EP4153198A1 - Probiotic bacteria for treating alzheimer's disease - Google Patents

Probiotic bacteria for treating alzheimer's disease

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Publication number
EP4153198A1
EP4153198A1 EP21727809.2A EP21727809A EP4153198A1 EP 4153198 A1 EP4153198 A1 EP 4153198A1 EP 21727809 A EP21727809 A EP 21727809A EP 4153198 A1 EP4153198 A1 EP 4153198A1
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EP
European Patent Office
Prior art keywords
use according
bacteria
disease
probiotic bacterium
probiotic
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EP21727809.2A
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German (de)
French (fr)
Inventor
Marjolein WILDWATER
Frederikus Gerardus Josephus Maria van de Wiel
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Rrw BV
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Rrw BV
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • 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
    • A61K31/12—Ketones
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/745—Bifidobacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/747—Lactobacilli, e.g. L. acidophilus or L. brevis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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

Definitions

  • the present invention relates to the technical field of treating amyloidoses such as Alzheimer's disease.
  • the invention relates to therapies for the treatment of Alzheimer's disease with probiotic bacteria, preferably in combination with cannabinoids and / or curcuminoids.
  • Alzheimer's disease is synonymous with Alzheimer's disease.
  • Alzheimer's disease occurs particularly in older people over the age of 65, whereby the corresponding precursors or preclinical or clinical preliminary stages can also occur significantly earlier.
  • Alzheimer's disease is the most widespread dementia. Alzheimer's disease is associated with an increasing deterioration in cognitive performance over time, which is usually associated with a decrease in daily activities, behavioral disorders and neuropsychological symptoms.
  • Alzheimer's disease Characteristic of Alzheimer's disease are the plaques that form in the brain of the person affected, which have largely incorrectly folded amyloid-ß-peptides, as well as the neurofibrils that accumulate in the neurons.
  • the intracellular bundles of neurofibrils essentially consist of the tau protein, which aggregates into fibrils when it is excessively phosphorylated.
  • the amyloid-ß-peptides which are also referred to synonymously as Aß-proteins, arise from the so-called amyloid precursor protein (APP).
  • APP amyloid precursor protein
  • a ⁇ peptides are generally 37 to 42 amino acids in length and are associated with the pathological development of Alzheimer's disease.
  • proteins such as the amyloid protein or the tau protein also play a decisive role in other diseases.
  • the protein deposits damage cells and tissues, whereby the clinical picture is defined depending on the location and type of deposit.
  • the present invention is based on the object of providing an improved prevention or treatment of these amyloidoses, in particular Alzheimer's disease.
  • the invention is based on the knowledge that the therapeutic effect of various active ingredients in the treatment of amyolidoses such as Alzheimer's disease can be enhanced by combining them with probiotic bacteria. Synergistic effects of these combination therapies were shown in an animal model. In addition, the probiotic bacteria on their own also show therapeutic activity.
  • the present invention provides, in a first aspect, the use of a probiotic bacterium for the production of a medicament for the treatment or prevention of amyloidosis.
  • the present invention relates to the use of a mixture of a probiotic bacterium and an active ingredient which is therapeutically effective in the treatment or prevention of amyloidosis for the manufacture of a medicament for the treatment or prevention of amyloidosis.
  • the active ingredient is a cannabinoid, a curcuminoid or a mixture thereof.
  • the present invention provides, in a first aspect, the use of a probiotic bacterium for the manufacture of a medicament for the treatment or prevention of amyloidosis.
  • the probiotic bacterium can be any probiotic bacterium as well as mixtures of different probiotic bacteria.
  • a “bacterium” in the context of the present invention generally relates to a large number of bacterial cells and not to a single bacterial cell.
  • the term "bacterium” refers to a plurality of bacterial cells of the same genus, species, or strain.
  • Probiotic bacteria in particular, are live bacteria that provide health benefits when given in adequate quantities.
  • the probiotic bacterium is selected from the group consisting of bacteria of the genus Lactobacillus, bacteria of the genus Streptococcus, bacteria of the genus Bifidobacterium, bacteria of the genus Enterococcus, bacteria of the genus Pseudomonas, and mixtures of bacteria containing bacteria of one or more of these genera .
  • the probiotic bacterium can be selected, for example, from the group consisting of bacteria of the genus Lactobacillus, bacteria of the genus Streptococcus, bacteria of the genus Bifidobacterium and bacteria of the genus Enterococcus.
  • the probiotic bacterium is a lactic acid bacterium.
  • the probiotic bacterium can be a bacterium of the genus Lactobacillus or a bacterial mixture containing a bacterium of the genus Lactobacillus.
  • the probiotic bacterium is selected from the group consisting of Enterococcus faecium, Bifidobacterium longum, Streptococcus thermophilus, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus rhamnosus, Bifidobacterium breve, Pseudomonas fluorescens containing bacteria of one or more of these species, and mixtures of these bacteria.
  • the probiotic bacterium can be selected, for example, from the group consisting of bacteria of the species Enterococcus faecium, Bifidobacterium longum, Streptococcus thermophilus, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus rhamnosus and Bifidobacterium breve.
  • the probiotic bacterium is a bacterium of the species Lactobacillus plantarum or Lactobacillus rhamnosus or a bacterial mixture containing a bacterium of the species Lactobacillus plantarum and / or Lactobacillus rhamnosus.
  • the probiotic bacterium is a bacterium of the species Pseudomonas fluorescens.
  • the probiotic bacterium is administered in combination with an agent that is therapeutically effective in treating or preventing amyloidosis.
  • the probiotic bacterium and the active ingredient can be present together in a mixture and administered to the patient will.
  • the probiotic bacterium and the active ingredient can each be in a separate composition and administered to the patient.
  • Several different probiotic bacteria and / or several different active ingredients can also be administered, it being possible for these to be administered together in one composition or separately from one another in several separate compositions. Multiple compositions can be administered simultaneously or sequentially. Successive administration takes place in particular on the same day, preferably within a period of 4 hours, 2 hours or particularly preferably one hour.
  • the present invention also relates to the use of a mixture of a probiotic bacterium and an active ingredient which is therapeutically effective in the treatment or prevention of amyloidosis for the production of a medicament for the treatment or prevention of amyloidosis.
  • the active ingredient which is therapeutically active in the treatment or prevention of amyloidosis can be any therapeutically active active ingredient, in particular an active ingredient which can be used for the treatment and / or prevention of Alzheimer's disease.
  • the active ingredient is a herbal active ingredient or an active ingredient obtainable from plants.
  • the active ingredient can in particular also be a mixture of different substances.
  • the active ingredient is a cannabinoid, a curcuminoid or a mixture thereof.
  • a therapeutic composition is in particular a composition which is suitable for being administered to a human or animal.
  • a therapeutic composition consists in particular of pharmaceutically acceptable substances.
  • a pharmaceutical composition preferably contains a probiotic bacterium and / or an active ingredient, in particular a cannabinoid and / or a curcuminoid, and a carrier, a solvent and / or other additives such as buffers and preservatives.
  • the therapeutic composition contains, in addition to the specified substances, probiotic bacterium, cannabinoid and / or curcuminoid, exclusively water.
  • curcuminoids include in particular curcumin, demethoxycurcumin and bisdemethoxycurcumin, as well as mixtures thereof.
  • the curcuminoid is curcumin or a mixture containing curcumin.
  • the curcuminoid is a mixture containing curcumin, optionally demethoxycurcumin and optionally bisdemethoxycurcumin.
  • the curcuminoid can be a mixture containing at least 60%, in particular at least 70% curcumin, at most 30%, in particular at most 20% demethoxycurcumin and at most 10%, in particular at most 5% bisdemethoxycurcumin.
  • Curcumin is also known as diferuloylmethane or (E, E) -1, 7-bis (4-hydroxy-3-methoxyphenyl) -1,6-heptadiene-3,5, -dione.
  • the curcuminoid, in particular curcumin can be obtained from a natural source such as, for example, from the rhizome of the turmeric plant (Curcuma longa) or synthetically.
  • cannabinoids include in particular cannabidiol (CBD), delta-9-tetrahydrocannabinol (THC), cannabichromene, cannabielsoin, delta-8-tetrahydrocannabinol, iso-tetrahydrocannabinol, cannabicyclol, cannabicitran, and acids of these compounds such as cannabidiolic acid (CBDA) and Delta-9-tetrahydrocannabinolic acid (THCA) and mixtures thereof.
  • CBD cannabidiolic acid
  • THCA Delta-9-tetrahydrocannabinolic acid
  • the cannabinoid is CBD or a mixture containing CBD.
  • the cannabinoid is THCA or a mixture containing THCA.
  • the cannabinoid is THC or a mixture containing THC.
  • the cannabinoid, especially CBD, THC and / or THCA can be obtained from a natural source such as
  • the probiotic bacterium and the active ingredient or corresponding mixtures are used in the form of a therapeutic composition. In certain embodiments, the probiotic bacterium and the active ingredient are present together in a therapeutic composition.
  • Administration to the patient can be by any suitable route of administration.
  • the substances or mixtures of substances, in particular the therapeutic compositions are administered orally.
  • the treatment or prevention takes place in particular via regular administration over a longer period of time, preferably continuously.
  • the substances are administered in a therapeutically effective amount.
  • Amyloidosis is a condition in which proteins accumulate.
  • the enriched proteins form insoluble deposits (amyloid) such as fibrils.
  • the amyloidosis is a tauopathy.
  • tauopathies the tau protein is deposited in nerve and glial cells.
  • the group of tauopathies includes in particular Alzheimer's disease, chronic traumatic encephalopathy (CTE), Parkinson's disease, corticobasal degeneration and frontotem poral dementia.
  • the amyloidosis is Alzheimer's disease.
  • plaques made up of incorrectly folded beta-amyloid (Aß) peptides form in the brain of the person affected, and defective tau proteins attach themselves to the axons from the cell body.
  • Aß beta-amyloid
  • Treatment is given to a patient who needs it. These are especially patients with amyloidosis such as Alzheimer's disease.
  • the treatment can take place in the beginning of the disease as well as in advanced disease.
  • Prevention can be done on any individual. In particular, the prevention is applied to individuals of older age, such as from the age of 60, 65, 70 or 75 years of age. However, individuals of younger age can also benefit from the prevention, e.g. individuals aged at least 20 years, at least 30 years, at least 40 years or at least 50 years. In individuals with incipient or undiagnosed amyloidosis, prevention and treatment can merge. The patients and individuals are especially people.
  • the probiotic bacterium and optionally the active ingredient are administered in one or more pharmaceutical compositions which, in addition to these substances, essentially only contain water.
  • the pharmaceutical compositions contain exclusively water in addition to these substances.
  • the pharmaceutical compositions contain these substances in high concentration.
  • the concentration of curcuminoid, especially curcumin is at least 1 g / l, for example at least 2 g / l, at least 3 g / l, at least 5 g / l, at least 10 g / l, at least 15 g / l or at about 20 g / l.
  • the concentration of the cannabinoid, in particular of CBD or THCA can, for example, be at least 0.5 mg / l, preferably at least 1 mg / l, at least 10 mg / l, at least 100 mg / l, at least 250 mg / l or at least 1 g / l.
  • containing or related expressions as used herein also means “consisting essentially of” and “consisting of” in addition to their normal meaning.
  • the term “containing” also relates to embodiments in which the object that “contains” certain listed elements does not contain any further elements, as well as to embodiments in which the object that “contains” certain listed elements additionally contains further elements contains.
  • the expression “consisting essentially of” relates in particular to embodiments in which the object contains 10% or less, in particular 5% or less, further elements in addition to the specifically listed elements of which the object essentially consists.
  • Figure 1 shows the results of an Alzheimer's disease paralysis assay.
  • a C. elegans nematode strain with inducible amyloid-ß accumulation (CL4176) was exposed to a mixture of different probiotic bacteria alone or in combination with. The percentage of nematodes which have not become immobile 72 hours after induction of A ⁇ accumulation is given. Untreated nematodes served as controls.
  • Figure 2 shows the results of an Alzheimer's disease paralysis assay.
  • a C. elegans nematode strain with inducible amyloid-ß accumulation (CL4176) was exposed to a mixture of different probiotic bacteria in different concentrations. The percentage of nematodes which have not become immobile 96 hours after induction of A ⁇ accumulation is given.
  • FIG 3 shows the results of an Alzheimer's disease paralysis assay.
  • a C. elegans nematode strain with inducible amyloid-ß accumulation (CL4176) was exposed to various drugs that reduce the effects of Aß accumulation without or together with the probiotic bacterium Lactobacillus rhamnosus. The percentage of nematodes which have not become immobile 96 hours after induction of A ⁇ accumulation is given. Untreated (MQ) or ethanol-treated nematodes served as controls.
  • Figure 4 shows the results of an Alzheimer's disease paralysis assay.
  • a C. elegans nematode strain with inducible amyloid-ß accumulation (CL4176) was exposed to various drugs that reduce the effects of Aß accumulation without or together with the probiotic bacterium Lactobacillus rhamnosus. The percentage of nematodes which have not become immobile 96 hours after induction of A ⁇ accumulation is given. Untreated (MQ) or ethanol-treated nematodes served as
  • elegans nematode strain with inducible amyloid-ß accumulation (CL4176) was exposed to various drugs that reduce the effects of Aß accumulation without or together with the probiotic bacterium Lactobacillus plantarum. The percentage of nematodes which have not become immobile 96 hours after induction of A ⁇ accumulation is given. Nematodes treated with the solvent (water) only served as controls.
  • Figure 5 shows the results of an Alzheimer's disease paralysis assay.
  • a C. elegans nematode strain with inducible amyloid-ß accumulation (CL4176) was exposed to various drugs that reduce the effects of Aß accumulation without or together with the probiotic bacterium Lactobacillus rhamnosus.
  • the percentage of nematodes which have not become immobile 96 hours after induction of A ⁇ accumulation is given.
  • Nematodes treated with the solvent (water) only served as controls.
  • Figure 6 shows the results of an Alzheimer's disease paralysis assay.
  • a C. elegans nematode strain with inducible amyloid-ß accumulation (CL4176) was exposed to various drugs that reduce the effects of Aß accumulation without or together with the probiotic bacterium Lactobacillus plantarum.
  • the percentage of nematodes which have not become immobile 96 hours after induction of A ⁇ accumulation is given.
  • Nematodes treated with the solvent (water) only served as controls.
  • Figure 7 shows the results of an Alzheimer's disease paralysis assay.
  • a C. elegans nematode strain with inducible amyloid-ß accumulation (CL4176) was exposed to curcumin, the probiotic bacterium Pseudomonas fluorescens, or a combination thereof.
  • the percentage of nematodes which have not become immobile 96 hours after induction of A ⁇ accumulation is given.
  • Nematodes treated with the solvent (water) only served as controls.
  • Figure 8 shows the results of an Alzheimer's disease paralysis assay.
  • a C. elegans nematode strain with inducible amyloid-ß accumulation (CL4176) was exposed to CBD, the probiotic bacterium Pseudomonas fluorescens, or a combination thereof.
  • the percentage of nematodes which have not become immobile 96 hours after induction of A ⁇ accumulation is given.
  • Nematodes treated with the solvent (water) only served as controls.
  • C. elegans nematode strains as an animal model for amyloidoses such as Alzheimer's disease. These strains accumulate amyloid-ß peptides, which form plaques in the nematodes and lead to paralysis of the animals. In certain tribes like the strain CL4176, A ⁇ accumulation only occurs in response to heat shock. The Alzheimer's disease is thus inducible in these strains.
  • the number of paralyzed nematodes after a certain period of time after induction of A ⁇ accumulation indicates the extent of Alzheimer's disease.
  • the effect of certain substances to which the nematodes are exposed on the number of paralyzed animals is therefore a measure of the anti-Alzheimer's effect of these substances.
  • Nematodes of strain CL4176 were synchronized in the young larval stage and allowed to grow to the L4 stage on normal growth medium for 72 h at 16 ° C.
  • the probiotic bacteria to be tested were added to the growth medium.
  • the nematodes were exposed to the test substance and the temperature was increased to 25 ° C. This heat shock induced the A ⁇ accumulation and thus simulated the onset of Alzheimer's disease.
  • the number of animals that were still mobile and of animals that were paralyzed as a result of the A ⁇ accumulation was determined approximately every 24 hours.
  • C. elegans of strain CL4176 were exposed to a mixture of different probiotic bacteria at a bacterial concentration of 50 cfu (colony-forming units) in this assay.
  • the bacterial mixture contained the following types of bacteria: Enterococcus faecium, Bifidobacterium longum, Streptococcus thermophilus, Lactobacillus acidophilus, Lactobacillus plantarum and Bifidobacterium breve.
  • the probiotic bacterial mixture showed a therapeutic effect in this Alzheimer's assay 72 h after induction of the A ⁇ accumulation.
  • the nematodes were also treated with cannabidiol (CBD). CBD significantly increased the effectiveness of the probiotic bacteria (see Figure 1).
  • the anti-Alzheimer's effect of the probiotic bacteria also showed a clear concentration dependency (see Figure 2).
  • probiotic bacteria protect against the effects of A ⁇ accumulation and help in the prevention and treatment of amyloidoses such as Alzheimer's disease.
  • Example 2 Probiotic bacterial species Lactobacillus rhamnosus and Lactobacillus plantarum
  • the two probiotic bacterial strains Lactobacillus rhamnosus and Lactobacillus plantarum were allowed to grow to the stationary phase and mixed with the normal feed of the nematodes (OP50) E. coli bacteria).
  • C. elegans of the strain CL4176 in the L4 larval stage were exposed to the probiotic bacteria and other active substances during the induction of A ⁇ accumulation by increasing the temperature to 25 ° C. The number of paralyzed animals was checked every 24 hours and determined after 96 hours.
  • Lactobacillus rhamnosus and Lactobacillus plantarum showed a reduction in paralysis due to the A ⁇ accumulation (see Figures 3 and 4).
  • the number of paralyzed nematodes was also reduced when treated with curcumin (0.08% (v / v)), CBD (0.08% (v / v)), THCA (60 mM) or combinations thereof.
  • the combination of Lactobacillus rhamnosus or Lactobacillus plantarum with these active ingredients showed a clear to synergistic prevention of the effects of A ⁇ accumulation (see Figures 3 and 4).
  • Corresponding results were also achieved when the probiotic bacterial strains were used in the growth phase, ie in a significantly lower concentration with an OD600 of 0.25 (see Figures 5 and 6).
  • the probiotic strains used thus showed a clear therapeutic effect against amyloidoses such as Alzheimer's disease, which could be synergistically increased by combining it with other active ingredients such as curcumin, CBD and THCA.
  • the effect of the bacterial strain Pseudomonas fluorescens was tested in the Alzheimer's animal model assay described.
  • the nematodes Pseudomonas fluorescens bacteria, curcumin or CBD or a combination of the bacteria and the active ingredient were exposed.
  • the number of paralyzed nematodes was determined 96 hours after induction of the A ⁇ accumulation.
  • the probiotic bacterial strain Pseudomonas fluorescens thus had a therapeutic effect against amyloidoses such as Alzheimer's disease, which could be synergistically increased when combined with active ingredients such as curcumin and CBD.

Abstract

The present invention relates to the treatment or prevention of amyloidoses by means of probiotic bacteria, in particular combined with plant active substances. According to particular embodiments, probiotic bacteria are used combined with a curcuminoid and/or a cannabinoid in the treatment or prevention of Alzheimer's disease.

Description

Probiotische Bakterien zur Behandlung der Alzheimer Krankheit Probiotic bacteria used to treat Alzheimer's disease
Gebiet der Erfindung Field of invention
Die vorliegende Erfindung betrifft das technische Gebiet der Behandlung von Amyloidosen wie der Alzheimer-Krankheit. Insbesondere betrifft die Erfindung Therapien zur Behandlung der Alzheimer-Krankheit mit probiotischen Bakterien vorzugsweise in Kombination mit Cannabinoiden und/oder Curcuminoiden. The present invention relates to the technical field of treating amyloidoses such as Alzheimer's disease. In particular, the invention relates to therapies for the treatment of Alzheimer's disease with probiotic bacteria, preferably in combination with cannabinoids and / or curcuminoids.
Technischer Hintergrund Technical background
Eine der häufigsten Formen der neurodegenerativen Erkrankungen stellt die Alzheimer- Krankheit dar, welche synonym auch als Morbus Alzheimer bezeichnet wird. Die Alzheimer- Krankheit tritt insbesondere bei älteren Menschen jenseits des 65. Lebensjahrs auf, wobei die entsprechenden Vorläuferformen bzw. präklinische oder klinische Vorstufen auch deutlich früher auftreten können. One of the most common forms of neurodegenerative diseases is Alzheimer's disease, which is synonymous with Alzheimer's disease. Alzheimer's disease occurs particularly in older people over the age of 65, whereby the corresponding precursors or preclinical or clinical preliminary stages can also occur significantly earlier.
Die Prävalenz neurodegenerativer Erkrankungen und insbesondere der Alzheimer-Krankheit ist starkzunehmend und ihre Verbreitung steigt weltweit stetig an, wodurch die öffentlichen Gesundheitssysteme in Zukunft schweren Belastungen ausgesetzt sein werden. Die Alzheimer-Krankheit ist hierbei die am weitesten verbreitete Demenzerkrankung. Die Alzheimer-Krankheit geht im zeitlichen Verlauf der Erkrankung mit einer zunehmenden Verschlechterung der kognitiven Leistungsfähigkeit und die in der Regel mit einer Abnahme der täglichen Aktivitäten, Verhaltensauffälligkeiten und neuropsychologischen Symptomen einher. The prevalence of neurodegenerative diseases, and Alzheimer's disease in particular, is growing rapidly and its prevalence is increasing worldwide, which will place severe strains on public health systems in the future. Alzheimer's disease is the most widespread dementia. Alzheimer's disease is associated with an increasing deterioration in cognitive performance over time, which is usually associated with a decrease in daily activities, behavioral disorders and neuropsychological symptoms.
Charakteristisch für die Alzheimer-Krankheit sind die sich im Gehirn des Betroffenen bildenden Plaques, welche maßgeblich fehlerhaft gefaltete Amyloid-ß-Peptide aufweisen, sowie die sich in den Neuronen anlagernden Neurofibrillen. Die intrazellulär gelegenen Neurofibrillenbündel bestehen im Wesentlichen aus dem Tau-Protein, welches dann zu Fibrillen aggregiert, wenn es übermäßig phosphoryliert ist. Die Amyloid-ß-Peptide, welche synonym auch als Aß-Proteine bezeichnet werden, entstehen aus dem so genannten Amyloid-Precursor-Protein (APP). APP ist ein Typ I-Transmembranprotein, das von bestimmten Proteinasen gespalten wird. Durch die Spaltung von APP kommt es zur Freisetzung der Aß-Peptide aus dem Vorläuferprotein. Aß-Peptide haben im Allgemeinen eine Länge von 37 bis 42 Aminosäuren und werden mit der pathologischen Ausbildung der Alzheimer-Krankheit in Zusammenhang gebracht. Characteristic of Alzheimer's disease are the plaques that form in the brain of the person affected, which have largely incorrectly folded amyloid-ß-peptides, as well as the neurofibrils that accumulate in the neurons. The intracellular bundles of neurofibrils essentially consist of the tau protein, which aggregates into fibrils when it is excessively phosphorylated. The amyloid-ß-peptides, which are also referred to synonymously as Aß-proteins, arise from the so-called amyloid precursor protein (APP). APP is a type I transmembrane protein that is cleaved by certain proteinases. The split from APP results in Release of the Aß peptides from the precursor protein. Aβ peptides are generally 37 to 42 amino acids in length and are associated with the pathological development of Alzheimer's disease.
Ablagerungen von Proteinen wie dem Amyloid-Protein oder dem Tau-Protein spielen auch bei anderen Erkrankungen eine entscheidende Rolle. Durch die Proteinablagerungen (Amyloide) kommt es zu Schädigungen von Zellen und Geweben, wobei sich das Krankheitsbild je nach Ort und Art der Ablagerung definiert. Deposits of proteins such as the amyloid protein or the tau protein also play a decisive role in other diseases. The protein deposits (amyloids) damage cells and tissues, whereby the clinical picture is defined depending on the location and type of deposit.
Der vorliegenden Erfindung liegt die Aufgabe zugrunde, eine verbesserte Prävention oder Behandlung dieser Amyloidosen, insbesondere der Alzheimer Krankheit, bereitzustellen. The present invention is based on the object of providing an improved prevention or treatment of these amyloidoses, in particular Alzheimer's disease.
Zusammenfassung der Erfindung Summary of the invention
Die Erfindung basiert auf der Erkenntnis, dass die therapeutische Wirkung verschiedener Wirkstoffe bei der Behandlung von Amyolidosen wie der Alzheimer Krankheit durch die Kombination mit probiotischen Bakterien verstärkt werden kann. Synergistische Effekte dieser Kombinationstherapien wurden in einem Tiermodell gezeigt. Zudem zeigen auch die probiotischen Bakterien alleine therapeutische Aktivität. The invention is based on the knowledge that the therapeutic effect of various active ingredients in the treatment of amyolidoses such as Alzheimer's disease can be enhanced by combining them with probiotic bacteria. Synergistic effects of these combination therapies were shown in an animal model. In addition, the probiotic bacteria on their own also show therapeutic activity.
Ausgehend von dieser Erkenntnis stellt die vorliegende Erfindung in einem ersten Aspekt die Verwendung eines probiotischen Bakteriums zur Herstellung eines Medikaments zur Behandlung oder Prävention einer Amyloidose. On the basis of this finding, the present invention provides, in a first aspect, the use of a probiotic bacterium for the production of a medicament for the treatment or prevention of amyloidosis.
In einem zweiten Aspekt betrifft die vorliegende Erfindung die Verwendung eines Gemisches aus einem probiotischen Bakterium und einem Wirkstoff, der bei der Behandlung oder Prävention einer Amyloidose therapeutisch wirksam ist, zur Herstellung eines Medikaments zur Behandlung oder Prävention einer Amyloidose. In a second aspect, the present invention relates to the use of a mixture of a probiotic bacterium and an active ingredient which is therapeutically effective in the treatment or prevention of amyloidosis for the manufacture of a medicament for the treatment or prevention of amyloidosis.
In bevorzugten Ausführungsformen ist der Wirkstoff ein Cannabinoid, ein Curcuminoid oder ein Gemisch hiervon. In preferred embodiments, the active ingredient is a cannabinoid, a curcuminoid or a mixture thereof.
Weitere Zwecke, Merkmale, Vorteile und Aspekte der vorliegenden Anmeldung werden dem Fachmann aus der folgenden Beschreibung und den beigefügten Ansprüchen ersichtlich. Verschiedene Änderungen und Modifikationen im Sinne und Umfang der offenbarten Erfindung werden für den Fachmann aus der folgenden Darstellung ersichtlich werden. Further purposes, features, advantages and aspects of the present application will become apparent to those skilled in the art from the following description and the appended claims. Various changes and modifications within the spirit and scope of the disclosed invention will become apparent to those skilled in the art from the following illustration.
Genaue Beschreibung der Erfindung Detailed description of the invention
Verschiedene Bakterienarten wie insbesondere probiotische Bakterien zeigten in einem Tiermodel positive Effekte bei der Behandlung und Prävention von Amyloidosen. Mit der zusätzlichen Gabe von anderen Wirkstoffen zur Behandlung von Amyloidosen, insbesondere Cannabinoid-Verbindungen wie Cannabidiol (CBD) und Delta-9-Tetrahydrocannabinolsäure (THCA) sowie Curcuminoid-Verbindungen wie Curcumin konnten diese Effekte überraschenderweise deutlich erhöht werden. Probiotischen Bakterien alleine oder in Kombination mit einem Cannabinoid und/oder einem Curcuminoid können somit bei der Behandlung oder Prävention von Amyloidosen wie der Alzheimer Krankheit eingesetzt werden, wobei eine deutlich verbesserte therapeutische Wirkung durch die beschriebene Kombination erhalten wird. Various types of bacteria, especially probiotic bacteria, showed positive effects in the treatment and prevention of amyloidoses in an animal model. With the additional administration of other active ingredients for the treatment of amyloidoses, in particular cannabinoid compounds such as cannabidiol (CBD) and delta-9-tetrahydrocannabinolic acid (THCA) as well as curcuminoid compounds such as curcumin, these effects could surprisingly be significantly increased. Probiotic bacteria alone or in combination with a cannabinoid and / or a curcuminoid can thus be used in the treatment or prevention of amyloidoses such as Alzheimer's disease , with a significantly improved therapeutic effect being obtained by the combination described.
Vor diesem Hintergrund stellt die vorliegende Erfindung in einem ersten Aspekt die Verwendung eines probiotischen Bakteriums zur Herstellung eines Medikaments zur Behandlung oder Prävention einer Amyloidose bereit. Against this background, the present invention provides, in a first aspect, the use of a probiotic bacterium for the manufacture of a medicament for the treatment or prevention of amyloidosis.
Das probiotische Bakterium kann jegliches probiotisches Bakterium sowie Gemische verschiedener probiotischer Bakterien sein. Ein "Bakterium" im Sinne der vorliegenden Erfindung bezieht sich im Allgemeinen auf eine Vielzahl an Bakterienzellen und nicht auf eine einzelne Bakterienzelle. In bestimmten Ausführungsformen bezieht sich der Ausdruck "Bakterium" auf eine Vielzahl an Bakterienzellen derselben Gattung, derselben Art oder desselben Stamms. Probiotische Bakterien sind insbesondere lebende Bakterien, die einen Nutzen für die Gesundheit bewirken, wenn sie in adäquaten Mengen verabreicht werden.The probiotic bacterium can be any probiotic bacterium as well as mixtures of different probiotic bacteria. A “bacterium” in the context of the present invention generally relates to a large number of bacterial cells and not to a single bacterial cell. In certain embodiments, the term "bacterium" refers to a plurality of bacterial cells of the same genus, species, or strain. Probiotic bacteria, in particular, are live bacteria that provide health benefits when given in adequate quantities.
In besonderen Ausführungsformen ist das probiotische Bakterium ausgewählt ist aus der Gruppe bestehend aus Bakterien der Gattung Lactobacillus, Bakterien der Gattung Streptococcus, Bakterien der Gattung Bifidobacterium, Bakterien der Gattung Enterococcus, Bakterien der Gattung Pseudomonas, und Gemischen von Bakterien enthaltend Bakterien einer oder mehrerer dieser Gattungen. Das probiotische Bakterium kann zum Beispiel ausgewählt sein aus der Gruppe bestehend aus Bakterien der Gattung Lactobacillus, Bakterien der Gattung Streptococcus, Bakterien der Gattung Bifidobacterium und Bakterien der Gattung Enterococcus. In speziellen Ausführungsformen ist das probiotische Bakterium ein Milchsäurebakterium. Insbesondere kann das probiotische Bakterium ein Bakterium der Gattung Lactobacillus oder ein Bakteriengemisch enthaltend ein Bakterium der Gattung Lactobacillus sein. In particular embodiments, the probiotic bacterium is selected from the group consisting of bacteria of the genus Lactobacillus, bacteria of the genus Streptococcus, bacteria of the genus Bifidobacterium, bacteria of the genus Enterococcus, bacteria of the genus Pseudomonas, and mixtures of bacteria containing bacteria of one or more of these genera . The probiotic bacterium can be selected, for example, from the group consisting of bacteria of the genus Lactobacillus, bacteria of the genus Streptococcus, bacteria of the genus Bifidobacterium and bacteria of the genus Enterococcus. In specific embodiments, the probiotic bacterium is a lactic acid bacterium. In particular, the probiotic bacterium can be a bacterium of the genus Lactobacillus or a bacterial mixture containing a bacterium of the genus Lactobacillus.
In bestimmten Ausführungsformen ist das probiotische Bakterium ausgewählt aus der Gruppe bestehend aus Enterococcus faecium, Bifidobacterium longum, Streptococcus thermophilus, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus rhamnosus, Bifidobacterium breve, Pseudomonas fluorescens, und Gemischen von Bakterien enthaltend Bakterien einer oder mehrerer dieser Arten. Das probiotische Bakterium kann zum Beispiel ausgewählt sein aus der Gruppe bestehend aus Bakterien der Art Enterococcus faecium, Bifidobacterium longum, Streptococcus thermophilus, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus rhamnosus und Bifidobacterium breve. In besonderen Ausführungsformen ist das probiotische Bakterium ein Bakterium der Art Lactobacillus plantarum oder Lactobacillus rhamnosus oder ein Bakteriengemisch enthaltend ein Bakterium der Art Lactobacillus plantarum und/oder Lactobacillus rhamnosus. In anderen Ausführungsformen ist das probiotische Bakterium ein Bakterium der Art Pseudomonas fluorescens. In certain embodiments, the probiotic bacterium is selected from the group consisting of Enterococcus faecium, Bifidobacterium longum, Streptococcus thermophilus, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus rhamnosus, Bifidobacterium breve, Pseudomonas fluorescens containing bacteria of one or more of these species, and mixtures of these bacteria. The probiotic bacterium can be selected, for example, from the group consisting of bacteria of the species Enterococcus faecium, Bifidobacterium longum, Streptococcus thermophilus, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus rhamnosus and Bifidobacterium breve. In particular embodiments, the probiotic bacterium is a bacterium of the species Lactobacillus plantarum or Lactobacillus rhamnosus or a bacterial mixture containing a bacterium of the species Lactobacillus plantarum and / or Lactobacillus rhamnosus. In other embodiments the probiotic bacterium is a bacterium of the species Pseudomonas fluorescens.
In bestimmten Ausführungsformen wird das probiotische Bakterium in Kombination mit einem Wirkstoff, der bei der Behandlung oder Prävention einer Amyloidose therapeutisch wirksam ist, verabreicht. In diesen Ausführungsformen können das probiotische Bakterium und der Wirkstoff gemeinsam in einem Gemisch vorliegen und an den Patienten verabreicht werden. Alternative können das probiotische Bakterium und der Wirkstoff jeweils in einer separaten Zusammensetzung vorliegen und an den Patienten verabreicht werden. Es können auch mehrere verschiedene probiotische Bakterien und/oder mehrere verschiedene Wirkstoffe verabreicht werden, wobei diese gemeinsam in einer Zusammensetzung oder getrennt voneinander in mehreren separaten Zusammensetzungen verabreicht werden können. Die Verabreichung mehrerer Zusammensetzungen kann gleichzeitig oder aufeinanderfolgend erfolgen. Eine aufeinanderfolgende Verabreichung erfolgt insbesondere am selben Tag, vorzugweise innerhalb eines Zeitraums von 4 Stunden, 2 Stunden oder besonders bevorzugt einer Stunde. In certain embodiments, the probiotic bacterium is administered in combination with an agent that is therapeutically effective in treating or preventing amyloidosis. In these embodiments, the probiotic bacterium and the active ingredient can be present together in a mixture and administered to the patient will. Alternatively, the probiotic bacterium and the active ingredient can each be in a separate composition and administered to the patient. Several different probiotic bacteria and / or several different active ingredients can also be administered, it being possible for these to be administered together in one composition or separately from one another in several separate compositions. Multiple compositions can be administered simultaneously or sequentially. Successive administration takes place in particular on the same day, preferably within a period of 4 hours, 2 hours or particularly preferably one hour.
In einem zweiten Aspekt betrifft die vorliegende Erfindung zudem die Verwendung eines Gemisches aus einem probiotischen Bakterium und einem Wirkstoff, der bei der Behandlung oder Prävention einer Amyloidose therapeutisch wirksam ist, zur Herstellung eines Medikaments zur Behandlung oder Prävention einer Amyloidose. In a second aspect, the present invention also relates to the use of a mixture of a probiotic bacterium and an active ingredient which is therapeutically effective in the treatment or prevention of amyloidosis for the production of a medicament for the treatment or prevention of amyloidosis.
Der Wirkstoff, der bei der Behandlung oder Prävention einer Amyloidose therapeutisch wirksam ist, kann jeglicher therapeutisch wirksame Wirkstoff sein, insbesondere ein Wirkstoff, der zur Behandlung und/oder Prävention der Alzheimer Krankheit eingesetzt werden kann. In besonderen Ausführungsformen ist der Wirkstoff ein pflanzlicher Wirkstoff oder ein aus Pflanzen erhältlicher Wirkstoff. Der Wirkstoff kann insbesondere auch ein Gemisch verschiedener Substanzen sein. In bestimmten Ausführungsformen ist der Wirkstoff ein Cannabinoid, ein Curcuminoid oder ein Gemisch hieraus. The active ingredient which is therapeutically active in the treatment or prevention of amyloidosis can be any therapeutically active active ingredient, in particular an active ingredient which can be used for the treatment and / or prevention of Alzheimer's disease. In particular embodiments, the active ingredient is a herbal active ingredient or an active ingredient obtainable from plants. The active ingredient can in particular also be a mixture of different substances. In certain embodiments, the active ingredient is a cannabinoid, a curcuminoid or a mixture thereof.
Eine therapeutische Zusammensetzung ist insbesondere eine Zusammensetzung, die geeignet ist, einem Menschen oder Tier verabreicht zu werden. Eine therapeutische Zusammensetzung besteht insbesondere aus pharmazeutisch verträglichen Stoffen. Vorzugsweise enthält eine pharmazeutische Zusammensetzung ein probiotisches Bakterium und/oder einen Wirkstoff, insbesondere ein Cannabinoid und/oder ein Curcuminoid, und einen Trägerstoff, ein Lösungsmittel, und/oder weitere Zusatzstoffe wie Puffer und Konservierungsmittel. In besonderen Ausführungsformen enthält die therapeutische Zusammensetzung neben den angegeben Stoffen probiotisches Bakterium, Cannabinoid und/oder Curcuminoid ausschließlich Wasser. A therapeutic composition is in particular a composition which is suitable for being administered to a human or animal. A therapeutic composition consists in particular of pharmaceutically acceptable substances. A pharmaceutical composition preferably contains a probiotic bacterium and / or an active ingredient, in particular a cannabinoid and / or a curcuminoid, and a carrier, a solvent and / or other additives such as buffers and preservatives. In particular embodiments, the therapeutic composition contains, in addition to the specified substances, probiotic bacterium, cannabinoid and / or curcuminoid, exclusively water.
Im Sinne der vorliegenden Erfindung umfassen Curcuminoide insbesondere Curcumin, Demethoxycurcumin und Bisdemethoxycurcumin, sowie Gemische hiervon. In einer besonderen Ausführungsform ist das Curcuminoid Curcumin oder ein Gemisch enthaltend Curcumin. In einer speziellen Ausführungsform ist das Curcuminoid ein Gemisch enthaltend Curcumin, gegebenenfalls Demethoxycurcumin und gegebenenfalls Bisdemethoxycurcumin. Zum Beispiel kann das Curcuminoid ein Gemisch enthaltend mindestens 60%, insbesondere mindestens 70% Curcumin, höchstens 30%, insbesondere höchstens 20% Demethoxycurcumin und höchstens 10%, insbesondere höchstens 5% Bisdemethoxycurcumin sein. Curcumin ist auch als Diferuloylmethan oder (E, E)-1 ,7-bis (4- hydroxy-3-methoxyphenyl)-1,6-heptadien-3,5,-dion bekannt. Das Curcuminoid, insbesondere Curcumin, kann aus einer natürlichen Quelle wie z.B. aus dem Rhizom der Pflanze Kurkuma (Curcuma longa) oder synthetisch erhalten werden. Im Sinne der vorliegenden Erfindung umfassen Cannabinoide insbesondere Cannabidiol (CBD), Delta- 9-Tetrahydrocannabinol (THC), Cannabichromen, Cannabielsoin, Delta-8- Tetrahydrocannabinol, Iso-Tetrahydrocannabinol, Cannabicyclol, Cannabicitran, und Säuren dieser Verbindungen wie Cannabidiolsäure (CBDA) und Delta-9-Tetrahydrocannabinolsäure (THCA), sowie Gemische hiervon. In einer besonderen Ausführungsform ist das Cannabinoid CBD oder ein Gemisch enthaltend CBD. In einer weiteren Ausführungsform ist das Cannabinoid THCA oder ein Gemisch enthaltend THCA. In einer weiteren Ausführungsform ist das Cannabinoid THC oder ein Gemisch enthaltend THC. Das Cannabinoid, insbesondere CBD, THC und/oder THCA, kann aus einer natürlichen Quelle wie z.B. der Hanfpflanze oder synthetisch erhalten werden. For the purposes of the present invention, curcuminoids include in particular curcumin, demethoxycurcumin and bisdemethoxycurcumin, as well as mixtures thereof. In a particular embodiment, the curcuminoid is curcumin or a mixture containing curcumin. In a special embodiment, the curcuminoid is a mixture containing curcumin, optionally demethoxycurcumin and optionally bisdemethoxycurcumin. For example, the curcuminoid can be a mixture containing at least 60%, in particular at least 70% curcumin, at most 30%, in particular at most 20% demethoxycurcumin and at most 10%, in particular at most 5% bisdemethoxycurcumin. Curcumin is also known as diferuloylmethane or (E, E) -1, 7-bis (4-hydroxy-3-methoxyphenyl) -1,6-heptadiene-3,5, -dione. The curcuminoid, in particular curcumin, can be obtained from a natural source such as, for example, from the rhizome of the turmeric plant (Curcuma longa) or synthetically. For the purposes of the present invention, cannabinoids include in particular cannabidiol (CBD), delta-9-tetrahydrocannabinol (THC), cannabichromene, cannabielsoin, delta-8-tetrahydrocannabinol, iso-tetrahydrocannabinol, cannabicyclol, cannabicitran, and acids of these compounds such as cannabidiolic acid (CBDA) and Delta-9-tetrahydrocannabinolic acid (THCA) and mixtures thereof. In a particular embodiment, the cannabinoid is CBD or a mixture containing CBD. In a further embodiment, the cannabinoid is THCA or a mixture containing THCA. In a further embodiment, the cannabinoid is THC or a mixture containing THC. The cannabinoid, especially CBD, THC and / or THCA, can be obtained from a natural source such as the hemp plant or synthetically.
In bestimmten Ausführungsformen werden das probiotische Bakterium und der Wirkstoff bzw. entsprechende Gemische in Form einer therapeutischen Zusammensetzung verwendet. In bestimmten Ausführungsformen liegen das probiotische Bakterium und der Wirkstoff gemeinsam in einer therapeutischen Zusammensetzung vor. In certain embodiments, the probiotic bacterium and the active ingredient or corresponding mixtures are used in the form of a therapeutic composition. In certain embodiments, the probiotic bacterium and the active ingredient are present together in a therapeutic composition.
Die Verabreichung an den Patienten kann über jeden geeigneten Verabreichungsweg erfolgen. In besonderen Ausführungsformen werden die Stoffe oder Stoffgemische, insbesondere die therapeutischen Zusammensetzungen, oral verabreicht. Die Behandlung oder Prävention erfolgt insbesondere über regelmäßige Verabreichung über einen längeren Zeitraum, vorzugsweise fortlaufend. In einer Ausführungsform werden die Stoffe in einer therapeutisch wirksamen Menge verabreicht. Administration to the patient can be by any suitable route of administration. In particular embodiments, the substances or mixtures of substances, in particular the therapeutic compositions, are administered orally. The treatment or prevention takes place in particular via regular administration over a longer period of time, preferably continuously. In one embodiment, the substances are administered in a therapeutically effective amount.
Eine Amyloidose ist eine Erkrankung mit Anreicherung von Proteinen. Die angereicherten Proteine bilden hierbei unlösliche Ablagerungen (Amyloid) wie zum Beispiel Fibrillen. In besonderen Ausführungsformen ist die Amyloidose eine Tauopathie. Bei Tauopathien lagert sich das Tau-Protein in Nerven- und Gliazellen ab. Die Gruppe der Tauopathien umfasst insbesondere Alzheimer Krankheit, Chronisch traumatische Enzephalopathie (CTE), Parkinson Krankheit, kortikobasale Degeneration und frontotem porale Demenz. In einer bevorzugten Ausführungsform ist die Amyloidose Alzheimer Krankheit. Bei der Alzheimer Krankheit bilden sich im Gehirn des Betroffenen Plaques, die aus fehlerhaft gefalteten Beta- Amyloid-(Aß-) Peptiden bestehen, und fehlerhafte Tau-Proteine lagern sich aus dem Zellkörper heraus an die Axone an. Amyloidosis is a condition in which proteins accumulate. The enriched proteins form insoluble deposits (amyloid) such as fibrils. In particular embodiments, the amyloidosis is a tauopathy. In tauopathies, the tau protein is deposited in nerve and glial cells. The group of tauopathies includes in particular Alzheimer's disease, chronic traumatic encephalopathy (CTE), Parkinson's disease, corticobasal degeneration and frontotem poral dementia. In a preferred embodiment, the amyloidosis is Alzheimer's disease. In Alzheimer's disease, plaques made up of incorrectly folded beta-amyloid (Aß) peptides form in the brain of the person affected, and defective tau proteins attach themselves to the axons from the cell body.
Die Behandlung erfolgt bei einem Patienten, der diese benötigt. Dies sind insbesondere Patienten, die unter einer Amyloidose wie der Alzheimer Krankheit leiden. Die Behandlung kann bei beginnender Erkrankung sowie bei fortgeschrittener Erkrankung erfolgen. Die Prävention kann bei jedem Individuum erfolgen. Insbesondere wird die Prävention bei Individuen höheren Alters angewandt, wie z.B. ab dem 60, 65, 70 oder 75 Lebensjahr. Allerdings können auch Individuen geringeren Alters von der Prävention profitieren, z.B. Individuen im Alter von mindestens 20 Jahren, mindestens 30 Jahren, mindestens 40 Jahren oder mindestens 50 Jahren. Bei Individuen mit beginnender bzw. noch nicht diagnostizierter Amyloidose können Prävention und Behandlung ineinander übergehen. Die Patienten und Individuen sind insbesondere Menschen. In bestimmten Ausführungsformen werden das probiotische Bakterium und optional der Wirkstoff in einer oder mehreren pharmazeutischen Zusammensetzungen verabreicht, die neben diesen Stoffen im Wesentlichen nur noch Wasser enthalten. In speziellen Ausführungsformen enthalten die pharmazeutischen Zusammensetzungen neben diesen Stoffen ausschließlich Wasser. In bestimmten Ausführungsformen enthalten die pharmazeutischen Zusammensetzungen diese Stoffe in hoher Konzentration. Zum Beispiel liegt die Konzentration des Curcuminoids, insbesondere des Curcumins, bei mindestens 1 g/l, z.B. bei mindestens 2 g/l, mindestens 3 g/l, mindestens 5 g/l, mindestens 10 g/l, mindestens 15 g/l oder bei etwa 20 g/l. Die Konzentration des Cannabinoids, insbesondere von CBD oder THCA, kann zum Beispiel bei mindestens 0,5 mg/l, vorzugsweise mindestens 1 mg/l, mindestens 10 mg/l, mindestens 100 mg/l, mindestens 250 mg/l oder mindestens 1 g/l liegen. Treatment is given to a patient who needs it. These are especially patients with amyloidosis such as Alzheimer's disease. The treatment can take place in the beginning of the disease as well as in advanced disease. Prevention can be done on any individual. In particular, the prevention is applied to individuals of older age, such as from the age of 60, 65, 70 or 75 years of age. However, individuals of younger age can also benefit from the prevention, e.g. individuals aged at least 20 years, at least 30 years, at least 40 years or at least 50 years. In individuals with incipient or undiagnosed amyloidosis, prevention and treatment can merge. The patients and individuals are especially people. In certain embodiments, the probiotic bacterium and optionally the active ingredient are administered in one or more pharmaceutical compositions which, in addition to these substances, essentially only contain water. In special embodiments, the pharmaceutical compositions contain exclusively water in addition to these substances. In certain embodiments, the pharmaceutical compositions contain these substances in high concentration. For example, the concentration of curcuminoid, especially curcumin, is at least 1 g / l, for example at least 2 g / l, at least 3 g / l, at least 5 g / l, at least 10 g / l, at least 15 g / l or at about 20 g / l. The concentration of the cannabinoid, in particular of CBD or THCA, can, for example, be at least 0.5 mg / l, preferably at least 1 mg / l, at least 10 mg / l, at least 100 mg / l, at least 250 mg / l or at least 1 g / l.
Der Ausdruck "enthaltend" oder verwandte Ausdrücke, soweit hierin verwendet, bedeutet neben seiner normalen Bedeutung auch "im Wesentlichen bestehend aus" und "bestehend aus". Somit bezieht sich der Ausdruck "enthaltend" auch auf Ausführungsformen, in denen der Gegenstand, der bestimmte aufgeführte Elemente "enthält", keine weiteren Elemente enthält, sowie auf Ausführungsformen, in denen der Gegenstand, der bestimmte aufgeführte Elemente "enthält", zusätzlich weiteren Elemente enthält. Der Ausdruck "im Wesentlichen bestehend aus" betrifft insbesondere Ausführungsformen, in denen der Gegenstand 10% oder weniger, insbesondere 5% oder weniger weitere Elemente zusätzlich zu den speziell aufgelisteten Elementen enthält, aus denen der Gegenstand im Wesentlichen besteht. The term “containing” or related expressions as used herein also means “consisting essentially of” and “consisting of” in addition to their normal meaning. Thus, the term “containing” also relates to embodiments in which the object that “contains” certain listed elements does not contain any further elements, as well as to embodiments in which the object that “contains” certain listed elements additionally contains further elements contains. The expression "consisting essentially of" relates in particular to embodiments in which the object contains 10% or less, in particular 5% or less, further elements in addition to the specifically listed elements of which the object essentially consists.
Abbildungen Illustrations
Abbildung 1 zeigt die Ergebnisse eines Alzheimer-Krankheit Paralyseassays. Ein C. elegans Nematodenstamm mit induzierbarer Amyloid-ß Akkumulation (CL4176) wurde einem Gemisch verschiedener probiotischer Bakterien alleine oder in Kombination mit ausgesetzt. Der prozentuale Anteil an Nematoden, die 72 h nach Induktion der Aß Akkumulation noch nicht bewegungsunfähig geworden sind, ist angegeben. Unbehandelte Nematoden dienten als Kontrolle. Figure 1 shows the results of an Alzheimer's disease paralysis assay. A C. elegans nematode strain with inducible amyloid-ß accumulation (CL4176) was exposed to a mixture of different probiotic bacteria alone or in combination with. The percentage of nematodes which have not become immobile 72 hours after induction of Aβ accumulation is given. Untreated nematodes served as controls.
Abbildung 2 zeigt die Ergebnisse eines Alzheimer-Krankheit Paralyseassays. Ein C. elegans Nematodenstamm mit induzierbarer Amyloid-ß Akkumulation (CL4176) wurde einem Gemisch verschiedener probiotischer Bakterien in unterschiedlichen Konzentrationen ausgesetzt. Der prozentuale Anteil an Nematoden, die 96 h nach Induktion der Aß Akkumulation noch nicht bewegungsunfähig geworden sind, ist angegeben. Figure 2 shows the results of an Alzheimer's disease paralysis assay. A C. elegans nematode strain with inducible amyloid-ß accumulation (CL4176) was exposed to a mixture of different probiotic bacteria in different concentrations. The percentage of nematodes which have not become immobile 96 hours after induction of Aβ accumulation is given.
Abbildung 3 zeigt die Ergebnisse eines Alzheimer-Krankheit Paralyseassays. Ein C. elegans Nematodenstamm mit induzierbarer Amyloid-ß Akkumulation (CL4176) wurde verschiedenen Wirkstoffen, die die Auswirkungen der Aß Akkumulation verringern, ohne oder zusammen mit dem probiotischen Bakterium Lactobacillus rhamnosus ausgesetzt. Der prozentuale Anteil an Nematoden, die 96 h nach Induktion der Aß Akkumulation noch nicht bewegungsunfähig geworden sind, ist angegeben. Unbehandelte (MQ) bzw. mit Ethanol behandelte Nematoden dienten als Kontrolle. Abbildung 4 zeigt die Ergebnisse eines Alzheimer-Krankheit Paralyseassays. Ein C. elegans Nematodenstamm mit induzierbarer Amyloid-ß Akkumulation (CL4176) wurde verschiedenen Wirkstoffen, die die Auswirkungen der Aß Akkumulation verringern, ohne oder zusammen mit dem probiotischen Bakterium Lactobacillus plantarum ausgesetzt. Der prozentuale Anteil an Nematoden, die 96 h nach Induktion der Aß Akkumulation noch nicht bewegungsunfähig geworden sind, ist angegeben. Nur mit dem Lösungsmittel (Wasser) behandelte Nematoden dienten als Kontrolle. Figure 3 shows the results of an Alzheimer's disease paralysis assay. A C. elegans nematode strain with inducible amyloid-ß accumulation (CL4176) was exposed to various drugs that reduce the effects of Aß accumulation without or together with the probiotic bacterium Lactobacillus rhamnosus. The percentage of nematodes which have not become immobile 96 hours after induction of Aβ accumulation is given. Untreated (MQ) or ethanol-treated nematodes served as controls. Figure 4 shows the results of an Alzheimer's disease paralysis assay. A C. elegans nematode strain with inducible amyloid-ß accumulation (CL4176) was exposed to various drugs that reduce the effects of Aß accumulation without or together with the probiotic bacterium Lactobacillus plantarum. The percentage of nematodes which have not become immobile 96 hours after induction of Aβ accumulation is given. Nematodes treated with the solvent (water) only served as controls.
Abbildung 5 zeigt die Ergebnisse eines Alzheimer-Krankheit Paralyseassays. Ein C. elegans Nematodenstamm mit induzierbarer Amyloid-ß Akkumulation (CL4176) wurde verschiedenen Wirkstoffen, die die Auswirkungen der Aß Akkumulation verringern, ohne oder zusammen mit dem probiotischen Bakterium Lactobacillus rhamnosus ausgesetzt. Der prozentuale Anteil an Nematoden, die 96 h nach Induktion der Aß Akkumulation noch nicht bewegungsunfähig geworden sind, ist angegeben. Nur mit dem Lösungsmittel (Wasser) behandelte Nematoden dienten als Kontrolle. Figure 5 shows the results of an Alzheimer's disease paralysis assay. A C. elegans nematode strain with inducible amyloid-ß accumulation (CL4176) was exposed to various drugs that reduce the effects of Aß accumulation without or together with the probiotic bacterium Lactobacillus rhamnosus. The percentage of nematodes which have not become immobile 96 hours after induction of Aβ accumulation is given. Nematodes treated with the solvent (water) only served as controls.
Abbildung 6 zeigt die Ergebnisse eines Alzheimer-Krankheit Paralyseassays. Ein C. elegans Nematodenstamm mit induzierbarer Amyloid-ß Akkumulation (CL4176) wurde verschiedenen Wirkstoffen, die die Auswirkungen der Aß Akkumulation verringern, ohne oder zusammen mit dem probiotischen Bakterium Lactobacillus plantarum ausgesetzt. Der prozentuale Anteil an Nematoden, die 96 h nach Induktion der Aß Akkumulation noch nicht bewegungsunfähig geworden sind, ist angegeben. Nur mit dem Lösungsmittel (Wasser) behandelte Nematoden dienten als Kontrolle. Figure 6 shows the results of an Alzheimer's disease paralysis assay. A C. elegans nematode strain with inducible amyloid-ß accumulation (CL4176) was exposed to various drugs that reduce the effects of Aß accumulation without or together with the probiotic bacterium Lactobacillus plantarum. The percentage of nematodes which have not become immobile 96 hours after induction of Aβ accumulation is given. Nematodes treated with the solvent (water) only served as controls.
Abbildung 7 zeigt die Ergebnisse eines Alzheimer-Krankheit Paralyseassays. Ein C. elegans Nematodenstamm mit induzierbarer Amyloid-ß Akkumulation (CL4176) wurde Curcumin, dem probiotischen Bakterium Pseudomonas fluorescens oder einer Kombination davon ausgesetzt. Der prozentuale Anteil an Nematoden, die 96 h nach Induktion der Aß Akkumulation noch nicht bewegungsunfähig geworden sind, ist angegeben. Nur mit dem Lösungsmittel (Wasser) behandelte Nematoden dienten als Kontrolle. Figure 7 shows the results of an Alzheimer's disease paralysis assay. A C. elegans nematode strain with inducible amyloid-ß accumulation (CL4176) was exposed to curcumin, the probiotic bacterium Pseudomonas fluorescens, or a combination thereof. The percentage of nematodes which have not become immobile 96 hours after induction of Aβ accumulation is given. Nematodes treated with the solvent (water) only served as controls.
Abbildung 8 zeigt die Ergebnisse eines Alzheimer-Krankheit Paralyseassays. Ein C. elegans Nematodenstamm mit induzierbarer Amyloid-ß Akkumulation (CL4176) wurde CBD, dem probiotischen Bakterium Pseudomonas fluorescens oder einer Kombination davon ausgesetzt. Der prozentuale Anteil an Nematoden, die 96 h nach Induktion der Aß Akkumulation noch nicht bewegungsunfähig geworden sind, ist angegeben. Nur mit dem Lösungsmittel (Wasser) behandelte Nematoden dienten als Kontrolle. Figure 8 shows the results of an Alzheimer's disease paralysis assay. A C. elegans nematode strain with inducible amyloid-ß accumulation (CL4176) was exposed to CBD, the probiotic bacterium Pseudomonas fluorescens, or a combination thereof. The percentage of nematodes which have not become immobile 96 hours after induction of Aβ accumulation is given. Nematodes treated with the solvent (water) only served as controls.
Beispiele Examples
Beispiel 1 - Therapeutische Wirkung probiotischer Bakterien Example 1 - Therapeutic Effect of Probiotic Bacteria
Die Wirkung von probiotischen Bakterien und deren Kombinationen mit weiteren Wirkstoffen wurde an C. elegans Nematodenstämmen als Tiermodell für Amyloidosen wie der Alzheimer Krankheit untersucht. Diese Stämme akkumulieren Amyloid-ß Peptide, die in den Nematoden Plaques ausbilden und zur Paralyse der Tiere führen. In bestimmten Stämmen wie dem Stamm CL4176 erfolgt die Aß Akkumulation erst als Reaktion auf einen Hitzeschock. Das Alzheimer Krankheitsbild ist somit bei diesen Stämmen induzierbar. Die Anzahl an paralysierten Nematoden nach einer bestimmten Zeitspanne nach Induktion der Aß Akkumulation zeigt das Ausmaß der Alzheimer Krankheit an. Die Auswirkung bestimmter Stoffe, denen die Nematoden ausgesetzt werden, auf die Anzahl der paralysierten Tiere ist somit ein Maß für die Anti-Alzheimer Wirkung dieser Stoffe. The effect of probiotic bacteria and their combinations with other active ingredients was investigated on C. elegans nematode strains as an animal model for amyloidoses such as Alzheimer's disease. These strains accumulate amyloid-ß peptides, which form plaques in the nematodes and lead to paralysis of the animals. In certain tribes like the strain CL4176, Aβ accumulation only occurs in response to heat shock. The Alzheimer's disease is thus inducible in these strains. The number of paralyzed nematodes after a certain period of time after induction of Aβ accumulation indicates the extent of Alzheimer's disease. The effect of certain substances to which the nematodes are exposed on the number of paralyzed animals is therefore a measure of the anti-Alzheimer's effect of these substances.
Nematoden des Stamms CL4176 wurden im jungen Larvenstadium synchronisiert und bis zum L4-Stadium auf normalem Wachstumsmedium für 72 h bei 16°C wachsen gelassen. Die zu testenden probiotischen Bakterien wurden dem Wachstumsmedium beigesetzt. Dann wurden die Nematoden der der Testsubstanz ausgesetzt und die Temperatur wurde auf 25°C erhöht. Dieser Hitzeschock induzierte die Aß Akkumulation und simulierte somit den Ausbruch der Alzheimer Krankheit. Etwa alle 24 h wurde die Anzahl der Tiere ermittelt, die noch mobil waren, und der Tiere, die infolge der Aß Akkumulation paralysiert waren. Nematodes of strain CL4176 were synchronized in the young larval stage and allowed to grow to the L4 stage on normal growth medium for 72 h at 16 ° C. The probiotic bacteria to be tested were added to the growth medium. Then the nematodes were exposed to the test substance and the temperature was increased to 25 ° C. This heat shock induced the Aβ accumulation and thus simulated the onset of Alzheimer's disease. The number of animals that were still mobile and of animals that were paralyzed as a result of the Aβ accumulation was determined approximately every 24 hours.
C. elegans des Stamms CL4176 wurden in diesem Assay einem Gemisch unterschiedlicher probiotischer Bakterien bei einer Bakterienkonzentration von 50 cfu (Kolonie-bildende Einheiten) ausgesetzt. Das Bakteriengemisch enthielt folgende Bakterienarten: Enterococcus faecium, Bifidobacterium longum, Streptococcus thermophilus, Lactobacillus acidophilus, Lactobacillus plantarum und Bifidobacterium breve. Das probiotische Bakteriengemisch zeigte 72 h nach Induktion der Aß Akkumulation einen therapeutischen Effekt in diesem Alzheimer-Assay. In einer weiteren Testreihe wurden die Nematoden zusätzlich noch mit Cannabidiol (CBD) behandelt. CBD erhöhte die Wirkung der probiotischen Bakterien deutlich (siehe Abbildung 1). Die Anti-Alzheimer-Wirkung der probiotischen Bakterien zeigte zudem eine deutliche Konzentrationsabhängigkeit (siehe Abbildung 2). C. elegans of strain CL4176 were exposed to a mixture of different probiotic bacteria at a bacterial concentration of 50 cfu (colony-forming units) in this assay. The bacterial mixture contained the following types of bacteria: Enterococcus faecium, Bifidobacterium longum, Streptococcus thermophilus, Lactobacillus acidophilus, Lactobacillus plantarum and Bifidobacterium breve. The probiotic bacterial mixture showed a therapeutic effect in this Alzheimer's assay 72 h after induction of the Aβ accumulation. In a further series of tests, the nematodes were also treated with cannabidiol (CBD). CBD significantly increased the effectiveness of the probiotic bacteria (see Figure 1). The anti-Alzheimer's effect of the probiotic bacteria also showed a clear concentration dependency (see Figure 2).
Somit schützen probiotische Bakterien gegen die Auswirkungen der Aß Akkumulation und helfen bei der Prävention und Behandlung von Amyloidosen wie der Alzheimer Krankheit.Thus, probiotic bacteria protect against the effects of Aβ accumulation and help in the prevention and treatment of amyloidoses such as Alzheimer's disease.
Beispiel 2 Probiotische Bakterienarten Lactobacillus rhamnosus und Lactobacillus plantarum Example 2 Probiotic bacterial species Lactobacillus rhamnosus and Lactobacillus plantarum
Die beiden probiotischen Bakterienstämme Lactobacillus rhamnosus und Lactobacillus plantarum wurde bis zur stationären Phase wachsen gelassen und mit dem normalen Futter der Nematoden (OP50) E. coli Bakterien) gemischt. C. elegans des Stamms CL4176 im L4- Larvenstadium wurden den probiotischen Bakterien und weiteren Wirkstoffen bei der Induktion der Aß Akkumulation durch eine Temperaturerhöhung auf 25°C ausgesetzt. Die Anzahl an paralysierten Tieren wurde alle 24 h überprüft und nach 96 h bestimmt. The two probiotic bacterial strains Lactobacillus rhamnosus and Lactobacillus plantarum were allowed to grow to the stationary phase and mixed with the normal feed of the nematodes (OP50) E. coli bacteria). C. elegans of the strain CL4176 in the L4 larval stage were exposed to the probiotic bacteria and other active substances during the induction of Aβ accumulation by increasing the temperature to 25 ° C. The number of paralyzed animals was checked every 24 hours and determined after 96 hours.
Sowohl Lactobacillus rhamnosus und Lactobacillus plantarum zeigten eine Verringerung der Paralyse durch die Aß Akkumulation (siehe Abbildungen 3 und 4). Ebenso war die Anzahl an paralysierten Nematoden bei der Behandlung mit Curcumin (0,08% (v/v)), CBD (0,08% (v/v)), THCA (60 mM) oder Kombinationen hiervon verringert. Die Kombination von Lactobacillus rhamnosus bzw. Lactobacillus plantarum mit diesen Wirkstoffen zeigte eine deutliche bis synergistische Verhinderung der Auswirkungen der Aß Akkumulation (siehe Abbildungen 3 und 4). Entsprechende Ergebnisse wurden ebenfalls erzielt, wenn die probiotischen Bakterienstämme in der Wachstumsphase, d.h. in einer deutlich geringeren Konzentration bei einer OD600 von 0,25 eingesetzt wurden (siehe Abbildungen 5 und 6). Both Lactobacillus rhamnosus and Lactobacillus plantarum showed a reduction in paralysis due to the Aβ accumulation (see Figures 3 and 4). The number of paralyzed nematodes was also reduced when treated with curcumin (0.08% (v / v)), CBD (0.08% (v / v)), THCA (60 mM) or combinations thereof. The combination of Lactobacillus rhamnosus or Lactobacillus plantarum with these active ingredients showed a clear to synergistic prevention of the effects of Aβ accumulation (see Figures 3 and 4). Corresponding results were also achieved when the probiotic bacterial strains were used in the growth phase, ie in a significantly lower concentration with an OD600 of 0.25 (see Figures 5 and 6).
Die eingesetzten probiotischen Stämme zeigten somit eine deutliche therapeutische Wirkung gegen Amyloidosen wie der Alzheimer Krankheit, die durch Kombination mit weiteren Wirkstoffen wie Curcumin, CBD und THCA noch synergistisch erhöht werden konnte. The probiotic strains used thus showed a clear therapeutic effect against amyloidoses such as Alzheimer's disease, which could be synergistically increased by combining it with other active ingredients such as curcumin, CBD and THCA.
Beispiel 3 - Probiotische Bakterienart Pseudomonas fluorescens Example 3 - Probiotic Species Pseudomonas fluorescens
In dem beschriebenen Alzheimer-Tiermodell-Assay wurde die Wirkung des Bakterienstamms Pseudomonas fluorescens getestet. Bei Induktion der Aß Akkumulation durch eine Temperaturerhöhung auf 25°C wurden die Nematoden Pseudomonas fluorescens Bakterien, Curcumin bzw. CBD oder einer Kombination aus den Bakterien und dem Wirkstoff ausgesetzt. Die Anzahl an paralysierten Nematoden wurde 96 h nach Induktion der Aß Akkumulation bestimmt. The effect of the bacterial strain Pseudomonas fluorescens was tested in the Alzheimer's animal model assay described. When the Aβ accumulation was induced by increasing the temperature to 25 ° C, the nematodes Pseudomonas fluorescens bacteria, curcumin or CBD or a combination of the bacteria and the active ingredient were exposed. The number of paralyzed nematodes was determined 96 hours after induction of the Aβ accumulation.
Die Pseudomonas fluorescens Bakterien sowie Curcumin und CBD zeigten einzeln eine Verringerung der paralysierten Nematoden. Bei der Kombination aus Pseudomonas fluorescens und Curcumin bzw. CBD war ein starker synergistischer Anstieg der Wirkung zu beobachten (siehe Abbildungen 7 und 8). The Pseudomonas fluorescens bacteria as well as curcumin and CBD individually showed a reduction in paralyzed nematodes. With the combination of Pseudomonas fluorescens and curcumin or CBD, a strong synergistic increase in the effect was observed (see Figures 7 and 8).
Der probiotische Bakterienstamm Pseudomonas fluorescens hatte somit eine therapeutische Wirkung gegen Amyloidosen wie der Alzheimer Krankheit, die bei Kombination mit Wirkstoffen wie Curcumin und CBD synergistisch erhöht werden konnte. The probiotic bacterial strain Pseudomonas fluorescens thus had a therapeutic effect against amyloidoses such as Alzheimer's disease, which could be synergistically increased when combined with active ingredients such as curcumin and CBD.

Claims

Patentansprüche Claims
1. Verwendung eines probiotischen Bakteriums zur Herstellung eines Medikaments zur Behandlung oder Prävention einer Amyloidose. 1. Use of a probiotic bacterium for the manufacture of a medicament for the treatment or prevention of amyloidosis.
2. Verwendung gemäß Anspruch 1, wobei das probiotische Bakterium in Kombination mit einem Wirkstoff, der bei der Behandlung oder Prävention einer Amyloidose therapeutisch wirksam ist, verabreicht wird. 2. Use according to claim 1, wherein the probiotic bacterium is administered in combination with an active substance which is therapeutically effective in the treatment or prevention of amyloidosis.
3. Verwendung gemäß Anspruch 2, wobei der Wirkstoff ausgewählt ist aus der Gruppe bestehend aus Cannabinoiden, Curcuminoiden und Gemischen hiervon. 3. Use according to claim 2, wherein the active ingredient is selected from the group consisting of cannabinoids, curcuminoids and mixtures thereof.
4. Verwendung gemäß Anspruch 3, wobei das Cannabinoid ein Gemisch ist, das Cannabidiol und/oder THCA enthält. 4. Use according to claim 3, wherein the cannabinoid is a mixture containing cannabidiol and / or THCA.
5. Verwendung gemäß Anspruch 3, wobei das Cannabinoid Cannabidiol ist. 5. Use according to claim 3, wherein the cannabinoid is cannabidiol.
6. Verwendung gemäß Anspruch 3, wobei das Cannabinoid THCA ist. 6. Use according to claim 3, wherein the cannabinoid is THCA.
7. Verwendung gemäß einem der Ansprüche 3 bis 6, wobei das Curcuminoid ein Gemisch ist, das Curcumin enthält. 7. Use according to any one of claims 3 to 6, wherein the curcuminoid is a mixture containing curcumin.
8. Verwendung gemäß einem der Ansprüche 3 bis 6, wobei das Curcuminoid Curcumin ist. 8. Use according to any one of claims 3 to 6, wherein the curcuminoid is curcumin.
9. Verwendung gemäß einem der Ansprüche 1 bis 8, wobei das probiotische Bakterium ausgewählt ist aus der Gruppe bestehend aus Bakterien der Gattung Lactobacillus, Bakterien der Gattung Streptococcus, Bakterien der Gattung Bifidobacterium, Bakterien der Gattung Enterococcus, und Bakterien der Gattung Pseudomonas. 9. Use according to any one of claims 1 to 8, wherein the probiotic bacterium is selected from the group consisting of bacteria of the genus Lactobacillus, bacteria of the genus Streptococcus, bacteria of the genus Bifidobacterium, bacteria of the genus Enterococcus, and bacteria of the genus Pseudomonas.
10. Verwendung gemäß einem der Ansprüche 1 bis 8, wobei das probiotische Bakterium ein Milchsäurebakterium ist. 10. Use according to any one of claims 1 to 8, wherein the probiotic bacterium is a lactic acid bacterium.
11. Verwendung gemäß einem der Ansprüche 1 bis 8, wobei das probiotische Bakterium ausgewählt ist aus der Gruppe bestehend aus Enterococcus faecium, Bifidobacterium longum, Streptococcus thermophilus, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus rhamnosus, Bifidobacterium breve und Pseudomonas fluorescens. 11. Use according to any one of claims 1 to 8, wherein the probiotic bacterium is selected from the group consisting of Enterococcus faecium, Bifidobacterium longum, Streptococcus thermophilus, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus rhamnosus, Bifidobacterium breve and Pseudomonas.
12. Verwendung gemäß einem der Ansprüche 1 bis 8, wobei das probiotische Bakterium Lactobacillus rhamnosus oder Lactobacillus plantarum ist. 12. Use according to any one of claims 1 to 8, wherein the probiotic bacterium is Lactobacillus rhamnosus or Lactobacillus plantarum.
13. Verwendung gemäß einem der Ansprüche 1 bis 12, wobei das probiotische Bakterium und optional der weitere Wirkstoff in einer pharmazeutischen Zusammensetzung enthalten sind. 13. Use according to one of claims 1 to 12, wherein the probiotic bacterium and optionally the further active ingredient are contained in a pharmaceutical composition.
14. Verwendung gemäß Anspruch 13, wobei die pharmazeutische Zusammensetzung neben dem probiotischen Bakterium und optional dem weiteren Wirkstoff ausschließlich Wasser enthält. 14. Use according to claim 13, wherein the pharmaceutical composition contains exclusively water in addition to the probiotic bacterium and optionally the further active ingredient.
15. Verwendung gemäß einem der Ansprüche 1 bis 14, wobei die Amyolidose Alzheimer- Krankheit ist. 15. Use according to any one of claims 1 to 14, wherein the amyolidosis is Alzheimer's disease.
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