WO1999052508A1 - Method for the treatment of asthma - Google Patents
Method for the treatment of asthma Download PDFInfo
- Publication number
- WO1999052508A1 WO1999052508A1 PCT/US1999/008226 US9908226W WO9952508A1 WO 1999052508 A1 WO1999052508 A1 WO 1999052508A1 US 9908226 W US9908226 W US 9908226W WO 9952508 A1 WO9952508 A1 WO 9952508A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- asthma
- treatment
- composition
- esters
- acid
- Prior art date
Links
Classifications
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
- A61K31/231—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having one or two double bonds
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Definitions
- the present invention relates to the treatment of symptoms of inflammatory responses and, more specifically, to the inflammatory responses attendant to asthma.
- An allergic reaction is any abnormal or altered reaction to an antigen or allergen. Typically, such a reaction is characterized by hypersensitivity of the body to specific substances, whether protein, lipid or carbohydrate in nature. Among allergic diseases, asthma is one of the most significant.
- Asthma is a chronic condition that affects 14 to 15 million persons in the United States and is the most frequent cause for hospitalizations among children as well as adults. Asthma related morbidity and mortality rates have been increasing for more than a decade in the U.S. Hospital admissions and visits to doctors' offices have also increased for acute episodes of this condition.
- Current medical practice accepts asthma in afflicted individuals to be an unavoidable, incurable illness. While suppression of symptoms is usually achieved to a degree sufficient to avoid death, urgent medical visits, disturbed sleep and days lost from work are typically unavoidable.
- Inhalation of allergens by sensitized subjects typically results in an early phase response characterized by bronchoconstriction within 10 minutes of inhalation, reaching a maximum within one to two hours. In some subjects, the airway narrowing reoccurs after three to four hours (i.e. a late phase response) reaching a maximum during the next few hours (O'Byrne, P.M., et al. Am. Rev. Respir. Dis. 136:740 (1987)). This late phase reaction is thought to be due to the cellular phase of inflammation (Hargreave, F.E., et al , Eur. J. Respir. Dis. 69 (Suppl. 147): 16 (1986); O'Byrne, P.M. Chest 90:575 (1986); Dolovich, J. et al, J. Allergy Clin. Immunol.
- inhaled beta-2 agonists are used for treatment of mild intermittent asthma.
- inhaled corticosteroids along with inhaled beta-2 agonists are the treatments of choice.
- the underlying pathophysiology results from the release of potent leukotrienes acting as inflammatory mediators which cause broncho constriction and increased vascular permeability and mucus production.
- These inhaled corticosteroids are currently the anti-inflammatory medication of choice. Less effective are chromolyn and nedocromil, which inhibit release of histamine from the mast cells.
- the present invention provides a method for the remediation of the inflammatory response symptoms of asthma which comprises administering a composition comprising an effective amount of at least one compound selected from the group consisting of esters of myristic acid and esters of myristoleic acid to a patient in need of such remediation.
- the present invention provides a method for the remediation of the inflammatory response symptoms of asthma which comprises administering a composition comprising an effective amount of at least one compound selected from the group consisting of esters of myristic acid and esters of myristoleic acid to a patient in need of such remediation.
- the medicament of the present invention will comprise at least one ester of myristic or myristoleic acid.
- esters will be alkyl esters, such as methyl
- esters of the invention will include even longer chain alky Is, such as cetyl
- SRS-A slow-reacting substance of anaphylaxis
- SRS-A was purified and found to be composed of leukotrienes, which are inflammatory mediators that were presumed to be released from leukocytes when they were identified in the late 1970's.
- SRS-A is made up of three types of leukotrienes, LTC 4 , LTD 4 , and LTE 4 , which are collectively known as the cysteinyl or sulfidopeptide leukotrienes because each contains a thioether-linked peptide.
- the leukotrienes are products of intracellular arachidonic acid metabolism, but the metabolic pathways are not the same.
- the cyclooxygenase pathway which produces the prostaglandins and thromboxanes, uses arachidonic acid either as free lipid or released from membrane phospholipid by phopholipase A 2 .
- Leukotrienes are produced by the lipoxygenase pathway, and here arachidonic acid is utilized from phopholipid pools.
- the lipoxygenase pathway also involves an enzyme-activating protein that has no counterpart in the cyclooxygenase pathway.
- an enzyme-activating protein that has no counterpart in the cyclooxygenase pathway.
- FLAP 5-lipoxygenase activating protein
- Leukotrienes B 4 and C 4 are the secreted products of the lipoxygenase pathway. They are produced mainly by mast cells and eosinophils, but they can also be released by other inflammatory cells such as basophils and macrophages. Both can exert proinflammatory effects, but LTC 4 is also converted extracellular ly to LTD 4 , a more potent inflammatory mediator. LTD 4 is further converted to LTE 4 , which has a lesser effect and which is the form in which leukotrienes are excreted. Urinary LTE 4 is widely used as a marker of leukotriene synthesis.
- the leukotrienes are also found in plasma, bronchoalveolar lavage fluid, and nasal fluid, but they may be hard to detect, because only small amounts are synthesized and released.
- Leukotriene binding sites which are presumed to be receptors, have been found in epithelial and endothelial cells, smooth muscle cells, and nerve cells. Besides the lung, airways, and skin, binding sites exist in myocardium and gastric mucosa, so leukotrienes may act to depress myocardial contractility and gastric acid secretion. High-affinity binding sites for LTD 4 have been found in human lung, and LTE 4 also binds to these sites, but with lesser affinity.
- LTB 4 is a strong chemoattractant for neutrophils and eosinophils but has not been shown to have the same effects as the cysteinyl leukotrienes in asthma.
- Research into LTB 4 receptor antagonists has been done mainly in conditions such as psoriasis and ulcerative colitis, not in asthma. Even when they were collectively known as SRS-A, the leukotrienes were understood to be involved in asthma.
- SRS-A the leukotrienes were found to be involved in bronchospasm and most of the inflammatory processes in asthma. In fact, their effects on the bronchial tree are much more intense and potent than those of previously studied mediators such as histamine. -6-
- LTC 4 and LTD 4 are 1000 times more potent than histamine. LTD 4 is the strongest bronchoconstrictor. The onset of action of LTC 4 is slower than for LTD 4 and LTE 4 , whereas LTE 4 has the longest duration of action.
- the extent of mast cell contribution to the late-phase response is controversial, but leukotrienes are present in brochoalveloar lavage fluid in both the early and late phase responses. Leukotrienes in the late phase may be produced by eosinophils and macrophages.
- the leukotrienes are also more potent than stamine, platelet-activating factor, or prostaglandins in inducing the other features of inflammation, namely increased vascular permeability and mucus production.
- Discovering the potency of the inflammatory effects of the leukotrienes led to research on ways to inhibit their production or block their effects.
- With formulation of the earliest antileukotriene agents the major contribution of leukotrienes to asthmatic inflammation was confirmed.
- the present compositions serve to remedy the inflammatory response by one or more of a series of mechanisms involving the reduction of the leukotriene mediators.
- the medicament of the present invention will comprise at least one ester of myristic acid (tetradecanoic acid):
- myristoleic acid (cis 9 tetradecanoic acid):
- myristic acid and myristoleic acid there are numerous sources known for obtaining myristic acid and myristoleic acid, including both natural and synthetic means.
- both myristic and myristoleic acid can be obtained for botanic sources, such as plants of the genus Myristicaceae (including Nutmeg), and palm seeds, as well as animal sources, such as milk and sperm whale oil.
- botanic sources such as plants of the genus Myristicaceae (including Nutmeg)
- animal sources such as milk and sperm whale oil.
- animal sources such as milk and sperm whale oil.
- One particularly desirable natural source of the subject compounds is a botanical source such as the plant Pycnanthus angolensis.
- the therapeutic medicament will be ad'ministered to a host in need of such treatment at a therapeutically effective dosage level.
- the compositions of the present invention will desirably be administered orally, in the form of capsules, tablets or suspensions, after first preparing the esters in powder form.
- the compositions can be administered topically, parenterally, or be any other means considered desirable.
- the lowest effective dosage levels can be determined routinely by initiating treatment at higher dosage levels and reducing the dosage level until relieved from inflammatory reaction is no longer obtained.
- therapeutic dosage levels will range from about 0.01 to 100 milligrams per kilogram of host body weight.
- typically 1 gm. to 1.5 gm of the present composition is given three times a day for the first 7 to 10 days.
- the composition can also be administered at 2.5 to 6000 milligrams per kilogram of body weight. Response generally occurs between 7 to 10 days, a maintenance dose of approximately 500 mg to 1 gram is recommended.
- the -9- amount necessary to achieve therapeutic effect for a particular individual will depend upon a number of factors such as body weight, severity of asthma and age of the individual.
- compositions can be provided together with pharmaceutically acceptable and physiologically tolerable liquid, gel or solid carriers, diluents, adjuvents and excipients.
- These therapeutic preparations can be administered to mammals, both for veterinary use, such as with domestic animals, and clinical use in humans in a manner similar to other therapeutic agents.
- the dosage required for therapeutic efficacy will vary according to the type of use and mode of administration, as well as the particularized requirements of individual hosts.
- Such compositions are typically prepared for oral administration, or as sprays (e.g. intra nasal aerosols) for topical use.
- Oral formulations e.g. for gastrointestinal absorption usually includes such normally employed additives such as binders, fillers, carriers, preservatives, stabilizing agents, emulsif ⁇ ers, buffers and excipients such as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like.
- binders such as binders, fillers, carriers, preservatives, stabilizing agents, emulsif ⁇ ers, buffers and excipients such as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like.
- binders such as binders, fillers, carriers, preservatives, stabilizing agents, emulsif ⁇ ers, buffers and excipients such as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate
- compositions of the present invention are also capable of being prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for solution in, or suspension in, liquid prior to injection may also be prepared.
- the compounds of the present invention are often mixed with diluents or excipients which are physiologically tolerable and compatible. Suitable diluents and excipients are, for example, water, saline, dextrose, glycerol, or the like, and combinations thereof.
- the compositions may contain minor amounts of auxiliary substances such as wedding or emulsifying agents, stabilizing or pH buffering agents. -10-
- Additional formulations which are suitable for other modes of administration, such as topical administration, includes salves, tinctures, creams, lotions and, in some cases, suppositories.
- traditional binders, carriers and excipients may include, for example, poly alky lene glycols or triglycerides.
- One week after starting the treatment of the present invention she reported that not only was her breathing significantly improved, but her energy level had improved significantly as well.
- a 45-year old female from Mexico displayed chronic cough in the mornings. She denied any history of asthma, but had noted that she coughs with exertion and any vigorous physical activity, such as brisk walking. She began a course of treatment receiving 1 teaspoon (9 grams) of the powdered version of the present composition in the evening. The following morning she displayed no coughing spells, and after approximately one week she was free from her symptoms even when engaging in vigorous physical activity.
- Example 6 An 8-year old female with history of eczema and asthma, was also documented as reactive to house dust and household cleaning chemicals.
Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP99918570A EP1071405A1 (en) | 1998-04-16 | 1999-04-15 | Method for the treatment of asthma |
JP2000543118A JP2002511401A (en) | 1998-04-16 | 1999-04-15 | Asthma treatment |
CA002328344A CA2328344A1 (en) | 1998-04-16 | 1999-04-15 | Method for the treatment of asthma |
AU36449/99A AU762102B2 (en) | 1998-04-16 | 1999-04-15 | Method for the treatment of asthma |
MXPA00010103A MXPA00010103A (en) | 1998-04-16 | 1999-04-15 | Method for the treatment of asthma. |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US6149798A | 1998-04-16 | 1998-04-16 | |
US09/061,497 | 1998-04-16 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1999052508A1 true WO1999052508A1 (en) | 1999-10-21 |
Family
ID=22036172
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1999/008226 WO1999052508A1 (en) | 1998-04-16 | 1999-04-15 | Method for the treatment of asthma |
Country Status (6)
Country | Link |
---|---|
EP (1) | EP1071405A1 (en) |
JP (1) | JP2002511401A (en) |
AU (1) | AU762102B2 (en) |
CA (1) | CA2328344A1 (en) |
MX (1) | MXPA00010103A (en) |
WO (1) | WO1999052508A1 (en) |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000064436A1 (en) * | 1999-04-28 | 2000-11-02 | Cg And Associates | Methods of delivery of cetyl myristoleate |
WO2001041783A1 (en) * | 1999-12-09 | 2001-06-14 | Bruce Levin | Methods and compositions for treatment of inflammatory disease |
WO2003045374A1 (en) * | 2001-09-28 | 2003-06-05 | Meracol Corporation Limited | Treating asthma, chronic obstructive pulmonary disease and/or other respiratory difficulties |
US6677321B1 (en) | 1999-12-09 | 2004-01-13 | Bruce Levin | Methods and compositions for treatment of inflammatory disease |
US7582317B2 (en) | 2001-09-04 | 2009-09-01 | Loders Croklaan Usa Llc | Food supplements comprising, as a health component, sargahydroquinoic acid or derivative thereof |
US8147851B2 (en) | 2000-05-12 | 2012-04-03 | Lypanosys Pte Limited | Treating eczema and/or psoriasis |
US8299120B2 (en) | 2004-06-03 | 2012-10-30 | Lypanosis Pte Limited | Therapy for multiple sclerosis |
WO2018081694A1 (en) * | 2016-10-31 | 2018-05-03 | The Cleveland Clinic Foundation | Capric acid and myristic acid compositions for treating conditions |
CN114544812A (en) * | 2022-02-18 | 2022-05-27 | 复旦大学附属中山医院 | Application of metabolic combination type marker in asthma diagnosis |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7612111B2 (en) * | 2003-03-20 | 2009-11-03 | Imagenetix, Inc. | Esterified fatty acid composition |
US9511016B2 (en) * | 2007-06-12 | 2016-12-06 | Epicentrx, Inc. | Topical composition for treating pain |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5721270A (en) * | 1995-03-08 | 1998-02-24 | Environmental Research Institute, Inc. | Drugs for allergic and eosinophilic diseases |
-
1999
- 1999-04-15 JP JP2000543118A patent/JP2002511401A/en active Pending
- 1999-04-15 EP EP99918570A patent/EP1071405A1/en not_active Withdrawn
- 1999-04-15 CA CA002328344A patent/CA2328344A1/en not_active Abandoned
- 1999-04-15 WO PCT/US1999/008226 patent/WO1999052508A1/en not_active Application Discontinuation
- 1999-04-15 MX MXPA00010103A patent/MXPA00010103A/en active IP Right Grant
- 1999-04-15 AU AU36449/99A patent/AU762102B2/en not_active Ceased
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5721270A (en) * | 1995-03-08 | 1998-02-24 | Environmental Research Institute, Inc. | Drugs for allergic and eosinophilic diseases |
Cited By (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6417227B1 (en) | 1999-04-28 | 2002-07-09 | Cg And Associates | Methods of delivery of cetyl myristoleate |
WO2000064436A1 (en) * | 1999-04-28 | 2000-11-02 | Cg And Associates | Methods of delivery of cetyl myristoleate |
WO2001041783A1 (en) * | 1999-12-09 | 2001-06-14 | Bruce Levin | Methods and compositions for treatment of inflammatory disease |
US6677321B1 (en) | 1999-12-09 | 2004-01-13 | Bruce Levin | Methods and compositions for treatment of inflammatory disease |
US7112578B2 (en) | 1999-12-09 | 2006-09-26 | Bruce H. Levin | Methods and compositions for treatment of inflammatory disease |
US8586064B2 (en) | 2000-05-12 | 2013-11-19 | Lypanosys Pte Limited | Treating eczema and/or psoriasis |
US8535696B2 (en) | 2000-05-12 | 2013-09-17 | Lypanosys Pte Limited | Treating eczema and/or psoriasis |
US8147851B2 (en) | 2000-05-12 | 2012-04-03 | Lypanosys Pte Limited | Treating eczema and/or psoriasis |
US7582317B2 (en) | 2001-09-04 | 2009-09-01 | Loders Croklaan Usa Llc | Food supplements comprising, as a health component, sargahydroquinoic acid or derivative thereof |
EP1448185A1 (en) * | 2001-09-28 | 2004-08-25 | Meracol Corporation Limited | Treating asthma, chronic obstructive pulmonary disease and/or other respiratory difficulties |
AU2002343270B2 (en) * | 2001-09-28 | 2007-12-20 | Lypanosys Pte Limited | Treating asthma, chronic obstructive pulmonary disease and/or other respiratory difficulties |
EP1448185A4 (en) * | 2001-09-28 | 2005-06-22 | Meracol Corp Ltd | Treating asthma, chronic obstructive pulmonary disease and/or other respiratory difficulties |
WO2003045374A1 (en) * | 2001-09-28 | 2003-06-05 | Meracol Corporation Limited | Treating asthma, chronic obstructive pulmonary disease and/or other respiratory difficulties |
US8299120B2 (en) | 2004-06-03 | 2012-10-30 | Lypanosis Pte Limited | Therapy for multiple sclerosis |
WO2018081694A1 (en) * | 2016-10-31 | 2018-05-03 | The Cleveland Clinic Foundation | Capric acid and myristic acid compositions for treating conditions |
CN110234315A (en) * | 2016-10-31 | 2019-09-13 | 克利夫兰诊所基金会 | For treating the capric acid and myristic acid composition of symptom |
EP3532030A4 (en) * | 2016-10-31 | 2020-04-22 | The Cleveland Clinic Foundation | Capric acid and myristic acid compositions for treating conditions |
CN110234315B (en) * | 2016-10-31 | 2023-04-21 | 克利夫兰诊所基金会 | Capric and myristic acid compositions for the treatment of pathologies |
AU2017348410B2 (en) * | 2016-10-31 | 2023-11-02 | The Cleveland Clinic Foundation | Capric acid and myristic acid compositions for treating conditions |
US11826331B2 (en) | 2016-10-31 | 2023-11-28 | The Cleveland Clinic Foundation | Capric acid and myristic acid compositions for treating conditions |
CN114544812A (en) * | 2022-02-18 | 2022-05-27 | 复旦大学附属中山医院 | Application of metabolic combination type marker in asthma diagnosis |
CN114544812B (en) * | 2022-02-18 | 2023-06-30 | 复旦大学附属中山医院 | Application of metabolic combination type marker in diagnosis of asthma |
Also Published As
Publication number | Publication date |
---|---|
CA2328344A1 (en) | 1999-10-21 |
AU3644999A (en) | 1999-11-01 |
MXPA00010103A (en) | 2002-08-06 |
JP2002511401A (en) | 2002-04-16 |
EP1071405A1 (en) | 2001-01-31 |
AU762102B2 (en) | 2003-06-19 |
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