DE202004009689U1 - Combating stress states or nervous system or metabolic disorders, using glycine as neurotransmission modulator showing antistress, stress protective, nootropic and toxin binding actions - Google Patents

Abstract

Preparations (A) for the prophylaxis and therapy of stress states or functional and organic nervous system or metabolic disorders contain glycine (I). ACTIVITY : Tranquilizer; Cerebroprotective; Vulnerary; Antialcoholic; Hypnotic; Nootropic; Antidepressant; Neuroprotective; Antiinflammatory; Antiaddictive; Gynecological: Vasotropic; Metabolic. MECHANISM OF ACTION : Glycinergic receptor inhibitor; neurotransmitter; synaptic signal transfer mediator; regulator of intrinsic chloride channels in the bone-marrow and cortex; N-methyl-D-aspartate (NMDA) receptor modulator; toxin binder. In particular (I) acts as co-transmitter for the excitatory NMDA receptors, such that external supply of (I) has a beneficial effect on NMDA receptors, specifically in normalizing the balance between excited and inhibited neurone transmission.

Description

The The invention relates to a glycine-containing preparation for prophylaxis and therapy of stress states as well as functional and organic disorders of the nervous system and the metabolism.

application areas The invention relates to medicine and pharmacy.

Glycine has the molecular formula H ₂ N-CH ₂ -COOH and is the simplest (nonessential) amino acid. Glycine is formed from serine (cleavage of activated formaldehyde by serine hydroxymethyltransferase), from L-threonine (acetaldehyde cleavage by threonine aldolase) or from glyoxylate (by transamination).

The Function of glycine in the context of synaptic signal transmission consists in the inhibitory effect on the glycine receptors for the regulation of intrinsic chloride channels in the spinal cord and cortex.

Ion channels are Membrane proteins that pull through the cell membrane from the inside out. The Membrane itself is a very efficient diffusion barrier for ions. The hydrophobic inner region of the membrane prevents access of ions and allows thus the maintenance of ion gradients between the cytoplasm and extracellular Room. ion channels have a narrow pore, through which ions out of the cell or can get into the cell. At the heart of signal transmission at chemical synapses are the so-called ligand-controlled Ion channels. The ligands are referred to as neurotransmitters posing as chemical messengers to associated receptors on the surface of a Bind target cell.

component of the channels are usually several protein segments. These trans-membranal segments consist of many hydrophobic and few hydrophilic amino acid residues, being outside the Membrane polar and charged amino acids predominate.

The Pore is going for the passage of a particular ion is opened at the moment, though ligands a ligand to a specialized protein domain (ligand binding site), what a change in conformity the pore proves.

at channels, which opened by neurotransmitters are the ligand binding sites (receptors) on the outside of the cell.

Here are the receptors for the neurotransmitters acetylcholine, glutamate, glycine, γ-aminobutyric acid and Serotonin positioned. All of these receptors have a homologous one Structure and are grouped into a superfamily. The am the best studied representative of this group is the nicotinic Acetylcholine receptor, which is mostly used as an explanatory model.

The said neurotransmitters have ion selectivity, i. When the transmitter is docked to the receptor, the ion channel becomes only for certain Ions throughout. So opens e.g. Acetylcholine the passage of sodium, potassium and calcium ions at the motor end plate of the musculature or the autonomic ganglia and leads to Activation of the target cells (excitatory effect, depolarization the membrane).

Of the Neurotransmitter Glycine regulates the passage of chloride ions and bicarbonate ions especially in the nerve cells of the spinal cord and the brain stem and has an inhibitory effect on the affected nerve cell (inhibiting Effect, hyperpolarization). Channels passing through cytoplasmic Ligands are controlled, have binding sites for cellular messengers on the inside the membrane (guanine adenosine phosphate controlled).

Of the strychnine-sensitive glycine receptor (specific antagonist strychnine) as a ligand-controlled chloride channel of the postsynaptic membrane is an important mediator of synaptic inhibition in the central nervous system. Glycine is mainly involved in the neuronal regulation of muscle tone through the centers in spinal cord and brainstem involved.

Equally, the glycinerge carries Inhibition also to the formation of the respiratory rhythm in the respiratory Centers of the brain stem at.

By The loss of glycine inhibition can be excitatory impulses unfold unhindered, e.g. in a Strychninvergiftung. The neuromuscular disinhibition It causes painful tetany, caused by sensory stimuli further strengthened become.

The means that e.g. a disorder the glycinergen interneurone of the spinal cord (Renshaw cells), which together with the motor neurons of skeletal muscle form a loop, to a skeletal muscle dysregulation with training of painful cramps leads.

These disorders within the function of the chloride channels, which may also be hereditary, are also referred to as ion channel diseases (channelelopathies). These show up in hypertonic movement disorders. A well-known example is the clinical picture of myotonia congenita. Other agonists at the glycine receptors are excluded the amino acids β-alanine and taurine.

stress is present a common one from humanity, from the toddler to the very old, and in all Languages used term in everyday life. simultaneously There are extremely divergent among professionals and laymen Views on this term, but also for prevention, therapy, diagnostics and to experience stress.

following becomes a holistic-oriented and regulation-theoretical sound opinion.

Under Attention to the human being in his biopsychophysiological unit referring to regulation-theoretical findings, according to which loads and influences regulatory changes in the sense of a strain (beam theory) cause, and that Every living being undergoes a wake-sleep cycle is understood a temporary or permanent change under emotional stress the individual psychophysiological homeostasis.

• EUSTRESS = PHYSIOLOGISCHE FUNKTION
• DISSTRESS = PATHOLOGISCHE ABART DES STRESS

Emotional stress is a complex, holistic function. Stressor is the stress-inducing stimulus that comes from both the exogenous and endogenous milieu. Emotional stress can manifest itself in two manifestations:

• EUSTRESS = PHYSIOLOGICAL FUNCTION
• DISSTRESS = PATHOLOGICAL ABARTMENT OF STRESS

eustress promotes health, performance motivation and adaptability of the individual. The relationship between Eustress and performance is not linear, but is subject to a bell-shaped curve (Yerkes-Dodsonsches Law).

Of the Newest state of knowledge of stress assumes that during the emotional eustress providing life energy via vegetative, metabolic and hormonal systems (usually in excess) take place to the Adaptation to changed Environmental conditions or requirements and pressures to meet. After completing the emotional stress all functions return to normal steady state (homeostasis) one. If the provision e.g. Not done by relaxation can cause emotional distress which causes damage to health during durability can. The emergence of disstress, the pathological form of the emotional Stress, depends on many factors, according to the latest findings disorders the emotions (conflicts, suppressed emotions, fear and others) and the time regulation (acting against the internal clock) and under-demand be able to exert a strong pathogenic effect.

distress is promoter for 80 percent of all diseases including cancer, allergies, AIDS, cardiovascular disease and mental disorders. Disstress is in many countries the disturbance factor No. 1 for Life quality, capacity and health (e.g., USA, Japan, Germany, Switzerland). nowadays are most people and even the kids disrupts, mentally and physically cramped, tense or overstretched and also aggressive. You can as a result, do not fall asleep, suffer from performance degradation and commit mistakes. Many people have inner unrest that Psyche and body tense, without them being aware of it. These tensions Reflect on head, neck and back pain without one organic damage. Mental self-talk, brooding, negative Thinking also disrupts and involuntarily prevents relaxation.

• nur 19 Prozent ihr Gestresstsein real einschätzen können,
• 58 Prozent unterschätzten ihr Gestresstsein und
• 23 Prozent überschätzten ihr Gestresstsein.

In Germany and Europe every fourth person has disstress-induced sleep problems. Every third person feels tired during the day. Chronic disstress, however, has one more feature that is little considered, but crucial to self-assessment of being stressed. As a result of chronic distress, endorphins, criticality, symptom perception, real self-assessment regarding resilience, decision-making ability, assessment of situations affecting one's own person and interpersonal life are lost as a result of the release of messenger substances. Research shows that over 100 people

• only 19 percent can really gauge their stress
• 58 percent underestimated their stress and strain
• 23 percent overestimated her stress.

health threat especially among those who underestimate their stress. They absolutely need assistance by special technical warning systems, d. H. a distress warning device and immediately accessible Biofeedback systems that are objectively able to control the relaxation and also systems that indicate or signal that all 90 - 100 Minutes a break is necessary.

Further Investigations show that only one in six is capable of his ability to assess real relaxation. For the other 5 is mostly an overestimation, d. H. the belief to relax, which is not really the case. This ability let yourself but learn with biofeedback systems.

Furthermore affected Disstress relevant the quality of life. Standard for the assessment the quality of life is the new version of the health definition (Ottawa Charter) of the World Health Organization (WHO), which requires a corresponding level of mental health, social, physical and economic well-being and self-care ability calls into old age. An objective monitoring system based Measured vital signs do not exist so far.

• a) Prophylaxe und Therapie von Streßzuständen,
• b) Prophylaxe und Therapie von funktionellen und organischen Störungen des Nervensystems,
• c) Prophylaxe und Therapie von Stoffwechselstörungen,
• d) Bindung toxischer Stoffe,
• e) physiologischen Aktivierung von Hemmungsprozessen im ZNS,
• f) Prophylaxe und Therapie von psychischen Störungen,
• g) Prophylaxe und Therapie des Syndroms der Verminderung der Arbeitsfähigkeit und psychischer Überbelastung.

Object of the present invention was to develop substances or mixtures that can be used for

• a) prophylaxis and therapy of stress states,
• b) prophylaxis and therapy of functional and organic disorders of the nervous system,
• c) prophylaxis and treatment of metabolic disorders,
• d) binding of toxic substances,
• e) physiological activation of inhibition processes in the CNS,
• f) prophylaxis and therapy of mental disorders,
• g) Prophylaxis and therapy of the syndrome of reduction of work ability and mental overload.

in the Under the invention it has been found that glycine also acts as a co-transmitter at the excitatory NMDA receptors (N-methyl-D-aspartate receptor) Effect shows by having one specific binding domain the glutamate-induced opening promotes this ion channel.

The NMDA receptors play except in the excitatory signal transmission and the training of the nervous system even in diseases of the CNS a special role. The apoplexy and other central nervous disorders, due to neurotoxic cell deaths are the result of excessive activation of NMDA receptors. Here are also excessive states of excitement and others to classify mental illnesses.

According to the invention was found that by external delivery of glycine a positive Influencing the NMDA receptors can be brought about.

It has been surprising found that by the application of glycine already at a low application dose to a very rapid flooding of Glycine enters the central nervous system, resulting in an effective positive influence of the nervous Metabolism leads.

So inhibition of central nervous disorders, the reduction of stress situations, change Psychosomal tension and improvement of the personal Performance.

Pharmacological properties:
The preparation according to the invention is a regulator of metabolism, it normalizes processes of excitement and inhibition in the CNS, has an anti-stress effect and increases intellectual ability to work.

Application - Indication:
The product may be administered to healthy children, aged one year, adolescents and adults, for increased intellectual capacity, stressful situations, psycho-emotional tension (exams, conflicts, etc.). As an anti-stress and nootropic agent, it may be used on children (including those with behavioral changes) in adolescents (including those with behavioral changes) in adults with various functional and organic disorders of the nervous system (neuroses, neurotic states and autonomic dystonia) functional and organic consequences of brain trauma, in various forms of encephalopathies, including alcohol pathogenesis), which are accompanied by increased excitability, emotional lability, limitation of intellectual work ability and sleep disorders.

Application method and dosage:
Glycine is preferably administered orally, intranasally (as a gel) or vaginally, more preferably sublingually (placed under the tongue) in tablet form of 0.1 g each. In de facto healthy children, adolescents and adults, the preparation is to be used in cases of memory impairment, restriction of attention and concentration, limitation of intellectual ability to work, as well as child and adolescent development inhibition of intellectual work ability and altered behavior in doses of 2 - 3 × 1 tablet / Be administered for a period of 14 - 30 days. The daily dosage is thus 0.3 g.

at Psychoemotional tension is used in the preparation Dosages of 2 - 3 × 1 tablet per day over the duration of 14 - 30 Days.

at functional and organic consequences of traumas of the nervous system, those with increased excitability, of emotional lability and sleep disorders should be dosed as follows: children up to 3 Years ½ tablet (0.05 g) 2 - 3 times a day for the duration from 7 - 14 Days and further for the duration of 7 - 10 Days 1 × daily ½ tablet be administered. Daily dose: 0.1 - 0.15 g. Treatment cycle Dose: 2.0 - 2.6 g glycine.

Children older than 3 years and adults 2 - 3 × 1 tablet / day should be administered for a period of 7 - 14 days. If necessary, the therapy cycle can be repeated.

at sleep disorders should glycine 20 minutes before bedtime or immediately before in a dosage of ½ tablet (dependent on of age).

In In narcology, glycine is used as an agent, which is intellectual ability to work elevated, and as a remedy for psycho-emotional tension during the Remission of encephalopathological phenomena as well as organic changes of the central and peripheral nervous system are dosed as follows: 2 - 3 × daily for the duration of 14 - 30 Days. If necessary, such a treatment cycle 4 - 6 × a year be repeated.

The preparation reinforced not the effects of sleeping pills and alcoholic drinks.

It There were no negative effects of glycine with other drug applications detected. No side effects were noted.

• – Prophylaxe und Therapie von Stresszuständen,
• – funktionelle und organische Störungen des Nervensystems. Die Wiederherstellung dieser Funktionen wird mit der Anwesenheit der Aminoessigsäure als aktiver Stoff erreicht. (Glycin, Glykokoll)
• – Hemmungsmediator, der in Wechselwirkung mit glycinergischen Rezeptoren des Rückenmarkes und des Gehirns steht und dadurch zur Normalisierung der Bilanz zwischen erregenden und hemmenden Neuronsmittersystemen beiträgt. Außerdem hat Glycin die Fähigkeit, verschiedene endogene toxische Stoffe zu binden (neutralisieren: Phenole, Aldehyde, Barbiturate u.a.), wodurch ermöglicht wird, Glycin auch als Therapeutikum und Prophylaktikum in Bezirken mit ungünstiger Ökologie (Umweltbelastungen) anzuwenden.

Main indications of glycine are:

• - prophylaxis and therapy of stress conditions,
• - functional and organic disorders of the nervous system. The restoration of these functions is achieved with the presence of aminoacetic acid as active substance. (Glycine, glycine)
• - Inhibitory mediator, which interacts with glycinergic receptors of the spinal cord and the brain and thereby contributes to the normalization of the balance between excitatory and inhibitory neuronal systems. In addition, glycine has the ability to bind (neutralize: phenols, aldehydes, barbiturates, etc.) various endogenous toxic substances, thereby making it possible to use glycine also as a therapeutic and prophylactic in districts with unfavorable ecology (environmental pollution).

• – In seinem Wirkungsmechanismus und pharmakologischen Effekt hat Glycin keine Analoge (vereinigt in sich Antistress-, Stressprotektions- und nootrope Wirkungen).
• – Der Effekt wird erreicht durch physiologische Aktivierung von Hemmungsprozessen im ZNS.
• – Glycin hat einen schnellen pharmakologischen Effekt. (Das Präparat wirkt bereits innerhalb von 5 – 10 Minuten und benötigt keine Ersatztherapie.)
• – Glycin wird in 10-fach kleineren Dosierungen als andere nootrope Präparate verabreicht.
• – Kontraindikationen und unerwünschte Nebeneffekte wurden nicht nachgewiesen.
• – Eine Überdosierung des Präparates ist nicht möglich.
• – Im Unterschied zu Tranquilizern werden bei einer dauerhaften Einnahme von Glycin keine Abhängigkeits- und keine Entzugssymptome beobachtet.
• – Glycin kann in beliebigem Alter eingenommen werden („Familienpräparat").

Benefits of Glycine:

• - In its mechanism of action and pharmacological effect, glycine has no analogues (combined antistress, stress protection and nootropic effects).
• - The effect is achieved by physiological activation of inhibition processes in the CNS.
• - Glycine has a rapid pharmacological effect. (The preparation works within 5 to 10 minutes and does not require any replacement therapy.)
• - Glycine is administered in 10-fold smaller doses than other nootropic preparations.
• - Contraindications and undesirable side effects have not been demonstrated.
• - An overdose of the drug is not possible.
• - In contrast to tranquillizers no dependence and no withdrawal symptoms are observed in a permanent intake of glycine.
• - Glycine can be taken at any age ("family preparation").

Indications for glycine:

• – Störungen des Gehirnkreislaufs (Durchblutungsstörungen des Gehirns),
• – Residualerscheinungen von Störungen des Gehirnkreislaufes (Durchblutungsstörungen des Gehirns),
• – Ischämische Insulte,
• – Residualerscheinungen von ischämischen Insulten,
• – Stoffwechseldystrophische Erkrankungen des Nervensystems,
• – Hirnschädeltraumen,
• – Residualerscheinungen von Hirnschädeltraumen,
• – Gehirnerschütterung,
• – Zerebrovaskuläre Insuffizienz.

Diseases of the nervous system
eg:

• - disorders of the brain circulation (circulatory disorders of the brain),
• - Residualerscheinungen of disorders of the brain circulation (circulatory disorders of the brain),
• - Ischemic insults,
• - Residual symptoms of ischemic insults,
• - metabolic dystrophic diseases of the nervous system,
• - cranial skull trauma,
• - Residual phenomena of cranial skull trauma,
• - concussion,
• - Cerebrovascular insufficiency.

• – bei Kindern in der Periode des intensiven Wachstums,
• – bei Alterserscheinungen.

Metabolic disorders
eg

• - in children in the period of intensive growth,
• - with signs of aging.

• – Abstinenzerscheinungen,
• – Alkoholismus,
• – Schlaflosigkeit,
• – Störungen der Wahrnehmung von Informationen,
• – Koma,
• – Störungen der intellektuellen Funktionen,
• – Demenz,
• – Konzentrationsschwäche,
• – Gedächtnisstörungen,
• – Aggressivität,
• – Störungen des Verhaltens (Erregungen oder Hemmungen),
• – Zwangsvorstellungen, Zwangsneurosen,
• – Emotionelle Anspannungen,
• – Pseudomelancholie im hohen Alter,
• – Gereiztheit,
• – Depressive Zustände,
• – innere Unruhe,
• – emotionelle Labilität,
• – Neurosthenie,
• – Alkoholpsychose,
• – Toximanie,
• – Enzephalopathien,
• – juvenile und andere Verhaltensstörungen.

Mental disorders
eg

• - abstinence symptoms,
• - alcoholism,
• - insomnia,
• - disruptions to the perception of information,
• - coma,
• - disturbances of intellectual functions,
• - dementia,
• - lack of concentration,
• - memory disorders,
• - aggressiveness,
• - disorders of behavior (excitement or inhibitions),
• - obsessions, obsessional neuroses,
• - emotional tensions,
• - pseudomelancholia in old age,
• - irritability,
• - Depressed states,
• - inner unrest,
• - emotional lability,
• - neurosthenia,
• - alcohol psychosis,
• - Toximanie,
• - encephalopathies,
• - juvenile and other behavioral disorders.

• – Benzolintoxikationen,
• – Arsenintoxikationen,
• – Rauschgiftintoxikationen,
• – Hypnotika- und Tranquilizer-Intoxikationen.

intoxications
eg

• - benzene intoxications,
• - arsenic intoxication,
• - intoxicants,
• - Hypnotics and tranquilizers intoxications.

Further Applications are the prophylaxis and therapy of the syndrome of Reduction of working capacity and mental overload as well as acute conditions while delivery (e.g., asphyxia of the fetus).

Claims (7)

A preparation for the prophylaxis and therapy of stress states and of functional and organic disorders of the nervous system and of the metabolism, characterized in that the preparation contains glycine. Preparation according to claim 1, characterized by the following composition: sorbic acid 0.10% glycine 2.00% Water, cleaned 73.80% Carbopol 940 Ph. Eur 0.60% Sodium hydroxide lsg.10% 1.70% Kollidon 1.50% Water, cleaned 20.30% preparation according to claim 1 and 2, characterized in that the preparation is administered orally, intranasally or administered vaginally. preparation according to claim 1 to 3, characterized in that it is in tablet form or in Gel form is present. preparation according to one of the preceding claims, characterized in that each tablet contains 0.01 g to 1 g glycine contains. preparation according to one of the preceding claims, characterized in that each tablet contains 0.05g to 0.5g of glycine contains. preparation according to one of the preceding claims, characterized in that each tablet contains 0.1 g of glycine.