WO1987000047A1 - Method and composition for the treatment of chronic obstructive pulmonary disease - Google Patents
Method and composition for the treatment of chronic obstructive pulmonary disease Download PDFInfo
- Publication number
- WO1987000047A1 WO1987000047A1 PCT/US1986/001419 US8601419W WO8700047A1 WO 1987000047 A1 WO1987000047 A1 WO 1987000047A1 US 8601419 W US8601419 W US 8601419W WO 8700047 A1 WO8700047 A1 WO 8700047A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- calcium channel
- channel blocker
- verapamil
- beta
- composition
- 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.)
- Ceased
Links
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
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/275—Nitriles; Isonitriles
-
- 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
Definitions
- the present invention is directed to the treatment of chronic obstructive pulmonary diseases such as asthma and chronic bronchitis. More particularly, the present invention is directed to increasing the duration of action and the peak effect of conventional treatments, 10 so that treatment is more convenient and effective. It has been discovered that administering a calcium channel blocker with the standard beta-adrenergic agonist will result in greater bronchodilation and an increased acting time in treating chronic obstructive pulmonary 15 diseases.
- a safe, effective treatment for patients suffering from chronic obstructive pulmonary diseases such as asthma and chronic bronchitis currently is the oral or 20 aerosol administration of a beta-adrenergic agonist.
- the beneficial effect of this treatment wears off in about four hours, thus requiring the incon ⁇ venience of four to six treatments per day. It would be advantageous if three or fewer treatments were required 25 and nighttime coverage against potential bronchospasm would be ensured.
- calcium channel blockers such as Verapamil and Nifedipine has been considered for treating allergen and antigen-induced bronchoconstric- 30 tions.
- calcium channel blockers have not been considered as possible agents for increasing the duration of action and peak effectiveness in reducing ? bronchoconstriction for beta-adrenergic agonists.
- the above objects and others are obtained by administering a calcium channel blocker with a beta- adrenergic agonist to a person suffering from a chronic obstructive pulmonary disease.
- the use of the calcium channel blocker can as much as double the effective treatment time of the beta-agonist, thus reducing the number of daily dosages required and providing nighttime coverage.
- a calcium channel blocker can be used to enhance the bronchodilation to increase the effective treating time of beta-agonists, presently used in treating chronic obstructive pulmonary diseases such as asthma, chronic bronchitis, and emphysema. It is believed that the increased effective ⁇ ness of the beta-adrenergic agonist is caused by the calcium channel blocker preventing reversal of the calcium depletion initiated by the beta-agonist.
- this is only a proposed theory, and the present invention is not limited to this particular theory.
- the calcium channel blocker may be administered concurrently with a beta-adrenergic agonist, using the same administration route as the beta-adrenergic agonist, i.e. aerosol, oral, parenteral, etc.
- the amount of beta-adrenergic agonist administered at a given time is not changed from the levels presently known. However, the frequency of the administration may be decreased. It has been discovered that the calcium channel blocker doubles the effective treatment time of the beta-adrenergic agonist. Of course, it also would be possible to lower the dosage of beta-adrenergic agonist if, for some reason, more frequent adminis ⁇ tration is desired. For any given dosage of beta-adrenergic agonist, the calcium channel blocker increases the effective treatment time. 5 Any calcium channel blocker suitable for adminis ⁇ tration via the treatment routes mentioned heretofore is useful in the present invention. Two representative calcium channel blockers are Verapamil and Gallopamil. Nifedipine is an example of a calcium channel blocker
- Nifedipine is inactivated by light, use of this compound in aerosol applications may be difficult.
- any of the known beta- adrenergic agonists presently used in broncho-dilator is a known beta- adrenergic agonists presently used in broncho-dilator
- beta-adrenergic agonists examples include Albuterol (Ventolin) , Isoetharine, Metaproterenol, and Isoproterenol. Aerosol administration is preferred, although other forms of administration, such as oral or
- Aerosol administration may be through use of a metered dose inhaler, such as is commonly used in this type of therapy at present.
- a preferred method for aerosol administration is use of a metered dose inhaler with the
- the amount of calcium channel blocker in a given ⁇ dosage depends to some extent upon the method of admin ⁇ istration. For example, when a one-percent by weight
- 35 solution of Verapamil in saline is to be delivered by nebulization, the amount of solution in a given dosage is chosen to provide about 10 to 20 milligrams of Verapamil. This has been found to provide an effective dose of about one-half milligram to the lungs. However, aerosol delivery using a metered dose inhaler and Freon results in a much greater amount of the active ingredient reaching the lungs. Thus, one-half to one milligram of Verapamil delivered in this fashion would be necessary to achieve the same effect as the 10-20 milligrams delivered via the nebulized saline solution. Dosages of other calcium channel blockers will depend upon their potency.
- Gallopamil is more potent than Verapamil, so that a 5 or 10 milligram dose could be delivered via nebulized saline solution, preferably about J-1% by weight. 8 milligrams of Gallopamil in 2ml of saline (0.4%) solution is as effec- tive as 20 milligrams of Verapamil. Both Gallopamil and Verapamil prolong the effective bronchodilation of Ventolin to up to 10-11 hours. Also, the magnitude of Ventolin-induced bronchodilation is enhanced by both Gallopamil and Verapamil.
- compositions according to the present invention comprise a beta-adrenergic agonist in an amount sufficient to relieve broncho constriction and a calcium channel blocker in an amount effective to increase the effective treating time provided by the beta-agonist.
- suitable carriers, adjuvants and diluents also may be present in the composition of the present invention.
- an oral dosage form could include known polymer matrix - forming compounds and suitable lubricants and tableting ingredients. Particles of given ingredients could be coated and provided in the form of capsules. Pulmonary introduction through an aerosol form can be accomplished using appropriate saline solutions, with known solubilizers if necessary for the specific active ingre- der.
- the active ingredients alternatively could be dispersed in a carrier such as Freon.
- the following example is provided to further illustrate the present invention.
- a patient suffering from severe asthma is treated by administration of a total of 180 micrograms of Ventolin in two "puffs" through a metered dose inhaler connected to an inhaling device according to U.S. Patent 4,484,577.
- Measurements of Forced Expired Volume in One Second (FEV..) are taken immediately after administration and at one-half hour intervals thereafter.
- the bronchodilation effect (change in FEV..) is shown in Figure 1.
- Significant bronchodilation effects last for about 5 hours.
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- Health & Medical Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Engineering & Computer Science (AREA)
- Otolaryngology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Chronic obstructive pulmonary diseases are treated with a beta-adrenergic agonist and a calcium channel blocker. The calcium channel blocker increases magnitude of dilation and the effective treatment time of the beta-adrenergic agonist.
Description
-I-
METHOD AND COMPOSITION FOR THE TREATMENT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE BACKGROUND OF THE INVENTION ■• Field of the Invention " 5 The present invention is directed to the treatment of chronic obstructive pulmonary diseases such as asthma and chronic bronchitis. More particularly, the present invention is directed to increasing the duration of action and the peak effect of conventional treatments, 10 so that treatment is more convenient and effective. It has been discovered that administering a calcium channel blocker with the standard beta-adrenergic agonist will result in greater bronchodilation and an increased acting time in treating chronic obstructive pulmonary 15 diseases.
2. Description of the Prior Art
A safe, effective treatment for patients suffering from chronic obstructive pulmonary diseases such as asthma and chronic bronchitis currently is the oral or 20 aerosol administration of a beta-adrenergic agonist. Unfortunately, the beneficial effect of this treatment wears off in about four hours, thus requiring the incon¬ venience of four to six treatments per day. It would be advantageous if three or fewer treatments were required 25 and nighttime coverage against potential bronchospasm would be ensured.
The effect of calcium channel blockers such as Verapamil and Nifedipine has been considered for treating allergen and antigen-induced bronchoconstric- 30 tions. However, calcium channel blockers have not been considered as possible agents for increasing the duration of action and peak effectiveness in reducing ? bronchoconstriction for beta-adrenergic agonists.
SUMMARY OF THE INVENTION 35 It is an object of this invention to increase the magnitude of bronchodilation and effective treatment
time of conventional beta-agonist treatments for chronic obstructive pulmonary disease.
It is a further object of this invention to improve the effectiveness of such conventional treatments in a manner that is simple and easy to administer to patients.
The above objects and others are obtained by administering a calcium channel blocker with a beta- adrenergic agonist to a person suffering from a chronic obstructive pulmonary disease. The use of the calcium channel blocker can as much as double the effective treatment time of the beta-agonist, thus reducing the number of daily dosages required and providing nighttime coverage. DETAILED DESCRIPTION OF THE INVENTION
It has been discovered that a calcium channel blocker can be used to enhance the bronchodilation to increase the effective treating time of beta-agonists, presently used in treating chronic obstructive pulmonary diseases such as asthma, chronic bronchitis, and emphysema. It is believed that the increased effective¬ ness of the beta-adrenergic agonist is caused by the calcium channel blocker preventing reversal of the calcium depletion initiated by the beta-agonist. However, this is only a proposed theory, and the present invention is not limited to this particular theory.
The calcium channel blocker may be administered concurrently with a beta-adrenergic agonist, using the same administration route as the beta-adrenergic agonist, i.e. aerosol, oral, parenteral, etc. The amount of beta-adrenergic agonist administered at a given time is not changed from the levels presently known. However, the frequency of the administration may be decreased. It has been discovered that the calcium channel blocker doubles the effective treatment time of the beta-adrenergic agonist. Of course, it also would be possible to lower the dosage of beta-adrenergic
agonist if, for some reason, more frequent adminis¬ tration is desired. For any given dosage of beta-adrenergic agonist, the calcium channel blocker increases the effective treatment time. 5 Any calcium channel blocker suitable for adminis¬ tration via the treatment routes mentioned heretofore is useful in the present invention. Two representative calcium channel blockers are Verapamil and Gallopamil. Nifedipine is an example of a calcium channel blocker
10 which may not be useful for some methods of treatment. Since Nifedipine is inactivated by light, use of this compound in aerosol applications may be difficult.
As noted previously, any of the known beta- adrenergic agonists presently used in broncho-dilator
15 constriction therapy are useful in this invention. Examples of such beta-adrenergic agonists include Albuterol (Ventolin) , Isoetharine, Metaproterenol, and Isoproterenol. Aerosol administration is preferred, although other forms of administration, such as oral or
20 parenteral administration, would be useful also. Aerosol administration may be through use of a metered dose inhaler, such as is commonly used in this type of therapy at present. A preferred method for aerosol administration is use of a metered dose inhaler with the
25 inhaling device disclosed in Sackner et al. U.S. Patent
4,484,577, the disclosure of which is incorporated
. herein by reference. Simultaneous administration of the beta-adrenergic agonist and calcium channel blocker is preferred. However, the calcium channel blocker could
30 be administered a short time, e.g. within about an hour, after administration of the beta-adrenergic agonist.
The amount of calcium channel blocker in a given § dosage depends to some extent upon the method of admin¬ istration. For example, when a one-percent by weight
35 solution of Verapamil in saline is to be delivered by nebulization, the amount of solution in a given dosage is chosen to provide about 10 to 20 milligrams of
Verapamil. This has been found to provide an effective dose of about one-half milligram to the lungs. However, aerosol delivery using a metered dose inhaler and Freon results in a much greater amount of the active ingredient reaching the lungs. Thus, one-half to one milligram of Verapamil delivered in this fashion would be necessary to achieve the same effect as the 10-20 milligrams delivered via the nebulized saline solution. Dosages of other calcium channel blockers will depend upon their potency. For example, Gallopamil is more potent than Verapamil, so that a 5 or 10 milligram dose could be delivered via nebulized saline solution, preferably about J-1% by weight. 8 milligrams of Gallopamil in 2ml of saline (0.4%) solution is as effec- tive as 20 milligrams of Verapamil. Both Gallopamil and Verapamil prolong the effective bronchodilation of Ventolin to up to 10-11 hours. Also, the magnitude of Ventolin-induced bronchodilation is enhanced by both Gallopamil and Verapamil. Therapeutic compositions according to the present invention comprise a beta-adrenergic agonist in an amount sufficient to relieve broncho constriction and a calcium channel blocker in an amount effective to increase the effective treating time provided by the beta-agonist. Depending on the dosage form, suitable carriers, adjuvants and diluents also may be present in the composition of the present invention. For example, an oral dosage form could include known polymer matrix - forming compounds and suitable lubricants and tableting ingredients. Particles of given ingredients could be coated and provided in the form of capsules. Pulmonary introduction through an aerosol form can be accomplished using appropriate saline solutions, with known solubilizers if necessary for the specific active ingre- dient. The active ingredients alternatively could be dispersed in a carrier such as Freon.
The following example is provided to further illustrate the present invention.
A patient suffering from severe asthma is treated by administration of a total of 180 micrograms of Ventolin in two "puffs" through a metered dose inhaler connected to an inhaling device according to U.S. Patent 4,484,577. Measurements of Forced Expired Volume in One Second (FEV..) are taken immediately after administration and at one-half hour intervals thereafter. The bronchodilation effect (change in FEV..) is shown in Figure 1. Significant bronchodilation effects last for about 5 hours.
The effect is measured for similar administration of Ventolin, followed immediately by administration of 20 milligrams of Verapamil or 8 milligrams of Gallopamil via a nebulized saline (0.4%) solution containing 1% by weight of the active ingredient. The results are shown in Figure 1. It can be seen that the effective time of treatment is extended to 10-11 hours. The peak is increased to 790 ml (Ventolin plus Verapamil) or 1000 ml (Gallopamil plus Ventolin) over the 720 ml from Ventolin alone. The two runs with the calcium channel blockers also show a more gradual decline from the point of peak effectiveness, and a prolonged period near the point of peak effectiveness.
Claims
1. A method for treating a chronic obstructive pulmonary disease, comprising administering to a subject suffering from a chronic obstructive pulmonary disease a therapeutically effective amount of a beta-adrenergic agonist and a calcium channel blocker, said calcium channel blocker being present in an amount effective to increase the period of effectiveness of said beta- adrenergic agonist, said calcium channel blocker being administered via a pulmonary route.
2. The method of Claim 1, wherein said calcium channel blocker and beta-adrenergic agonist are aerosolized and administered together via a pulmonary route.
3. The method of Claim 2, wherein said calcium channel blocker is Verapamil or Gallopamil.
4. The method of Claim 3, wherein said calcium channel blocker is Gallopamil.
5. The method of Claim 3, wherein said calcium channel blocker is Verapamil and an effective dosage of one-half milligram of Verapamil is administered.
6. The method of Claim 3, wherein Verapamil is provided in the form of a saline solution having about one-percent by weight Verapamil and about 10 to 20 milligrams of Verapamil are delivered by nebulization.
7. The method of Claim 3, wherein said calcium channel blocker is Gallopamil, provided in a saline solution of no more than about one-percent by weight Gallopamil, and about 5 to 10 milligrams of Gallopamil are delivered by nebulization.
8. The method . of claim 2, wherein said calcium channel blocker and said beta-adrenergic agonist are administered via a metered dose inhaler.
9. A composition for treatment of chronic obstructive pulmonary disease, comprising a therapeutically effective amount of a beta-adrenergic agonist and a calcium channel blocker, said calcium channel blocker being present in an amount effective to increase the period of effectiveness of said beta- adrenergic agonist and a pharmaceutically acceptable carrier, adjuvant or diluent for pulmonary administration of the composition.
10. The composition of Claim 9, wherein said composition is suitable for pulmonary administration to a patient.
11. The composition of Claim 9, wherein said calcium channel blocker is Verapamil or Gallopamil.
12. The composition of Claim 11, wherein said calcium channel blocker is Verapamil and the composition delivers an effective dosage of about one-half milligram of Verapamil.
13. The composition of Claim 11, wherein said calcium channel blocker is in a saline solution at a concentration of about 1% by weight.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FI870731A FI870731L (en) | 1985-07-02 | 1986-07-01 | FOERFARANDE OCH BLANDNING FOER BEHANDLING AV CHRONISK OBSTRUKTIV LUNGA COMMA. |
| KR1019870700179A KR890004691B1 (en) | 1985-07-02 | 1986-07-01 | Treatment and composition for chronic obstructive pulmonary disease |
| NO870827A NO870827L (en) | 1985-07-02 | 1987-02-27 | PROCEDURE AND PREPARATION FOR TREATMENT OF CHRONIC OBSTRUCTIVE LUNG DISEASE. |
| DK103087A DK103087A (en) | 1985-07-02 | 1987-02-27 | MEDICINE FOR THE TREATMENT OF CHRONIC STOPPING LUNG DISEASES |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US75111485A | 1985-07-02 | 1985-07-02 | |
| US751,114 | 1985-07-02 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1987000047A1 true WO1987000047A1 (en) | 1987-01-15 |
Family
ID=25020531
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1986/001419 Ceased WO1987000047A1 (en) | 1985-07-02 | 1986-07-01 | Method and composition for the treatment of chronic obstructive pulmonary disease |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0231266A1 (en) |
| JP (1) | JPS63500243A (en) |
| KR (1) | KR890004691B1 (en) |
| AU (1) | AU601695B2 (en) |
| DK (1) | DK103087A (en) |
| FI (1) | FI870731L (en) |
| MY (1) | MY100519A (en) |
| WO (1) | WO1987000047A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4430128A1 (en) * | 1994-08-25 | 1996-02-29 | Hoechst Ag | Combination preparation with immunosuppressive, cardiovascular and cerebral effects |
| US20120245145A1 (en) * | 2009-12-03 | 2012-09-27 | Adams Kenneth W | Method and compositions for treatment and prevention of broad spectrum virus ailments comprising a calcium channel blocker or a calmodulin blocker |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TR201007251A2 (en) * | 2010-09-01 | 2012-03-21 | Bi̇lgi̇ç Mahmut | Calcium channel blocker formulation. |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3440881A1 (en) * | 1984-11-06 | 1986-05-15 | Schering AG, Berlin und Bergkamen, 1000 Berlin | PHARMACEUTICAL COMPOSITION, ITS PRODUCTION AND USE |
-
1986
- 1986-07-01 JP JP61504010A patent/JPS63500243A/en active Pending
- 1986-07-01 AU AU61414/86A patent/AU601695B2/en not_active Ceased
- 1986-07-01 KR KR1019870700179A patent/KR890004691B1/en not_active Expired
- 1986-07-01 WO PCT/US1986/001419 patent/WO1987000047A1/en not_active Ceased
- 1986-07-01 EP EP86904627A patent/EP0231266A1/en not_active Ceased
- 1986-07-01 FI FI870731A patent/FI870731L/en not_active Application Discontinuation
-
1987
- 1987-02-27 DK DK103087A patent/DK103087A/en not_active Application Discontinuation
- 1987-09-22 MY MYPI87001843A patent/MY100519A/en unknown
Non-Patent Citations (3)
| Title |
|---|
| CHEMICAL ABSTRACTS, Vol. 85, No. 15, 11 October 1976 (Columbus, Ohio, US) H. BOBBAERS et al.: "Action of Isoprenaline on the Mechanical Properties of Lungs and Airways in Healthy People and Patients with Obstructive Lung Diseases", see page 64, Abstract No. 104169h, & Bull. Eur. Physiopathol. Respir. 1976, 12(4), 515-31 * |
| CHEMICAL ABSTRACTS, Vol. 88, No. 17, 24 April 1978 (Columbus, Ohio, US) M.A. SACKNER et al.: "The Pulmonary Hemodynamic Effects of Aerosols of Isoproterenol and Ipratropium in Normal Subjects and Patients with Reversible Airway Obstruction", see page 56, Abstract No. 115427d, & Am. Rev. Respir. Dis. 1977, 116(6), 1013-22 * |
| CHEMICAL ABSTRACTS, Vol. 97, No. 11, 13 September 1982 (Columbus, Ohio, US) P. EYRE et al.: "Equine Influenza Virus Enhances Responsiveness of Quinea Pig Tracheal Muscle to Isoprenaline", see page 564, Abstract No. 89884q, & Res. Commun. Chem. Pathol. Pharmacol. 1982, 37(1), 3-10 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4430128A1 (en) * | 1994-08-25 | 1996-02-29 | Hoechst Ag | Combination preparation with immunosuppressive, cardiovascular and cerebral effects |
| US20120245145A1 (en) * | 2009-12-03 | 2012-09-27 | Adams Kenneth W | Method and compositions for treatment and prevention of broad spectrum virus ailments comprising a calcium channel blocker or a calmodulin blocker |
| US10350190B2 (en) * | 2009-12-03 | 2019-07-16 | Dr. Kenneth Adams Medicine Professional Corporation | Method and compositions for treatment and prevention of broad spectrum virus ailments comprising a calcium channel blocker or a calmodulin blocker |
| US10888541B2 (en) | 2009-12-03 | 2021-01-12 | Dr. Kenneth Adams Medicine Professional Corporation | Method and compositions for treatment and prevention of broad spectrum virus ailments comprising a calcium channel blocker or a calmodulin blocker |
Also Published As
| Publication number | Publication date |
|---|---|
| MY100519A (en) | 1990-10-30 |
| DK103087D0 (en) | 1987-02-27 |
| AU6141486A (en) | 1987-01-30 |
| KR870700349A (en) | 1987-12-28 |
| EP0231266A1 (en) | 1987-08-12 |
| KR890004691B1 (en) | 1989-11-25 |
| JPS63500243A (en) | 1988-01-28 |
| AU601695B2 (en) | 1990-09-20 |
| FI870731A7 (en) | 1987-02-20 |
| DK103087A (en) | 1987-02-27 |
| FI870731A0 (en) | 1987-02-20 |
| FI870731L (en) | 1987-02-20 |
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