) .
  • Heparin a sulfated mucopolysaccharide
  • Heparin is synthesized in mast cells as a proteoglycan and is particularly abundant in the lungs of various animals.
  • Heparin is not a specific compound of fixed molecular weight but is actually a heterogenous mixture of variably sulfated polysaccharide chains composed of repeating units of D-glucosamine and either L-iduronic or D-glucuronic acids.
  • the average molecular weight of heparin isolated from animal tissues ranges from about 6,000 to about 30,000 Da.
  • heparin is known primarily as an anticoagulant. This activity results from heparin 1 s ability to bind to some of the residues of antithrombin III (AT-I I) , accelerating the neutralization by AT-III of activated clotting factors and preventing the conversion of prothrombin to thrombin. Larger amounts of heparin can inactivate thrombin and earlier clotting factors, preventing 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 (for example, fragments having a molecular weight of less than 6,000) have moderate to low antithrombin and hemorrhagic effects. Similarly, low molecular weight heparins isolated from animal tissue have reduced anticoagulant properties because they consist primarily of the lower molecular weight fragments or fractions.
  • heparin which is generally derived from beef lung or pork intestinal mucosa, has an average molecular weight of about 15,000-17,500.
  • the method of the present invention comprises the intrabronchial administration to a patient suffering from antigen-induced or exercise-induced asthma of a pharmaceutical composition containing about 300 to about 2,000 units of heparin per kilogram of body weight in each dose, and preferably about 500 to about 1000 units/kg per dose.
  • heparin dosage is prescribed in units rather than milligrams.
  • the U.S.P. standard for minimal heparin potency is 120 units/mg of dry material derived from lung tissue and 140 units/mg of dry material derived from other sources, with the U.S.P. unit being about 10% greater than the international unit (IU) .
  • the potency of commercial preparations ranges from 140 to 190 units/mg.
  • a patient suffering from allergic or antigen-induced asthma is administered one dose of a heparin-containing inhalant composition from 1 to about 4 times daily, and preferably from 2 to 4 times daily, although more frequent administration can be utilized in the case of severe bronchospastic episodes.
  • a patient suffering from exercise-induced asthma is administered one dose of a heparin-containing inhalant composition from about 30 minutes to about 3 hours before exercising. Additional doses may be given as needed during and after exercise.
  • low molecular weight heparins or heparin fragments having an average molecular weight of about 1,500 to about 6,000, and preferably from about 4000 to about 5000. Because of the reduced anticoagulant potency of the lower molecular weight heparin materials, there is little risk of adverse hemorrhagic effects associated with their usage; yet they exhibit excellent antiasthmatic properties.
  • low molecular weight heparin examples include: Fraxiparine (Choay, Paris, France) , Lovenox (Pharmuka, Gennevilliers, France) , Fragmin (Kabivitrum, Swiss, Sweden) , OP 2123 (Opocrin, Corlo, Italy) , RD heparin (Hepar, Franklin, Ohio) , LHN-1 (Novo, Copenhagen, Denmark) , CY222 (Choay) and unfractionated porcine mucosal heparins of sodium salt (Choay and Hepar) .
  • Natural and synthetic heparin fragments may also be used with great effectiveness in the subject method of treatment. Natural heparin fragments are those obtained by fractionation of commercial heparins by degree of affinity for antithrombin and subsequent extraction or chemical or enzymatic depolymerization to yield active and inactive fractions. Synthetic heparin fragments are sulfated oligosaccharides generally synthesized starting from glucose and glucosamine. Several examples of such fragments are set forth in Petitou, Nouv. Rev. Fr. He atol.. 26: 221-226 (1984) , the disclosure of which is incorporated by reference herein.
  • heparin Another form of heparin which is of particular value for use in the present method because of its almost total lack of anticoagulant activity is partially N- desulfated heparin. Whereas unfractionated heparin contains 100% N-sulfate groups, partially N-desulfated heparin preparations may have only 25-85% N-sulfate groups. Many heparins of this type have been found to have high antithro botic activity and low hemorrhagic effects. Several examples of N-desulfated heparin preparations are disclosed in Sache et al., Thromb.Res.. 55: 247-258 (1989) and Nagasawa et al., J. Biochem. 81: 989-993 (1977), the disclosures of which are incorporated by reference herein.
  • heparin or heparin fragment which has little or no anticoagulant activity may also be used in the method of the present invention.
  • heparin as used hereinafter in unqualified form shall be understood as comprehending heparin (heparinic acid) , commercial heparin, and those low molecular heparins, natural and synthetic heparin fragments or fractions, partially N-desulfated heparins and other non-anticoagulant heparins which exhibit anti- bronchospastic and anti-bronchoconstrictive activity.
  • the inhalant heparin compositions used in the present invention may comprise liquid or powdered compositions of heparin suitable for nebulization and intrabronchial use or aerosol compositions administered via an aerosol unit dispensing metered doses.
  • Suitable liquid compositions comprise heparin in an aqueous, pharmaceutically acceptable inhalant solvent, e.g., isotonic saline or bacteriostatic water.
  • the solutions are administered by means of a pump or squeeze- actuated nebulized spray dispenser, or by any other conventional means for causing or enabling the requisite dosage amount of the liquid composition to be inhaled into the patient's lungs.
  • Suitable powder compositions include, by way of illustration, powdered preparations of heparin thoroughly intermixed with lactose or other inert powders acceptable for intrabronchial administration.
  • the powder composition can be administered via an aerosol dispenser or encased in a breakable capsule which may be inserted by the patient into a device that punctures the capsule and blows the powder out in a steady stream suitable for inhalation.
  • Aerosol formulations for use in the subject method typically include chlorofluorocarbon propellants, surfactants and co-solvents and my be filled into aluminum or other conventional aerosol containers which are then closed by a suitable metering valve and pressurized with propellant.
  • the concentration of heparin in any vehicle suitable for use in accordance with the present invention must be sufficiently high to provide the required dose of about 300-2,000 units of heparin/kg.
  • concentration of heparin in the aerosol in the case of a patient weighing 75 kg should be 5,625-37,500 units/ml.
  • heparin compositions described herein provide highly effective and long-acting prophylaxis for antigen- induced and exercise-induced asthma. Many patients will require no more than two doses of intrabronchial heparin daily to remain symptom- ree.
  • EXAMPLE 1 Effect of inhaled heparin on antigen-induced bronchoconstriction. These experiments were conducted in 8 allergic sheep. Each animal was studied on 5 different experiment days, at least 2 weeks apart. For the control antigen experiment, after baseline measurements of specific lung resistance (SR,) the sheep were challenged with aerosolized Ascaris suum antigen (400 breaths, 1:20 dilution) , and measurements of SR L repeated within 5 min. In order to evaluate the effect of aerosolized heparin on antigen-induced bronchoconstriction, on 3 separate days the sheep were pretreated with increasing doses of heparin (100, 300 and 1,000 units/kg), and antigen challenge was performed immediately thereafter. Measurements of SR L were obtained before and after nebulization of heparin, and immediately after the antigen challenge (12) .
  • EXAMPLE 2 Specificity of heparin action. - To study the specificity of heparin action and to exclude the possibility that antiallergic action of heparin may be related to its ionic charge or alcohol preservative, additional experiments were conducted in allergic sheep on 3 separate days, and compared to control antigen data. Measurements of SR L were obtained before and after the sheep were pretreated with 3 ml of either inhaled dextran sulfate (lOmg/kg) , benzyl alcohol preservative (O.Olml/ml) or De-N-sulfated heparin (lOmg/kg) . The sheep were then challenged with Ascaris suum antigen and measurements of SRL were repeated.
  • additional experiments were done in sheep challenged with compound 48/80 which causes non- immunologic, non-cytolytic mast cell degranulation. These experiments were conducted on 2 separate days. After baseline measurements of SR, ⁇ the sheep received an inhalation challenge with compound 48/80 (400 breaths, 5% solution) and measurements of SR L were repeated immediately thereafter.
  • EXAMPLE 4 Effect of heparin on agonist-induced bronchoconstriction.
  • SR L measurements of SR L were repeated.
  • the sheep were pretreated with inhaled heparin (1,000 units/kg) and the agonist challenges were repeated immediately thereafter, as described above.
  • EXAMPLE 5 Effect of inhaled heparin on partial thromboplastin time.
  • SR L was measured in 8 sheep allergic to Ascaris suum antigen, before and after inhalation challenge with antigen. On 4 different days, antigen challenge was repeated after pretreatment with aerosol heparin (1,000 units/kg) administered 20 min, 6 hrs, 12 hrs and 24 hrs prior to antigen challenge. SR L (mean ⁇ SE) increased by 374 ⁇ 116% above baseline with antigen alone (p ⁇ 0.05). Aerosol heparin attenuated the antigen effects in a time-dependent fashion.
  • heparin blocked i munologically-induced tracheal smooth muscle contraction in vitro.
  • Tracheal smooth muscle was obtained from sheep allergic to Ascaris suum antigen, and was suspended in an organ bath containing warmed (39°C) oxygenated (95% 0 2 , 5% C0 2 ) Krebs-Henseleit buffer. Tissues were allowed to equilibrate for 1 hr at resting tension of 1 g. After the equilibration period, the tissues were treated with heparin (injection USP, Elkin-Sinn) at concentrations of 10, 100, or 1000 ⁇ g/ml (final concentration in the bath) dissolved in 10 ⁇ l DMSO.
  • nedocromil sodium 10 "5 M”
  • Tissues were challenged, after a 30 min pretreatment, with 10, 30 and 100 ⁇ l of antigen (162,000 protein nitrogen units/ml). Contractions induced by antigen were expressed as a percentage of the contraction elicited by a maximally effective concentration of acetylcholine (100 mM) . Antigen produced dose-dependent increases in tension, which were blocked by heparin and nedocromil sodium (fig. 5) .
  • heparin nor nedocromil sodium affect the maximum response to acetylcholine.
  • dose response curves to acetylcholine were unaffected by any concentration of heparin used.
  • the addition of the heparin preservative benzyl alcohol did not reverse acetylcholine- induced contractions or inhibit antigen-induced contractions in sheep tracheal smooth muscle, as has been observed in dog bronchi.
  • - Preliminary studies were conducted in 3 subjects with history of marked exercise- induced bronchoconstriction (EIB) . These subjects were studied on 3 different days, 7 days apart. On day 1, after obtaining resting pulmonary function tests, the subjects were screened for EIB. The subjects exercised on a treadmill, with increasing speed and degree of inclination, until their heart rate reached 85% of predicted maximum. The achieved exercise work-load was then continued for 10 min. Throughout the study, the heart rate was monitored continuously with an EKG. Minute ventilation, estimated with a calibrated respiratory inductive plethysmograph, measuring specific airway conductance (SG aH ) before, immediately after the exercise, and serially every 5 min for 30 min post-exercise.
  • SG aH specific airway conductance
  • the subjects were studied on 2 separate days, in a single-blind randomized fashion.
  • the work-load estimated on the initial screening day was kept constant on the two test days.
  • the subjects were pretreated with an aerosol (4ml) of either heparin (1,000 units/kg) or a placebo solution (0.01 ml/ml benzyl alcohol in bacteriostatic injection water) .
  • SG aw was obtained before and 45 min after nebulization of heparin or placebo solution.
  • Exercise challenge was then performed, as stated above, and measurements of SG aH were obtained immediately after exercise and every 5 min for 30 min post-exercise. On both test days, the heart rate and minute ventilation were monitored as on a control day.

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  • Health & Medical Sciences (AREA)
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Abstract

Procédé de traitement d'un malade atteint d'asthme provoqué par un antigène ou par l'effort comprenant l'administration intrabronchique d'une composition d'inhalation contenant entre 300 et 2000 unités environ d'héparine par kilo de poids dudit malade dans chaque dose. On peut utiliser l'héparine commerciale, des héparines ou des fragments d'héparine de faible poids moléculaire et des héparines partiellement N-désulfatées ou d'autres héparines non anticoagulantes. L'invention décrit également les compositions d'inhalation appropriées mises en application dans le nouveau procédé de traitement.
PCT/US1993/002880 1992-04-02 1993-03-26 Procede et composition de traitement de l'asthme provoque par un antigene et par l'effort WO1993019734A1 (fr)

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US07/862,448 1992-04-02

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5990097A (en) * 1996-07-29 1999-11-23 Cavalier Pharmaceuticals Methods of treating asthma with o-desulfated heparin
WO2001093876A1 (fr) * 2000-06-09 2001-12-13 Shanghai Institute Of Cell Biology, Cas Utilisation de l'heparine n-desulfatee dans la prevention et le traitement des inflammations
AU2002224408B8 (en) * 2000-10-18 2002-04-29 Massachusetts Institute Of Technology Methods and products related to pulmonary delivery of polysaccharides
EP0844869A4 (fr) * 1995-08-18 2003-04-09 Baker Norton Pharma Procede et composition de traitement de l'asthme
US6869789B2 (en) 2000-03-08 2005-03-22 Massachusetts Institute Of Technology Heparinase III and uses thereof
US7056504B1 (en) 1998-08-27 2006-06-06 Massachusetts Institute Of Technology Rationally designed heparinases derived from heparinase I and II
US7083937B2 (en) 2000-09-12 2006-08-01 Massachusetts Institute Of Technology Methods and products related to the analysis of polysaccarides
US7412332B1 (en) 1999-04-23 2008-08-12 Massachusetts Institute Of Technology Method for analyzing polysaccharides
US7560106B2 (en) 1998-08-27 2009-07-14 Massachusetts Institute Of Technology Rationally designed heparinases derived from heparinase I and II and methods of sequencing therewith
US10052346B2 (en) 2015-02-17 2018-08-21 Cantex Pharmaceuticals, Inc. Treatment of myelodysplastic syndromes with 2-O and,or 3-O desulfated heparinoids
US11229664B2 (en) 2012-05-09 2022-01-25 Cantex Pharmaceuticals, Inc. Treatment of myelosuppression

Citations (3)

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US5032679A (en) * 1988-12-15 1991-07-16 Glycomed, Inc. Heparin fragments as inhibitors of smooth muscle cell proliferation
JPH03169821A (ja) * 1989-11-28 1991-07-23 Kissei Pharmaceut Co Ltd プロスタグランジンｉ↓２産生増強剤
US5037810A (en) * 1987-03-17 1991-08-06 Saliba Jr Michael J Medical application for heparin and related molecules

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US5037810A (en) * 1987-03-17 1991-08-06 Saliba Jr Michael J Medical application for heparin and related molecules
US5032679A (en) * 1988-12-15 1991-07-16 Glycomed, Inc. Heparin fragments as inhibitors of smooth muscle cell proliferation
JPH03169821A (ja) * 1989-11-28 1991-07-23 Kissei Pharmaceut Co Ltd プロスタグランジンｉ↓２産生増強剤

Non-Patent Citations (7)

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Title
BIOLOGICAL ABSTRACTS, Vol. 85, No. 5, issued 01 March 1988, ONO et al., "Studies on Heparin in Allergic Reactions: 3. Therapeutic Use of Heparin in Bronchial Asthma", Abstract No. 51021; & OKAYAMA IGAKKAI ZASSHI, 99(5/6):559-568. *
CHEMCIAL ABSTRACTS, Vol. 113, No. 3, issued 16 July 1990, LANDYSHEV et al., "Method of Treating Respiratory Insufficiency in Patients with Nonspecific Pulmonary Diseaese", see page 62, Abstract No. 17897x. *
CHEMICAL ABSTRACTS, Vol. 102, issued 1985, BREITENSTEIN et al., "Heparin Formulation Containing a Surfactant wiht Action on the Mucous Membranes of the Mouth, Nose, and/or the Throat", see page 352, Abstract No. 154804b. *
CHEMICAL ABSTRACTS, Vol. 108, issued 1988, BROWN et al., "Dimethyl Sulfoxide with Heparin in the Treatment of Smoke Inhalation Injury", see page 69, Abstract No. 198373p; & J. BURN CARE REHABIL., 9(1):22-5. *
CHEMICAL ABSTRACTS, Vol. 109, issued 1988, JOHANSEN et al., "Nasal Pharmaceuticals Containing Low-Molecular Weight Heparin and a Fusidate", see page 370, Abstract No. 116061u. *
CHEMICAL ABSTRACTS, Vol. 90, issued 1979, MOREAU et al., "Pharamaceutical Based on Heparin for Tracheobronchial and Alveolar Administration", see page 312, Abstract No. 43816w. *
VUTR. BOLES, Vol. 26, No. 6, issued 1987, PETROV et al., "Inhalation Treatment with Low Doses of Heparin in Bronchial Asthma Patients". *

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0844869A4 (fr) * 1995-08-18 2003-04-09 Baker Norton Pharma Procede et composition de traitement de l'asthme
US5990097A (en) * 1996-07-29 1999-11-23 Cavalier Pharmaceuticals Methods of treating asthma with o-desulfated heparin
EP0918461A4 (fr) * 1996-07-29 2002-11-13 Cavalier Pharmaceuticals Procedes de traitement de l'asthme au moyen d'heparine o-desulfatee
US7056504B1 (en) 1998-08-27 2006-06-06 Massachusetts Institute Of Technology Rationally designed heparinases derived from heparinase I and II
US7560106B2 (en) 1998-08-27 2009-07-14 Massachusetts Institute Of Technology Rationally designed heparinases derived from heparinase I and II and methods of sequencing therewith
US7412332B1 (en) 1999-04-23 2008-08-12 Massachusetts Institute Of Technology Method for analyzing polysaccharides
US7455986B2 (en) 2000-03-08 2008-11-25 Massachusetts Institute Of Technology, Inc. Heparinase III and methods of specifically cleaving therewith
US6869789B2 (en) 2000-03-08 2005-03-22 Massachusetts Institute Of Technology Heparinase III and uses thereof
US7390633B2 (en) 2000-03-08 2008-06-24 Massachusetts Institute Of Technology Methods for preparing low molecular weight heparin with modified heparinase III
US7939292B2 (en) 2000-03-08 2011-05-10 Massachusetts Institute Of Technology Modified heparinase III and methods of sequencing therewith
WO2001093876A1 (fr) * 2000-06-09 2001-12-13 Shanghai Institute Of Cell Biology, Cas Utilisation de l'heparine n-desulfatee dans la prevention et le traitement des inflammations
US7083937B2 (en) 2000-09-12 2006-08-01 Massachusetts Institute Of Technology Methods and products related to the analysis of polysaccarides
AU2002224408B2 (en) * 2000-10-18 2007-08-23 Massachusetts Institute Of Technology Methods and products related to pulmonary delivery of polysaccharides
WO2002032406A3 (fr) * 2000-10-18 2002-10-10 Massachusetts Inst Technology Procedes et produits associes a l'administration pulmonaires de polysaccharides
AU2002224408B8 (en) * 2000-10-18 2002-04-29 Massachusetts Institute Of Technology Methods and products related to pulmonary delivery of polysaccharides
US11229664B2 (en) 2012-05-09 2022-01-25 Cantex Pharmaceuticals, Inc. Treatment of myelosuppression
US10052346B2 (en) 2015-02-17 2018-08-21 Cantex Pharmaceuticals, Inc. Treatment of myelodysplastic syndromes with 2-O and,or 3-O desulfated heparinoids

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