DE2916880C2 - Medicines with sedative and sleep-inducing effects - Google Patents

Description

The invention relates to a medicament with sedative sleep-inducing and anticonvulsive effects, characterized by a content of S-adenosyl-L-homocysteine (SAH) or one of its pharmacological harmless salts

The SAH is a naturally occurring substance that corresponds to the following formula:

20th

COOH

H ₂ N-CH- (CHj) ₂ -S-CH ₂

HO

25th

JO

OH

The pharmacologically acceptable salts are, in particular, addition salts with non-toxic acids, which are commonly used in pharmacy be e.g. The hydrochloride, sulfate, phosphate, citrate, malate, succinate, aryl sulfonate and others.

The SAH, as well as its salts, are produced by a chemical process developed by S. and R. Hildesheim and E. Lederer in "Biochemie" 1971, vol. 53, pages 1067-1071 or in DE-PS 1803978 is described.

The SAH and its salts have interesting pharmacological properties. In particular, it has a sedative effect on the central nervous system and induces sleep and has an anticonvulsant effect.

A pharmacological study of the medicament according to the invention shows, in particular, a reduction in the level of alertness and the cortical excitability in the awakened animal and induces one Sleep similar to natural sleep.

Most of the drugs currently in use for inducing sleep in animals and disadvantages in humans: an unnatural sleep; an awakening that with a Reduction in reflexes is associated; a habit; the use of synthetic and toxic Products,

The medicament according to the invention does not have any of these disadvantages.

In particular, the pharmacological properties of the agent are very weak Toxicity, which makes the agent particularly useful in the treatment of insomnia and epilepsy and as a preparatory agent for anesthesia.

The invention also extends to pharmaceutical preparations containing the active ingredient according to the invention in a pharmaceutical suitable for administration by the oral, parenteral or rectal routes Excipients.

In particular, useful pharmaceutical excipients include the following:

for oral administration:

solid or liquid diluents as well as lubricants, coating agents, lubricants and Flavoring agents; for the particular case of gelatin-coated agents, the excipient simply be the envelope of the capsule z. B. is formed by protein derivatives of gelatin;

for parenteral administration:

solid diluent (in the case of powders, which by means of a sterile isotonic solution too an injectable solution) or liquid diluents (possibly glucose-containing physiological serum) ;.

for rectal administration:

in particular an excipient that makes it possible to produce suppositories and from one or consists of several ingredients, through which the finished preparation at a temperature in the Near body temperature softens or melts. Common ones used for these purposes The ingredients are in particular cocoa butter, gelatine, agarose, etc.

In general, the excipient is the main component of the preparations according to the invention, on the Based on weight.

The preparations according to the invention can be presented in the form of tablets, molding compounds, Pills, coated tablets, gelatin capsules, granules, syrups, drinkable or injectable solutions, dilutable Powders, suppositories, etc.

The pharmaceutical preparations can by mixing the medicament according to the invention with the pharmaceutical excipients suitable for the selected administration and then processing the mixture into the desired form will. The method is also part of the invention.

For example, mixing is used to produce tablets, molding compounds, pills, coated tablets and others similar preparations for oral administration the medicament according to the invention with diluents, lubricants, lubricants and others Adjuvants as commonly used under conditions compatible with the drug. The diluents and other commonly used adjuvants are e.g. E.g .: sucrose, Lactose, levulose, starch, etc. Gelatin, gum arabic, agar, tragacanth gum, pectin can be used as lubricants and so on. As a lubricant, stearic acid, talc, magnesium stearate, etc. can be mentioned will. In particular, the drug can be diluted in that a powdery solid Diluent is incorporated and then the agent is crushed to the desired degree of fineness. You can also use the solid support in crushed or powdered form with a solution of the drug in a solvent such as water, Impregnate alcohol or a mixture of these solvents and then the solvent remove.

For the production of suppositories you can, for. B. the active ingredient and the excipient at the softening temperature mix and then shape.

For parenteral administration, the medicament according to the invention is in the form of an aqueous isotonic ι see sterile solution used which is optionally mixed with glucose

The pharmaceutical preparations according to the invention can contain 0.1 to 95% by weight of that according to the invention Medicinal products contain and generally contain i <> 1 to 95 wt .-%, preferably not more than 40 % By weight (except in the case of gelatin capsules, which may contain the pure drug).

The dosage varies in particular depending on the mode of administration, the body weight ι > and the therapeutic effect found. In general, the dosage varies between 0.1 and 50 mg / kg Body weight of the active ingredient per day.

Pharmacological effectiveness of SAH

2 (1

30th

The following pharmacological study concerns on the one hand the level of alertness and the cortical one Excitability in alert animals, the permanent electrodes in the cerebral cortex, in the muscles and the Wear eyes and on the other hand also a modification? Ϊ the physiological effects of serotonin from SAH.

Changes in the level of alertness and cortical excitability in alert animals

Effectiveness in the electroencephalogram and in behavior induced by SAH

The impulses occurring in the electroencephalogram due to the action of SAH, which in the rat, the Rabbits and cats show a slow increase in the duration of the sleep phases paradoxically at the expense of awakening. This is achieved through modifications in the level of alertness and a Frequency analysis of the signals from the electroencephalogram demonstrated

The following points deserve to be highlighted:

Analysis of the wavelengths in the electroencephalogram during sleep, slowly induced by SAH show that the frequency and amplitude are comparable to those of the cells in the slow are natural sleep. This is confirmed by the possibility of an electroencephalographic awakening induce (cortical desynchronization) and behavior on a succession of acoustic Vibration shocks or nociceptive stimuli.

The effects appear 1 hour after the administration of SAH and persist for 4 to 6 hours.

The effect manifests itself at an amount of 0.1 mg / kg body weight and depends on the dose between the values 0.5 to 5 or 10 mg / kg depending on the intended route of administration. Beyond the dose of 10 mg / kg she remains stationary or tends to get smaller again.

The effect of SAH is independent of the mode of administration. An effectiveness is identical each according to whether the administration was intravenous, intraperitoneal or oral.

Decrease in cortical excitability induced by SAH

The visibly awakened activity and the paroxystic (paroxysmal) by electrical stimulation of the The cortical crises in rabbits that can be identified by the cerebral cortex are represented by means of a physiological index. The study shows that

the SAH (1 mg / kg / intravenous) lowers the optimal frequency of onset of cortical action which has been stimulated by intermittent light stimuli (S.L.I.) and

the SAH (1 mg / kg / intravenous) inhibits the paroxystic electroencephalographic activity induced by electrical stimulation of the cortical layer of the lens in the eye the duration is up to 3 hours

Modification of the physiological effects
of 5-hydroxytryptamine (5-HT) by SAH

3 tests were carried out:

The contraction effect of 5-HT in the isolated rat uterus "in vitro",

the excitomotor effects on the digestive tract that are caused by 5-HT and that are studied by means of electromyography in the alert dog and
behavioral hyperactivity induced by 5-hydroxytryptophan in mice treated with an inhibitor of monoamine oxidase (nialamide 100 mg / kg / intraperitoiieal).

Contraction effect of 5-HT in the isolated
Rat uterus "in vitro"

The uterine processes of female virgin rats previously treated with gonadotrophin (500 Internationale Units / kg / intraperitoneal) were immersed in physiological fluid (Tyrode) brought the thermostatically kept at 37 ° C and ventilated. The study shows that the 5-HT (1 μg / ml) has a contracting effect caused by SAH in concentrations of at least 0.5 to 1 μg / ml is inhibited.

Excitomotor effects of the digestive tract from 5-HT in the dog

The excitimotor hyperactivity those in propulsions of the digestive tract and is caused and accompanied by serotonin Accelerated breathing and anxiety syndrome is brought to the electromyographic level by the The presence of continued volleys of potential of those points corresponding to those transmitted by the Insert the bed of the circular muscles. The SAH is inhibited at a concentration of 200 μg / kg / intravenous all of these symptoms for a duration equal to that of the onset of electroencephalographic Effects is.

Behavioral hyperactivity caused by
5-hydroxytryptophan is induced in the mouse

The SAH reduces the intensity of the behavioral crisis caused by 5-hydroytryptophan in doses of 3 to 40 mg / kg / intraperitoneally is induced.

toxicity

A study on 200 mice shows that after administration of a single dose of 1 g / kg Body weight (oral or intraperitoneal), which corresponds to 100 times the effective dose, not toxic

Symptoms appear.

Summary of the pharmacological study

The barbiturates and classic hypnotics induce a sleep that differs from natural sleep In general, Elektroer.cephalography shows a decrease in the return of slow sleep versus the paradoxical sleep and the appearance of slow waves with frequencies ranging from are different from those of the cells in natural sleep. Furthermore, there is an abnormal drop in Miiukeltonus on and the person affected by the effect of this Being subjected to drugs is very difficult to wake up.

The SAH allows a certain number of these disadvantages to be avoided, the following being various Points deserve special mention;

1. The SAH is a naturally occurring molecule. The risk of getting used to it is thus greatly diminished

2. The SAH is already active in very small doses. The minimum effective dose is around 1 mg / kg body weight

3. The toxicity of the SAH is very reduced.

4. The sleep induced by SAH is similar to natural sleep, like that Shows frequency analysis of electroencephalographic signals. He's not at the loss of muscle tone and the animal retains its ability to wake up when it is out of the environment the environment is stimulated to do so.

10

15th

20th

25 Effects of the SAH with the other sleep-inducing substances that the mode of action of SAH differs from the comparison with other drugs and especially with the barbiturates

Production examples for pharmaceutical preparations are given below

Example 1 Capsules are produced according to the usual methods.

which contain: 5 mg
95 mg SAW
Lactose Example 2 Capsules that contain: One prepares 10 mg
90 mg SAW
Lactose

Example 3 Capsules are produced which contain:

SA H (in the form of the citrate) 25 mg lactose 75 mg

Example 4

Capsules are produced that contain citrate as a powder from SAH contain:

Furthermore, the comparison of the biochemical

SAH (as citrate) 50 mg

Coating substance

(Peptides) 5 mg

Claims (1)

Claim: Medicinal products with sedative, sleep-inducing and anticonvulsive effects, characterized by a content of S-adenosyl-L-homocysteine (SAH) or a pharmacologically acceptable salt thereof in addition to the usual excipients.