WO2010027266A1 - Moyens et méthodes pour corriger les troubles neurologiques - Google Patents

Moyens et méthodes pour corriger les troubles neurologiques Download PDF

Info

Publication number
WO2010027266A1
WO2010027266A1 PCT/NL2009/050535 NL2009050535W WO2010027266A1 WO 2010027266 A1 WO2010027266 A1 WO 2010027266A1 NL 2009050535 W NL2009050535 W NL 2009050535W WO 2010027266 A1 WO2010027266 A1 WO 2010027266A1
Authority
WO
WIPO (PCT)
Prior art keywords
therapeutically effective
effective amount
day
analogue
metabolite
Prior art date
Application number
PCT/NL2009/050535
Other languages
English (en)
Inventor
Hendrikus Theodorus Ardina Hubertus VAN DE LANGENBERG
Original Assignee
Van De Langenberg, Hendrikus Theodorus Ardina Hubertus
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Van De Langenberg, Hendrikus Theodorus Ardina Hubertus filed Critical Van De Langenberg, Hendrikus Theodorus Ardina Hubertus
Publication of WO2010027266A1 publication Critical patent/WO2010027266A1/fr

Links

Classifications

    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4415—Pyridoxine, i.e. Vitamin B6
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants

Definitions

  • the invention relates to the fields of biology and medicine. More particularly, the invention relates to neurological disorders.
  • neurological disorder involves impaired function of brain cells, impaired function of nerve cells and/or impaired transmission of neurological impulses. It embraces a wide variety of disorders of the nervous system.
  • the nervous system is a network of specialized nerve cells that conduct impulses from or to areas of the body to the brain and spinal cord and within the brain. It is composed of neurons and other specialized cells, like glial cells and neuroglia, that aid in the function of the neurons. Nerve cells are interconnected in complex arrangements and use electrochemical signals to transmit impulses between cells, they respond to a great variety of stimuli and form neural circuits that regulate an organism's perception and behavior.
  • the nervous system is connected into many systems that function together.
  • the human nervous system can be grouped into the central nervous system, the peripheral nervous system and the autonomic nervous system.
  • the central nervous system (CNS) of vertebrates contains the majority of the nervous system, and consists of the brain (in vertebrates which have brains), and the spinal cord (which is a long, thin, tubular bundle of nerves that is an extension of the central nervous system from the brain and is enclosed in and protected by the bony vertebral column.
  • the CNS is contained within the dorsal cavity, with the brain within the cranial cavity, and the spinal cord in the spinal cavity.
  • the CNS is covered by the meninges.
  • the brain is also protected by the skull, and the spinal cord is also protected by the vertebrae.
  • the main function of the spinal cord is transmission of neural inputs between the periphery and the brain).
  • the central nervous system has, together with the peripheral nervous system, a fundamental role in the control of behavior.
  • the peripheral nervous system resides or extends outside the central nervous system (CNS), to serve the limbs and organs. Unlike the central nervous system, however, the PNS is not protected by bone, leaving it exposed to mechanical injuries.
  • the autonomic nervous system also called visceral nervous system, is the part of the peripheral nervous system that acts as a control system in the body. The activities of the ANS are generally performed without conscious control or sensation. The ANS for instance affects heart rate, digestion, respiration rate, salivation, perspiration and the diameter of the pupils. Whereas most of its actions are involuntary, some, such as breathing, work in tandem with the conscious mind.
  • Vertebrate brains are extremely complex.
  • the human brain contains roughly 100 billion neurons, linked with up to 10,000 connections each.
  • the brain is composed of two broad classes of cells, neurons and glia, both of which contain several different cell types which perform different functions.
  • Interconnected neurons form neural networks (or neural ensembles). These networks are similar to man-made electrical circuits in that they contain circuit elements (neurons) connected by biological wires (nerve fibers). These do not form simple one-to-one electrical circuits like many man-made circuits, however. Typically neurons connect to at least a thousand other neurons. These highly specialized circuits make up systems which are the basis of perception, different types of action, and higher cognitive function. Neurons are the cells that convey information to other cells; these constitute the essential class of brain cells.
  • Neurons are electrically excitable cells in the nervous system that process and transmit information.
  • Neurons are the core components of the brain, the vertebrate spinal cord, the invertebrate ventral nerve cord, and the peripheral nerves.
  • Glial cells are non-neuronal cells that provide support and nutrition, maintain homeostasis, form myelin, and participate in signal transmission in the nervous system. Glial cells (“glia” is Greek for "glue”) provide support and protection for neurons. They are thus known as the "glue” of the nervous system.
  • the four main functions of glial cells are to surround neurons and hold them in place, to supply nutrients and oxygen to neurons, to insulate one neuron from another, and to destroy pathogens and remove dead neurons. Glial cells create the insulating myelin, provide structure to the neuronal network, manage waste, and clean up neurotransmitters.
  • glia in the brain are present in the entire nervous system. Exceptions include the oligodendrocytes which myelinate neural axons (a role performed by Schwann cells in the peripheral nervous system). The myelin in the oligodendrocytes insulates the axons of some neurons.
  • White matter in the brain is myelinated neurons, while gray matter contains mostly cell soma, dendrites, and unmyelinated portions of axons and glia. The space between neurons is filled with dendrites as well as unmyelinated segments of axons; this area is referred to as the neuropil.
  • the junction between two neurons is called a synapse.
  • a synaptic cleft There is a very narrow gap (about 20nm in width) between neurons which is called the synaptic cleft, where an action potential is transmitted from one neuron to a neighboring one. They do this by relaying the message with the use of neurotransmitters which the next neuron then receives, known as a nerve impulse.
  • the nerve impulse is determined by the neurotransmitter which carries the message to its appropriate destination.
  • These nerve impulses are a change in ion balance in the nerve cell, which the nervous system then interprets.
  • the fact that the nervous system uses a mixture of electrical and chemical signals makes it incredibly fast, which is necessary to acknowledge the presence of danger such as, for example, a hand touching a hot stove. If the nervous system was only comprised of chemical signals, the body would not tell the arm to move fast enough to escape dangerous burns. So the speed of the nervous system is a necessity for life.
  • the brain In mammals, the brain is surrounded by connective tissues called the meninges, a system of membranes that separate the skull from the brain.
  • This three- layered covering is composed of (from the outside in) the dura mater, arachnoid mater, and pia mater.
  • the arachnoid and pia are physically connected and thus often considered as a single layer, the pia-arachnoid.
  • Below the arachnoid is the subarachnoid space which contains cerebrospinal fluid, a substance that protects the nervous system.
  • Blood vessels enter the central nervous system through the perivascular space above the pia mater. The cells in the blood vessel walls are joined tightly, forming the blood-brain barrier which protects the brain from toxins that might enter through the blood.
  • Hypersensitivity of the dura mater and/or the pia mater results in various neurological symptoms, such as for instance seizures as a result of temperature changes.
  • the symptoms are partly similar to Hydrocephalus.
  • Hydrocephalus can be caused by impaired cerebrospinal fluid (CSF) flow, reabsorption, or excessive CSF production.
  • CSF cerebrospinal fluid
  • disorders of CSF flow occur, they may therefore affect not only CSF movement, but also the intracranial blood flow, with subsequent neuronal and glial vulnerabilities.
  • the venous system is also important in this equation.
  • CSF disorders including hydrocephalus and impaired CSF lymphatic transport.
  • An individual suffering from hydrocephalus may have motivation and visual problems, problems with coordination, and may be clumsy. About one in four develops epilepsy.
  • the brain is bathed in CSF, which circulates between layers of the meninges and through cavities in the brain called ventricles. It is important both chemically for metabolism and mechanically for shock-prevention.
  • CSF CSF
  • the human brain weighs about 1-1.5 kg or about 2-3 Ib.
  • the mass and density of the brain are such that it will begin to collapse under its own weight if unsupported by the CSF.
  • the CSF allows the brain to float, easing the physical stress caused by the brain's mass.
  • Vertebrate brains receive signals through nerves arriving from the sensors of the organism. These signals are then processed throughout the central nervous system; reactions are formulated based upon reflex and learned experiences. A similarly extensive nerve network delivers signals from a brain to control important muscles throughout the body. Anatomically, the majority of afferent and efferent nerves (with the exception of the cranial nerves) are connected to the spinal cord, which then transfers the signals to and from the brain.
  • Sensory input is processed by the brain to recognize danger, find food, identify potential mates, and perform more sophisticated functions.
  • Visual, touch, and auditory sensory pathways of vertebrates are routed to specific nuclei of the thalamus and then to regions of the cerebral cortex that are specific to each sensory system, the visual system, the auditory system, and the somatosensory system.
  • Olfactory pathways are routed to the olfactory bulb, then to various parts of the olfactory system.
  • Taste is routed through the brainstem and then to other portions of the gustatory system.
  • the motor system controls voluntary muscle movement, aided by the motor cortex, cerebellum, and the basal ganglia. The system eventually projects to the spinal cord and then out to the muscle effectors. Nuclei in the brain stem control many involuntary muscle functions such as heart rate and breathing. In addition, many automatic acts (simple reflexes, locomotion) can be controlled by the spinal cord alone. Brains also produce a portion of the body's hormones that can influence organs and glands elsewhere in a body — conversely, brains also react to hormones produced elsewhere in the body. In mammals, the hormones that regulate hormone production throughout the body are produced in the brain by the structure called the pituitary gland.
  • Hormones, incoming sensory information, and cognitive processing performed by the brain determine the brain state. Stimulus from any source can trigger a general arousal process that focuses cortical operations to processing of the new information. This focusing of cognition is known as attention. Cognitive priorities are constantly shifted by a variety of factors such as hunger, fatigue, belief, unfamiliar information, or threat. The simplest dichotomy related to the processing of threats is the fight-or-flight response mediated by the amygdala and other limbic structures.
  • Neurological disorders are disorders that affect the central nervous system, the peripheral nervous system, and/or the autonomic nervous system. Neurological disorders involve a wide variety of different conditions. Non-limiting examples include muscle spasms and cramps, paralysis, dystrophy, dystonia, ataxia, behavioral/cognitive syndromes, headache disorders such as migraine, cluster headache and tension headache, epilepsy, traumatic brain injury, whiplash, neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease, cerebrovascular disease, such as transient ischemic attack and stroke, sleep disorders, cerebral palsy, movement disorders, demyelinating diseases of the central nervous system, such as multiple sclerosis (MS), and demyelinating diseases of the peripheral nervous system, such as Guillain-Barre syndrome and chronic inflammatory demyelinating polyneuropathy (CIDP), spinal cord disorders caused by trauma, disorders of peripheral nerves, muscle disorders (myopathy), disorders of neuromuscular junctions, exciting injuries to the brain, spinal cord and peripheral nerves, altered mental higher status, and speech and language disorders
  • the present inventor has developed therapies which are capable of alleviating neurological disorder-related symptoms such as, preferably, symptoms of myelin damage-related disorders, whiplash, dystrophy, dystonia, paralysis, quada equina syndrome, ataxia, epilepsy, multiple sclerosis, hypersensitivity disorder, spasm, hypersensitivity of the dura mater, hypersensitivity of the pia mater, liquor hypotension and/or complex regional pain syndrome (CRPS).
  • said therapies are capable of restoring sense and motion, demonstrating that the therapies according to the present invention are also capable of inducing and/or enhancing the repair and/or production of myelin, brain cells, brain systems, nerve cells and/or nerve systems.
  • the present inventor has developed novel combinations of medicaments which appear to be more effective then current treatments.
  • the present invention provides the insight that neurological disorders are particularly well treated by increasing the glycine level and increasing the gamma amino butyric acid (GABA) level in an individual suffering from such neurological disorder.
  • One aspect of the invention therefore provides a method for treating a neurological disorder, and/or alleviating at least one symptom of a neurological disorder, and/or inducing or enhancing the repair and/or production of myelin, brain cells, at least one brain system, nerve cells and/or at least one nerve system, comprising increasing the glycine level and the GABA level in an individual in need thereof.
  • the vitamin B6 level in said individual is increased as well in order to obtain even better results.
  • said glycine level and said GABA level are increased by administering to said individual a therapeutically effective amount of glycine and GABA (or an analogue or metabolite thereof, preferably Baclofen).
  • Said individual is preferably a human individual.
  • a combination of glycine (especially at a high dose of at least 20 mg/kg/day) and GABA (or an analogue or metabolite of GABA) has never been administered to human individuals because severe side effects were feared, as explained in more detail below. According to the present invention, however, such combination does not involve unacceptable side effects. Contrary, beneficial results are obtained.
  • One aspect of the present invention thus provides a combination comprising glycine, or an analogue or metabolite thereof, and gamma amino butyric acid (GABA) or an analogue or metabolite of GABA, which analogue or metabolite of GABA is preferably capable of specifically binding a GABA receptor of a brain cell or nerve cell.
  • GABA analogue preferably comprises 4-amino-3-(4-chlorophenyl)-butanoic acid (Baclofen).
  • a high glycine dosage of at least 20 mg/kg/day is preferably used in order to obtain particularly good results.
  • Glycine (abbreviated as GIy or G) with the formula NH 2 CH 2 COOH is the smallest of the 20 amino acids commonly found in proteins. Because it has specialized structural properties in protein architecture, this compact amino acid is often evolutionarily conserved. For example, cytochrome c, myoglobin, and hemoglobin all contain conserved glycines. Glycine is the only natural amino acid that is not chiral. Most proteins contain only small quantities of glycine. A notable exception is collagen, which contains about 35% glycine. In its solid, i.e., crystallized, form, glycine is a free- flowing, sweet-tasting crystalline material.
  • Glycine is an inhibitory neurotransmitter in the central nervous system, especially in the spinal cord, brainstem, and retina. When released into a synapse, glycine binds to a receptor of an adjacent nerve cell (neuron). When glycine receptors are activated, chloride enters the neuron via ionotropic receptors. As a result, the membrane of said neuron becomes more permeable to chloride ions and the membrane is hyperpolarized, causing an inhibitory postsynaptic potential (IPSP). As a result, said neuron is less likely to fire. Hence, undesired impulses are counteracted. Glycine is currently prescribed against spasms and MS. According to some studies it may have anti-psychotic and anti- schizophrenia activity as well. It is known to readily cross the blood-brain barrier and can therefore be given orally.
  • IPSP inhibitory postsynaptic potential
  • glycine (or an analogue or metabolite thereof) is combined with gamma amino butyric acid (GABA) or an analogue or metabolite of GABA, preferably 4-amino-3-(4-chlorophenyl)- butanoic acid (Baclofen), which analogue or metabolite of GABA is capable of specifically binding a GABA receptor of a brain cell or nerve cell.
  • GABA is the chief inhibitory neurotransmitter in the mammalian central nervous system. It plays an important role in regulating neuronal excitability throughout the nervous system. GABA is also directly responsible for the regulation of muscle tone.
  • GABA In spastic cerebral palsy in humans, GABA cannot be absorbed properly by damaged nerve rootlets corresponding to affected muscles, which leads to hypertonia in those muscles. Disrupted GABAergic signaling has been implicated in numerous and varied neurological and psychiatric pathologies including movement and anxiety disorders, epilepsy, schizophrenia, and addiction.
  • GABA acts at inhibitory synapses in the brain by binding to specific transmembrane receptors in the plasma membrane during both pre- and postsynaptic neuronal processes. This binding causes the opening of ion channels to allow the flow of either negatively-charged chloride ions into the cell or positively- charged potassium ions out of the cell. This action results in a negative change in the transmembrane potential, usually causing hyperpolarization.
  • GABAA and GABAc ionotropic receptors which are ion channels themselves
  • GABAB metabotropic receptors which are G protein- coupled receptors that open ion channels via intermediaries (G proteins).
  • GABAergic neurons Neurons that produce GABA as their output are called GABAergic neurons, and have chiefly inhibitory action at receptors in the adult vertebrate.
  • Medium Spiny Cells are a typical example of inhibitory CNS GABAergic cells.
  • GABA has primarily excitatory effects early in development, and is in fact the major excitatory neurotransmitter in many regions of the brain prior to the maturation of glutamate synapses
  • Organisms synthesize GABA from glutamate using the enzyme L-glutamic acid decarboxylase and using pyridoxal phosphate as a cofactor. It is worth noting that this process converts the principal excitatory neurotransmitter (glutamate) into the principal inhibitory one (GABA).
  • GABA barely crosses the blood-brain barrier, it is normally synthesized in the brain.
  • Drugs that act as agonists of GABA typically have relaxing, anti-anxiety and anti-convulsive effects.
  • GABA analogues known in the art, is 4-amino-3-(4-chlorophenyl)- butanoic acid. This drug is called Baclofen.
  • Baclofen is prescribed as a muscle relaxant and antispasticity agent. Like GABA, Baclofen does not readily cross the blood-brain barrier. Therefore, Baclofen is preferably administered directly into the intrathecal space surrounding the spinal cord.
  • Baclofen (brand names are also Kemstro and Lioresal) affects the spinal cord, which is the main connection between the brain and the rest of the body.
  • the spinal cord plays a role as a reflex system that functions as a feedback loop.
  • GABA slows this reflex circuit down.
  • Baclofen mimics these effects of GABA.
  • the dose of intrathecal Baclofen necessary to slow down the reflex circuit is variable but is generally one thousand times (three orders of magnitude) smaller than the oral dose of Baclofen.
  • Baclofen is a direct agonist of GABAB receptors, which upon activation utilize a
  • intrathecal Baclofen is used in combination with oral glycine.
  • intrathecal Baclofen is used in combination with oral glycine and vitamin B6 (or an analogue or metabolite of any of these compounds).
  • CRPS complex regional pain syndrome
  • a combination comprising glycine and vitamin B6 (or analogues or metabolites thereof) has the same kind of positive effects (in kind, not necessarily in amount) and gives a proper follow up after a combination comprising Baclofen, glycine and vitamin B6, since the inventor retained his capability of moving his toes, feet and legs while the number and duration of his epileptic seizures remained diminished as compared to his situation before administration of any of the above mentioned combinations.
  • the invention provides a method for treating a neurological disorder, and/or alleviating at least one symptom of a neurological disorder, and/or inducing or enhancing the repair and/or production of myelin, brain cells, nerve cells, at least one brain system and/or at least one nerve system, comprising administering to an individual in need thereof:
  • GABA gamma amino butyric acid
  • This combination preferably also comprises a therapeutically effective amount of vitamin B6, or an analogue or metabolite thereof.
  • Said analogue of GABA preferably comprises 4-amino- 3-(4-chlorophenyl)-butanoic acid (Baclofen).
  • a combination comprising Baclofen, glycine and vitamin B6 is used.
  • a method for treating a neurological disorder, and/or alleviating at least one symptom of a neurological disorder, and/or inducing or enhancing the repair and/or production of myelin, brain cells, nerve cells, at least one brain system and/or at least one nerve system comprising administering to an individual in need thereof a therapeutically effective amount of:
  • a combination comprising glycine, or an analogue or metabolite thereof, and gamma amino butyric acid (GABA) or an analogue or metabolite of GABA (preferably 4-amino-3-(4-chlorophenyl)-butanoic acid (Baclofen)) which analogue is preferably capable of specifically binding a GABA receptor of a brain cell or nerve cell.
  • GABA gamma amino butyric acid
  • Baclofen 4-amino-3-(4-chlorophenyl)-butanoic acid
  • Said combination preferably also comprises vitamin B6, or an analogue or metabolite thereof.
  • One preferred embodiment of the present invention provides a combination comprising glycine, or an analogue or metabolite thereof, and vitamin B6, or an analogue or metabolite thereof, and Baclofen, or an analogue or metabolite thereof. These combinations are particularly suitable for counteracting neurological disorders and/or the symptoms thereof. Furthermore provided is therefore a combination as mentioned above for use as a medicament.
  • a combination comprising glycine, or an analogue or metabolite thereof and gamma amino butyric acid (GABA) or an analogue or metabolite of GABA, which analogue is preferably capable of specifically binding a GABA receptor of a brain cell or nerve cell, for the preparation of a medicament, a combination of medicaments, or a kit of parts for treating a neurological disorder, and/or alleviating the symptoms of a neurological disorder, and/or inducing or enhancing the repair or production of myelin, brain cells, at least one brain system, nerve cells and/or at least one nerve system.
  • GABA gamma amino butyric acid
  • said GABA analogue preferably comprises 4-amino-3-(4-chlorophenyl)-butanoic acid (Baclofen).
  • Said combination preferably also comprises vitamin B6, or an analogue or metabolite thereof.
  • treating a neurological disorder comprises counteracting a neurological disorder. Hence, complete recovery is not necessary as long as a patient's status is improved.
  • a neurological disorder is defined herein as a disorder of the central, peripheral, and/or autonomic nervous system, involving impaired function of brain cells, impaired function of nerve cells and/or impaired transmission of neurological impulses. When an individual suffers from a neurological disorder, signal transmission between at least some brain cells and/or nerve cells is at least in part impaired or increased as compared to a natural, healthy situation.
  • a neurological order is preferably a disorder involving damage of myelin, damage of brain cells, damage of nerve cells, damage of a brain system, damage of a nerve system, death of brain cells, a decrease of brain cells, death of nerve cells and/or a decrease of nerve cells.
  • Said neurological disorder most preferably comprises a whiplash, a myelin damage-related disorder, (muscle) dystrophy, dystonia, paralysis, quada equina syndrome, ataxia, epilepsy, multiple sclerosis, hypersensitivity disorder, spasm, hypersensitivity of the dura mater, hypersensitivity of the pia mater, liquor hypotension and/or complex regional pain syndrome (CRPS).
  • one embodiment of the invention provides a method for treating whiplash, myelin damage-related disorder, (muscle) dystrophy, dystonia, paralysis, quada equina syndrome, ataxia, epilepsy, multiple sclerosis, hypersensitivity disorder, spasm, hypersensitivity of the dura mater, hypersensitivity of the pia mater, liquor hypotension and/or complex regional pain syndrome (CRPS), comprising administering to an individual in need thereof:
  • a therapeutically effective amount of glycine, or an analogue or metabolite thereof (preferably in combination with a therapeutically effective amount of vitamin B6, or an analogue or metabolite thereof), and a therapeutically effective amount of gamma amino butyric acid (GABA) or an analogue or metabolite of GABA, preferably A- amino-3-(4-chlorophenyl)-butanoic acid (Baclofen), which analogue or metabolite is preferably capable of specifically binding a GABA receptor of a brain cell or nerve cell.
  • GABA gamma amino butyric acid
  • Baclofen A- amino-3-(4-chlorophenyl)-butanoic acid
  • a combination comprising glycine, vitamin B6 and Baclofen is administered to said individual. Subsequently, after positive therapeutic effects have been achieved, the administration of Baclofen is optionally discontinued.
  • glycine or an analogue or metabolite thereof (preferably in combination with a therapeutically effective amount of vitamin B6, or an analogue or metabolite thereof), and a therapeutically effective amount of gamma amino butyric acid (GABA) or an analogue or metabolite of GABA, preferably 4- amino-3-(4-chlorophenyl)-butanoic acid (Baclofen), which analogue or metabolite is preferably capable of specifically binding a GABA receptor of a brain cell or nerve cell for the preparation of a combination of medicaments or a kit of parts for treating a whiplash, a myelin damage-related disorder, (muscle) dystrophy, dystonia, paralysis, quada equina syndrome, ataxia, epilepsy, hypersensitivity disorder, spasm, hypersensitivity of the dura mater, hypersensitivity of the pia mater, liquor hypotension and/or complex regional pain syndrome (CRPS).
  • GABA gamma amino butyric acid
  • a combination comprising glycine, vitamin B6 and Baclofen is used for the preparation of said combination of medicaments or said kit of parts. All of the above mentioned conditions improved after administration of glycine in combination with Baclofen and vitamin B6 to the present inventor. Even after subsequent discontinuation of Baclofen the symptoms remained alleviated.
  • a combination comprising glycine, vitamin B6 and Baclofen is used for the preparation of a combination of medicaments or a kit of parts for treating multiple sclerosis. Symptoms of MS are also alleviated by a combination according to the invention.
  • Dystonia (or muscle dystonia) is defined as any disorder involving abnormal muscle tone of one or more muscles and/or muscle spasms.
  • Dystonia is a neurological movement disorder in which sustained muscle contractions cause twisting and/or repetitive movements and/or abnormal postures.
  • the disorder may be inherited or caused by other factors such as birth-related or other physical trauma, infection, poisoning (eg. lead poisoning) or reaction to drugs.
  • the causes of dystonia are not yet known or understood; however, they are categorized as follows on a theoretical basis:
  • Primary dystonia is suspected to be caused by a pathology of the central nervous system, likely originating in those parts of the brain concerned with motor function, such as the basal ganglia, and the GABA producing Purkinje neurons.
  • the precise cause of primary dystonia is unknown. In many cases it may involve some genetic predisposition towards the disorder combined with environmental conditions.
  • Secondary dystonia refers to dystonia brought on by some identified cause, usually involving brain damage, or by some unidentified cause such as chemical imbalance. Some cases of (particularly focal) dystonia are brought on after trauma, are induced by certain drugs (tardive dystonia), or may be the result of diseases of the nervous system such as Wilson's disease.
  • (Muscle) dystrophy is defined herein as at least partial degeneration of at least one muscle. (Muscle) dystrophy may have various causes. As used herein, the term "muscle dystrophy” is defined as a muscle dystrophy involving a neurological disorder, preferably muscle dystrophy associated with and/or resulting from brain damage and/or nerve damage and/or myelin damage.
  • CRPS Complex Regional Pain Syndrome
  • brain system refers to distinct systems formed by neurons which express a certain type of neurotransmitter. Neurons expressing certain types of neurotransmitters form distinct systems which are called brain systems or neurotransmitter systems. Activation of a brain system causes effects in large volumes of the brain, called volume transmission.
  • Major brain systems are the noradrenaline (norepinephrine) system, the dopamine system, the serotonin system and the cholinergic system. Drugs targeting the neurotransmitter of such systems affects the whole system, which explains the mode of action of many drugs. Cocaine, for example, blocks the reuptake of dopamine, leaving these neurotransmitters in the synaptic gap longer. Prozac is a selective serotonin reuptake inhibitor (SSRI), hence potentiating the effect of naturally released serotonin. Diseases may affect specific brain systems. For example, Parkinson's disease is at least in part related to failure of dopaminergic cells in deep- brain nuclei, for example the substantia nigra. Treatments potentiating the effect of dopamine precursors have been proposed and effected, with moderate success. Table 1 shows a brief comparison of the major brain systems: Table 1
  • Dopamine • mesolimbic pathway motor system, reward, cognition, system • nigrostriatal pathway endocrine, nausea
  • Serotonin caudal dorsal raphe nucleus Increase introversion, mood, system satiety, body temperature and rostral dorsal raphe nucleus sleep, while decreasing nociception.
  • vitamin B6 embraces a group of closely related chemical compounds with related names - non limiting examples include pyridoxine, pyridoxal and pyridoxamine - that are transformed within the body to yet another form of vitamin B6, pyridoxal phosphate that acts as a coenzyme.
  • Vitamin B6 is a water-soluble vitamin. Pyridoxal phosphate (PLP) is the active form and is a cofactor in many reactions of amino acid metabolism, including transamination, deamination, and decarboxylation. PLP also is necessary for the enzymatic reaction governing the release of glucose from glycogen. Vitamin B6 was discovered in the 1930s during nutrition studies on rats. The vitamin was named pyridoxine to indicate its structural homology to pyridine. Later it was shown that vitamin B6 could exist in two other, slightly different, chemical forms, termed pyridoxal and pyridoxamine.
  • vitamin B6 all three forms of vitamin B6 are precursors of an activated compound known as pyridoxal 5'-phosphate (PLP), which plays a vital role as a cofactor of a large number of essential enzymes in the human body.
  • PPP pyridoxal 5'-phosphate
  • vitamin B6 encompasses pyridoxine, pyridoxal, pyridoxamine and pyridoxal 5'-phosphate (PLP).
  • Enzymes dependent on PLP focus a wide variety of chemical reactions mainly involving amino acids.
  • the reactions carried out by the PLP-dependent enzymes that act on amino acids include transfer of the amino group, decarboxylation, racemization, and beta- or gamma-elimination or replacement.
  • Such versatility arises from the ability of PLP to covalently bind a substrate, and then to act as an electrophilic catalyst, thereby stabilizing different types of carbanionic reaction intermediates.
  • Vitamin B6 is especially important to the function of the central nervous system, skin, and blood.
  • the term "vitamin B6" also encompasses analogues and metabolites of vitamin B6. Such analogues are capable of performing the same function as vitamin B6 in kind, not necessarily in amount.
  • a non-limiting example of an analogue of vitamin B6 is pyridoxal phosphate with a substitution so that the overall function is not seriously affected.
  • a metabolite of a compound is defined herein as either a molecule which is formed when said compound is processed in vivo, or a substance which, after processing in vivo, results in the formation of said compound. After administration of a substance such as for instance a prodrug to an animal, said substance is sometimes altered within said animal. Said substance is for instance cleaved, resulting in the therapeutically active drug of interest.
  • said substance is modified by conjugation with an endogenous molecule such as for instance glucuronic acid, glutathione and/or sulfate. A metabolite resulting from such modification may subsequently be cleaved, and/or a cleavage product may subsequently be modified.
  • a metabolite of vitamin B6 is defined as any compound which, after processing in vivo, results in the formation of pyridoxal phosphate.
  • a method according to the invention further comprises administering to said individual a therapeutically effective amount of glutamine and/or arginine and/or taurine.
  • a combination comprising: 1) glycine or an analogue or metabolite thereof, and 2) Vitamin B6, or an analogue or metabolite thereof and 3) GABA or a GABA analogue or metabolite such as Baclofen and 4) at least one compound chosen from the group consisting of glutamine and arginine and taurine, provides improved results in treating a neurological disorder, and/or alleviating the symptoms of a neurological disorder, and/or inducing or enhancing the repair and/or production of myelin, brain cells, nerve cells, at least one brain system and/or at least one nerve system.
  • a combination comprising 1) glycine and 2) vitamin B6 and 3) at least one compound chosen from the group consisting of glutamine and arginine and taurine.
  • a combination comprising glycine and vitamin B6 and at least one compound chosen from the group consisting of glutamine and arginine and taurine is used after initial therapy comprising said combination and Baclofen.
  • any of these compounds may be replaced by therapeutically effective analogues and/or metabolites thereof.
  • Glutamine is a precursor of GABA and has an anti-depressive effect. Glutamine is the most abundant naturally occurring, non-essential amino acid in the human body and one of the few natural amino acids which are capable of directly crossing the blood-brain barrier. In the body it is circulating in the blood as well as stored in skeletal muscles.
  • Glutamine and glutamate are both used for the production of GABA in the brain.
  • Glutamine has a variety of biochemical functions. It is a substrate for DNA synthesis and plays a major role in protein synthesis. It is also a primary source of fuel for enterocytes (cells lining the inside of the small intestine). Glutamine is furthermore a precursor for rapidly dividing immune cells, thus aiding in immune function. Glutamine is also involved with regulation of acid-base balance in the kidney by producing ammonium. It is an alternative source of fuel for the brain and helps to block cortisol-induced protein catabolism.
  • Glutamine is advantageous because of his blood/brain crossing capacity and because it is a natural ingredient that the brain uses for forming a natural GABA. Furthermore, without wishing to be bound to theory, the inventor believes that neurological disorders mentioned herein before involve a huge deficiency of several natural c.q. ortomolecular compounds such as glutamine. Long term shortage of such compounds results in a generalized or specific deregulation of the brain and triggers seizures. Glutamine has a positive effect on epileptic and dystonic seizures, especially in combination with taurine (explained in more detail below).
  • glutamine and taurine are forming a cluster, meaning that they enhance each other's effects when present in certain ratio, and are therefore preferably used in a fixed ratio.
  • the ratio glutamine: taurine is preferably between 1:1 and 4:1, more preferably about 2:1 — 3:1, when both glutamine and taurine are administered via the same route of administration, preferably via oral administration.
  • Said cluster effect has increased benefits to reduction of the seizures and also on regaining of movement capabilities, reflexes etc.
  • glutamine is combined with at least two compounds selected from the group consisting of glycine, GABA (or Baclofen) and vitamin B6, the regaining of neurological functions improves rapidly.
  • taurine is used as well.
  • a minimal oral dosage of 20 mg/kg/day glutamine stimulates the production of hormones which has a positive effect on forming of GABA.
  • arginine is classified as a semi essential or conditionally essential amino acid, depending on the developmental stage and health status of the individual. Arginine is firstly oxidized into N-hydroxyl-arginine, which is then further oxidized to citrulline concomitant with release of nitric oxide. Proteins that normally contain citrulline residues include myelin basic protein (MBP). Therefore, arginine is also beneficial for improving neurological conditions. In one embodiment, therefore, arginine is administered to an individual as well, either in combination with glutamine or in place of glutamine.
  • the ratio arginine: taurine is preferably between 1:1 and 4:1, more preferably about 2:1 - 3:1 when both arginine and taurine are administered via the same route of administration, preferably via oral administration.
  • a method for treating a neurological disorder, and/or alleviating at least one symptom of a neurological disorder, and/or inducing or enhancing the repair and/or production of myelin, brain cells, nerve cells, at least one brain system and/or at least one nerve system comprising administering to an individual in need thereof:
  • GABA gamma amino butyric acid
  • Baclofen 4-amino-3-(4-chlorophenyl)-butanoic acid
  • - a therapeutically effective amount of glutamine and/or arginine, or an analogue or metabolite thereof, and - preferably, a therapeutically effective amount of vitamin B6, or an analogue or metabolite thereof.
  • GABA gamma amino butyric acid
  • Baclofen 4-amino-3-(4-chlorophenyl)-butanoic acid
  • a therapeutically effective amount of vitamin B6, or an analogue or metabolite thereof is also provided.
  • said combination is used for the preparation of a combination of medicaments (kit of parts) for treating a neurological disorder, and/or alleviating the symptoms of a neurological disorder, and/or inducing or enhancing the repair or production of myelin, brain cells, at least one brain system, nerve cells and/or at least one nerve system.
  • any of the above mentioned compounds may be replaced by therapeutically effective analogues and/or metabolites thereof.
  • Said neurological disorder preferably comprises at least one of the conditions as described herein before.
  • the use of glycine, glutamine and/or arginine, vitamin B6 and Baclofen is preferred.
  • One particularly preferred embodiment of the invention therefore provides a method for treating whiplash, myelin damage-related disorder, (muscle) dystrophy, dystonia, paralysis, quada equina syndrome, ataxia, epilepsy, multiple sclerosis, hypersensitivity disorder, spasm, hypersensitivity of the dura mater, hypersensitivity of the pia mater, liquor hypotension and/or complex regional pain syndrome (CRPS), comprising administering to an individual in need thereof:
  • vitamin B6 preferably, a therapeutically effective amount of vitamin B6.
  • the inventor has shown that the beneficial effects are also experienced when the Baclofen is subsequently omitted. Further provided is therefore a method for treating whiplash, myelin damage-related disorder, muscle dystrophy, dystonia, paralysis, quada equina syndrome, ataxia, epilepsy, multiple sclerosis, hypersensitivity disorder, spasm, hypersensitivity of the dura mater, hypersensitivity of the pia mater, liquor hypotension and/or complex regional pain syndrome (CRPS), comprising administering to an individual in need thereof: - a therapeutically effective amount of glycine, and
  • vitamin B6 a therapeutically effective amount of vitamin B6.
  • Said individual has preferably been treated with Baclofen before the above mentioned treatment.
  • a combination for use as a medicament is also provided.
  • Said combination is preferably used for the preparation of a combination of medicaments (kit of parts) for treating whiplash, myelin damage-related disorder, muscle dystrophy, dystonia, paralysis, quada equina syndrome, ataxia, epilepsy, multiple sclerosis, hypersensitivity disorder, spasm, hypersensitivity of the dura mater, hypersensitivity of the pia mater, liquor hypotension and/or complex regional pain syndrome (CRPS).
  • kit of parts for treating whiplash, myelin damage-related disorder, muscle dystrophy, dystonia, paralysis, quada equina syndrome, ataxia, epilepsy, multiple sclerosis, hypersensitivity disorder, spasm, hypersensitivity of the dura mater, hypersensitivity of the pia mater, liquor hypotension and/or complex regional pain syndrome (CRPS).
  • CRPS complex regional pain syndrome
  • any of these compounds may be replaced by therapeutically effective analogues and/or metabolites thereof.
  • taurine is used.
  • Taurine is a non-protein amino acid. It is an end product of cysteine-metabolism and the principal free intracellular amino acid in many tissues. Taurine has antioxidant and membrane- stabilizing activities. Taurine also reacts as a glycine receptor It has until the present invention not been prescribed for alleviating the effects of a neurological disorder in humans.
  • a combination comprising: 1) glycine and 2) GABA or a GABA analogue such as Baclofen, preferably in combination with vitamin B6, and 3) glutamine and/or arginine and 4) taurine is particularly suitable for treating a neurological disorder and/or alleviating at least one symptom of a neurological disorder, and/or inducing or enhancing the repair and/or production of myelin, brain cells, nerve cells, at least one brain system and/or at least one nerve system.
  • a method for treating a neurological disorder, and/or alleviating at least one symptom of a neurological disorder, and/or inducing or enhancing the repair and/or production of myelin, brain cells, nerve cells, at least one brain system and/or at least one nerve system comprising administering to an individual in need thereof:
  • GABA gamma amino butyric acid
  • Baclofen 4-amino-3-(4-chlorophenyl)-butanoic acid
  • a therapeutically effective amount of vitamin B6, or an analogue or metabolite thereof preferably, a therapeutically effective amount of vitamin B6, or an analogue or metabolite thereof.
  • the inventor has shown that the beneficial effects are also experienced when the Baclofen is subsequently omitted. Further provided is therefore a method for treating a neurological disorder, and/or alleviating at least one symptom of a neurological disorder, and/or inducing or enhancing the repair and/or production of myelin, brain cells, nerve cells, at least one brain system and/or at least one nerve system, comprising administering to an individual in need thereof:
  • vitamin B6, or an analogue or metabolite thereof Said individual has preferably been treated with Baclofen before the above mentioned treatment.
  • Baclofen any of these compounds may be replaced by therapeutically effective analogues and/or metabolites thereof.
  • GABA gamma amino butyric acid
  • Baclofen 4-amino-3-(4-chlorophenyl)-butanoic acid
  • GABA gamma amino butyric acid
  • Baclofen 4-amino-3-(4-chlorophenyl)-butanoic acid
  • analogue or metabolite is preferably capable of specifically binding a GABA receptor of a brain cell or nerve cell
  • glycine or an analogue or metabolite thereof
  • vitamin B6, or an analogue or metabolite thereof preferably, a therapeutically effective amount of vitamin B6, or an analogue or metabolite thereof.
  • combination for use as a medicament is also provided.
  • said combination is used for the preparation of a combination of medicaments (kit of parts) for treating a neurological disorder, and/or alleviating the symptoms of a neurological disorder, and/or inducing or enhancing the repair or production of myelin, brain cells, at least one brain system, nerve cells and/or at least one nerve system.
  • Said neurological disorder preferably comprises at least one of the conditions as described herein before.
  • the use of glycine, glutamine/arginine, taurine, vitamin B6 and Baclofen is preferred.
  • One particularly preferred embodiment of the invention therefore provides a method for treating whiplash, myelin damage-related disorder, (muscle) dystrophy, dystonia, paralysis, quada equina syndrome, ataxia, epilepsy, multiple sclerosis, hypersensitivity disorder, spasm, hypersensitivity of the dura mater, hypersensitivity of the pia mater, liquor hypotension and/or complex regional pain syndrome (CRPS), comprising administering to an individual in need thereof: - a therapeutically effective amount of glycine, and
  • vitamin B6 - a therapeutically effective amount of vitamin B6 and - a therapeutically effective amount of 4-amino-3-(4-chlorophenyl)-butanoic acid (Baclofen).
  • vitamin B6 a therapeutically effective amount of vitamin B6.
  • Said individual has preferably been treated with Baclofen before the above mentioned treatment.
  • Baclofen any of these compounds may be replaced by therapeutically effective analogues and/or metabolites thereof.
  • the above mentioned combination for use as a medicament is also provided.
  • Said combination is preferably used for the preparation of a combination of medicaments (kit of parts) for treating myelin damage-related disorder, (muscle) dystrophy, dystonia, paralysis, quada equina syndrome, ataxia, epilepsy, hypersensitivity disorder, spasm, hypersensitivity of the dura mater, hypersensitivity of the pia mater, liquor hypotension and/or complex regional pain syndrome (CRPS).
  • CRPS complex regional pain syndrome
  • said combination is used for the preparation of a combination of medicaments (kit of parts) for treating multiple sclerosis.
  • a combination comprising glutamine and taurine is used in order to counteract epileptic seizures.
  • Said combination preferably also comprises GABA or an analogue or metabolite of GABA, preferably 4-amino-3-(4-chlorophenyl)-butanoic acid (Baclofen), which analogue or metabolite is preferably capable of specifically binding a GABA receptor of a brain cell or nerve cell.
  • said combination also comprises vitamin B6.
  • a particularly preferred embodiment provides a method for counteracting epileptic seizures, comprising administering to an individual in need thereof a therapeutically effective amount of glutamine, taurine and Baclofen. Preferably, the number and/or duration of epileptic seizures are counteracted.
  • vitamin B6 is also administered to said individual.
  • a combination comprising:
  • Said combination preferably also comprises vitamin B6.
  • the above mentioned combination for use as a medicament is also provided.
  • Said combination is preferably used for the preparation of a combination of medicaments (kit of parts) for treating epilepsy.
  • Yet another embodiment provides a use of glycine, taurine and either glutamine and/or arginine in order to counteract epilepsy.
  • Said combination preferably also comprises vitamin B6.
  • a further embodiment therefore provides a method for counteracting epileptic seizures, comprising administering to an individual in need thereof a therapeutically effective amount of glycine, taurine, vitamin B6, in combination with glutamine and/or arginine.
  • a combination comprising:
  • vitamin B6 a therapeutically effective amount of vitamin B6.
  • the above mentioned combination for use as a medicament is also provided.
  • Said combination is preferably used for the preparation of a combination of medicaments or a kit of parts for treating epilepsy.
  • any of these compounds may be replaced by therapeutically effective analogues and/or metabolites thereof.
  • the present invention furthermore provides the insight that addition of magnesium and/or aspartate and/or kalium to any combination of medicaments provided herein furthermore improves the efficiency of counteracting neurological disorders. For instance, after addition of magnesium, the present inventor experienced further improvements, in particular concerning muscle movements. Furthermore edema in his legs was significantly reduced. His former size 46 became size 42.
  • Magnesium is needed for more than 300 biochemical reactions in the body. It helps maintaining normal muscle and nerve function, keeps heart rhythm steady, supports a healthy immune system, and keeps bones strong. Magnesium also helps regulating blood sugar levels, promotes normal blood pressure, and is known to be involved in energy metabolism and protein synthesis.
  • Mg++ ions close certain types of calcium channels, which conduct a positively charged calcium ion into the neuron. With an excess of magnesium, more channels will be blocked and the nerve will have less activity.
  • Aspartate the conjugate base of aspartic acid
  • Aspartate stimulates NMDA receptors, though not as strongly as the amino acid neurotransmitter glutamate does. It serves as an excitatory neurotransmitter in the brain and is an excitotoxin.
  • Aspartic acid is non-essential in mammals, being produced from oxaloacetate by transamination. In plants and microorganisms, aspartic acid is the precursor to several amino acids, including four that are essential: methionine, threonine, isoleucine, and lysine.
  • K + ions are larger than Na + ions, and ion channels and pumps in cell membranes can distinguish between the two types of ions, actively pumping or passively allowing one of the two ions to pass, while blocking the other.
  • a method according to the invention further comprising administering to said individual a therapeutically effective amount of magnesium and/or aspartate and/or kalium, is therefore also herewith provided.
  • magnesium ascorbate is administered.
  • Magnesium ascorbate provides both magnesium and vitamin C (as ascorbate). This provides the advantage that vitamin C levels are raised as well, which is, amongst other things, beneficial for metabolic reactions.
  • the combination of magnesium and ascorbate or vitamin C has the effect that less
  • magnesium ascorbate is 390 mg (which is already 130% of the Recommended Daily Intake (RDI)) and the amount of ascorbatic acid is 5610 mg (which is as much as 9350% RDI).
  • RDI Recommended Daily Intake
  • a method for treating a neurological disorder, and/or alleviating at least one symptom of a neurological disorder, and/or inducing or enhancing the repair and/or production of myelin, brain cells, nerve cells, at least one brain system and/or at least one nerve system comprising administering to an individual in need thereof:
  • GABA gamma amino butyric acid
  • Baclofen 4-amino-3-(4-chlorophenyl)-butanoic acid
  • taurine is administered as well. Also provided is a combination comprising:
  • GABA gamma amino butyric acid
  • Baclofen 4-amino-3-(4-chlorophenyl)-butanoic acid
  • a therapeutically effective amount of vitamin B6, or an analogue or metabolite thereof preferably also comprises taurine.
  • a combination comprising: - optionally, a therapeutically effective amount of gamma amino butyric acid (GABA) or an analogue or metabolite of GABA, preferably 4-amino-3-(4-chlorophenyl)- butanoic acid (Baclofen), which analogue or metabolite is preferably capable of specifically binding a GABA receptor of a brain cell or nerve cell, and
  • magnesium preferably magnesium ascorbate
  • vitamin B6 preferably an analogue or metabolite thereof
  • Such combination is used for the preparation of a combination of medicaments or kit of parts for treating a neurological disorder, and/or alleviating the symptoms of a neurological disorder, and/or inducing or enhancing the repair or production of myelin, brain cells, at least one brain system, nerve cells and/or at least one nerve system.
  • Said neurological disorder preferably comprises at least one of the conditions as described herein before.
  • the use of glycine, glutamine/arginine, taurine, magnesium, vitamin B6 and Baclofen is particularly preferred.
  • One particularly preferred embodiment of the invention therefore provides a method for treating a whiplash, a myelin damage-related disorder, (muscle) dystrophy, dystonia, paralysis, quada equina syndrome, ataxia, epilepsy, multiple sclerosis, hypersensitivity disorder, spasm, hypersensitivity of the dura mater, hypersensitivity of the pia mater, liquor hypotension, spasm and/or complex regional pain syndrome (CRPS), comprising administering to an individual in need thereof:
  • magnesium preferably magnesium ascorbate
  • taurine and glutamine are both administered.
  • magnesium preferably magnesium ascorbate
  • vitamin B6 preferably, a therapeutically effective amount of vitamin B6. Also provided is a combination comprising:
  • magnesium preferably magnesium ascorbate
  • said combination comprises both taurine and glutamine (or arginine). Further provided is therefore a combination comprising:
  • magnesium preferably magnesium ascorbate
  • vitamin B6 a therapeutically effective amount of vitamin B6.
  • Such combination is preferably used for the preparation of a combination of medicaments or kit of parts for treating a whiplash, a myelin damage-related disorder, (muscle) dystrophy, dystonia, paralysis, quada equina syndrome, ataxia, epilepsy, multiple sclerosis, hypersensitivity disorder, hypersensitivity of the dura mater, spasm, hypersensitivity of the pia mater, liquor hypotension and/or complex regional pain syndrome (CRPS).
  • a myelin damage-related disorder e.g., myelin damage-related disorder
  • (muscle) dystrophy dystonia, paralysis, quada equina syndrome, ataxia
  • epilepsy multiple sclerosis
  • hypersensitivity disorder hypersensitivity of the dura mater
  • spasm hypersensitivity of the pia mater
  • CRPS complex regional pain syndrome
  • Alpha lipoic acid is a natural fatty acid. It is involved in energy production since it converts glucose into energy. Alpha lipoic acid is also an antioxidant. Alpha lipoic acid functions in water and fat, unlike more common antioxidants and it is able to recycle antioxidants such as vitamin C and glutathione. Glutathione is an important antioxidant that helps the body to eliminate potentially harmful substances. Alpha lipoic acid increases the formation of glutathione.
  • One of the most visible roles of lipoic acid is as a cofactor in aerobic metabolism, specifically the pyruvate dehydrogenase complex.
  • Lipoate participates in transfer of acyl in 2-oxoacid dehydrogenases (2-OADH) and in transfer of methylamine groups in glycine cleavage complexes (GCV), which are protein complexes that catalyze the reversible oxidation of glycine.
  • glycine cleavage complexes GCV
  • methylamine is transferred from lipoate to tetrahydrofolate (THF) yielding methylene-THF and ammonia.
  • THF tetrahydrofolate
  • Methylene-THF is then used by serine hydroxymethyltransferase (SHMT) to synthesize serine from glycine.
  • Serine is important in metabolism in that it participates in the biosynthesis of purines and pyrimidines.
  • alpha lipoic acid enhances methylation processes.
  • a compound capable of enhancing methylation processes (such as alpha lipoic acid) is particularly beneficial for improving neurological disorders, amongst other things via DNA damage repair.
  • any of the above mentioned combinations is combined with acetyl-L-carnithine, which enhances fatty acid oxidation and has neuroprotective benefit.
  • Carnitine is a quaternary ammonium compound bio synthesized from the amino acids lysine and methionine. In living cells, it is required for the transport of fatty acids from the cytosol into the mitochondria during the breakdown of lipids (or fats) for the generation of metabolic energy. Vitamin C (ascorbic acid) is essential for the synthesis of carnitine.
  • Acetyl L-carnitine stimulates the production of acetylcholine or ACh (muscarinic acetylcholine receptor and nicotinic acetylcholine receptor) which is a neurotransmitter that is important for excitation and contraction of the muscle.
  • Acetylcholine mediates fast synaptic transmission at all neuromuscular junctions.
  • Studies of rat aging have suggested that the use of acetyl-L-carnitine and lipoic acid results in improved memory performance and delayed structural mitochondrial decay.
  • a method, combination, use or kit of parts according to the invention further comprising (administering to said individual) a therapeutically effective amount of acetyl-L-carnithine.
  • Methionine is an essential amino acid, which is not synthesized by humans. Methionine is a precursor of glutathione, which is a potent antioxidant. Methionine is also a histidine inhibitor and it detoxifies heavy metal toxins and diminishes muscle weakness. Together with cysteine, methionine is one of two sulfur-containing amino acids. Its derivative S-adenosyl methionine (SAM) serves as a methyl donor. Hence, addition of methionine or an analogue or a metabolite thereof also enhances methylation processes, which is particularly beneficial for improving neurological disorders, amongst other things via DNA damage repair. Methionine is furthermore an intermediate in the biosynthesis of cysteine, carnitine, taurine, lecithin, phosphatidylcholine, and other phospholipids.
  • tryptophan Another amino acid which is preferably combined with a combination according to the present invention is tryptophan. This is also an essential amino acid. Tryptophan is an important building block in protein biosynthesis. Moreover, tryptophan is a biological precursor for the neurotransmitter serotonin. Serotonin, in turn, can be converted to melatonin, which hormone is important in the regulation of circadian rhythms. Tryptophan is also a precursor of Niacin (Vitamin B3), which is involved in the repair of DNA, and of Auxin, which is essential for cell growth.
  • Niacin Vitamin B3
  • Tryptophan synthase catalyzes the formation of tryptophan from indole and the amino acid serine. Further provided is therefore a method, combination, use or kit of parts according to the invention, further comprising (administering to said individual) a therapeutically effective amount of tryptophan.
  • a combination according to the present invention is combined with selenium.
  • Selenium is important for cellular function and it forms the active center of the enzyme glutathione peroxidase which protects organisms from oxidative damage.
  • Selenium is a component of the unusual amino acids selenocysteine and selenomethionine.
  • Selenium is a trace element nutrient which functions as cofactor for reduction of antioxidant enzymes such as glutathione peroxidases.
  • Selenomethionine is an amino acid containing selenium.
  • the L-isomer of selenomethionine, known as Se-met and Sem, is a common natural food source of selenium. In vivo, selenomethionine is randomly incorporated instead of methionine and is readily oxidized.
  • the present inventor has experienced that a combination of alpha-lipoic acid, acetyl-L-carnithine, methionine, tryptophan and selenium, together with glycine, glutamine, vitamin B6 and magnesium, significantly improved his condition, even after the Baclofen pump had become dysfunctional.
  • a method for treating a neurological disorder, and/or alleviating at least one symptom of a neurological disorder, and/or inducing or enhancing the repair and/or production of myelin, brain cells, nerve cells, at least one brain system and/or at least one nerve system comprising administering to an individual in need thereof: - a therapeutically effective amount of glycine, or an analogue or metabolite thereof, and
  • magnesium preferably magnesium ascorbate
  • vitamin B6 a therapeutically effective amount of vitamin B6, or an analogue or metabolite thereof
  • acetyl-L-carnithine or an analogue or metabolite thereof such as acetylcholine
  • GABA gamma amino butyric acid
  • Baclofen 4-amino-3-(4-chlorophenyl)- butanoic acid
  • magnesium preferably magnesium ascorbate
  • vitamin B6 a therapeutically effective amount of vitamin B6, or an analogue or metabolite thereof
  • acetyl-L-carnithine or an analogue or metabolite thereof such as acetylcholine
  • GABA gamma amino butyric acid
  • Baclofen 4-amino-3-(4-chlorophenyl)- butanoic acid
  • analogue or metabolite is preferably capable of specifically binding a GABA receptor of a brain cell or nerve cell.
  • such combination is used for the preparation of a combination of medicaments or kit of parts for treating a neurological disorder, and/or alleviating the symptoms of a neurological disorder, and/or inducing or enhancing the repair or production of myelin, brain cells, at least one brain system, nerve cells and/or at least one nerve system.
  • Said neurological disorder preferably comprises at least one of the conditions as described herein before.
  • One particularly preferred embodiment of the invention therefore provides a method for treating a whiplash, a myelin damage-related disorder, (muscle) dystrophy, dystonia, paralysis, quada equina syndrome, ataxia, epilepsy, multiple sclerosis, hypersensitivity disorder, spasm, hypersensitivity of the dura mater, hypersensitivity of the pia mater, liquor hypotension, spasm and/or complex regional pain syndrome (CRPS), comprising administering to an individual in need thereof:
  • vitamin B6 a therapeutically effective amount of vitamin B6, or an analogue or metabolite thereof
  • acetyl-L-carnithine or an analogue or metabolite thereof such as acetylcholine
  • GABA gamma amino butyric acid
  • Baclofen 4-amino-3-(4-chlorophenyl)- butanoic acid
  • a combination comprising: - a therapeutically effective amount of glycine, or an analogue or metabolite thereof, and
  • magnesium preferably magnesium ascorbate
  • vitamin B6 a therapeutically effective amount of vitamin B6, or an analogue or metabolite thereof
  • acetyl-L-carnithine or an analogue or metabolite thereof such as acetylcholine
  • GABA gamma amino butyric acid
  • Baclofen 4-amino-3-(4-chlorophenyl)- butanoic acid
  • analogue or metabolite is preferably capable of specifically binding a GABA receptor of a brain cell or nerve cell, for the preparation of a combination of medicaments or kit of parts for treating a whiplash, a myelin damage-related disorder, (muscle) dystrophy, dystonia, paralysis, quada equina syndrome, ataxia, epilepsy, multiple sclerosis, hypersensitivity disorder, hypersensitivity of the dura mater, spasm, hypersensitivity of the pia mater, liquor hypotension and/or complex regional pain syndrome (CRPS).
  • GABA gamma amino butyric acid
  • Baclofen 4-amino-3-(4-chlorophenyl)- butanoic acid
  • any of the above mentioned combinations is combined with soy protein.
  • a method according to the invention, further comprising administering to said individual a therapeutically effective amount of soy protein, is therefore also herewith provided.
  • Soy proteins provide several amino acids and essential minerals to the body within a very short time, and can be seen as a short boost. It is therefore advantageously used in addition to the above mentioned ingredients.
  • the present invention furthermore provides the insight that addition of an omega-3 polyunsaturated fatty acid (also called a long chain omega-3 fatty acid) to any combination of medicaments provided herein furthermore improves the efficiency of counteracting neurological disorders.
  • Omega-3 polyunsaturated fatty acids are a family of unsaturated fatty acids that have in common a carbon— carbon double bond in the n-3 position; that is, the third bond from the methyl end of the fatty acid.
  • Omega-3 fatty acids are considered essential fatty acids. They are essential to human health but cannot be manufactured by the body. For this reason, omega-3 fatty acids must be obtained from food.
  • Omega-3 fatty acids can be found in fish, such as salmon, tuna, and halibut, other marine life such as algae and krill, certain plants (including purslane), and nut oils. Omega-3 fatty acids play a crucial role in brain function as well as normal growth and development.
  • omega 3 fatty acids There are three major types of omega 3 fatty acids that are ingested in foods and used by the body: alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Once eaten, the body converts ALA to EPA and DHA, the two types of omega-3 fatty acids more readily used by the body.
  • ALA alpha-linolenic acid
  • EPA eicosapentaenoic acid
  • DHA docosahexaenoic acid
  • Vitamin B- 12 is a vitamin which is important for the normal functioning of the brain and nervous system, and for the formation of blood. It is normally involved in the metabolism of most kinds of cells of the body, especially affecting DNA synthesis and regulation, but also fatty acid synthesis and energy production.
  • a common form of the vitamin, cyanocobalamin does not occur in nature, but is used as a supplement and food additive, due to its stability.
  • vitamin B- 12 refers to all forms of the vitamin.
  • Vitamin B- 12 is the most chemically complex of all the vitamins.
  • the structure of B- 12 is based on a corrin ring, which is similar to the porphyrin ring found in heme, chlorophyll, and cytochrome.
  • the central metal ion is cobalt.
  • folic acid also known as Vitamin M and Folacin
  • Folate the anion form
  • Folate is necessary for the production and maintenance of new cells. This is especially important during periods of rapid cell division and growth such as infancy and pregnancy. Folate is needed to synthesize DNA bases (most notably thymine, but also purine bases) needed for DNA replication.
  • omega-3 polyunsaturated fatty acid also called a long chain omega-3 fatty acid
  • said omega-3 polyunsaturated fatty acid preferably comprising alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA) and/or docosahexaenoic acid (DHA), preferably in combination with a therapeutically effective amount of vitamin B12 and/or folic acid.
  • said omega-3 polyunsaturated fatty acid is combined with a therapeutically effective amount of at least one compound selected from the group consisting of vitamin B12, folic acid, vitamin E, zinc and magnesium.
  • said omega-3 polyunsaturated fatty acid is combined with vitamin B12 and folic acid.
  • said omega-3 polyunsaturated fatty acid is combined with vitamin B12, folic acid, vitamin E, zinc and magnesium.
  • a method for treating a neurological disorder, and/or alleviating at least one symptom of a neurological disorder, and/or inducing or enhancing the repair and/or production of myelin, brain cells, nerve cells, at least one brain system and/or at least one nerve system comprising administering to an individual in need thereof: - a therapeutically effective amount of gamma amino butyric acid (GABA) or an analogue or metabolite of GABA, preferably 4-amino-3-(4-chlorophenyl)-butanoic acid (Baclofen), which analogue or metabolite is preferably capable of specifically binding a GABA receptor of a brain cell or nerve cell, and
  • GABA gamma amino butyric acid
  • Baclofen 4-amino-3-(4-chlorophenyl)-butanoic acid
  • taurine is administered as well.
  • a method for treating a neurological disorder, and/or alleviating at least one symptom of a neurological disorder, and/or inducing or enhancing the repair and/or production of myelin, brain cells, nerve cells, at least one brain system and/or at least one nerve system comprising administering to an individual in need thereof:
  • GABA gamma amino butyric acid
  • Baclofen 4-amino-3-(4-chlorophenyl)-butanoic acid
  • omega-3 polyunsaturated fatty acid preferably a composition comprising ALA, EPA and/or DHA, and
  • vitamin B6, or an analogue or metabolite thereof preferably, a therapeutically effective amount of vitamin B6, or an analogue or metabolite thereof. Also provided is a combination comprising:
  • GABA gamma amino butyric acid
  • Baclofen 4-amino-3-(4-chlorophenyl)- butanoic acid
  • omega-3 polyunsaturated fatty acid preferably a composition comprising ALA, EPA and/or DHA, and
  • vitamin B6, or an analogue or metabolite thereof preferably also comprises taurine.
  • said combination also comprises vitamin B12, folic acid, vitamin E and/or zinc.
  • GABA gamma amino butyric acid
  • Baclofen 4-amino-3-(4-chlorophenyl)-butanoic acid
  • a therapeutically effective amount of magnesium and/or aspartate and/or kalium and - a therapeutically effective amount of at least one omega-3 polyunsaturated fatty acid, preferably a composition comprising ALA, EPA and/or DHA, and
  • vitamin B6 a therapeutically effective amount of vitamin B6, or an analogue or metabolite thereof, and - preferably, a therapeutically effective amount of vitamin B12, folic acid, vitamin E and/or zinc.
  • Such combination is used for the preparation of a combination of medicaments (kit of parts) for treating a neurological disorder, and/or alleviating the symptoms of a neurological disorder, and/or inducing or enhancing the repair or production of myelin, brain cells, at least one brain system, nerve cells and/or at least one nerve system.
  • Said neurological disorder preferably comprises at least one of the conditions as described herein before.
  • the use of glycine, glutamine/arginine, taurine, magnesium, a composition comprising ALA and/or DHA and/or EPA, vitamin B6 and Baclofen is particularly preferred.
  • One particularly preferred embodiment of the invention therefore provides a method for treating a whiplash, a myelin damage- related disorder, (muscle) dystrophy, dystonia, paralysis, quada equina syndrome, ataxia, epilepsy, multiple sclerosis, hypersensitivity disorder, spasm, hypersensitivity of the dura mater, hypersensitivity of the pia mater, liquor hypotension and/or complex regional pain syndrome (CRPS), comprising administering to an individual in need thereof: - a therapeutically effective amount of 4-amino-3-(4-chlorophenyl)-butanoic acid (Baclofen), and
  • a therapeutically effective amount of vitamin B12, folic acid, vitamin E and/or zinc is administered as well.
  • taurine is administered as well.
  • myelin damage-related disorder (muscle) dystrophy, dystonia, paralysis, quada equina syndrome, ataxia, epilepsy, multiple sclerosis, hypersensitivity disorder, spasm, hypersensitivity of the dura mater, hypersensitivity of the pia mater, liquor hypotension and/or complex regional pain syndrome (CRPS), comprising administering to an individual in need thereof:
  • - a therapeutically effective amount of alpha-linolenic acid and/or DHA and/or EPA, and - preferably, a therapeutically effective amount of vitamin B6 and
  • vitamin B12 preferably, a therapeutically effective amount of vitamin B12, folic acid, vitamin E and/or zinc.
  • Said combination preferably comprises at least vitamin B12 and folic acid.
  • vitamin B12 is used instead of DHA or EPA.
  • a therapeutically effective amount of vitamin B6 preferably, a therapeutically effective amount of vitamin B6.
  • Said combination preferably also comprises taurine.
  • said combination also comprises vitamin B12, folic acid, vitamin E, zinc and/or magnesium.
  • Said combination preferably comprises at least vitamin B12 and folic acid.
  • vitamin B12 is used instead of DHA or EPA.
  • the above mentioned combination for use as a medicament is also provided.
  • Said combination is preferably used for the preparation of a combination of medicaments (kit of parts) for treating myelin damage-related disorder, whiplash, muscle dystrophy, dystonia, paralysis, quada equina syndrome, ataxia, epilepsy, multiple sclerosis, hypersensitivity disorder, spasm, hypersensitivity of the dura mater, hypersensitivity of the pia mater, liquor hypotension and/or complex regional pain syndrome (CRPS).
  • kit of parts for treating myelin damage-related disorder, whiplash, muscle dystrophy, dystonia, paralysis, quada equina syndrome, ataxia, epilepsy, multiple sclerosis, hypersensitivity disorder, spasm, hypersensitivity of the dura mater, hypersensitivity of the pia mater, liquor hypotension and/or complex regional pain syndrome (CRPS).
  • CRPS complex regional pain syndrome
  • Chlorophyll is a green pigment found in most plants, algae, and cyanobacteria. Chlorophyll is the molecule that absorbs sunlight and uses its energy to synthesise carbohydrates from CO2 and water. Chlorophyll is known for its detoxifying capability. Chlorophyll is a chlorin pigment, which is structurally similar to and produced through the same metabolic pathway as other porphyrin pigments such as heme. At the center of the chlorin ring is a magnesium ion. Chlorophyll is similar to the human hemoglobin but has a magnisium core instead of an iron one.
  • chlorophyll in therapy against anti-neurological disorders has not been described before. Further provided is therefore a method according to the invention, further comprising administering to said individual a therapeutically effective amount of chlorophyll.
  • a combination or use according to the invention, wherein said combination further comprises chlorophyll is also provided, as well as a combination or use according to the invention, wherein said combination comprises a therapeutically effective amount of glycine and a therapeutically effective amount of Baclofen and a therapeutically effective amount of glutamine and/or arginine and/or taurine and/or magnesium and/or aspartate and/or kalium and/or soy protein and/or omega-3 polyunsaturated fatty acid, said omega-3 polyunsaturated fatty acid preferably comprising alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA) and/or docosahexaenoic acid (DHA).
  • said combination also comprises vitamin B12 and folic acid.
  • Dose ranges and modes of administration of the above mentioned components of combinations according to the invention can of course vary to some extent, for instance dependent on the weight and age of the patient and the kind and severity of his/her neurological disorder and the mode of administration.
  • Glycine is preferably administered orally in a dose of about 20-60 mg/kg/day, preferably about 30-50 mg/kg/day, more preferably about 35-45 mg/kg/day. Glycine readily crosses the blood-brain barrier. Glycine for oral administration is readily available in the art. Of course, all other routes of administration can be used, such as for instance injections. In such case, the dose will mostly be adapted. Suitable doses for different routes of administration are either known in the art or readily determined in the clinic using well known rising doses studies. Preferably, a dosage of glycine is used which corresponds to an oral dosage of 20-60 mg/kg/day. This means that a dosage is used which results in a similar effect of glycine as compared to the effect that is obtained with oral administration of glycine in a dosage of 20-60 mg/kg/day.
  • Baclofen is preferably administered directly into the intrathecal space surrounding the spinal cord because Baclofen does not readily cross the blood-brain barrier. Baclofen is thus preferably administered intra thecally. A preferred dosage is between 0.75 — 20 microgram/kg/day.
  • the dosage of Baclofen for intrathecal administration can be much higher (up to about 20 microgram/kg/day) as compared to dosages for oral administration (up to about 0.70 — 1.20 microgram/kg/day).
  • Intrathecal use of drugs has the benefit that the blood/brain barrier does not need to be crossed.
  • varying doses are preferably administered initially in order to establish an optimal dose for a given patient.
  • Glutamine, arginine and taurine are capable of crossing the blood-brain barrier and are therefore preferably administered orally.
  • Glutamine and/or arginine are preferably administered orally in a dose of about 20-60 mg/kg/day, preferably about 30-50 mg/kg/day.
  • Taurine is preferably administered orally in a dose of about 5-30 mg/kg/day, preferably about 10 — 20 mg/kg/day.
  • suitable doses are either known in the art or readily determined in the clinic using well known rising doses studies.
  • a dosage of glutamine and/or arginine is used which corresponds to an oral dosage of 20- 60 mg/kg/day.
  • a dosage is used which results in a similar effect of glutamine and/or arginine as compared to the effect that is obtained with oral administration of glutamine and/or arginine in a dosage of 20-60 mg/kg/day.
  • taurine a dosage of taurine is preferably used which corresponds to an oral dosage of 5-30 mg/kg/day. This means that a dosage is used which results in a similar effect of taurine as compared to the effect that is obtained with oral administration of taurine in a dosage of 5-30 mg/kg/day.
  • magnesium and/or aspartate and/or kalium are administered orally, they are preferably combined with a compound that enhances their capability of crossing the blood-brain barrier.
  • Non-limiting examples of such compounds are vitamin B12 and docosahexaenoic acid.
  • Solutio methylparabeni concentrate may be used.
  • other known compounds capable of enhancing crossing of the blood-brain barrier are suitable as well.
  • a dose of about 5- 50 mg/kg/day is preferably used. Said dose is preferably about 20-40 mg/kg/day.
  • Suitable doses are either known in the art or readily determined in the clinic using well known rising doses studies.
  • a dosage of magnesium is used which corresponds to an oral dosage of 5-50 mg/kg/day.
  • a dosage is used which results in a similar effect of magnesium as compared to the effect that is obtained with oral administration of magnesium in a dosage of 5-50 mg/kg/day.
  • a dose of about 2-10 mg/kg/day is suitable.
  • Said dose is preferably about 4-8 mg/kg/day, more preferably about 5-6 mg/kg/day.
  • Alpha-lipoic acid, acetyl-L-carnithine, methionine, tryptophan and selenium are preferably administered orally.
  • Alpha-lipoic acid is preferably administered orally in a dose of about 5-30 mg/kg/day, preferably about 10-20 mg/kg/day.
  • Acetyl- L-carnithine is preferably administered orally in a dose of about 5-45 mg/kg/day, preferably about 20-40 mg/kg/day.
  • Methionine is preferably administered orally in a dose of about 4-20 microgram/kg/day, preferably about 5-16 microgram/kg/day.
  • Tryptophan is preferably administered orally in a dose of about 5-35 mg/kg/day, preferably about 10-30 mg/kg/day.
  • Selenium is preferably administered orally in a dose of about 4-20 microgram/kg/day, preferably about 5-16 microgram/kg/day.
  • Vitamin C is preferably administered orally in a dose of about 20 — 100 mg/kg/day, preferably about 20-40 mg/kg/day.
  • Suitable doses are either known in the art or readily determined in the clinic using well known rising doses studies.
  • dosages are used which correspond to the above mentioned oral dosages of alpha-lipoic acid, acetyl-L-carnithine, methionine, tryptophan, selenium and/or vitamin C.
  • ratios between individual components are used.
  • the use of fixed ratios is preferred because, according to the present invention, certain types of amino acids, vitamins and minerals form clusters when administered in combination with each other in certain dosages. Components of the same cluster enhance each other's effects when present in a certain ratio. Hence, the overall effects of a combination of compounds of the same cluster are larger than the sum of the effects of each individual compound when administered separately.
  • different clusters are also capable of enhancing each other's effect if the components of each cluster are present in certain ratios.
  • glutamine forms a cluster with taurine.
  • glycine, Baclofen and vitamin B6 form a cluster.
  • glycine forms a cluster with magnesium.
  • Vitamin C, selenium and tryptophan also form a cluster, as well as acetyl-L-carnithine, alpha-lipoic acid and methionine.
  • the ratio between glutamine and taurine and/or the ratio between arginine and taurine is preferably between 1:1 and 4:1, more preferably about 2:1-3:1.
  • this ratio is preferably applied if glutamine and taurine are both administered orally and within a time frame of 1- I 1 /, hours. Glutamine administered outside this time frame is preferably not taken into account for determining said ratio.
  • magnesium as well as glycine is administered via the same route of administration, preferably orally
  • the ratio between magnesium and glycine is preferably between 1:4 and 2:1, more preferably between 1:3 and 1:1.
  • the ratio between glycine and aspartate is preferably between 2:1 and 4:1, more preferably about 3:1.
  • the ratio between vitamin C (in mg) and selenium (in ⁇ g) and tryptophan (in mg) is preferably between 10: 1: 5 and 4: 1: 2, more preferably between 8: 1: 4 and 6: 1: 3.
  • the ratio between acetyl-L-carnithine (in mg) and alpha-lipoic acid (in mg) and methionine (in ⁇ g) is preferably between 8: 4: 1 and 3: 1.5: 1, more preferably between 6: 3: 1 and 4: 2: 1.
  • the above mentioned ratios result in particular good therapeutic effects, while adverse side effects are at least in part avoided.
  • the dosages will be adapted. Therefore, in such cases, the above mentioned ratios will change accordingly.
  • the route of administration of both components of any of the above mentioned combinations is the same, said ratio preferably remains the same.
  • the ratio between magnesium and glycine remains preferably the same when both magnesium and glycine are administered by injection instead of orally.
  • Figure 1 shows a schematic, non-limiting, overview of possible embodiments according to the present invention.
  • a patient does not need to be provided with all the listed compounds.
  • Figure 1 merely provides a non-limiting overview of various embodiments according to the invention. Components shown in a circle form a cluster. However, because of the simplification to show the principle, it is not possible to depict all relations.
  • An example is the glycine-magnesium and the glycine- vitamin B6 clustering.
  • Figure 1 should be seen as a non-limiting indication of the principle of cluster forming.
  • a kit of parts comprising a therapeutically effective amount of:
  • kit of part preferably also comprising:
  • vitamin B6 a therapeutically effective amount of vitamin B6, and/or
  • vitamin B12 and folic acid a therapeutically effective amount of vitamin B12 and folic acid
  • magnesium and/or aspartate and/or kalium a therapeutically effective amount of magnesium and/or aspartate and/or kalium
  • omega-3 polyunsaturated fatty acid also called a long chain omega-3 fatty acid
  • said omega-3 polyunsaturated fatty acid preferably comprising alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA) and/or docosahexaenoic acid (DHA), preferably in combination with a therapeutically effective amount of at least one compound selected from the group consisting of vitamin B12, folic acid, vitamin E, zinc and magnesium, and/or
  • GABA gamma amino butyric acid
  • Baclofen 4-amino-3- (4-chlorophenyl)-butanoic acid (Baclofen), which analogue is capable of specifically binding a GABA receptor of a brain cell or nerve cell.
  • a method, combination or use according to the invention is preferably used for counteracting a myelin damage-related disorder, whiplash, dystrophy, dystonia, paralysis, quada equina syndrome, ataxia, epilepsy, multiple sclerosis, hypersensitivity disorder, spasm, hypersensitivity of the dura mater, hypersensitivity of the pia mater, liquor hypotension and/or complex regional pain syndrome (CRPS).
  • a myelin damage-related disorder whiplash, dystrophy, dystonia, paralysis, quada equina syndrome, ataxia, epilepsy, multiple sclerosis, hypersensitivity disorder, spasm, hypersensitivity of the dura mater, hypersensitivity of the pia mater, liquor hypotension and/or complex regional pain syndrome (CRPS).
  • CRPS complex regional pain syndrome
  • FIG. 1 non-limiting overview of possible embodiments according to the present invention.
  • the drawing indicates relations between several compounds of various clusters.
  • the inventor believed that a certain level of vitamins and minerals is beneficial to improve metabolism of the body and brain and is preferably brought to a certain level to have optimal benefit. It is also in a way a start point for possible recovery. As known, several body systems and processes are reduced during illness and sleep. If there is not a certain level of vitamins and minerals then after prolonged periods of time a deficiency is the result and such deficiency is an extra trigger for adverse neurological reactions. The inventor therefore used vitamin B6. Beneficial effects were indeed obtained using vitamin B6 in a high dosage up to 500 mg a day.
  • Vitamin A 1200 ug - 150% Recommended Daily Intake (RDI)
  • Vitamin D 5ug- 100% RDI
  • Vitamin E 83.9 mg - 840% RDI
  • Vitamin B6 80 mg - 4000% RDI
  • Pantothenic acid (vitamin B5), 80 mg - 1333% RDI
  • the inventor had a vitamin B6 dosage of 160 mg/day.
  • the Baclofen pump at that time delivered 390 microgram/day. Surprisingly, remarkable results were obtained. Within 8 hours the inventor was able to lift his left arm up while he had a frozen shoulder and dystonic problems with using this arm. Moreover, he was not only able to use his left shoulder but also the durations of his seizures shortened and the seizures were less heavy. One part of his body seemed to react on the Baclofen and another part on the glycine or the combinations of Glycine/Baclofen/vitamin B6 and multivitamins. After two weeks the blood levels stabilized. Then, a remarkable and unpleasant side effect occurred. The duration of the seizures increased again and the seizures became much heavier.
  • the weight of the inventor was 115 kg.
  • the dosage of Baclofen was reduced to 340 micrograms a day. This took place on 16 August 2006. On 11 October 2006 the output of the Baclofen pump was reduced to 330 micrograms a day. During 2 V- months the dosage of glycine was increased to 3000 milligrams a day (dosage of 3000 mg/day reached on 8 November 2006). On 1 December 2006 the glycine dosage was increased to 4000 milligrams a day. Suddenly the inventor was totally free of seizures. This lasted for a longer period. During the period between August and December 2006 it was apparent that a different situation was underway. Each upgrade with 500 mg glycine gave a short improvement but was not lasting until 4000 mg/day was reached. The dosage of vitamin B6 was 160 mg a day, the dosage of vitamin B12 was 160 microgram a day, the dosage of vitamin B9 or folic acid was 800 microgram a day, and the dosage of vitamin E was 167.8 mg/day.
  • magnesium in this case magnesium sulphate
  • the intended dosage was 1500 milligrams a day. If needed the dosage would be increased to 4500 milligrams a day. Again is a cluster forming expected; this time between magnesium and glycine.
  • the following results were obtained:
  • vitamin B12 and vitamin B9 folic acid
  • the dosages remained the same as before. Both vitamin B12 and DHA are capable to cross the blood-brain barrier. It looks like that they are also positively influenced by each other when used in high amounts. Glutamine was brought up to 4000 miligrams a day.
  • Alpha-liponic acid and methionine were added mainly because of their glutathion increasing capacity and their capability of enhancing methylation processes (which is beneficial for DNA repair).
  • Acetyl-L-carnithine was added because it enhances fatty acid oxidation and has neuroprotective benefits and forms acetylcholine.
  • Selenium was added because it forms the active center of the enzyme glutathione peroxidase which protects organisms from oxidative damage.
  • Tryptophan was added because this is converted into serotonine in vivo which, in turn, is converted to melatonin. It was therefore expected that the inventor would sleep and awake more easily. Although these effects were not completely accomplished due to the liquor hypothension, it will be an additional benefit for people who don't have this specific problem.
  • the inventor has also replaced the magnesium in liquid form by magnesium ascorbate in order to obtain more vitamin C.
  • the overall vitamin C dosage has now been increased from 500 mg/day to 4250 mg/day.
  • the inventor has furthermore reduced the glycine and glutamine dosages to 3000 mg/day. This appears to be sufficient.
  • the weight of the inventor is 105 kg.
  • the condition of the inventor has been further improved.
  • the inventor is now capable of walking at least 360 - 550 meters. In the morning he awakes more easily. Furthermore, the number of seizures is still reduced.
  • the inventor has significantly improved his quality of life. Instead of no longer being able to move and becoming completely dependable to others in a bed laying situation, the inventor is now capable of standing and walking and using his arms and hands. He is again capable of working, something that was deemed impossible before the present invention.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Neurosurgery (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pain & Pain Management (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne des moyens et des méthodes permettant de traiter les troubles neurologiques et/ou d'atténuer au moins un symptôme d'un trouble neurologique et/ou d'induire ou de renforcer la réparation et/ou la production de la myéline, des cellules cérébrales, des centres cérébraux, des neurones et/ou des centres nerveux. L'invention concerne notamment des associations de médicaments qui s'avèrent plus efficaces que les traitements actuels.
PCT/NL2009/050535 2008-09-05 2009-09-04 Moyens et méthodes pour corriger les troubles neurologiques WO2010027266A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP08163730 2008-09-05
EP08163730.8 2008-09-05

Publications (1)

Publication Number Publication Date
WO2010027266A1 true WO2010027266A1 (fr) 2010-03-11

Family

ID=39863078

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/NL2009/050535 WO2010027266A1 (fr) 2008-09-05 2009-09-04 Moyens et méthodes pour corriger les troubles neurologiques

Country Status (1)

Country Link
WO (1) WO2010027266A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2859889A1 (fr) * 2013-10-14 2015-04-15 Abbott Laboratories Compositions et procédés pour améliorer la fonction cognitive
WO2016163886A3 (fr) * 2015-04-10 2017-02-09 Clues2Cure International B.V. Administration de taurine ou d'un analogue de celle-ci pour le traitement de lésions de cellules nerveuses
US9662347B2 (en) 2010-05-11 2017-05-30 Gachon University Of Industry-Academic Cooperation Foundation Method for inhibiting the induction of cell death by inhibiting the synthesis or secretion of age-albumin in cells of the mononuclear phagocyte system
WO2022186015A1 (fr) * 2021-03-02 2022-09-09 ユーハ味覚糖株式会社 Agent améliorant la fonction neuropsychologique

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000044361A2 (fr) * 1999-01-27 2000-08-03 Laxdale Limited Acide eicosapentanoique ethylique hautement purifie et autres derives de l'acide eicosapentanoique pour le traitement des troubles psychiatriques et neurologiques
WO2001010432A1 (fr) * 1999-08-10 2001-02-15 Uab Research Foundation Utilisation d'agonistes gaba pour traiter des troubles spastiques, convulsifs et d'epilepsie
WO2002043507A2 (fr) * 2000-11-30 2002-06-06 The Health Research Institute Complements nutritifs et procedes de traitement de l'autisme et de prevention de l'apparition de l'autisme
US20030194453A1 (en) * 2002-04-15 2003-10-16 Coleman Henry D. Dietary supplement
WO2007098020A2 (fr) * 2006-02-16 2007-08-30 Reliant Pharmaceuticals, Inc. Procedes d'identification et de traitement de patients pour lesquels une therapie avec des acides gras omega-3 est susceptible d'etre benefique pour la demence, la demence vasculaire, la demence de parkinson, la maladie d'alzheimer et/ou un trouble cognitif
WO2007096694A1 (fr) * 2006-02-22 2007-08-30 Ramiro Vergara Combinaison de principes actifs neuro-activateurs
WO2007145520A1 (fr) * 2006-06-14 2007-12-21 N.V. Nutricia Composition anti-inflammatoire contenant de la glycine et de la lactoferrine et utilisation de celle-ci
WO2008010222A2 (fr) * 2006-07-17 2008-01-24 Ramot At Tel Aviv University Ltd. Conjugués innovants, compositions pharmaceutiques les comprenant et leurs utilisations
WO2008100727A2 (fr) * 2007-02-14 2008-08-21 The Trustees Of Columbia University In The City Of New York Glycine à haute dose comme traitement de troubles obsessionnels compulsifs et de troubles du spectre obsessionnel compulsif

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000044361A2 (fr) * 1999-01-27 2000-08-03 Laxdale Limited Acide eicosapentanoique ethylique hautement purifie et autres derives de l'acide eicosapentanoique pour le traitement des troubles psychiatriques et neurologiques
WO2001010432A1 (fr) * 1999-08-10 2001-02-15 Uab Research Foundation Utilisation d'agonistes gaba pour traiter des troubles spastiques, convulsifs et d'epilepsie
WO2002043507A2 (fr) * 2000-11-30 2002-06-06 The Health Research Institute Complements nutritifs et procedes de traitement de l'autisme et de prevention de l'apparition de l'autisme
US20030194453A1 (en) * 2002-04-15 2003-10-16 Coleman Henry D. Dietary supplement
WO2007098020A2 (fr) * 2006-02-16 2007-08-30 Reliant Pharmaceuticals, Inc. Procedes d'identification et de traitement de patients pour lesquels une therapie avec des acides gras omega-3 est susceptible d'etre benefique pour la demence, la demence vasculaire, la demence de parkinson, la maladie d'alzheimer et/ou un trouble cognitif
WO2007096694A1 (fr) * 2006-02-22 2007-08-30 Ramiro Vergara Combinaison de principes actifs neuro-activateurs
WO2007145520A1 (fr) * 2006-06-14 2007-12-21 N.V. Nutricia Composition anti-inflammatoire contenant de la glycine et de la lactoferrine et utilisation de celle-ci
WO2008010222A2 (fr) * 2006-07-17 2008-01-24 Ramot At Tel Aviv University Ltd. Conjugués innovants, compositions pharmaceutiques les comprenant et leurs utilisations
WO2008100727A2 (fr) * 2007-02-14 2008-08-21 The Trustees Of Columbia University In The City Of New York Glycine à haute dose comme traitement de troubles obsessionnels compulsifs et de troubles du spectre obsessionnel compulsif

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
AKHONDIAN J ET AL: "High-dose oral pyridoxine in treatment of paediatric recurrent intractable seizures", EPILEPSIA, vol. 45, no. Suppl. 3, 2004, & 6TH EUROPEAN CONGRESS ON EPILEPTOLOGY; VIENNA, AUSTRIA; MAY 30-JUNE 03, 2004, pages 159, XP002502891, ISSN: 0013-9580 *
ALCANIZ-FOLCH ET AL: "804 USE OF INTRATHECAL BACLOFEN IN THE CASE OF A PATIENT WITH FOCAL DYSTONIA", EUROPEAN JOURNAL OF PAIN, SAUNDERS, LONDON, GB, vol. 10, 1 September 2006 (2006-09-01), pages S209, XP005741898, ISSN: 1090-3801 *
AWAAD Y ET AL: "Progressive dystonia in a child with chromosome 18p deletion, treated with intrathecal baclofen", JOURNAL OF CHILD NEUROLOGY, DECKER PERIODICALS, HAMILTON, CA, vol. 14, no. 2, 1 February 1999 (1999-02-01), pages 75 - 77, XP009098835, ISSN: 0883-0738 *
CHERUBINI E ET AL: "The action of glycine on rat epileptic foci", NEUROSCIENCE LETTERS, LIMERICK, IE, vol. 21, no. 1, 1 January 1981 (1981-01-01), pages 93 - 97, XP023799011, ISSN: 0304-3940, [retrieved on 19810101] *
DYKSTRA D D ET AL: "Treatment of cervical dystonia and focal hand dystonia by high cervical continuously infused intrathecal baclofen: A report of 2 cases", ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION, W.B. SAUNDERS, vol. 86, no. 4, 1 April 2005 (2005-04-01), pages 830 - 833, XP004836048, ISSN: 0003-9993 *
HAWKINS J E ET AL: "On the efficacy of asparagine, glutamine, gamma-aminobutyric acid and 2-pyrrolidinone in preventing chemically induced seizures in mice", CLINICA CHIMICA ACTA, ELSEVIER BV, AMSTERDAM, NL, vol. 2, no. 6, 1 December 1957 (1957-12-01), pages 481 - 484, XP023618337, ISSN: 0009-8981, [retrieved on 19571201] *
WANG WEI-SHU ET AL: "Oral glutamine is effective for preventing oxaliplatin-induced neuropathy in colorectal cancer patients.", THE ONCOLOGIST MAR 2007, vol. 12, no. 3, March 2007 (2007-03-01), pages 312 - 319, XP002560323, ISSN: 1083-7159 *
WOLF S ET AL: "Chemotherapy-induced peripheral neuropathy: Prevention and treatment strategies", EUROPEAN JOURNAL OF CANCER, PERGAMON PRESS, OXFORD, GB, vol. 44, no. 11, 1 July 2008 (2008-07-01), pages 1507 - 1515, XP022808031, ISSN: 0959-8049, [retrieved on 20080618] *
ZUNIGA ROBERT E ET AL: "Intrathecal baclofen: A useful agent in the treatment of well-established complex regional pain syndrome", REGIONAL ANESTHESIA AND PAIN MEDICINE, vol. 27, no. 1, January 2002 (2002-01-01), pages 90 - 93, XP002502892, ISSN: 1098-7339 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9662347B2 (en) 2010-05-11 2017-05-30 Gachon University Of Industry-Academic Cooperation Foundation Method for inhibiting the induction of cell death by inhibiting the synthesis or secretion of age-albumin in cells of the mononuclear phagocyte system
EP2859889A1 (fr) * 2013-10-14 2015-04-15 Abbott Laboratories Compositions et procédés pour améliorer la fonction cognitive
WO2015057662A1 (fr) 2013-10-14 2015-04-23 Abbott Laboratories Compositions et procédés pour améliorer la fonction cognitive
WO2016163886A3 (fr) * 2015-04-10 2017-02-09 Clues2Cure International B.V. Administration de taurine ou d'un analogue de celle-ci pour le traitement de lésions de cellules nerveuses
WO2022186015A1 (fr) * 2021-03-02 2022-09-09 ユーハ味覚糖株式会社 Agent améliorant la fonction neuropsychologique

Similar Documents

Publication Publication Date Title
US10517322B1 (en) Dietary supplement formulations for promoting sleep
Kravitz et al. Cortico-striatal circuits: Novel therapeutic targets for substance use disorders
US6294583B1 (en) Methods of treating tardive dyskinesia and other movement disorders
US20090104171A1 (en) Metabolic Enhancement Therapy
CA2366915A1 (fr) Compositions biochimiques utilisees dans des traitements pour l'homme
US20070004639A1 (en) Methods and compositions for treating Parkinson's disease
JP2017061483A (ja) β−ヒドロキシ−β−メチルブチラートを用いて脳の発達および認知機能を改善する方法
CN106349058A (zh) 多不饱和脂肪酸的衍生物作为药物的用途
Rashid et al. The neuroprotective effects of exercise on cognitive decline: a preventive approach to Alzheimer disease
US20220378731A1 (en) Composition For Treating Tauopathy In The Brain, Brain Stem and Spinal Column
US20040054006A1 (en) Use of creatine or creatine analogs for the prevention and treatment of Transmissible Spongiform Encephalopathies
WO2010027266A1 (fr) Moyens et méthodes pour corriger les troubles neurologiques
US20210251929A1 (en) Anti-rds compounds and method of manufacture and administration thereof to induce dopamine homeostasis
US20160050961A1 (en) Food supplement for people with down syndrome, autism spectrum disorder and/or attention deficit disorder with or without hyperactivity
Kidd Bipolar disorder as cell membrane dysfunction. Progress toward integrative management
Meletis et al. Therapeutic uses of amino acids
US20130123355A1 (en) Fatty acids and metal ions compositions and uses thereof
TW201524372A (zh) 用於提升認知能力的方法及組合物
CN114887028A (zh) 修复受损味觉细胞配方、胶囊剂
Nartsissov Amino Acids as Neurotransmitters. The Balance between Excitation and Inhibition as a Background for Future Clinical Applications
CN112089709A (zh) 维生素k2在制造延缓脑老化药物的新用途
Afreen Treatment options of Parkinson’s disease: How far we are from the cure?
WO2024200609A1 (fr) Association de trigonelline et d'oleuropéine ou de métabolite d'oleuropéine pour le traitement ou la prévention d'états liés aux mitochondries chez un animal de compagnie
Russell The Effects of Exercise on Anxiety and Motor Symptoms of Parkinson’s Disease in Adult Zebrafish (Danio rerio)
UA78886C2 (en) Oxygen cocktail for rehabilitation of children with the nervous system abnormality

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09788307

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 09788307

Country of ref document: EP

Kind code of ref document: A1