EP3880224A1 - Utilisation d'extraits de feuilles de verveine citronnelle (aloysia citriodora) pour augmenter la disponibilité neuronale cérébrale de neurotransmetteurs choisis dans le groupe de la sérotonine, de la dopamine et de la noradrénaline - Google Patents

Utilisation d'extraits de feuilles de verveine citronnelle (aloysia citriodora) pour augmenter la disponibilité neuronale cérébrale de neurotransmetteurs choisis dans le groupe de la sérotonine, de la dopamine et de la noradrénaline

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Publication number
EP3880224A1
EP3880224A1 EP19813247.4A EP19813247A EP3880224A1 EP 3880224 A1 EP3880224 A1 EP 3880224A1 EP 19813247 A EP19813247 A EP 19813247A EP 3880224 A1 EP3880224 A1 EP 3880224A1
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Prior art keywords
extracts
extract
use according
leaves
lemon
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EP19813247.4A
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German (de)
English (en)
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Björn FEISTEL
Bernd Walbroel
Bernd L. Fiebich
Kurt Appel
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Finzelberg GmbH and Co KG
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Finzelberg GmbH and Co KG
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/85—Verbenaceae (Verbena family)
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7016—Disaccharides, e.g. lactose, lactulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30—Extraction of the material

Definitions

  • the lemon verbena (plant species: Aloysia citriodora PAL ⁇ U) belongs to the genus of lemon shrubs (Aloysiae) and the verbena family (Verbenaceae).
  • Aloysia citriodora (formerly Lippia citriodora) refers to the specific scent and taste of the leaves of citrus aromas by referring to "citriodora”.
  • the genus of lemon shrubs differs from both the sweet herbs (Lippiae) with, for example, the representative "Aztec sweet herb” (Lippia dulcis TREV.) Or the “Mexican oregano” (Lippia graveolens HB & K.), as well as the approximately 250 verbena (Verbenae), which include the traditional medicinal plant "Verbena” (Verbena officinais L.).
  • the lemon verbena is a plant that comes from South America and is found mainly in the regions of Chile and Brazil. Because of the lack of frost tolerance, the lemon verbena is only grown in southern Europe, especially in France and Spain.
  • the leaves of the lemon verbena are usually light green, slightly serrated at the edge, lanceolate or tapering and hairless.
  • the length of the leaves (leaf blade) varies between 3 and 10 cm, while the leaf width can be between 0.5 and 3 cm.
  • the fresh or dried leaves of the lemon verbena are used as an aroma ingredient or as a medicinal plant.
  • the healing treatments described include the following properties: antioxidant, milk flow stimulator, pain reliever, antibacterial, antipyretic, muscle relaxant and diuretic.
  • the constituents of the essential oils and the group of flavonoids should be jointly responsible for the very broad spectrum of active ingredients. Consequently, the Ph. Eur. Monograph for lemon verbena leaves (Lemon verbena, leaf) specifies in the quality description for dried whole leaves a minimum content of 3ml / kg essential oil and 2.5% acteoside and a DC fingerprint for the presence of flavonoids .
  • the essential oil is very often cited as an active ingredient group, characteristic chromatographic analyzes are for the specific ingredients of the oil in connection with their effects not exactly described.
  • the essential oil components of the lemon verbena are used in aromatherapy. There they serve, among other things, for the treatment of nervous restlessness and stress-related exhaustion or when taking tea orally as a remedy for difficulty falling asleep or minor digestive problems.
  • Wannmacher et al. investigated the postulated sedative and anxiolytic effects of lemon verbena tea preparations, but were unable to determine any significant effects in a human randomized double-blind parallel group study in 40 healthy volunteers (Wannmacher L. et al. - Plants employed in the treatment of anxiety and insomnia: II. Effect of infusions of Aloysia triphylla on experimental anxiety in normal volunteers. Fitorick 1990; 61: 449-453). Thus, a simple aqueous liquid extract with a small amount of essential oil was not sufficiently significantly effective on the central nervous system (CNS).
  • CNS central nervous system
  • Verbena is verbena, not lemon verbena.
  • CN 102309622 (B) relates to individual glycosides from Verbena for use in cerebral ischemia. From paragraph [0007] it follows that it is verbena (Verbena officinalis).
  • Carpinella et al. in Phytotherapy Research 24 (2010) 259 - 263 describes purely ethanolic extracts from 73 different plants, which are then separated into an aqueous and an organic fraction.
  • the applied measurement system "acetyl-choline esterase inhibition” is used as a screening for diseases such as Alzheimer's.
  • WO 2005/058338 A1 relates to extracts from lemon verbena. No depletion of essential oils is described for the extracts thus obtained.
  • Veisi et al. who also produced aqueous dry extracts with thermal drying and administered this orally to rats. No anxiolytic effects in the Elevated Plus Maze from 10 mg extract / kg body weight were found (Veisi M, Shahidi S, Komaki A, Sarihi A.: Assessment of aqueous extract of Lemon verbena on anxiety-like behavior in rats. J Pharm Negative Results 2015; 6: 37-9.), But an anxiety-like behavior. Ceuterick et al.
  • the object of the present invention is to find further fields of application for lemon verbena.
  • the task is solved by extracts from leaves of the lemon shrub (Aloysia citriodora) for use in the treatment and prophylaxis of neuronal or cerebral disorders.
  • the invention describes the standardized production of extracts from the leaves of lemon verbena (Aloysia citriodora) in correlation to a specific CNS-mediated clinical picture by influencing neurotransmitters.
  • the previous areas of application can thus be expanded to include the attention deficit syndrome and / or the increase in cognitive performance as a preliminary stage of Alzheimer's disease.
  • Attention Deficit Hyperactivity Disorder (ADHD) is a mental disorder that begins in childhood and is characterized by problems with attention, impulsiveness and often also hyperactivity. Up to ten percent of all children in Europe show symptoms in the sense of ADHD (boys significantly more often than girls). The symptoms can persist into adulthood with different forms. Between 30% and 70% of adolescents affected by ADHD persist in adulthood (persistence).
  • ADHD hyperactivity takes on a different character by acting as an increased restlessness. People with ADHD often show various other mental disorders, e.g. Depression, anxiety disorders and disorders of self-image and self-esteem as well as social phobias. Attention deficit hyperactivity syndrome is currently a multifactorial disorder with an inherited disposition that favors the development of the disease.
  • striatofrontal dysfunction Areas affected are areas of the brain, more precisely the frontal brain, in which motivation, cognition (information transformation), emotion and movement behavior are regulated or their interaction is coordinated. Since areas of the so-called striatum (part of the basal ganglia belonging to the cerebrum) are also affected in addition to the frontal brain, doctors speak of striatofrontal dysfunction.
  • Medicinal treatment of ADHD primarily uses stimulants that influence the dopamine metabolism in the brain. These include methylphenidate and amphetamine derivatives (DL amphetamine), which have been used around the middle of the last century. Approx. 2/3 of those affected respond to this. Antidepressants which act on the dopamine or norepinephrine household can also be used for the treatment.
  • stimulants that influence the dopamine metabolism in the brain. These include methylphenidate and amphetamine derivatives (DL amphetamine), which have been used around the middle of the last century. Approx. 2/3 of those affected respond to this.
  • Antidepressants which act on the dopamine or norepinephrine household can also be used for the treatment.
  • One cause of ADHD is an abnormality in signal processing in the brain.
  • This disorder is based on a deficiency or a reduced effect of the messenger substances (neurotransmitters) noradrenaline and dopamine.
  • attention is controlled via norepinephrine, motivation via dopamine.
  • the result of a disturbed signal processing is correspondingly difficult for those affected to concentrate on one thing and to filter external stimuli according to their importance or unimportance, i.e. an easy distraction and overstimulation of stimuli.
  • An involvement of the messenger serotonin in ADHD was also proven. Serotonin controls impulsivity and can accordingly lead to increased impulsivity, low frustration tolerance and poor behavior adjustment of those affected to the respective circumstances in the event of a disorder.
  • methylphenidate which inhibits the reuptake of dopamine and norepinephrine in the presynapses and thus increases their concentration in the synaptic cleft. This leads to an increased Signal generation at the receptor and, among other things, an increase in sympathetic tone.
  • substances that inhibit the selective noradrenaline and dopamine (also slightly serotonin) reuptake represent successful candidates for the treatment of ADHD.
  • this drug also has extensive side effects. Common side effects include: nasopharynx inflammation, decreased appetite, moderately reduced weight and size gain (after prolonged use in children), mental imbalance, anxiety, depression, irritability, cardiac arrhythmia, etc.
  • methylphenidate may aggravate the symptoms of behavioral and thinking disorders in psychotic children. There is no treatment recommendation for children under 6 years of age. With long-term use, the side effects are most likely to occur. With chronic improper use, methylphenidate can even lose its effect (development of tolerance) and lead to mental dependence.
  • Cognition information transformation
  • cognitive processes in humans are conscious, “cognition” and “consciousness” do not have the same meaning.
  • Certain processes in humans can be unconscious and yet cognitive. An example of this is unconscious learning.
  • a person's cognitive skills include, for example, attention, memory, learning, creativity, planning, orientation, imagination, reasoning, introspection, will, belief and some more. Cognitive skills are studied by various sciences, such as psychiatry, psychology, philosophy, and neuroscience.
  • Cognitive performance is therefore a complex process that can be quantified using measurable parameters of brain performance.
  • the ability to learn includes memorizing (duration and amount of input retained), the influence on the speed of reaction, the ability to perform logical operations (quickly and correctly) or spatial thinking, e.g. in an orientation phase under new or changed conditions.
  • Disorders of this cognitive performance are described with the syndrome MCI (Mild Cognitive Impairment).
  • MCI is a special condition of age-related reduction in cognitive functions and skills. The examination of MCI in healthy people can be seen as a pre-indicator for later dementia.
  • the invention thus relates to the use of extracts from the leaves of the species Aloysia citriodora (or their synonyms) for the treatment of ADHD and / or cognition and / or mild cognitive impairment and / or stress-related exhaustion /
  • somatoform disorders burn-out syndrome
  • acute and post-traumatic stress disorders chronic fatigue syndrome
  • chronic fatigue syndrome a syndrome that can be treated or prevented according to the invention
  • nervous restlessness mental stress
  • anxiety and depression as symptoms of neurotic disorders as well as stress symptoms such as fatigue and weakness.
  • the neuronal disorder is preferably not a neurodegenerative disease which is associated with accumulated proteins / peptides, that is to say in particular not Alzheimer's disease or Parkinson's.
  • the invention also relates to the use of extracts from the leaves of the species Aloysia citriodora (or their synonyms) for the manufacture of a medicament for the treatment of ADHD.
  • the invention further relates to the use of extracts from the leaves of the species Aloysia citriodora (or their synonyms) for the production of a therapeutic agent for improving cognitive performance and / or mild cognitive impairment.
  • the invention also relates to the use of extracts from the leaves of the species Aloysia citriodora (or their synonyms) for the production of a therapeutic agent for nervous restlessness (mental stress).
  • Preferred solvents are methanol, ethanol, isopropanol and mixtures thereof, with ethanol being particularly preferred.
  • the volume ratio of the alcohol-water mixture for extracting the extracts from the leaves of the lemon verbena can vary within wide limits. It is particularly preferably 99: 1 to 1:99 vol.%, Still more preferably 70: 30 to 30: 70 vol.%, Most preferably 55: 45 to 45: 55 vol on the ratio of alcohol to water in the entire mixture used for extraction).
  • Preferred ratios are 10:90 to 70:30 or 10:90 to 60:40 or 20:80 to 70:30 or 20:80 to 60:40, in each case as vol% and as alcohol: water.
  • a mixture of ethanol and water is preferably used as the extracting agent, mixing ratios of 70:30 to 30:70 vol.%, In particular 60:40 to 40:60 vol.% Or 55:45 to 45:55 vol. % are particularly suitable.
  • particularly suitable extractants are mixtures of water with contents between 10:90 to 30:90% by volume. Preferred ratios are 10:90 to 70:30 or 10:90 to 60:40 or 20:80 to 70:30 or 20:80 to 60:40, in each case as vol% and as ethanol: water. All vol .-% data refer to the volume at 21 ° C.
  • mixtures for example mixtures of water with organic solvents such as ketones or organic acids, can also be used as extractants.
  • organic solvents such as ketones or organic acids.
  • the characteristic of the selected organic solvents is that after the extraction process they have been removed again from the enriched extract by distillation, sublimation or freezing.
  • the extracts produced by means of the extracting agents mentioned above by way of example not used as such, but subjected to further purification as the primary extract.
  • Such treatment steps can be
  • extracts from the leaves of the lemon verbena and / or fractions produced from such extracts can be used individually or in combination with one another.
  • it is also preferred according to the invention to extract extracts from the leaves of the lemon verbena and / or fractions produced from such extracts individually or in combination with one another in combination with chemically synthetic substances for example non-selective monoamine reuptake inhibitors (NSMRIs), selective serotonin reuptake inhibitors (SSRIs), selective noradrenaline reuptake inhibitors (NARIs), serotonin-norad renal in reuptake inhibitors (SNRIs), dopamine reuptake inhibitors (DRIs), selective noradrenaline dopamine reuptake inhibitors (NDRIs) or MAO inhibitors.
  • NSMRIs non-selective monoamine reuptake inhibitors
  • SSRIs selective serotonin reuptake inhibitors
  • NARIs selective noradrenaline reuptake inhibitors
  • the use according to the invention according to the embodiments described above can be a use in the form of a pharmaceutical preparation.
  • dosage forms which are generally customary and known to the person skilled in the art as such and which contain a certain concentration of lemon verbena extracts in a form which enables metered administration in pharmaceutically customary dosage forms.
  • the dosage form depends on the route of administration (oral, intravenous, intramuscular, nasal) in the manner known to the person skilled in the art and can be a solid, semi-solid, liquid, mist-like, gaseous or other form which allows administration in the desired way.
  • the use according to the invention with one of the aforementioned dosage forms can also be used as a food supplement.
  • FIG. 1 shows a thin-layer fingerprint comparison on flavonoid substances (yellow) and CCS compounds (light blue) using the example of extract fractions from lemon verbena vs. Primary extract EtOH 50% v / v. The same native proportions of the extracts were applied).
  • Figure 2b shows the Morris-Water-Maze behavior test test setup.
  • FIG. 3b shows a tele-stereo EEG determination in vivo in a control group in rats with the administration of water 1 ml / kg body weight.
  • This 70% native extract preparation is spray dried to a beige powder (temperature at the spray head 185 ° C, outlet temperature from the spray tower 105 ° C).
  • the resulting extract preparation is a beige-colored powder, characterized by an essential oil content of ⁇ 0.01%, a content of 0.06% flavonoids and 1.8% verbascoside.
  • Example 2 Extraction with 20 vol% ethanol in water
  • 1700 g of lemon verbena leaves (Folia Aloysia citriodora) are mixed twice with 10 L ethanol 20% V / V at 50 ° C and percolated for 8 hours (agitated extraction). The mixture is separated from the extracted starting material and clearly filtered through a cellulose filter at 40 pm. The filtrate is freed of the ethanol portion in a Sambay evaporator and becomes a homogeneous thick extract evaporated. The extract is freed from volatile constituents by repeated addition of water and renewed steaming in the vacuum. 182 g of drying aids are added to 611 g of a thick extract evaporated to 69.5% solids.
  • This 70% native extract preparation contains 28% maltodextrin and 2% Aerosil (silicon dioxide) and is dried in a vacuum drying cabinet at 45 ° C. The extract is then ground to a homogeneous beige-brown powder using a sieve mill with a 0.315 mm sieve. The resulting extract preparation is characterized by an essential oil content of ⁇ 0.01%, a content of 0.06% flavonoids and 4.3% verbascoside.
  • Example 3 Extraction with 50 vol% ethanol in water
  • 1700 g lemon verbena leaves (Folia Aloysia citriodora) are mixed twice with 10 L ethanol 50% V / V at 50 ° C and percolated for 8 hours (agitated extraction).
  • the batch is separated from the extracted starting material and clearly filtered through a cellulose filter 40 pm.
  • the filtrate is pre-evaporated on a plate evaporator and finally evaporated on a rotary evaporator in vacuo at 45 ° C to form the thick extract without solvents.
  • the evaporation process is repeated twice with the addition of water in order to remove all volatile constituents.
  • 206 g of drying aids are added to 750 g of a thick extract evaporated to 64.3% solids.
  • This 70% native extract preparation contains 28% maltodextrin and 2% Aerosil (silicon dioxide) and is dried in a vacuum drying cabinet at 45 ° C. The extract is then ground to a homogeneous brown powder using a sieve mill with a 0.315 mm sieve. The resulting extract preparation is characterized by an essential oil content of ⁇ 0.01%, a content of 0.51% flavonoids and 11.6% verbascoside.
  • the increasing silicon dioxide content is necessary for binding and drying the increased chlorophyll content in this lipophilic extracting agent. Finally, it is dried in a vacuum drying cabinet at 45 ° C and ground to powder in a ball mill.
  • the resulting extract preparation is a green-brown powder and is characterized by an essential oil content of ⁇ 0.1%, a content of 1.70% flavonoids and 19.6% verbascoside.
  • Table 1 Extract characterization depending on the extraction solvent
  • the drug-to-extract ratio indicates the concentration factor; it is arithmetically the reciprocal of the native extractive substance yield.
  • Example 5 Determination of the neurotransmitter noradrenaline, dopamine and serotonin influencing properties by extracts from lemon verbena leaves
  • Lemon verbena leaves compared to methylphenidate Surprisingly, all four lemon verbena extracts tested showed very good potential for inhibiting the reuptake of the three neurotransmitters. The strongest potential is shown in norepinephrine, where all four extracts show a very potent reuptake inhibition ⁇ 25 pg / mL. All four extracts are also able to inhibit the reuptake of dopamine in a dose-dependent manner.
  • the three hydroethanolic extracts show good IC50 values of max. 30 pg / mL; the aqueous extract still has a good effect, falling at least by a factor of 2.6 compared to the hydroethanolic extracts. A similar picture emerges for the influence of serotonin.
  • an aqueous extract shows the least activity. From good (extract 4) and very good (extract 2) to moderate activity (extract 3), the hydroethanolic extracts show a clear dependence on the extractant. Overall, however, the extracts show a significantly stronger activity in the serotonin reuptake inhibition compared to methylphenidate. The activity ratio of serotonin to noradrenaline is factor 86 for methylphenidate, while extract 2 or extract 4 has a factor of approx. 4.1 have. Surprisingly, a similar activity profile for influencing norepinephrine and dopamine is shown for the extracts from lemon verbena leaves, in addition to an improved serotonin influence. Based on the three most important neurotransmitters tested, the extracts are very suitable candidates for the treatment of ADHD.
  • extract 4 lipophilic extracts with pure ethanol
  • extract 2 also includes the active ingredient-determining ingredients of the starting material at the same level as a medium-polar aqueous-ethanolic extract (extract 2), if the same extract yields (here DEV 4: 1) are used.
  • extract yields here DEV 4: 1
  • extract No. 4 results in poorer galenical properties in terms of appearance (green-brown), handling (hygroscopic dry extract) and solubility (practically insoluble in an aqueous medium) compared to extract No. 2 and 3.
  • the cause here is that of the extraction agent EtOH 96% V / V favored transitions of cuticula wax and chlorophyll parts from leaves.
  • n-butanol was added three times, each with a third of the volume of the primary solution, and the mixture was stirred vigorously.
  • the phases were then separated in the separating funnel.
  • the combined three butanol phases were evaporated in vacuo on a rotary evaporator.
  • This extract phase was then dried 70% native / 30% drying aids (28% maltodextrin and 2% silicon dioxide) in a vacuum drying cabinet at 45 ° C. and ground to a homogeneous powder.
  • the remaining aqueous phase was also worked up and dried as a 70% native extract powder.
  • the filter action of the adsorber traps substances inside the adsorber. These were washed down by elution with two bed volumes of ethanol 96% v / v. The ethanolic eluate obtained was evaporated in vacuo on a rotary evaporator in a solvent-free manner. This extract phase was then dried 70% native / 30% drying aids (28% maltodextrin and 2% silicon dioxide) in a vacuum drying cabinet at 45 ° C. and ground to a homogeneous powder. Likewise, the previously collected aqueous phase, which has passed through the adsorber, was worked up and dried to a dry extract powder with 70% native content and 30% auxiliaries.
  • extract no. 9 and 10 which resulted from the adsorber resin separation.
  • the adsorber selectively separated the target substances from the water phase (extract No. 9), whereby its activity compared to the primary extract with serotonin and dopamine clearly declined.
  • norepinephrine was influenced in roughly the same order of magnitude also shows that the total extract determines the effect and not just individual lead substances / groups of substances.
  • the ethanolic extract phase from the adsorber (extract no. 10) was able to achieve a concentration of a factor of 3.2 purely in terms of manufacturing technology (12.9 for fractionation vs. 4.0 for primary extract). Exactly this order of magnitude improved the overall neurotransmitter influence.
  • nematode C. elegans is a nematode that is primarily researched in developmental biology and genetics as a model organism. An important reason is that, despite its almost 1000 body cells, it has more than 20,000 genes (human: almost 40,000), many of which have functions similar to those in mammals. Almost half of all proteins encoded in the worm genome have homologs in Homo sapiens, including a large number of known human disease genes. It is therefore a representative model organism in terms of metabolism, targeted gene expression and neuronal behavior.
  • the complete nervous system of nematodes consists of approx. 300 neurons and is made up of 2 independent parts: a larger, somatic and a smaller, pharyngeal nervous system.
  • C. elegans lives in temperate climates where it feeds on bacteria.
  • the animals are about 1 mm long and have a transparent cuticle.
  • C. elegans has a short lifespan of around 15 to 20 days (depending on the temperature and the amount of feed). They can be cultivated in a reproducible manner by placing Escherichia co // bacteria on agar plates as feed.
  • transgenic worms are used in a targeted manner, whose reaction products with defined substances can be detected directly by fluorescence measurements or by behavioral tests.
  • 6-hydroxydopamine (6-OHDA) damages dopaminergic neurons, which is used in various animal models.
  • the transgenic C. elegans strain BZ555 expresses green fluorescent protein in the dopaminergic neurons.
  • the 6-OHDA-induced neurodegeneration, or the reduction thereof, can thus be quantified by fluorescence microscopy.
  • the worms were exposed to 50 mM 6-OHDA, which reduces the fluorescence intensity of the neurons due to their degeneration.
  • Bupropion a selective noradrenaline and dopamine reuptake inhibitor (NDRI), serves as a positive control.
  • Bupropion prevents the neurotoxin 6-OHDA from entering the nerve cells and damaging them by inhibiting the norepinephrine (NA) or dopamine (DA) transporters (reuptake).
  • NA norepinephrine
  • DA dopamine
  • the damage to nerve cells with 6-OHDA in the animal model is a recognized experimental approach for ADHD (Kostrzewa RM et al.: Pharmacological models of ADHD; J Neural Transm (Vienna) 2008; 115: 287-98.)
  • the positive control confirms this in the applied here C.elegan's model.
  • the A. citriodora extract according to the invention is described, as is the positive control for the reuptake inhibition of NA and DA (see Example 5 above).
  • the A. citriodora extract according to the invention can be approx. Achieve 1/3 of the protective function of the positive control.
  • Example 10 Influence on ⁇ -amyloid-induced toxicity in the C.eleaans model:
  • the transgenic C. elegans strain CL4176 was used, which is able to express human ⁇ -amyloid (Aß 1-42).
  • Aß expression can be induced by increasing the temperature.
  • Age-synchronized and treated worms were incubated for 48 hours at 16 ° C. After raising the temperature to 25 ° C and incubating for 24 hours, the worms began to paralyze due to the toxicity of the Aß oligomer.
  • the paralysis was assessed every 2 hours (experiment according to Heiner et al: Sideritis scardica extra cts inhibit the aggregation of a-synuclein and ß-amyloid peptides in Caenorhabditis elegans used as a model for neurodegenerative diseases. Planta Medica 81 - PW_127,2015.) . Substances that counteract this toxic effect of ß-amyloid lead to a slower or later paralysis of the animals. Such substances delay neurodegeneration among others in Alzheimer's dementia. The median (PTso) was used as a comparison value, i.e. the point in time at which exactly 50% of the roundworms were paralyzed.
  • the transgenic C. elegans strain CL2355 expresses pan-neuronal human ⁇ -amyloid. This leads to cognitive disorders such as reduced chemotactic movement towards an attractant (benzaldehyde).
  • the chemotaxis index was measured, i.e. the proportion of worms that had moved to the attractant on the agar plate.
  • the control strain CL2122 expresses no ⁇ -amyloid and shows no behavioral disorders; the chemotaxis index was accordingly high. The experiment was carried out according to Heiner et al.
  • mice are trained over several days to find a platform that is not visible under the water surface and find themselves to notice their spatial position. The mice are let into the water at a distance of approx. 30 cm from the edge, whereupon the animals immediately attempt to swim with swimming movements to reach the saving platform.
  • the advantage of this measuring system which has been known since the beginning of the 1980s, compared to conventional simple labyrinths in animal experiments is that there are no local landmarks, only global ones and that the task has a high motivation factor due to the animals' flight behavior.
  • the experiment aims above all to study the (spatial) learning (recognition and memorization) of the animals under stress conditions and to measure possible influences on them.
  • the measurement parameters are the time until the platform is found, the distance traveled there, and the relative time spent in the correct quadrant of the pool. These parameters are influenced by the training effect. This typically reduces the time it takes to find and the distance to the rescue platform, as well as the quadrant stay time.
  • the training effect can also be influenced by different neurotransmitter concentrations [dissertation, Uni Freiburg 2004, Theresa Schweizer: 3,4-diaminopyridine-evoked release of neurotransmitters from brain sections of rats: examinations in the cortex and hippocampus in old rats, as well as in rats with serotonergic hippocampal lesions Afferents and intrahippocampal raphe grafts].
  • 2 groups of 6 mice were examined.
  • the first control group was formed from water-treated transgenic animals (strain AD-B6), which due to their genetic disposition manifest a strong ß-amyloid deposition within 50 days after birth, or who develop Alzheimer's.
  • the dosage was 400 mg native extract / kg body weight.
  • a behavioral biological test using Morris Water Maze starts.
  • the test includes a daily early and late test / learning session over four days.
  • the early session begins with a run without a platform for 30 seconds, recording the time the mouse is in the quadrant in which the platform is located (target quadrant).
  • the other four runs take place with an invisible platform and with 4 different starting positions.
  • Electroencephalography (from Greek encephalon brain, gräphein write) -EEG abbreviated- is a method of medical diagnostics for measuring the total electrical activity of the brain by recording the voltage fluctuations.
  • the electroencephalogram offers a standard examination method in neurology as a graphic representation of these fluctuations. For clinical evaluation, recording in at least twelve channels of different electrode combinations is required. The resulting data can be examined by trained specialists for striking patterns.
  • a common mathematical method for analyzing the EEG is the Fourier transform in the frequency domain.
  • the EEG is often divided into frequency bands (so-called EEG bands), whereby the number of bands and the exact division sometimes is specified differently. The division of the frequency bands and their limits are historically determined and do not consistently coincide with limits that are considered reasonable based on more modern studies.
  • theta band was divided into a range Theta 1 and Theta 2 in order to take into account the different meanings of the sub-areas.
  • software algorithms for assisted or automatic evaluation are used that emulate pattern recognition.
  • Brain waves can not only be measured, they can also be influenced. This can happen, among other things, as neurofeedback - a special form of biofeedback - as a result of pharmacologically active substances, such as psychotropic drugs [Dimpfel W, et al. (1996) Source Density Analysis of Functional Topographical EEG: Monitoring of Cognitive Drug Action. Eur J Med Res 1: 283-290].
  • the evaluation is also referred to as an electropharmacogram.
  • neurofeedback it is customary to subdivide the EEG bands more precisely and interpret them in more detail than in clinical EEG. An increased amplitude within the frequency ranges is associated with certain mental states or Activities correlated.
  • Theta 2 waves can be associated, for example, with memory and learning ability, concentration, and / or creativity. After extensive calibrations, conclusions can also be drawn about neurotransmitter-mediated CNS activities, which can be divided into dopaminergic, serotonergic, cholinergic or noradrenergic subgroups.
  • n 7 Fischer-344 rats were each implanted with 4 semi-microelectrodes in the 4 brain areas "frontal cortex”, “hippocampus”, “striatum” and “formatio reticularis”. The measurable potential field changes were transmitted by radio and were evaluated for an electropharmacogram.
  • the animals were treated with lemon verbena dry extract preparation according to Example 3 at a dose equivalent of 150 mg / kg body weight.
  • the single dose was dissolved in water and administered once. Water was used as a control experiment.
  • the test liquid was administered to the animals orally by gavage, followed by a 5-minute calming phase for the animal.
  • the measurement was then started over a measurement period of 5 hours.
  • the frequency data were obtained using Fast Fourier Transformation (FFT) and averaged over 60-minute periods.
  • FFT Fast Fourier Transformation
  • Comparable electropharmacograms have, for example, moclobemide, a monoamine oxidase inhibitor approved as an antidepressant, but also methylphenidate, a dopamine and norepinephrine reuptake inhibitor, with additional agonistic activity at the serotonergic receptors 5-HT1A and 5-HT2B, which is approved for the treatment of ADHD.

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Abstract

La présente invention a pour but de fournir des préparations et des extraits de verveine citronnelle (Aloysia citriodora ou ses désignations synonymes) pour la prophylaxie du stress mental, pour augmenter les capacités cognitives ainsi que dans le traitement du TDAH. À cet effet, l'invention concerne l'utilisation de préparations et d'extraits de verveine citronnelle (Aloysia citriodora ou ses désignations synonymes), en particulier l'utilisation d'extraits hydroalcooliques. Lesdits extraits peuvent être utilisés dans des aliments, des compléments alimentaires, des régimes équilibrés complémentaires ou des préparations pharmaceutiques.
EP19813247.4A 2018-11-14 2019-11-14 Utilisation d'extraits de feuilles de verveine citronnelle (aloysia citriodora) pour augmenter la disponibilité neuronale cérébrale de neurotransmetteurs choisis dans le groupe de la sérotonine, de la dopamine et de la noradrénaline Pending EP3880224A1 (fr)

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EP18206340 2018-11-14
PCT/EP2019/081392 WO2020099595A1 (fr) 2018-11-14 2019-11-14 Utilisation d'extraits de feuilles de verveine citronnelle (aloysia citriodora) pour augmenter la disponibilité neuronale cérébrale de neurotransmetteurs choisis dans le groupe de la sérotonine, de la dopamine et de la noradrénaline

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CN (1) CN113329757A (fr)
AU (1) AU2019380654A1 (fr)
BR (1) BR112021009427A2 (fr)
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JP4979181B2 (ja) * 2003-01-31 2012-07-18 株式会社ヤクルト本社 グリケーション阻害剤及びその利用
DE10359384A1 (de) 2003-12-18 2005-07-28 Anoxymer Gmbh Verwendung eines Extraktes von Aloysia triphylla als Matrixprotektor
JPWO2007119578A1 (ja) * 2006-03-29 2009-08-27 株式会社カネカ 神経系細胞機能改善剤
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DE102009013225A1 (de) 2009-03-17 2010-09-23 IBAM GbR (vertretungsberechtigte Gesellschafter: Dr. Rainer Knörle u. Dr. Peter Schnierle, 79211 Denzlingen) Verwendung von Pflanzen der Gattung Sideritis und Extrakten daraus zur Behandlung des Aufmerksamkeitsdefizit-Hyperaktivitätssyndroms
DE102011078432A1 (de) 2011-06-30 2013-01-03 Barbara Engels-Wehr Verwendung von Monoterpen-Estern zur Behandlung von hyperkinetischen Störungen
CN102309622B (zh) 2011-07-05 2014-02-19 河南中医学院 马鞭草总苷在制备防治脑缺血药物中的应用
CA2843775A1 (fr) * 2011-10-04 2013-04-11 Psychnostics, Llc Procedes de diagnostic et d'identification de modulateurs de potentiels membranaires dans psychose periodique et trouble d'hyperactivite avec deficit de l'attention
US20140234488A1 (en) * 2013-02-15 2014-08-21 Alice Chang Beverage system, including bubble beverage, instant beverage, beverage with dissolved gas, and beverage with ingredient
CN103232503A (zh) * 2013-05-17 2013-08-07 南京泽朗医药科技有限公司 一种马鞭草苷的制备方法
US20150283072A1 (en) * 2014-03-20 2015-10-08 Santé, Llc Pre-operative beverages
CN107397011A (zh) 2017-08-23 2017-11-28 宁波甬基生物科技有限公司 一种提神醒脑中草药保健茶饮及其制备方法

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JP2022507586A (ja) 2022-01-18
CN113329757A (zh) 2021-08-31
KR20210138559A (ko) 2021-11-19
US20220031794A1 (en) 2022-02-03
WO2020099595A1 (fr) 2020-05-22
BR112021009427A2 (pt) 2021-08-17
AU2019380654A1 (en) 2021-05-27
MX2021005604A (es) 2021-08-11

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