DE2349186C2 - Medicines to improve cell respiration, heart muscle performance and brain function - Google Patents

Description

The invention relates to a medicament according to the Preamble of claim I.

The dialyzed extract from Kälberbi-jt, freed from proteins and other high molecular weight components, according to the method of the German patent specification 10 76 888 promotes cell respiration, increases and improves oxygen uptake in isolated mitochondria oxygen utilization even where the partial pressure has dropped: jaeger et al, Arzneimittel-Forschung (Drug Research) 15, 750-754 (1965). The preparation increased according to Quadbeck - Austrian monthly journals for medical. Further education, Symposium Salzburg (1964), p. 49 - the glucose and phosphate transition from the blood to the brain. It increases the maintenance, energy and reserve metabolism with glycogen and potassium accumulation simultaneous reduction in 6-phosphogluconic acid dehydrogenasc [K. H. Schwabe. Drug Research 16,364 (1966)}

It also causes faster healing of homoisoplastic bone grafts: A. Lanzetta et al, Arch. Orlop. 73,488 (1960). There were also impressive therapeutic successes with this blood extract in severe peripheral arterial circulatory disorders [A. Caps, medicine. Welt 752 (1965)], at arleriosclerotic and diabetic angiopathies [Meythaler, Therapy Week 15:57 (1965), Stembergeret al, Therapeutische Umschau 15. 96 (1958)] and achieved in arterial occlusive diseases.

According to one of the main pharmacodynamic effects, the preparation was also used to improve the Metabolic function when there is a risk of infarction [J. Bosse, Country Doctor 36, 588 (1960)] and for follow-up treatment Myocardial infarction [Stemberger et al, Wiener med. 508 (1958). Lubich et al, Il Polyclinico 67, 1381 (1960)] with applied with good success.

It has now been found, surprisingly, that by adding a physiologically tolerable salt of Heptaminol (= 6-amino-2-methyl-heptan-2-ol) or to this blue extract, which is the one described above has pharmacodynamic spectrum of activity that The effectiveness of the latter can be increased considerably, far beyond the effects of the Individual components also; this also applies in particular for otherwise pharmacologically inert doses of Heptaminols.

The effect on the heart has been demonstrated, for example, by Professor J. La Barre, University of Brussels, in the following Test set-up measured:

The calcium ions were largely removed from isolated ears of rabbits by injection of the disodium salt of ethylenediamine acetic acid so that the ability of the organ to contract after adding digitalis is suppressed in this way an artificial fatigue of the heart was produced. The addition of Ve units of action of digitalis extract no longer produced an increase in contraction.

a) If one sets this arrangement 1 ml of the standardized blood extract with a dry content of 40/45 mg / ml to measure a very weak Köritraktiönsätigerürig of the organ.

b) If 1 ml of a solution containing 2 mg of heptamino hydrochloride is added, one observes no measurable effect.

c) If, however, the medicament according to the invention is made up of 1 ml of blood extract and 2 mg of the arrangement Heptaminol hydrochloride, a significant auricular response and a

Increase the contraction amplitude from 100 to

175 to 250%.

The experiments were carried out on a larger number of organs (around 80). Different salts of heptaminol various amounts of blood extract were added. The effect picture was always the same thing. The characteristic increase in contraction was already achieved with the addition of 2 mg Heptaminol to just 0.5 ml of blood extract with one Dry content of 40/45 mg / ml was observed. One lets the preparation of 3 to 1 ml of blood extract and 2 mg of haptaminol hydrochloride for 1 to 2 hours If the isolated organ is acting, one measures contractions of such strength as they were in the same organ

Start of the experiment - i.e. before the artificial damage

- were by no means achieved. Through this

Observation will be the heart repairing effects of the Combination preparation particularly clearly visible. Similar experiments were carried out on isolated frog hearts

(Rana temporaria) carried out. Fi <; show hearts Severe fatigue after only 60 to 120 minutes, which can be recognized by a marked reduction in the contraction amplitudes, that of a bradycardic are accompanied. Even with these! Preparation of blood extract (1 ml) and heptaminol salt (2 mg) a cardiotonic and cardiorepairing Effect, which is not only due to the immediately onset of greatly increased contraction amplitudes, but also through a prolonged state of activity, d. H. the persistent disappearance of cardiac fatigue, which is characterized by the blood extract alone or by Heptaminol cannot be produced. A contractility that is about 40% too high lasts for over 30 minutes, for example.

Any undesirable toxic side effects, bradycardia, extrasystoles, etc., were with Use of the preparation according to the invention never observed. Such symptoms disappeared with

Application of the preparations according to the invention.

An amazing effect of the preparation from Blood Exiract and Heptaminol in the form of a physiological tolerable acid addition salt was determined regarding the learning ability of adult white rats observed. By administering the blood extract, a standardized learning process became significant accelerated. By administering the preparation from blood extract and the heptaminol salt according to Invention, the learning process is again significantly increased

Experimental set-up

J.'s method]. Desmarez, Ann. Soc. Roy. Sc. med. et nat. Bruxelles 1960. 113, was applied. Rats were placed in cages equipped with irregularly arranged, labyrinth-like baffles that are changed according to a specific program. The permitted route to feed is marked by yellow light. Taking a wrong path wii <i by a light electric one Punished blow. The experiments were carried out with white female rats weighing 230 to 250 g For each measurement, 2 groups of 8 animals in 4 cages each were used.

Results

Control animals (8 x 2), soak one intraperitoneal daily Injections of 0.5 ml of normal saline solution took 20 to 22 days to get theirs Lesson, learned.

The second group of test animals (8 x 2), which daily 01.5 ml of blood extract intraperitor.:al injected took 13 days to reach the same learning success.

The third group of 8 x 2 test animals received 0.25 ml of blood extract and 0.25 ml of heptaminol daily - containing 15.5 mg of heptaminol hydrochloride - intrapentoneal administered This third group of animals only took 8 days to master its lesson.

Due to the combination with heptaminol, which on its own has no effect on the learning process, the teaching line: even with halved the dose of blood extract was shortened significantly.

See Tables I and II.

Taoelle I Control group prohibited Rats treated with 0.5 ml prohibited Blood extract prohibited 5th / 6th Pair prohibited 778. couple " prohibited K) number 127 (administered i.p.) : i6 96 Contacts: 38 Contacts: 86 UJ Days 132 1./2. Pair 37 3rd / 4th Pair 82 allowed 12th allowed 46 φ> Contacts: 168 Contacts: 79 Contacts: 77 42927 16 36731 52 v £> allowed 98 allowed 86 allowed 100 42789 36 32167 42 I * 5318 82 24792 72 39176 90 33 627 12th 41267 86 oo 1 5728 118 47280 92 16762 76 31 202 34 31726 59 2 10382 91 41262 39 26789 19th 29917 45 32676 18th 3 5200 78 42290 53 31292 26th 19836 18th 31786 24 4th 9271 62 17 392 67 47296 46 40126 26th 26709 42 5 7754 102 91129 24 30129 19th 26729 16 32176 14th 6th 5 892 46 16212 31 21762 4th 36750 7th 76020 24 7th 6112 26th 41726 7th 18967 2 34672 3 16782 2 8th 6704 74 18976 3 60724 2 1439 1 1423 2 9 8007 32 34678 1 12719 0 4429 0 4164 0 10 5172 91 23 634 6459 19272 19276 11th 7547 27 10069 5218 34967 67290 12th 5313 18th 21768 19092 13th 7995 16 19276 51678 14th 92bl 22nd 15th 4772 8th 16 3 787 4th 17th 8273 0 18th 7412 0 19th 6025 20th 3,289 21 2382 22nd 1686 23

Table II

Number of repayments "

Control group prohibited Contacts: 34 allowed 14th 874 11th 35 780 10 1262 73 5467 75 696 18th 2172 18th 1507 18th 3076 30th 6679 31 1076 35 5 336 11th 462 9 1789 10 3761 8th 69 7th 5788 16 3 202 4th 1537 6th 907 2 3456 0 1567 0 2,382 1686

Rats treated with a preparation made from 5 ml blood extract and (containing 15.5 mg heptaminol hydrochloride)

172nd pair 374th pair

Contacts: Contacts:

allowed forbidden allowed forbidden

ml of lleplaminol prohibited 778. couple prohibited K) 576. couple 67 Contacts: 42 CO Contacts: 92 allowed 215 allowed 34 11726 76 14328 T) 26782 34 ,. 13079 16 32 671 21 OO 31290 4th 26876 8th CT) 21321 3 36721 4th 36 721 2 62171 2 27 621 1 21672 2 19962 1 36789 1 26032 1 16782 0 47621 1 42 761 1 20092 0 27622 1 12714 32761 41792 27 893 33 662

1762 28 11 609 38 27612 21 29 100 29 36 782 14th 18076 9 26 702 7th 3 1 729 4th 22446 3 18 762 1 21769 0 22316 1 3 1 245 0

28 768 72 15627 47 12 768 18th 4 687 15th 3 176 12th 5 147 7th 55362 7th 21763 5 31 992 1 20710 0 14789 2 33021 0 41 126 1

The improvement in learning is likely to be attributed to an increase in brain metabolism. This result is extremely surprising. So far, no substance has been found that accelerates learning. Neither the neuroenergy. Meclofe- ^r > noxattp-chlorophenoxy-cssetic acid / J-diethylaminoethyl ester hydrochloride] or the dynamizing neurotropic pyritinol [bis- (3-hydroxy-4-hydroxymethyl-2-meth>; -5-pyridylmethyl) disulfide] or mixtures of recommended as neuroenergetics Aminodicarboxylic acids in or their salts accelerate the learning process.

The amazing effect of the invention Preparation from blood extract and Hcptaminol silz is based most likely due to an improvement in the permeability of the active ingredients of the blood extract the cell membranes through the heptaminol.

A preparation with such pronounced her / - and ki ■. 'slaufstüt / ends and neuro-energetically positive Effects is in particular; / ir .Si.ii kuiip dos Alicrs'if "-;.". zens as well as for the regeneration of age-related reduced accumulations. That claimed The preparation is ideally suited as a geriatric. Tonic and reconstitution.

The surprising effect-increasing effect of: ί Heptaminol on the blood extra! t has no direct parallels. F; s is known that heptaminol the Antihypertensive effect of etifelmin [2-ethyl-3,3-diphenyl-prop-2-cnylamineJ reinforced. Between the effect of the preparation according to the invention from Blutex- jn trakt / Hepiaminol and Etifelmin / Heptaminol but no functional relationship.

On the basis of the parmakodynamischcn results described above, a new drug was developed to improve cellular respiration, cardiac muscle performance and brain function, consisting of a blood extract from calf blood, which is gently freed from protein and then subjected to dialysis against water or diluted ethanol in a large dilution was finally gently to a concen- tration of 40/45 w mg dry substance per ml of solution concentrated, which is characterized. that it contains a physiologically tolerable acid addition salt of 6-amino-2-methyl-heptan-2-ol (= heptaminol) as a potentiating factor.

The agent can be used as an injection solution (possibly stored as a lyophilisate) or in capsules. Tablets. Globules and coated tablets. In suppositories and syrups or in other pharmaceutical preparations.

A single dose contains about 1 to 5 ml, preferably 2 ml of blood extract or the equivalent amount of dry c) extract, e.g. B. lyophilisate or adsorbate, and about 15 to 100 mg, preferably 20 to 80 mg, of a heptaminol salt.

The method for the preparation of the preparation consists in that blood extract obtained from calf blood in In a known manner, gently freed from protein, then in a large dilution of a dialysis against a) Submits to water or dilute ethanol and finally gently to a concentration of Concentrates 40/45 mg of dry matter per ml of solution, with an acid addition salt of heptaminol in the ratio 1: 03 to 1: 1, based on the dry weights, added and added to injection solutions. Syrups or 65 b) Lyophilisates or after adsorption of the blood extract active ingredients on surface-active substances or lyophilisa- c) tion to tablets, coated tablets. Processed globules or suppositories.

Dry preparations are prepared by adding blood extract and Hcptaminol salt to the preparation an adsorbent, e.g. B. Aerosil, and then drying the resulting thixotropic gel in vacuo or by lyophilization of solutions made from blood extract and Hcptaminol salt.

The solution of blood extract and Hcptaminolsalz can also be used as a liquid or lyophilisate known methods in doses of up to 0.5 ml in gelatin capsules and in this form orally administered.

In terms of the preparation of the various dosage forms care is taken that they contain 1 to 5 ml, preferably 2 ml of blood extract per administration dose or equivalent Lyophilisa! or adsorbate and 15 bis 100. preferably 20 to 80 mg of b-amino-2-methylheptane-2-nl contained as hydrochloride or sulfate.

With the preparations obtained in this way, after

skii!; irer, oral oc'c *

Administration a large increase in the rate of breathing. animal cardiac muscle performance and brain function.

The new preparations are particularly suitable as geriatrics.

Examples

1. Solution for injection

ml blood extracl. produced by the method of German patent 10 76 888, with a Dry content of 40/45 mg / ml are mixed with 18 g of heptaminol hydrochloride, sterile filtered and in Filled ampoules.

Administration dose: 1/1 to 2 ampoules.

2. Tablets / dragees

2000 ml of blood extract according to the method of German patent specification 10 76 888 are mixed with 90 g of heptaminol hydrochloride. The solution is mixed with 1000 g of Aerosil and the adsorbate paste is dried ^{in vacuo at a maximum of 30 ° C.} After adding corn starch or wheat starch or dried red algae extracts (carrageenan), the dried adsorbate is granulated and then compressed into 4000 tablets. As a rule, the tablets are then coated in a stomach-soluble sugar-coating.

80 g of heptaminol hydrochloride are added to 2000 ml of blood extract. The solution is lyophilized, the lyophilizate is mixed with carrageenan, corn starch and a little magnesium stearate and processed into tablets or dragees.
The lyophilizate from 2000 ml of blood extract is mixed with 80 g of heptaminol hydrochloride and then further processed into tablets or dragees as in Example 2b).
Dosage: 2 to 6 tablets or dragees per day.

3. Capsules

2000 ml of blood extract are mixed with 40 g of heptaminol sulfate and according to known methods in 8000 gelatine capsules filled or microencapsulated in a known manner.

Dosage: 4 to 8 capsules per day or equivalent amount of microcapsules.
The dried adsorbate produced according to Example 2a) is filled into 4000 capsules.
The lyophilizate produced according to example 2b) or 2c) is filled into 1000 capsules.

4. Syrup

1000 ml of blood extract according to the method of the German Patent 10 76 888 are mixed with 2000 ml of syrupus simplex (Syrupus sacchari), in which /. Before 18 g of heplamiriol hydrochloride were dissolved. The solution is also treated with a taste correction (lemon or orange aroma) and poured in

12th

bottles of 50 ml: fills. F. single dose: I teaspoon ^ ml)

5. Suppositories

The dried adsorbate produced according to ßrisr / iei '<;) wi.cl with cocoa fat (3500 g) and the usual additives processed into a suppository mass and prepared for 2500 suppositories.

Claims (3)

Patent claims: 1. Medicines to improve cell respiration, cardiac muscle performance and brain function, consisting of a blood extract from calf blood, which is gently freed from protein and then in subjected to a large dilution of dialysis against water or dilute ethanol and finally gently to a concentration of 40/45 mg Dry substance was concentrated per 1 ml of solution, characterized in that it is as potentiating factor contains a physiologically tolerable acid addition salt of 6-amino-2-methyl-heptan-2-ol (= heptaminol) 2. Medicament according to claim!, Characterized in that it is about 1 to 5 ml (with a Dry content from 40 to 225 mg), preferably 2 ml, blood extract from calf blood or the equivalent Amount of lyophilizate or adsorbate thereof and 15 to 100 mg, preferably 29 to 80 mg, of a salt of Contains 6-amino-2-methyl-heptan-2-ol per single dose. 3. Medicament according to claim 1 and 2, characterized in that it is the hydrochloride or the Contains sulfate of 6-amino-2-methyl-heptan-2-ol.