EP1789061A1 - Traitement de la mpoc et medicament associe - Google Patents

Traitement de la mpoc et medicament associe

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Publication number
EP1789061A1
EP1789061A1 EP05750477A EP05750477A EP1789061A1 EP 1789061 A1 EP1789061 A1 EP 1789061A1 EP 05750477 A EP05750477 A EP 05750477A EP 05750477 A EP05750477 A EP 05750477A EP 1789061 A1 EP1789061 A1 EP 1789061A1
Authority
EP
European Patent Office
Prior art keywords
petasites
copd
extract
patient
treating
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP05750477A
Other languages
German (de)
English (en)
Inventor
Axel Brattstroem
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Max Zeller Soehne AG
Original Assignee
Max Zeller Soehne AG
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
Publication date
Application filed by Max Zeller Soehne AG filed Critical Max Zeller Soehne AG
Publication of EP1789061A1 publication Critical patent/EP1789061A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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

Definitions

  • COPD chronic obstruc- tive pulmonary disease
  • equine COPD is a pathological state of various mammal patients, i.e. animals including humans. It is also a specific disease of horses and, in this form, is known as equine COPD.
  • drugs such as Ventipulmin® (clenbuterol hydrochloride), Sputolosin® (dismexine), SAIDS or NSAIDS, i.e. ster ⁇ oidal or non-steroidal anti-inflammatory drugs, e.g.
  • prednisolone or anti-allergic drugs, such as sodium chromoglycate.
  • Horses with COPD may exhibit clinical symptoms such as "heaving" to push air out of the lungs towards the end of exhalation, coughing, weight loss, and exercise in- tolerance. Wheezes may be heard towards the end of exhalation when listening to the airways with a stethoscope. A mucous nasal discharge may be seen, especially after ex ⁇ ercise.
  • COPD chronic myelolism
  • trachea the respiratory duct
  • bronchi the respiratory duct
  • bronchioles the respiratory duct
  • These air passages are lined with layers of cells which constitute the epithelium.
  • Below the epithelium is a layer of connective tissue called the sub-mucosa.
  • Smooth muscle surrounds the bronchi and bronchioles all the way to the level of the alveoli. Contraction of the smooth muscle encircling the respiratory duct is known as broncho- constriction or bronchospasm.
  • the respiratory duct of mammals is equipped with natural defence mechanisms to eliminate inhaled particles. These mechanisms include coughing, mucus secretion and removal, as well as bronchoconstriction.
  • COPD is recognized as a different clinical entity from asthma as the latter disease is predominantly reversible, as opposed to the former.
  • natural defence mechanisms against inhaled allergens in the airways are hyper-reactive and overreact when foreign particles are inhaled.
  • Inflamma- tion is also one of the defence mechanisms of the airways but in COPD inflammation occurs in great excess.
  • the airways of COPD patients and notably horses become acutely inflamed which causes the airways to become edematous.
  • Airway mucus is produced in the trachea and bronchi by goblet cells in the epi ⁇ thelium and sub mucosal glands. Mucus lining the airways is viscous and sticky so that it entraps and retains inhaled particles.
  • the epithelium of the trachea and bronchi is covered with cilia.
  • Air flow is also compromised by the increased production of mucus in response to inhaled allergens. Accumulated mucus and cellular debris in the airways further de ⁇ creases the diameter of the air passages and increases the effort required to breathe. This increased work of breathing is evidenced by the abdominal push ("heaving") seen when COPD-afflicted horses try to force air out through the narrowed airways during exhala ⁇ tion. Since the air passages of COPD-afflicted patients are obstructed, oxygen cannot be efficiently delivered to the alveoli. This results in a low partial pressure of oxygen in the arterial blood of COPD patients. Less oxygen is available, therefore, for delivery to the tissues.
  • Impairment of gas exchange in the lungs of COPD of afflicted horses pre- vents them from performing well and results in exercise intolerance.
  • Normal coughing expels inhaled particles from the airways.
  • Sensory nerve end ⁇ ings called irritant receptors lie below the airway epithelium.
  • the irritant receptors are stimulated when inhaled particles or accumulated mucus secretions compress the airway epithelium and deform the underlying receptors.
  • inflammation makes the cough reflex hyper-reactive because the epithe ⁇ lium is damaged, irritant receptors become exposed, and the nerves become more sensi ⁇ tive to stimuli.
  • Bronchoalveolar lavage is a process whereby a tube is passed through one nostril of the afflicted horse into the peripheral airways and then sterile sa ⁇ line is quickly injected and withdrawn from the air passages through the tube.
  • This sample is then analysed microscopically for both the total number of cells present and the number and percentage of each cell type present.
  • the predominant cells are macrophages and lymphocytes with neutrophils com ⁇ prising less than five percent of all the cells present.
  • the percentage of neutrophils in bronchoalveolar lavage fluid may be about 50-70% (or more) of the total cell count.
  • mammal patients and notably horses with greater than about 20% neutrophils will likely have impaired lung function and may have COPD.
  • Blood gas analysis can also be performed to assist in the diagnosis of COPD. An arterial blood sample taken when the horse has just been exercised will have a lower partial pressure of oxygen than normal.
  • the present invention pro ⁇ vides for a method of treating COPD in a patient comprising the step of administering to said animal an effective dose of an extract of Petasites sp.
  • the inventive method is of particular benefit for treating horses but other pa ⁇ tients including humans may benefit from such treatment as well, notably if corticoster- oids must not, or should not be used.
  • the invention provides for a phar ⁇ maceutical composition for treatment of COPD in a patient.
  • the invention provides the use of an extract of Petasites sp. for preparation of a medicament for treating COPD in a patient.
  • the invention provides a medicament for use in veterinary medicine containing an extract of Petasites sp.
  • Figure l is a diagram showing the results of a treatment accord ⁇ ing to the invention as applied to horses in terms of reduction of airway resistance which if abnormally high is a symptom of COPD.
  • Petasites extract has been known since antiquity as a medicament.
  • Such ex ⁇ tracts in a dry, liquid or semi-liquid form can be obtained with various extraction agents and from differing portions (roots, leaves, and/or stems) of various Petasites species, e.g. Petasites hybridus, Petasites albus, Petasites japonicus, Petasites paradoxus, and Petasites spurious.
  • Petasites hybridus also known as Petasites officinalis (L,) Moendi.
  • the chemical composition as well as the structure of the main components of Petasites extract are known, c.f. Chimia 48 (1994), p. 564 - 569 incorporated herein by way of reference.
  • the extracts contain a number of substances similar to petasin, such as iso petasin, neo petasin, desoxy neopetasol, desoxy isopetasol, desoxy neopetasol, the corresponding derivatives substituted in 13 -position, methly crotonly petasol and the corresponding isopetasol, methacryloyl petasol and the corresponding isopetasol, isobutyryl neopetasol, methyl thioacryloyl petasol and the neopetasol and isopetasol derivativatives hereof.
  • Petasites variety chemovarieties
  • Furano variety chemovarieties
  • Various agents have been used for extraction but it was only in the more recent past that a problem previously connected with the use of Petasites extract has been solved, i.e. efficient production of a Petasites extract that was free of pyrrolizidine alka ⁇ loids and/or the N-oxides thereof (commonly termed PA herein for short).
  • a Petasites sp. extract in the sense used herein and in the claims refers to such an extract which is substantially free of PA.
  • the phrase "substantially free” indicates that any PA trace must be below the sensitivity of the test method used, generally below 0.1 ppm.
  • extraction with an aqueous alcanolic ex ⁇ traction agent in counter current as disclosed in DE. 197 02 168 or with liquid carbon dioxide as disclosed in EP 0 908 185 yields a Petasites extract substantially free of PA.
  • the Petasites extract When used according to the present invention for treating COPD, the Petasites extract preferably is administered orally or by inhalation.
  • therapy usually be- gins with a high dose and, as the patient improves, the dose is reduced to a maintenance level.
  • the extract can be administered at a dosage of about 1 to about 50 milligrams (mg) or more of extract per each kilogram (kg) of body weight of the patient, one to four times daily.
  • the upper limit is not critical since no critical toxicity value of Petasites extract has been reported provided the extract is free of constituents that cause hepatotoxic, carcinogenic, cytostatic and mutagenic properties.
  • Inhaled extract offers the advantage of a high dose within the airways and mini- mal systemic side effects and preparations of Petasites extracts capable of being admin ⁇ istered to a patient by inhalation presents a preferred type of medicament.
  • Inhalation masks suitable for the animal patient in question are available commercially and can be used according to the invention.
  • Petasites extract can be used alone or in combina- tion with drugs known to be effective in the treatment of COPD, e.g.
  • Peta ⁇ sites extract can also be used in combination with conventional bronchodilators that re ⁇ lax airway smooth muscle and relieve airway obstruction.
  • Typical and preferred exam ⁇ ples of such drugs are clenbuterol (e.g. Ventipulmin® syrup), dembrexine (e.g. Sputolosin®), pirbuterol (e.g. Maxair®), albuterol (e.g. Ventoline®), ephedrine, atro- pin, ipratropinum bromide (e.g.
  • Atrovent® aminophyline, cromoglicinic acid and de ⁇ rivatives thereof, such as esters or salts, ketotifen, nedocromil, and the like.
  • Effective dosages of these medicaments are well known to those experienced in the art but can be reduced if applied together with Petasites extract.
  • effective dosages of the Petasites extract should not be reduced if used in combination with such prior art COPD medications.
  • Petasites extract is useful in treating symptoms of COPD in patients including humans, horses, cats, dogs, and other mammals.
  • Veterinary use is a preferred embodiment and treatment of horses afflicted with COPD is a particularly important embodiment.
  • the Petasites extract can be formulated into pharmaceutically acceptable dosage forms by conventional methods known to the pharmaceutical art.
  • the Petasites extract can be administered in such forms as tablets, capsules, pills, powders, granules or aerosols, and various diluents and adjuvants can be used as needed for a specific application form.
  • An effective quantity of the Petasites extract, alone or in combination with con ⁇ ventional drugs is employed in treatment.
  • the dosage regimen for preventing or treating the symptoms described above is selected in view of the above and in accordance with such conventional factors including body weight of patient, the severity of the symp- toms, and the route of administration.
  • COPD in horses frequently is associated with hay dust - which in turn is known to contain fungal spores
  • hay dust - which in turn is known to contain fungal spores
  • Zygospores spores of the Zygomycota class of fungi
  • treatment with Petasites extract or use of such an extract for preparation of a medicament, offers relief.
  • Petasites extract was prepared by extraction of dried material of Petasites hybridus with liquid carbon dioxide at sub-critical conditions of temperature and pressure as disclosed in EP 0 908 185. When tested by gas chromatog ⁇ raphy, no detectable amount of PA was found in the extract, such extract is also avail ⁇ able commercially from Zeller AG, Switzerland, as Extract Ze339. The extract was confectioned both as an edible preparation for oral administration as well as a fine pow- der for inhalation. Test Animals: Five mature mares and geldings with chronic obstructive pulmo ⁇ nary disease were identified on the basis of physical examination, response to mouldy hay exposure and medical history.
  • COPD horses considered for the trial demonstrated a marked maximum difference between peak inspiratory and peak expiratory intrapleural pressure expressed in centimetres of water (MDPP) response to intravenous atropine at a dosage of 8.8 ⁇ g per kg.
  • Study design A four-period crossover design using five horses with chronic ob ⁇ structive pulmonary disease (COPD) treated orally twice daily with the drug to be tested. Each horse served as its own control. The measurements of interest were objec ⁇ tively collected and the need for masking was eliminated. Measurements: The MDPP was monitored using the esophageal balloon tech- nique.
  • Treatment groups Horses were treated orally, twice daily, with 0.0 mg/kg, 10 mg/kg, 20 mg/kg and 50 mg/kg of Petasites extract in accordance with the trial design.
  • Test Duration Each horse was treated with each of the four dosages (0.0, 10, 20 and 50 mg/kg) of Petasites extract with over four treatment periods.
  • Each treatment pe- riod consisted of a 3-day pre-Petasites treatment baseline observation and 6 days of twice daily treatment by oral application at the scheduled dosage, with a minimum 96- hour washout between periods, for a complete crossover of doses in each animal.
  • Results Data obtained from this study indicated a significant linear dose response with progressive improvement in response as dose increased. The data were analyzed using an analysis of variance design for crossover studies.
  • Example 1 was repeated except that a combination of Petasites extract was used in combination with Ventipulmin® Syrup(clenbuterol hydrochloride). It was found that the amount of Ventilpulmin® Syrup could be reduced by at least 50 % by weight if combined with Petasites extract at a dosage level of about 20 mg/kg of extract for reaching an effetiveness as expected for the full dose of Ventilpulmin® Syrup.
  • Example 3 The purpose of this example was to evaluate the safety of Petasites hybridus ex ⁇ tract at the dosage levels of 10 mg/kg, 20 mg/kg and 50 mg/k.
  • Treatments and groups the Petasites extract was administered twice daily at oral dose rates of 0.0 mg/kg, 10 mg/kg, 20 mg/kg and 50 mg/kg
  • Pertinent parameters measured The determination of the long term effects of ad ⁇ ministration of Petasites extract was based on physical examination, clinical evaluation, and assessment of COPD symptoms. Results: All doses tested for 30 days were not associated with any clinically rele ⁇ vant changes. COPD symptoms were substantially alleviated at all dosages, the higher doses yielding less than a proportional increase.
  • the invention provides methods and means for treating chronic obstructive pulmonary disease (COPD) and similar bronchial disease caused by fungal spores in a patient by administering to said patient an effective dose of an extract of Petasites sp.
  • Preferred doses are in the range of from about 1 to about 50 mg/kg per day and have been shown to be effective in treating COPD in horses.
  • medica ⁇ ments for treating COPD can be provided.
  • the method of treating COPD is of particular advantage in the treatment of horses but it is expected that human and other mammal patients can be treated successfully to substantially alleviate or essentially eliminate breathing problems due to COPD.
  • Such treatment is of particular importance if use of corticosteroids for treating broncho- constrictive or broncho-obstructive diseases is impossible or undesirable, and generally provides the added advantage that treatment with an extract of Petasites sp. during ex ⁇ tended periods of time - as is the case in chronic diseases - is free of the side effects of long-term use of corticosteroids.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Pulmonology (AREA)
  • Engineering & Computer Science (AREA)
  • Botany (AREA)
  • Medical Informatics (AREA)
  • Mycology (AREA)
  • Biotechnology (AREA)
  • Alternative & Traditional Medicine (AREA)
  • Microbiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention porte sur un traitement de la MPOC (bronchopneumopathie obstructive chronique) consistant: à administrer à un patient une dose efficace d'un extrait de Petasites sp. Les dosages préférés allant d'environ 1 à environ 50 mg/kg par jour ou plus se sont montrés efficaces pour traiter la MPOC du cheval. L'invention porte également sur des médicaments de traitement de la MPOC à base d'extrait de Petasites sp, et sur leurs procédés de préparation. Ce nouveau traitement, particulièrement avantageux pour le cheval, et qui devrait pouvoir s'appliquer avec succès à l'homme, est particulièrement important lorsqu'il est impossible ou indésirable de traiter les maladies bronchoconstrictives ou bronchoobstructives par les corticostéroïdes.
EP05750477A 2004-06-23 2005-06-21 Traitement de la mpoc et medicament associe Withdrawn EP1789061A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US58172404P 2004-06-23 2004-06-23
PCT/CH2005/000344 WO2006000119A1 (fr) 2004-06-23 2005-06-21 Traitement de la mpoc et medicament associe

Publications (1)

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EP1789061A1 true EP1789061A1 (fr) 2007-05-30

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EP05750477A Withdrawn EP1789061A1 (fr) 2004-06-23 2005-06-21 Traitement de la mpoc et medicament associe

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EP (1) EP1789061A1 (fr)
WO (1) WO2006000119A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008052371A (ja) 2006-08-22 2008-03-06 Fujitsu Ltd アウトバンド認証を伴うネットワークシステム
CN113827636B (zh) * 2021-09-10 2022-03-29 中南大学湘雅二医院 藏四味清肺合剂及其在制备治疗呼吸系统疾病药物中的应用

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10217939A1 (de) * 2002-04-22 2003-11-13 Weber & Weber Gmbh & Co Kg Verwendung von Petasites enthaltenden Zusammensetzungen zur Behandlung von Krankheitszuständen

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ROBINSON N.E. ET AL: "The Pathogenesis of Chronic Obstructive Pulmonary Disease of Horses", BR. VET. J., vol. 152, 1996, pages 283 - 306, XP022501712 *
See also references of WO2006000119A1 *

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Publication number Publication date
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