EP1789061A1

EP1789061A1 - Copd treatment and medicament

Info

Publication number: EP1789061A1
Application number: EP05750477A
Authority: EP
Inventors: Axel Brattstroem
Original assignee: Max Zeller Soehne AG
Current assignee: Max Zeller Soehne AG
Priority date: 2004-06-23
Filing date: 2005-06-21
Publication date: 2007-05-30
Also published as: WO2006000119A1

Abstract

Chronic obstructive pulmonary disease (COPD) in a patient can be treated by administering to said patient an effective dose of an extract of Petasites sp. Preferred dosages are in the range of from about 1 to about 50 mg/kg per day or above and have been shown to be effective in treating COPD in horses. Thus, medicaments for treating COPD can be provided by using an extract of Petasites sp. for preparation of such medicaments. The novel treatment of COPD is of particular advantage in the case of horses but it is expected that human patients can be treated successfully as well. Such treatment is of particular importance if use of corticosteroids for treating broncho-constrictive or broncho-obstructive diseases is impossible or undesirable.

Description

COPD TREATMENT AND MEDICAMENT

The invention relates generally to the art of treating diseases and specifically to methods and means for treating what has become known in the art as chronic obstruc- tive pulmonary disease (COPD herein for brevity) and which is being recognised as a health problem of increasing importance. 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. According to the art, equine COPD is treated with drugs, such as Ventipulmin® (clenbuterol hydrochloride), Sputolosin® (dembrexine), 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. The abdominal muscles of COPD-afflicted horses may hypertrophy and form no¬ ticeable "heave lines." Physiologically, COPD is a disease of patients that affects the respiratory duct (the "airways": trachea, bronchi, and bronchioles) through which air flows into the lungs. 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. In COPD patients, 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. When in acute state, the airways of COPD patients and notably horses become acutely inflamed which causes the airways to become edematous. Repeated episodes of inflammation can cause the airway mucosal cells to proliferate. Both edema and prolif¬ eration of the mucosal cells tend to thicken the airway walls and obstruct normal air flow during breathing . 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. These tiny hair like projections on the epithelial surface beat con¬ tinuously and transport the overlying mucus layer up toward the larynx where the mu¬ cus can either be expelled (by coughing) or swallowed. The mucociliary system pro¬ vides a means by which inhaled foreign particles normally can be cleared from the air- ways. Stimulation of the irritant receptors lying below the airway epithelium promotes mucus secretion so that more mucus is available to transport inhaled allergens out of the airways. Inflammation of the airways stimulates mucus secretion and causes prolifera¬ tion of mucus producing cells. In COPD patients in general and horses in specific, ex¬ cess mucus in the airways is symptomatic and plugs the bronchioles. The smooth muscle that encircles the airways is controlled by the parasympa¬ thetic nervous system. Inhaled irritants stimulate the parasympathetic nervous system to release acetylcholine. The binding of acetylcholine to receptors located on airway smooth muscle cells causes broncho constriction (broncho spasm) which prevents irri¬ tants from penetrating deeper into the lungs. When the mucosa of a COPD patient is thickened by inflammation, even a little smooth muscle contraction can substantially narrow the airways and make breathing more difficult. 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. In COPD-afflicted mammal patients, such as horses, 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. As a result of the hyper-reactive cough reflex and mucus accumulation in the airways, COPD afflicted animals or horses, respectively, cough frequently. In horses, typical clinical signs are "heaving," coughing, or muco purulent nasal discharge. Abnormal lung sounds, especially wheezing, become more obvious as the disease in¬ creases in severity. If there is doubt about the diagnosis, endoscopy or bronchoalveolar lavage can be used. 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. In horses with severe COPD, the percentage of neutrophils in bronchoalveolar lavage fluid may be about 50-70% (or more) of the total cell count. However, 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. Although all horses usually become hypoxemic during exercise, the hypoxemia seen in COPD horses is more pronounced. In equine COPD, conventional treatment involves prevention of exposure to al¬ lergens by environmental management, reduction of inflammation by use of corticoster¬ oids, and relief of airway obstruction by use of bronchodilator drugs. At present, there is no cure for COPD and, therefore, treatment s need to be continued for life, primarily by changing the environment of a stabled COPD horse. In addition, it may be necessary to administer drugs. Up to the present, corticosteroids have been considered generally to be the drugs of choice for relieving COPD in animal patients. However, due to various undesirable side effects of corticosteroids, there is a need to find an effective agent capable of re- placing, at least in part, the corticosteroid when treating COPD in a patient. It has now been found according to the invention that administering of Pe tasites sp. extract, preferably oi Petasites hybridus, may be used effectively to complement or even replace conventional treatment with corticosteroids and other drugs for treating COPD in a patient. Both terms "animal" and "patient" as used herein to include humans. Thus and according to a first general embodiment, 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. According to a second general embodiment, the invention provides for a phar¬ maceutical composition for treatment of COPD in a patient. According to a further embodiment the invention provides the use of an extract of Petasites sp. for preparation of a medicament for treating COPD in a patient. According to a yet further embodiment the invention provides a medicament for use in veterinary medicine containing an extract of Petasites sp. In the drawings, 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. A preferred species for use in the invention is 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. In addition to petasin, 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. An even more detailed study is the the¬ sis by Dr. Siegenthaler, "Untersuchungen zur Struktur und Analytik der Inhaltsstoffe von Petasites albus und hybridus", Berne 1995, also incorporated herein by way of ref¬ erence. It appears that P. hybridus may occur in two chemovarieties termed Petasites variety and Furano variety, the former being preferred herein. 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). These PA components are known to have hepatotoxic, carcinogenic, cytostatic and mutagenic properties. Accordingly, a Petasites sp. extract in the sense used herein and in the claims refers to such an extract which is substantially free of PA. As used herein, the phrase "substantially free" indicates that any PA trace must be below the sensitivity of the test method used, generally below 0.1 ppm. To this end, applicants have found that 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. When used according to the present invention for treating COPD, the Petasites extract preferably is administered orally or by inhalation. Generally, therapy usually be- gins with a high dose and, as the patient improves, the dose is reduced to a maintenance level. Generally, 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. However, 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. Thus, dosages of from about 1 to about 100 mg/kg or even about 1 to about 500 mg/kg would be ac¬ ceptable for oral application if the dosage increase still leads to a significant improve¬ ment of therapeutic effectiveness. 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. 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. in combination with prednisolon, triamcinolone, dexamethasone or beclomethasone dipropionate. 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. On the other hand, effective dosages of the Petasites extract should not be reduced if used in combination with such prior art COPD medications. By virtue of the activity determined by the test procedures described below, 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. A phy¬ sician or veterinarian of ordinary skill readily determines a subject exhibiting COPD symptoms. Regardless of the route of administration selected, 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. In view of the fact that COPD in horses frequently is associated with hay dust - which in turn is known to contain fungal spores it can be assumed that whenever serious bronchial disease such as COPD can be linked to presence of fungal spores, such as Basidiospore (spores of the Basidiomycota class of fungi), Ascospores (spores of the Ascomycota class of fungi), or/and 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.

The invention will now be illustrated without limitation by reference to the fol- lowing examples. The term "about" preceding a numeric value indicates an allowable deviation of ±50% from said numeric value.

Example 1 Preparation of the Extract: 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 μg 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. The data support a linear dose response from 10 mg/kg to 50 mg/kg in horses. Adverse Drug Responses: No clinical adverse drug responses effects, such as sweating, muscle tremor and nervousness, were observed at any dose levels. Conclusions: No limit of the dosage was observed. The average response of horses was improvement in the COPD condition while on test drug, with a worsening of the condition after drug withdrawal.

Example 2

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. Conclusion: Petasites hybridus at all dosages was shown to be safe for use in horses.

Example 5

Identical results were obtained when the Petasites extract was obtained by extraction with aqueous ethanolic extraction agent in counter-current and treatment of the primary extract with cation exchange resin as described in DE 197 02 168.

Example 6

Nine horses (mares and geldings) having or not having typical COPD symptoms were examined by means of a standard device for measuring airway resistance before treatment with extract from Petasites hybridus (supplied under the trade name Ze 339 by Zeller AG, Romanshorn, Switzerland) at a single daily dosage of 50 mg/kg body weight in the form of tablets as well as 14 days after continued daily dosages of 50 mg/kg body weight. The tablets contained Ze 339 as the only therapeutically active in- gredient. The results are shown as a diagram in Fig. 1 of the drawings in which the airway resistance is indicated in centimeters (height of water column supported by pressure as standard of the metering device) on the ordinate. Only two time values are indicated on the abscissa, the first before start of the treatment (0 days) and the second after 14 days of treatment. As is clearly apparent from Fig. 1, the effect of the treatment is significant in the case of the horses suffering from COPD since an airway resistance of more then 10 cm H₂O is correlated with the severity of general COPD symptoms such that the degree of affliction is highest with the highest airway resistance values. Even such relatively short treatment did cause a significant drop of the initial air¬ way resistance of from about 30 to about 50% from the starting value in those horses where the affliction was medium to heavy (15 - 40 cm H₂O) while with those horses where the initial airway resistance was 10 cm H₂O or lower (indicating no significant COPD affliction) no significant change of the airway resistance was observed. This re¬ sult, again, is believed to be indicative of a substantial improvement in horses suffering from COPD by treatment according to the invention, i.e. by administering a medicament consisting essentially of an extract according to the invention. Summarizing the above, 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. Thus, 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.

Claims

1. A method of treating chronic obstructive pulmonary disease (COPD) in a patient comprising the step of administering to said patient an effective dose of an extract of Petasites sp.

2. The method of claim 1, wherein said extract of Petasites sp. is an extract of a plant portion selected from roots, leaves and/or stems of Petasites hybridus, Petasites albus, Petasites japonicus, Petasites paradoxus, and Petasites spurious, Petasites hy¬ bridus being preferred.

3. The method of claims 1 or 2, wherein said extract is administered orally to said patient.

4. The method of claim I₅ wherein said extract is administered by inhalation.

5. The method of any of claims 1 - 4, wherein at least one further drug selected from: (a) the group including clenbuterol, dembrexine, pirbuterol, albuterol, ephedrine, atropin, ipratropinum bromide, aminophyline; (b) steroids selected from the group comprising prednisolone, triamcinolone, ex- amethasone, or beclomethasone dipropionate; and (c) an anti-allergic agents selected from cromoglicinic acid and derivatives thereof, ketotifen, and nedocromil, is administered in combination with said extract.

6. The method of any of claims 1 - 5 wherein said patient is a horse.

7. The method of any of claims 1 - 6 wherein said step of administering is effected by inhalation, e.g. via the nose.

8. A pharmaceutical composition for treatment of COPD in an animal.

9. Use of an extract of Petasites sp. for preparation of a medicament for treating COPD in a patient.

10. Use according to claim 9 for preparation of a veterinary medicament for use in treating horses afflicted with COPD.

11. A method of treating a bronchial disease such as COPD linked to fungal spores, such as Basidiospore, Ascospores, or/and Zygospores comprising the step of administer¬ ing an effective dose of an extract of Petasites sp.

12. Use of an extract of Petasites sp. for preparation of a medicament for treating a bronchial disease such as COPD linked to fungal spores, such as Basidiospore, Asco¬ spores, or/and Zygospores. AMENDED CLAIMS [received by the International Bureau on 25 November 2005 (25.1 1.2005); original claims 1-12 replaced by amended claims 1-10 (2 pages)]