WO1996031222A1

WO1996031222A1 - Antiasthmatic preparation

Info

Publication number: WO1996031222A1
Application number: PCT/BG1995/000003
Authority: WO
Inventors: Ivan Dimitrov Hristov
Original assignee: Ivan Dimitrov Hristov
Priority date: 1994-03-23
Filing date: 1995-03-22
Publication date: 1996-10-10
Also published as: EP0760669A1; BG98678A; BG61430B1

Abstract

The problem solved by the present invention is the creation of an antiasthmatic remedy breaking of the disease fits and leading to full healing. The substance of the decision lies in the combination of active components and their proportion: atropine sulphate 0,25 - 1,00 mg; papaverine hydrochloride 30,00-200,00 mg; caffeine purum 30,00-250,00 mg; ergotamine tartrate 0,25-2,00 mg; zinc sulphate 10,00-220,00 mg; sex hormones 0,25-1,00 mg, the sex hormones being diethylstilbestrol propionate or methandrostenol. The advantages of the composition are that it leads to stopping the asthmatic fits for 30-40 min, averts any new fits, and leads in practice to full healing.

Description

Ant1asthmat1c preparation

Field of the Invention The invention relates to an antiasthmatic remedy used in human medicine for treatment of bronchial asthma and asthmatic bronchitis.

Prior Art There a number of remedies known for treatment of bron- chial asthma and asthmatic bronchitis.

Xanthins are known with their stimulating effect on breathing and relieving of bronchospasms (Martindale 1989) . There are known also their combinations with other medicinal substances, having a preventive and prophylactic effect mainly (BE 903065) .

Atropine sulphate is known as an antimuscarine agent, as well as its use in cases of asthma (Paterson J.W. £ Ta- rala R.A. , Med. J.Aust., 1985, 143,390).

Papaverine hydrochloride is known as an incontestable spasmolytic agent. It removes bronchial spasms and soothes the center of breathing and cough (Martindale, 1989).

Ergotamine is known as a sympatholitic agent (Martin¬ dale, 1989), as well as its specific effect in congestive states of the lungs, this probably being due to the vaso- constrictive effect on the bronchial vascula.

All those medicinal substances influence separate moments of the disease symptoms without staying its progress.

Corticosteroid preparations are known as medicines used in treating bronchial asthma and asthmatic bronchitis (Martindale, 1989). Their shotcomings consist in that they can lead to cases of medicinal hypercorticism, e.g. obesity, arterial hypertonia, osteoporosis, gastic and duodenal ul¬ cers, infections, etc. After medical treatment is started, the sick person becomes fully dependent on exogenous corti- costeroids, and new fits are not averted, although the con¬ dition of the patient improves to a certain extent. The problem consists in making an antiasthmatic remedy breaking off the disease fits and leading to a long remis¬ sion for years, i.e. to healing, without showing the grave side effects of corticosteroids.

Brief description of the Invention This problem is solved by the creation of an antiasth¬ matic medicinal substance containing atropine sulphate, papaverine hydrochloride, caffeine, ergotamine tartrate, zinc sulphate and sex hormones in the following quantita¬ tive proportions: atropine sulphate 0,25 - 1,00 mg papaverine hydrochloride 30,00 - 200,00 mg caffeine puru 30,00 - 250,00 mg ergotamine tartrate 0,25 - 2,00 mg zinc sulphate 10,00 - 220,00 mg sex hormones 0,25 - 1,00 mg

Where the remedy is used for patents of the female sex, the female sex hormone orestrone (diethylstilbestrol) is included in the combination. Where the remedy is used for males, the hormone methandienone is added.

The combination of active substances according to the invention is suitable for preparation of phar aceutic forms using subsidiary substances and carriers usual for the pharmaceutic technology.

Sex hormones shall obligatorily be added once to the daily dose of the combination. The advantages of the remedy according to the invention are: asthmatic fits are stopped within 30-40 min. ; new cases of painful asthmatic breathing and subsequent asthmatic fits are avoided for a period of 10 or more years; at the same time, the remedy is welltole- rated and does not show the grave side effects and compli¬ cations caused by corticosteroids

Detailed description of the Invention

The following examples illustrate the invention without resticting it: EXAMPLE 1

Atropine sulphate 0,25 mg

Papaverine hydrochloride 40,00 mg

Caffeine purum 50,00 mg Ergotamine tartrate 0,25 mg

Zinc sulphate 40,00 mg

Methandrostenol (Methandienone) 1,00 mg EXAMPLE 2

Atropine sulphate 1,00 mg Papaverine hydrochloride 100,00 mg Caffeine purum 100,00 mg

Ergotamine tartrate 1,00 mg

Zinc sulphate 200,00 mg

Mathandrostenol (Methandienone) 5,00 mg EXAMPLE 3

Atropine sulphate 0,25 mg

Papaverine hydrochloride 40,00 mg

Caffeine purum 50,00 mg

Ergotamine tartrate 0,25 mg Zinc sulphate 400,00 mg

Diethylstilbestrol propionate 0,25 mg EXAMPLE 4

Atropine sulphate 1,00 mg

Papaverine hydrochloride 100,00 mg Caffeine purum 100,00 mg

Ergotamine tartrate 1,00 mg

Zinc Sulphate 200,00 mg

Diethylstilbestrol propionate 1,00 mg EXAMPLE 5 Tests of the acute toxicity of the medicinal combina¬ tion according to the present invention.

For the tests were used male white rats of the Wistar breed with a weight of 180 to 200 grams. The rats were raised under standard food and water conditions. For the tests were used 300 rats altogether.

The following substances provided by the applicant were used: - ergotamine,

- atropine sulphate,

- papaverine hydrochloride,

- zinc sulphate, - caffeine purum

The substances were dissolved in Tween 80 upon through grinding, and then they were perorally introduced through a probe in a volume of lml/lOOg bodily weight (b.w.).

The following were mixed for making the preparation according to the invention: 1 part ergotamine; 1/4 part atropine sulphate; 40 parts zinc sulphate; 40 parts papave¬ rine hydrochloride and 50 parts caffeine purum. The prepa¬ ration was introduced in the same manner as the separate substances. Assessment of the acute toxicity: after the minimal and the maximal mortal for any creature doses were prede¬ termined, we introduced randomizely into the rats, separa¬ ted in groups of 6 rats in each group, different doses of the substances and the combination. Then we followed morta- lity till the 24th hour and the 7th day (the results contain data of the 24th hour, because they did not differ from those of the 7th day) .

The results were figured through an analysis in the nonlinear regression program REGRESS PC, determining LD50 and the respective confidence interval.

The test results are generalised in the table 1. It shows that the substances can be arranged as follows with a view to their toxicity: ergotamine is the most toxic; then come caffeine, papaverine, atropine and zinc sulphate. The combined preparation showed toxicity between those of papaverine and atropine.

If an analysis is made of the quantity of the separate components of the preparation, as well as of the part of the figured values for LD50 it represents, it will be possible to make the following calculations: 100 mg of the preparation contain:

- 0,762 mg ergotamine (which is a 1/105 part of the respective LD50) ;

- 30,47 mg zinc sulphate (1/50 part);

- 30,47 mg papaverine hydrochloride (1/14 part);

- 0,190 mg atropine sulphate (1/3158 part); - 38,09 mg caffeine (1/5 part)

The obtained LD50 values show that the quantities of ergotamine, atropine, zinc sulphate and somewhat papaverine in the combined preparation are far from the respective LD50 values obtained. This is enough to draw the conclusion that the combination toxicity is unlikely to be determined thereby.

The acute peroral toxicity value of the medicinal combination according to the invention tested on white rats, as well as that of its separate components, show that the latter are in such a quantitive proportion in the combina¬ tion, that they neither potentiate nor antagonize their own toxic effects. The preparation is a medicinal combination with a relatively low acute toxicity. EXAMPLE 6 Outline of treatment of patients with bronchial asthma or asthmatic bronchitis with the remedy according to the invention.

The remedy according to Example 1 is applied orally in the form of pills. During the first 30 days it is given four times a day, one pill at interval of at least 4 hour. The combination containing sex hormones is given to the patient once a day in the bedtime pill.

During the second 30 days the remedy is given twice a day at 12-hour intervals. The pill taken at bedtime shall contain sex hormones.

During the next 15 to 30 days the drug is given only once a day at bedtime, and it must contain sex hormones.

The medicine according to the invention was tested on 300 patients having bronchial asthma or chronic asthmatic bronchitis. In all cases there was improvement of the condition after the first 30-40 min. upon taking the pill. No side effects and complications, incidental to corti¬ costeroids, were observed in the patients under control. Healing is lasting, and no relapses have been observed.

The results back up the conclusion that the components of the combination according to the invention not only have an additive effect, but they also potentiate the effect on the bronchi, and that was proved by a number of clinical tests.

Table 1.

Dose Mortality LD50

Substance (mg/kg b.w.) (dead ones/test (mg/kg) animals)

50 1/6

65 2/6

75 3/6 80

Ergotamine 90 4/6 (63-97)

100 5/6

125 6/6

1000 0/6

1250 1/6

1500 3/6 1500

Zinc sulphate 1750 4/6 (1250-1750; 2000 5/6 2250 6/6

200 0/6

250 1/6

300 2/6 400

Papaverine 350 3/6 (390-490) 400 3/6 200 0/6

300 1/6

450 2/6 600

Atropine 500 2/6 (485-725)

650 3/6

750 5/6

100 0/6

125 1/6

150 2/6 192

Caffeine 200 4/6 (155-229)

250 5/6

300 6/6

200 0/6

350 1/6

^Remedy 500 3/6 510 according to _{60Q 4/(} ^, (385-635) the invention

800 6/6

Claims

PATENT CLAIMS

1. An antiasthmatic remedy characterized by that it con¬ tains atropine sulphate, papaverine hydrochloride, caffeine purum, ergotamine tartrate, zinc sulphate, and sex hormones in the following quantitative proportions: atropine sulphate 0,25 mg - 2,00 mg papaverine hydrochloride 30,00 mg - 200,00 mg caffeine purum 30,00 mg - 250,00 mg ergotamine tartrate 0,25 mg - 2,00 mg zinc sulphate 10,00 mg - 220,00 mg sex hormones 0,25 mg - 5,00 mg

2. An antiasthmatic remedy, according to claim 1, charac¬ terized by that the sex hormone is methandienone or methan¬ drostenol.

3. An antiasthmatic remedy, according to claim 1, characte¬ rized by that the sex hormone is diethylstilbestrol propio¬ nate.