WO2003013514A1 - Amelioration des fonctions neurologiques - Google Patents

Amelioration des fonctions neurologiques

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Publication number
WO2003013514A1
WO2003013514A1 PCT/US2002/022341 US0222341W WO03013514A1 WO 2003013514 A1 WO2003013514 A1 WO 2003013514A1 US 0222341 W US0222341 W US 0222341W WO 03013514 A1 WO03013514 A1 WO 03013514A1
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WIPO (PCT)
Prior art keywords
medication
disorder
compound
group
coch
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PCT/US2002/022341
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English (en)
Inventor
Michael G. Chez
Original Assignee
Carn-Aware Llc
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Application filed by Carn-Aware Llc filed Critical Carn-Aware Llc
Priority to US10/486,077 priority Critical patent/US8354438B2/en
Publication of WO2003013514A1 publication Critical patent/WO2003013514A1/fr

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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

Definitions

  • the present invention relates to materials and methods for treating neurological diseases and disorders including but not limited to epilepsy and autism, as well as general cognitive problems.
  • epilepsy One of the principal neurological disorders, independent of age, is epilepsy. Over 10% of the population will experience at least one seizure. However, the prevalence of epilepsy does vary with age, and is high during infancy, diminishes during childhood; reaches a nadir during both adolescence and adulthood, and then goes up significantly in old age. Epileptics are characterized by the incidence of seizures, although seizures also occur in other neurological disorders, and even in the absence of a disorder. Seizures are induced by transient, paroxysmal, and synchronous neuronal discharges.
  • epilepsy In contrast to the isolated seizure, epilepsy may be defined as reoccurring seizures and may be genetic or environmental in origin. Based on clinical and electroencephalographic criteria, the International League against Epilepsy developed a widely accepted classification scheme for epilepsy, which divides seizures into three major categories: partial, generalized, and unclassified. In addition to the epilepsy classification, there is also a classification of "epilepsy syndromes": benign childhood epilepsy with centrotemporal spikes, childhood absence epilepsy, juvenile myoclonic epilepsy, chronic progressive epilepsia partialis continua, and severe myoclonic epilepsy of childhood.
  • Drug therapy is the most common seizure treatment.
  • antiseizure medications known as antiepileptic drugs (AED) or anticonvulsants
  • AED antiepileptic drugs
  • anticonvulsants had been available earlier, the introduction of phenobarbital in the early twentieth century issued in the modern era of AEDs. Willmore, J. and Wheless, J. Scientific American Medicine, sect. 11, chp 12, www.samed.com. While most AEDs were introduced before 1980, several new drugs have been recently licensed for use in epilepsy, and additional drugs in the pipeline are destined for approval in the coming years.
  • Autistic spectrum disorders including, but not limited to Autistic Disorder (autism), pervasive developmental delay not otherwise specified, Rhett's disorder, childhood disintegrative disorder, and Asperger's syndrome (see American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4 ed., American Psychiatric Association, Washington, 1993, pp. 65-78), are long term, developmental disorders with no known or agreed upon nervous system pathology or definitive genetic site. Rodier, P.M, J.
  • Pervasive developmental disorders are characterized by severe and pervasive impairment in several areas of development, reciprocal social interaction skills, communication skills, or the presence of stereotyped behavior, interests and activities.
  • the principal criteria of autism include significantly abnormal or impaired development in social interaction and communication and a significantly restricted repertoire of activity and interests.
  • American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4 th ed., American Psychiatric Association, Washington, 1993, pp. 65-78 Depending on the developmental level and chronological age of the individual, how the disorder manifests itself can be very different.
  • Autism or autistic disorder is the most well known of the spectrum disorders, and is also known as early infantile autism, childhood autism and Kanner's autism.
  • Research in the past several years has shown an association between sleep electroencephalograms (EEGs) and autism.
  • EEGs sleep electroencephalograms
  • autism An approach that treats the symptoms and potentially the causes of autism is the individualized nutrient therapy for autism, such as that reported in Isaacson et al., Journal of Applied Nutrition, 48, 110-118 (1996), the Autism Research Publication "Patient Ratings of Behavioral Effects of Drugs, Nutrients, and Diets", ARI Publ. 34, Autism Research Institute, 4182 Adams Avenue, San Diego, CA 92116, September 2000, as well as in other references.
  • This individualized therapy relies on treatment optimized for the individual's particular chemical imbalance, with particular nutrients emphasized in certain imbalances, and others avoided. Such individualized therapy is expensive, and a need exists for effective, cost-effective therapies for autism. Attention Deficit and Disruptive Behavior Disorders constitute another, but related set of neurological disorders.
  • Attention Deficit Disorder also known as Attention Deficit Hyperactive Disorder (ADHD) is characterized by a persistent pattern of inattention and or hyperactivity-impulsivity that is both more frequent and more severe than what is typically observed in individuals of a comparable developmental stage.
  • ADHD Attention Deficit Hyperactive Disorder
  • the inattention may be manifest in academic, occupational, or social situations.
  • CP syndromes are a group of related motor disorders originating usually from either developmental abnormalities or perinatal or postnatal central nervous system (CNS) disorder damage occurring before 5 years of age.
  • CNS central nervous system
  • CP is characterized by impaired voluntary movement. While the term CP is not itself a diagnosis, the term does provide a useful classification of individuals who may suffer from nonprogressive spasticity, ataxia, or involuntary movements. Approximately a quarter of individuals with CP experience convulsive seizures. The Merck Manual, Merck Research Laboratories, 16 th ed. 1992.
  • Tourette's Syndrome comprises both multiple motor and one or more vocal tics, occurring over a period of at least one year, at least intermittently, but sometimes as frequently as many times daily. Obsessions, compulsions, hyperactivity, distractability, and impulsivity are often associated. Onset is in childhood, and tics often lessen in severity and frequency and may even remit during adolescence and adulthood. Dorland's Illustrated Medical Dictionary, 29 th ed., W.B. Saunders Co., 2000.
  • Apraxias are defined by the inability to execute purposeful learned motor acts, even though the patient has the physical ability and willingness to perform the relevant act. Apraxias are commonly found in many metabolic and structural diseases that involve the brain diffusely, particularly those that seem to impair frontal lobe function. In a typical case, a patient cannot follow a motor command even though he or she understand it and can perform individual components of the command. The defect appears to be caused by a lesion in the neural pathways that retain memories of learned movement patterns, resulting in an inability to conceptualize necessary patterns in order to perform actions. The Merck Manual, Merck Research Laboratories, 16 th ed. 1992.
  • apraxias include, but are not limited to, motor and speech apraxias.
  • Motor or innervatory apraxia are characterized by impairment of skilled movements that is greater than different in form from that caused by weakness of the affected parts with the patient appearing clumsy rather than weak.
  • Dorland's Illustrated Medical Dictionary 29 th ed., W.B. Saunders Co., 2000.
  • Speech apraxia is caused by apraxia of mouth and neck muscles due to a lesion interfering with coordination of impulses from Broca's region.
  • Dorland's Illustrated Medical Dictionary 29 th edreted during W.B. Saunders Co., 2000.
  • Central auditory processing disorders are characterized by hearing difficulties due to fundamental deficiencies in cognitive processing as well as to deficits in auditory perceptual processes. http://www.lindamoodbell.com/definitions/centralauditory.htm
  • Bipolar disorder usually begins with depression, and includes at least one period of elation. TTze Merck Manual, Merck Research Laboratories, 16 th ed. 1992.
  • Panic disorders are characterized by chronic, unrealistic anxiety often punctuated by acute attacks of anxiety or panic. Attacks associated with panic disorders can occur repeatedly over a period of time, with durations of anywhere between a few minutes to an hour or two.
  • the Merck Manual Merck Research Laboratories, 16 th ed. 1992.
  • the condition can be defined generally as a condition that interferes with learning to read even though an individual has average or above-average intelligence, adequate motivation and educational opportunities, socioeconomic advantage, and normal sensory acuity.
  • the Merck Manual Merck Research Laboratories, 16 th ed. 1992.
  • Down's syndrome is a trisomy resulting from an extra full or partial copy of chromosome twenty-one. Diagnosis and characterization of Down's syndrome is well known in the art.
  • the present invention addresses one or more needs in neurology by providing materials and methods for the treatment of human disorders, such as autism, epilepsy, seizures, pervasive developmental disorder, cerebral palsy, Tourette's Syndrome, attention deficit disorder, attention deficit hyperactive disorder, central auditory processing disorder, dyslexia, apraxia of speech, motor type apraxia, panic disorder, bipolar disorder, Down's Syndrome and Asperger's Syndrome.
  • the materials and methods generally involve compositions comprising a compound of the following formula:
  • the invention comprises a method of improving neurological function in a human subject comprising identifying a human subject having one or more of the foregoing neurological conditions, and administering to the subject a composition comprising one or more of the compounds represented by the above formula.
  • the invention comprises use of compounds represented by the above formula in the manufacture of a medicament for treating any of the aforementioned diseases.
  • the invention comprises materials and methods for improving such agents, and such therapy, for the various neurological conditions.
  • the invention provides an improved method that additionally comprises administering a composition comprising one or more of the above- described compounds.
  • the medicine and the composition are administered separately.
  • they are administered concurrently.
  • they are administered as a single composition containing both the compound and the medicine. Irrespective of the variation, it is contemplated that administration of such compounds will increase the efficacy of the medicine.
  • the invention comprises use of compounds of the formula provided above in the manufacture of a medicament for the treatment of any of the disorders identified above, where the medicament further includes other accepted medicines for the treatment of the disorder.
  • the invention provides methods of formulating the active ingredients of any medicines for treatment of the foregoing disorders, the method comprising including in the formulation one or more compounds having the structure set forth above.
  • the invention provides a composition comprising a neuromodulator, selected from the group consisting of anticonvulsant medication, selective serotonin reuptake inhibitor medication, acetylcholinesterase medication, pervasive developmental disorder medication, attention deficit disorder/attention deficit hyperactive disorder (ADD/ ADHD) medication, and stimulant medication, in admixture with a compound of the formula set forth above.
  • a neuromodulator selected from the group consisting of anticonvulsant medication, selective serotonin reuptake inhibitor medication, acetylcholinesterase medication, pervasive developmental disorder medication, attention deficit disorder/attention deficit hyperactive disorder (ADD/ ADHD) medication, and stimulant medication, in admixture with a compound of the formula set forth above.
  • the invention comprises a unit dose comprising: a first compound selected from the group consisting of anticonvulsant medication, selective serotonin reuptake inhibitor medication, acetylcholinesterase medication, pervasive developmental disorder medication, attention deficit disorder/attention deficit hyperactive disorder (ADD/ ADHD) medication, and stimulant medication; and a second compound of the formula set forth above.
  • Unit doses of the invention would embrace compositions of the invention, and would also embrace situations where the medicine and the compound are packaged together for co-administration, but are not in admixture.
  • the inclusion of a label with directions (treatment instructions) for usage of both agents in a combined therapy is indicative of a unit dose of the invention.
  • kits which comprise compounds or compositions packaged together in a manner which facilitates their use to practice methods of the invention.
  • a kit includes a composition comprising a compound of the formula set forth above, packaged in a container such as a sealed bottle or vessel, with a label affixed to the container or included in the package that describes use of the compound or composition to practice a method of the invention.
  • the compound or composition is packaged in a unit dosage form.
  • the invention includes, as an additional aspect, all embodiments of the invention narrower in scope in any way than the variations specifically mentioned above.
  • the applicant(s) invented the full scope of the claims appended hereto, the claims appended hereto are not intended to encompass within their scope the prior art work of others. Therefore, in the event that statutory prior art within the scope of a claim is brought to the attention of the applicants by a Patent Office or other entity or individual, the applicant(s) reserve the right to exercise amendment rights under applicable patent laws to redefine the subject matter of such a claim to specifically exclude such statutory prior art or obvious variations of statutory prior art from the scope of such a claim. Variations of the invention defined by such amended claims also are intended as aspects of the invention. DETAILED DESCRIPTION OF THE INVENTION
  • compositions comprising a compound of the following formula (hereinafter Formula I):
  • R is a hydrogen
  • both R 5 and R 6 are H
  • the compound described is carnosine.
  • n 2 and either Ri or R 2 is H(hydrogen)
  • R3 is a carboxyl group (COOH)
  • j is a hydrogen
  • both R 5 and R are H
  • the compound described is homocamosine.
  • R 5 or R ⁇ is an acetyl group (COCH 3 ), then the compound is an acetylated Formula I compound.
  • R3 is a hydrogen
  • R 4 is a hydrogen
  • both R 5 and Rj are H
  • the compound described is carnicine.
  • Y is a sulphonyl (SO 2 ), as opposed to a carbonyl group, one has the tauryl derivatives of Formula I compounds.
  • Preferred compounds include carnosine and homocamosine; and N- acetyl, methylated (anserine, ophidine), decarboxylated (carcinine) and tauryl derivates of carnosine and homocamosine.
  • carnosine and its pharmaceutically acceptable salts, hydrates, or prodrug formulations is highly preferred.
  • Use of both L and D isomers of carnosine and other compounds of Formula I, and mixtures thereof, are also contemplated by the present invention..
  • omega-aminoacyl amino acids are also synthesized by carnosine synthase, an enzyme with broad substrate specificity. Bakardjiev, A. and Bauer, K., Biochemistry (Mosc) 2000 Jul;65(7):779-82.
  • ⁇ -Alanine a non- proteinogenic amino acid, is produced mainly by the liver as the final metabolite of uracil and thymine degradation. Carnosine is digested not by regular peptidases, but by a specific enzyme, camosinase. Boldyrev, A. A. Biochemistry (Mosc) 2000; 65: 751-756.
  • Carnosine a commercially available compound, has the chemical formula C 9 H ⁇ 4 N 4 O 3 , and specifically L-camosine has the chemical name ⁇ -Alanlyl-L- histidine.
  • Turner has outlined the chemical synthesis of carnosine and other Formula I compounds. Quinn, P. J. et al., Molec. Aspects Med. 13:379-444 (1992). Carnosine and anserine can also be isolated efficiently from red muscle tissue by forming an aqueous extract and subsequent alcohol precipitation. Quinn, P. J. et al, Molec. Aspects Med. 13:379-444 (1992).
  • U.S. Patent 4,359,416 describes a process for preparing L-camosine.
  • Carnosine and other histidine-containing dipeptides are abundant in vertebrate tissues including brain, heart and skeletal muscles. Stvolinsky, S.L. and Dobrota, D. Biochemistry (Mosc) 2000; 65: 849-855. Camosine's greatest presence in the body is in muscles, where its principal role appears to be as a buffer. Carnosine may act to accept protons released by lactic acid during glycolysis. Stvolinsky, S.L. and Dobrota, D. Biochemistry (Mosc) 2000; 65: 849-855. In 1974, researchers first determined that carnosine is present in the olfactory bulb and nasal olfactory epithelium of rodents at concentrations higher than any other brain region.
  • Bakardjiev and Bauer Biochemistry (Mosc) 2000 Jul;65(7):779-82) These data agree with studies on the biosynthesis of camosine by primary cultures of rodent brain-derived glial cells.
  • Bakardjiev and Bauer used highly enriched cultures of astrocytes and oligodendrocytes to demonstrate that this camosine synthesis is restricted to the oligodendrocytes. Bakardjiev, A. and Bauer, K., Biochemistry (Mosc) 2000 Jul;65(7):779-82.
  • neurons also contain camosine. Trombly, P.Q., et al, Biochemistry (Mosc) 2000; 65:897-816.
  • the almost complete overlap of glial fibrillary acidic protein and camosine immunoreactivity, and the ability of cultured rat glial cells to synthesize carnosine suggest most camosine-containing cells are astrocytes, oligodendrocytes, or ensheathing cells.
  • Trombly, P.Q., et al Biochemistry (Mosc) 2000; 65:897-816.
  • the precise roles and mechanisms of action of camosine are not well understood, (see Bakardjiev and K.
  • Trombley reports that while carnosine may not act directly act as a neurotransmitter, research suggests that it may be a modulator of neuro transmitters, by influencing how zinc and copper ions interact with synaptic receptors. Trombly, P.Q., et al., Biochemistry (Mosc) 2000; 65:897-816. Homocamosine may also modulate synaptic transmission by controlling zinc availability. Petroff, O.A.C. et al. Neurology 2001; 56:709-715. Zinc and copper have been found in pools in brain regions (hippocampus, locus ceruleus, hypothalamus, olfactory bulb, and cortex) at concentrations that allow them to exert neuromodulator effects.
  • Camosine may have some beneficial effect on Alzheimer's patients (see Trombly, P.Q., et al, Biochemistry (Mosc) 2000; 65:897-816.). In addition to chelation discussed above, such an effect may be attributable to camosine's antiglycosylation abilities. Camosine, in high concentration, can even reverse protein-aldehyde cross-linking. Boldyrev, A.A. Biochemistry (Mosc) 2000; 65: 751- 756. The exact metabolic roles of camosine and other Formula I compounds remain obscure. Bakardjiev, A. and Bauer, K., Biochemistry (Mosc) 2000 Jul;65(7):779-82., Quinn, P. J.
  • Formulation of camosine (or other Formula I compounds) with certain metal cations (e.g., zinc or copper) or certain vitamins (e.g., vitamin B6, vitamin E) or pro-vitamins is specifically contemplated by the present invention.
  • Fontana and coworkers discuss synthesis of tauryl camosine derivatives, i.e. sulphonamide pseudopeptides. Fontana M, et al, Cell Mol Life Sci 2002 Mar;59(3):546-51. Homocamosine has the chemical formula C ⁇ oH ⁇ 6 N 4 O 3 , and specifically
  • L-homocamosine has the chemical name ⁇ -Aminobutyryl-L-histidine.
  • Anserine methylation on Nl of the imidazole ring, has the chemical formula C ⁇ oH ⁇ 6 N O , and specifically L- anserine has the chemical name ⁇ -Alanlyl-1-methyl-L-histidine.
  • Ophidine methylation on N3 of the imidazole ring, has the chemical formula C ⁇ oH ⁇ 6 N 4 O 3; and specifically L-ophidine has the chemical name ⁇ -Alanlyl-3-mefhyl- L-histidine.
  • Homocamosine is a dipeptide synthesized from Gamma-aminobutyric acid (GABA) and histidine.
  • GABA Gamma-aminobutyric acid
  • GABA itself acts as a major inhibitory chemical used by the body.
  • GABA is the major inhibitory neurotransmitter in the cortex.
  • Bradford, H.F. Progress in Neurobiology 1995; 47:477-511; Meldrum, B.S. International Review Neurobiology 1975; 17:1-36.
  • GABA has the ability to control seizure activity.
  • Pyrrolidinone the internal lactam of GABA, crosses the blood brain barrier more readily than GABA and also has anticonvulsant activity.
  • Petroff O.A.C. et al, Neurology 2001 ; 56:709-715.
  • Homocamosine was first identified in 1961 in cow brain. Takahashi, H., Brain Development 1981; 3: 263-270. Homocamosine levels change with age. Takahashi, H., Brain Development 1981; 3: 263-270. Homocamosine may act directly on GABA receptors or indirectly after it is broken down into its primary components, GABA and histidine. Petroff, O.A.C. et al, Neurology 2001 ; 56:709-715.
  • Homocamosine has anticonvulsant properties with several potential mechanisms of action.
  • Ognen A.C. Petroff, M.D. "Studies in patients with complex partial seizures suggest that above normal levels of CSF (cerebral spinal fluid) and occipital lobe homocamosine may contribute to improved seizure control . . .
  • Low homocamosine was associated with poor seizure control and higher levels with better control.” Neurology 2001; 56: 709-15.
  • Formula I compounds include pharmaceutically acceptable salts, particularly where a basic or acidic group is present in a Formula I compound.
  • a basic or acidic group is present in a Formula I compound.
  • an acidic substituent such as -COOH
  • the ammonium, sodium, potassium, calcium and the like salts are contemplated as preferred embodiments for administration to a biological host.
  • an acidic salt such as hydrochloride, hydrobromide, acetate, maleate, palmoate, phosphate, methanesulfonate, p-toluenesulfonate, and the like, is contemplated as a preferred form for administration to a biological host.
  • esters of the compound e.g., methyl, tert-butyl, pivaloyloxymethyl, succinyl, and the like
  • esters being known in the art for modifying solubility and/or hydrolysis characteristics for use as sustained release or prodrug formulations.
  • phrases "pharmaceutically or pharmacologically acceptable” refer to molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to an animal or a human, e.g., orally, topically, transdermally, parenterally, by inhalation spray, vaginally, rectally, or by intracranial injection.
  • parenteral includes subcutaneous injections, intravenous, intramuscular, intracistemal injection, or infusion techniques.
  • compositions that are essentially free of pyrogens, as well as other impurities that could be harmful to humans or animals.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art.
  • compositions containing Formula I compounds may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any known method, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, com starch, or alginic acid; binding agents, for example starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in the U.S. Patents 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for controlled release.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelating capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • an oil medium for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions may contain the active compounds in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymefhylcellulose, methylcellulose, hydroxypropylmefhylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyl- eneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n- propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • preservatives for example ethyl, or n- propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n- propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n- propyl, p-hydroxybenzoate
  • flavoring agents such as sucrose or saccharin.
  • sweetening agents such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
  • These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active compound in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
  • compositions may also be in the form of suppositories for rectal administration of the PTPase modulating compound.
  • compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in
  • the identification of appropriate subjects involves selecting individuals who have been medically evaluated and determined to have one or more of the aforementioned list of conditions (or performing a medical and diagnosing one or more of the conditions).
  • the human subjects are 0-18 years old, and patients 2-12 years old are highly preferred. Treatment of adults also is contemplated.
  • composition is administered in an amount effective to improve neurological function in the human subject. While there are many criteria for evaluating neurological function, it will be apparent to clinicians that each of the conditions referred to above is associated with one or more characteristic neurological abnormalities or deficits, which can be evaluated by physical (e.g., EEG, MRI), social, and psychological tests. Improvements by any such standard evaluation is scored as improved neurological function. Likewise, many of the conditions are associated with undesirable symptoms or physical manifestations, and to lessen the severity or occurrence of one or more symptoms associated with a disease state or disorder is also scored as improving neurological function.
  • physical e.g., EEG, MRI
  • Improvements by any such standard evaluation is scored as improved neurological function.
  • many of the conditions are associated with undesirable symptoms or physical manifestations, and to lessen the severity or occurrence of one or more symptoms associated with a disease state or disorder is also scored as improving neurological function.
  • any form of administration and pharmaceutical composition is contemplated, with oral administration of pills, powders, capsules, liquids, or food additives being preferred.
  • oral administration of pills, powders, capsules, liquids, or food additives being preferred.
  • Those of ordinary skill in the art will readily optimize effective dosages and administration regimens as determined by good medical practice and the clinical condition of the individual patient, taking into account such considerations as therapeutic efficacy, risk of toxicity, and side-effects. Appropriate dosages may be ascertained through the use of established assays for determining blood clotting levels in conjunction with relevant dose-response data.
  • the final dosage regimen will be determined by the attending physician, considering factors that modify the action of drugs, e.g., the drug's specific activity, severity of the damage and the responsiveness of the patient, the age, condition, body weight, sex and diet of the patient, the severity of any infection, time of administration and other clinical factors. As studies are conducted, further information will emerge regarding appropriate dosage levels and duration of treatment for specific diseases and conditions.
  • the frequency of dosing will depend on the pharmacokinetic parameters of the agents and the routes of administration. The optimal
  • Such materials are cocoa butter and polyethylene glycols, for example.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • a coating such as lecithin
  • surfactants for example, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulfate, sodium sorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars or sodium chloride.
  • Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • the invention provides methods of improving neurological function in a human subject comprising steps of identifying a human subject having at least one condition selected from the group consisting of: autism, epilepsy, seizures, pervasive developmental disorder, cerebral palsy, Tourette's Syndrome, attention deficit disorder, attention deficit hyperactive disorder, central auditory processing disorder, dyslexia, apraxia of speech, motor type apraxia, panic disorder, bipolar disorder, Down's Syndrome and Asperger's Syndrome; and administering to the human subject a composition comprising at least one Formula I compound or a pharmaceutically acceptable salt, hydrate, or prodrug thereof, wherein the composition is administered in an amount effective to improve neurological function in the human subject.
  • compositions will be determined by one of skill in the art depending on the route of administration and the desired dosage. See for example Remington's Pharmaceutical Sciences, 18th Ed. (1990, Mack Publ. Co, Easton PA 18042) pp 1435- 1712, incorporated herein by reference. Such formulations may influence the physical state, stability, rate of in vivo release and rate of in vivo clearance of the administered agents. Depending on the route of administration, a suitable dose may be calculated according to body weight, body surface areas or organ size. Further refinement of the calculations necessary to determine the appropriate treatment dose is routinely made as part of any medical treatment regimen, especially in light of the dosage information and assays disclosed herein as well as the pharmacokinetic data observed in animals or human clinical trials
  • administering 100-200 mg daily to a subject or administering between 200 mg and 2000 mg per day, or administering 100 mg to 5000 mg, or administering between 100 mg and 250 mg per day, or administering 400 mg twice daily are just a few of the contemplated embodiments.
  • the method of administration may be oral, topical, intraperitoneal, subcutaneous, sublingual, by inhaler, or other means.
  • the invention provides a method of improving neurological function in a human subject comprising identifying a human subject having at least one condition selected from the group consisting of: autism, epilepsy, seizures, pervasive developmental disorder, cerebral palsy, Tourette's Syndrome, attention deficit disorder, attention deficit hyperactive disorder, central auditory processing disorder, dyslexia, apraxia of speech, motor type apraxia, panic disorder, bipolar disorder, Down's Syndrome and Asperger's Syndrome; and administering to the human subject a composition comprising at least one compound selected from the group consisting of camosine, homocamosine, anserine, ophidine, carcinine, N-acetyl-carnosine, N-acetyl-homocamosine, N-acetyl-anserine, N-acetyl- ophidine, and N-acetyl-carnicine.
  • the invention provides a method of improving neurological function of a human subject comprising identifying a human subject in need of treatment for at least one condition selected from the group consisting of: autism, epilepsy, seizures, pervasive developmental disorder, and cerebral palsy; and administering to the human subject a composition comprising camosine in an amount effective to improve neurological function in the human subject.
  • the condition is autism or epilepsy
  • the compound is camosine.
  • Oral administration of the camosine is preferred.
  • epilepsy specifically contemplated is treatment of intractable forms of epilepsy, meaning forms which have failed to respond to two or more treatment regiments using approved anticonvulsant/antiepileptic drugs.
  • Formula I compounds can be used together with such medicines to improve efficacy. Improved efficacy can be any measurable improvement for the human subject observed as a consequence of the combination therapy. For example, further improvement in neurological function, as described more fully above, is scored as improvement of the efficacy of the medicine. Likewise, since many medicines are both expensive and exert physical and/or behavioral side effects, the ability of co- administration of a Formula I compound to reduce the effective dose of a medicine is also scored as improving efficacy of the medicine, especially if the reduced dose results in reduced side-effects.
  • the invention provides a method of increasing the efficacy of anticonvulsant medication, comprising administering to a human subject having epilepsy or a seizure disorder (or any other disorder for which anticonvulsants are prescribed) anticonvulsant medication and a composition comprising at least one Formula I compound, or a pharmaceutically acceptable salt, hydrate, or prodrug thereof, wherein the compound is administered in an amount effective to increase the efficacy of the anticonvulsant.
  • the Formula I compound can be administered separately from or concurrently with the medication, and can also be admixed with the medication prior to administration.
  • exemplary anticonvulsants/antiepileptics include, but are not limited to the following drugs, the formulation of which is known in the art and/or published in patent and trade literature:
  • Anticonvulsants/ Antiepileptics include, but are not limited to the following drugs:
  • the Formula I compound is camosine.
  • the anticonvulsant medication comprises at least one member selected from the group consisting of carbamazepine, phenytoin, mephenytoin, ethotoin, mephobarbital. phenobarbital, primidone, valproate, gabapentin, lamotrigine, clonazepam, clorazepate, diazepam, lorazepam, ethosuximide, trimefhadione, gama-vinyl GABA, GABA, acetazolamide, felbamate, tiagabine, levetiracetam, vigabatrin, and topiramate.
  • the anticonvulsant medication comprises at least one member selected from the group consisting of: carbamazepine, valproic acid, phenyloin, febamate, tiagabine, clonazepam, lamotrigine, primidone, gabapentin, phenobarbital, oxycarbazine, topiramate and ethosuximide.
  • the anticonvulsant medication comprises at least one member selected from the group consisting of valproate and lamotrigine.
  • the invention provides a method of increasing the efficacy of selective serotonin reuptake inhibitor (SSRI) medication, comprising administering to a human subject having a neurological disorder a selective serotonin reuptake inhibitor medication and a composition comprising at least one Formula I compound, or a pharmaceutically acceptable salt, hydrate, or prodmg thereof, wherein the compound is administered in an amount effective to increase the efficacy of the selective serotonin reuptake inhibitor.
  • SSRI agents that are employed in SSRI medications include the following:
  • Selective Serotonin Reuptake Inhibitors Selective Serotonin Reuptake Inhibitor (SSRI) Medication
  • the selective serotonin reuptake inhibitor medication comprises at least one compound selected from the group consisting of clomipramine hydrochloride, citalopram hydrobromide, venlafaxine hydrochloride, fluvoxamine maleate, paroxetine hydrochloride, fluoxetine hydrochloride, and setraline hydrochloride.
  • the invention provides a method of increasing the efficacy of acetylcholinesterase inhibitor medication, comprising: administering to a human subject having a neurological disorder acetylcholinesterase inhibitor medication and a composition comprising at least one Formula I compound or a pharmaceutically acceptable salt, hydrate, or prodmg thereof, wherein the compound is administered in an amount effective to increase the efficacy of the acetylcholinesterase inhibitor medication.
  • acetylcholinesterase inhibitors include the following:
  • Acetylcholinesterase Inhibitors (Acetylcholinesterase (ACE) inhibitor medication)
  • this invention encompasses a method of increasing the efficacy of pervasive developmental disorder medication.
  • a method of increasing the efficacy of pervasive developmental disorder medication involves administering to a human subject having a pervasive developmental disorder at least one pervasive developmental disorder medication and at least one Formula I compound, wherein the compound is administered in an amount effective to increase the efficacy of the pervasive developmental disorder medication.
  • a pharmaceutically acceptable salt, hydrate, or prodmg of the Formula I compound or drug can also be used in the aforementioned method.
  • Pervasive developmental disorder medications include, but are not limited to the following dmg categories: anticonvulsants (AEDs), selective serotonin reuptake inhibitors and acetylcholinesterase inhibitors.
  • this invention encompasses a method of increasing the efficacy of attention deficit hyperactive disorder medication.
  • This method involves administering to a human subject having a attention deficit/hyperactive disorder at least one attention deficit/hyperactive disorder medication and a composition comprising at least one Formula I compound, wherein the compound is administered in an amount effective to increase the efficacy of the attention deficit/hyperactive disorder medication.
  • a pharmaceutically acceptable salt, hydrate, or prodmg of the Formula I compound or dmg can also be used in the aforementioned method.
  • Attention deficit/hyperactive disorder medications include, but are not limited to the following drugs: atomoxetine, clonidine, dextroamphetamine, pemoline and methylphenidate.
  • this invention encompasses a method of increasing the efficacy of stimulants.
  • This method involves administering to a human subject having a neurological disorder at least one stimulant and a composition comprising at least one Formula I compound, wherein the compound is administered in an amount effective to increase the efficacy of the stimulant.
  • a pharmaceutically acceptable salt, hydrate, or prodmg of the Formula I compound or dmg can also be used in the aforementioned method.
  • Stimulants include, but are not limited to the following drugs: amineptine, amphetamine, amphtaminil, bemegride, benphetamine, brucine, caffeine, chlorphentermine, clofenciclan, clortermine, coca, demanyl phosphate, deoxadrol, dextroamphetamine sulfate, N-ethylamphetamine, ethamivan, etifelmin, etryptamine, fencamfamine, fenethylline, fenozolone, flurothyl, hexacyclonate sodium, homocamfin, inazindol, mefexamide, methamphetamine, methylphenidate, nikethamide, pemoline, pentylenetetrazole, phendimetrazine, phenmetrazine, phentermine, picrotoxin, pipradrol, prolintane
  • the invention includes compositions of matter that are useful for improving neurological functions in human subjects, particularly human subjects having neurological conditions discussed herein.
  • the invention includes a composition comprising a neuromodulator, selected from the group consisting of anticonvulsant medication, selective serotonin reuptake inhibitor medication, acetylcholinesterase medication, pervasive developmental disorder medication, attention deficit disorder/attention deficit hyperactive disorder (ADD/ ADHD) medication, and stimulant medication in admixture with a Formula I compound, or a pharmaceutically acceptable salt, hydrate, or prodmg thereof.
  • a neuromodulator selected from the group consisting of anticonvulsant medication, selective serotonin reuptake inhibitor medication, acetylcholinesterase medication, pervasive developmental disorder medication, attention deficit disorder/attention deficit hyperactive disorder (ADD/ ADHD) medication, and stimulant medication in admixture with a Formula I compound, or a pharmaceutically acceptable salt, hydrate, or prodmg thereof.
  • Preferred Formula I compounds are camosine, homocamosine, anserine, ophidine, carcinine, N-acetyl-camosine, N-acetyl-homocarnosine, N-acetyl- anserine, N-acetyl-ophidine, and N-acetyl-camicine.
  • a highly preferred Formula I compound is camosine.
  • the composition further comprises a pharmaceutically acceptable diluent, adjuvant, excipient, or carrier, to facilitate and improve administration to a human subject.
  • a pharmaceutically acceptable diluent, adjuvant, excipient, or carrier to facilitate and improve administration to a human subject.
  • Pharmaceutical formulation chemistry is a well developed art, and exemplary formulation materials and methods are discussed above. Moreover, most approved medications in the categories set forth above have already been formulated effectively for administration to humans. In one embodiment, it is contemplated that such formulations be minimally modified to include the Formula I composition in a stable manner.
  • the Formula I composition is preferably included in the composition in an amount effective to improve the efficacy of the medication, using parameters for evaluation such as those desribed elsewhere herein.
  • the neuromodulator comprises at least one anticonvulsant selected from the group consisting of carbamazepine, phenytoin, mephenytoin, ethotoin, mephobarbital, phenobarbital, primidone, valproate, gabapentin, lamotrigine, clonazepam. clorazepate, diazepam, lorazepam, ethosuximide, trimethadione, gama-vinyl GABA, GABA, acetazolamide, felbamate, tiagabine, levetiracetam, vigabatrin, and topiramate.
  • the Formula I compound is present in the composition in an amount effective to improve the therapeutic efficacy of the anticonvulsant medication in the treatment of seizures in a human subject.
  • the neuromodulator comprises at least one selective serotonin reuptake inhibitor selected from the group consisting of clomipramine hydrochloride, citalopram hydrobromide, venlafaxine hydrochloride, fluvoxamine maleate, paroxetine hydrochloride, fluoxetine hydrochloride, and setraline hydrochloride.
  • the Formula I compound is present in the composition in an amount effective to improve the therapeutic efficacy of the selective serotonin reuptake inhibitor medication in the treatment of seizures depression, obsessive-compulsive disorder or a panic disorder in a human subject.
  • the neuromodulator comprises at least one acetylcholinesterase inhibitor selected from the group consisting of donepezil hydrochloride, rivastigmine and galantamine.
  • the Formula I compound is present in an amount effective to improve the therapeutic efficacy of the acetylcholinesterase inhibitor medication in a human subject.
  • the neuromodulator comprises at least one pervasive developmental disorder medication selected from the group consisting of anticonvulsants (AEDs), selective serotonin reuptake inhibitors and acetylcholinesterase inhibitors.
  • the Formula I compound is present in an amount effective to improve the therapeutic efficacy of the pervasive developmental disorder medication in a human subject.
  • the neuromodulator comprises at least one ADD/ ADHD medication selected from the group consisting of atomoxetine, clonidine, dextroamphetamine, pemoline and methylphenidate.
  • the Formula I compound is present in an amount effective to improve the therapeutic efficacy of the ADD/ ADHD medication in a human subject.
  • the neuromodulator comprises at least one stimulant selected from the group consisting of amineptine, amphetamine, amphtaminil, bemegride, benphetamine, brucine, caffeine, chlorphentermine, clofenciclan, clortermine, coca, demanyl phosphate, deoxadrol, dextroamphetamine sulfate, N-ethylamphetamine, ethamivan, etifelmin, etryptamine, fencamfamine, fenethylline, fenozolone, flurothyl, hexacyclonate sodium, homocamfin, mazindol, mefexamide, mefhamphetamine, methylphenidate, nikethamide, pemoline, pentylenetetrazole, phendimetrazine, phenmetrazine, phentermine, picrotoxin, pipradrol
  • Camosine may enable improved auditory processing and development, as well as, improved attention span. Camosine may improve reading performance, memory or other neuropsychometric measures.
  • the medication is packaged or formulated together with the Formula I compound (e.g., in a kit or package or unit dose) to permit co-administration, but these two components are not in admixture.
  • the two components to the kit/unit dose are packaged with instmctions for administering the two agents to a human subject for treatment of one of the above-indicated diseases.
  • the invention can be characterized as providing a new use for Formula I compounds.
  • the invention provides the use of one or more Formula I compositions (or a pharmaceutically acceptable salt, hydrate, or prodmg thereof) for the manufacture of a medicament for the treatment of at least one condition selected from the group consisting of autism, epilepsy, seizures, pervasive developmental disorder, cerebral palsy Tourette's Syndrome, attention deficit disorder, attention deficit hyperactive disorder, central auditory processing disorder, dyslexia, apraxia of speech, motor type apraxia, panic disorder, bipolar disorder, Down's Syndrome and Asperger's Syndrome.
  • Preferred Formula I compounds include camosine, homocamosine, anserine, ophidine, carcinine, N- acetyl-carnosine, N-acetyl-homocamosine, N-acetyl-anserine, N-acetyl-ophidine, and N-acetyl-camicine.
  • Camosine is highly preferred, especially for manufacture of a medicament for the treatment of at least one condition selected from the group consisting of autism, epilepsy, seizures, pervasive developmental disorder, and cerebral palsy.
  • the medicament will optionally additionally include one or more of the neuromodulator medicines that have been identified herein (e.g., anticonvulsant medications, selective serotonin reuptake inhibitor medications, acetylcholinesterase medications, pervasive developmental disorder medications, attention deficit disorder/attention deficit hyperactive disorder (ADD/ ADHD) medications, and stimulant medications).
  • the neuromodulator medicines e.g., anticonvulsant medications, selective serotonin reuptake inhibitor medications, acetylcholinesterase medications, pervasive developmental disorder medications, attention deficit disorder/attention deficit hyperactive disorder (ADD/ ADHD) medications, and stimulant medications.
  • camosine may have anti-seizure effects as well as the ability to improve cognitive function.
  • anti-seizure drugs available that secondarily elevate camosine levels but as of now, there are no drugs available whose primary function is to elevate camosine levels as a treatment for seizure disorders.
  • camosine Prior to the applicant's invention, camosine has not been used as a treatment for seizure disorders. It is believed that by directly increasing camosine levels, the number of seizures will decrease and the effectiveness of additional prescribed anti-convulsants will increase.
  • CNS central nervous system
  • camosine in the form of a simple dietary supplement.
  • a gel capsule composed of 100 mg of powdered camosine with cellulose filler, will be taken orally at 100-200 mg/day.
  • the camosine dietary supplement has no known side effects.
  • a camosine supplement is now available in gel capsule form provided by the pharmaceutical company, Alfa Chem (Kings Point, New York). It is believed that by supplementing camosine, additional inhibitory neurotransmitters will be synthesized which will function to reduce the number of seizures, improve cognitive function, and increase the efficacy of prescribed anti-convulsants.
  • camosine may improve cognitive functions of patients suffering from various disorders. These disorders include autism, pervasive developmental disorder, brain injury, cerebral palsy and epilepsy. There are currently no drugs or treatments available whose primary function is to elevate camosine levels as a treatment for the previously mentioned disorders. Patients afflicted with the above disorders were treated with a dietary supplement of camosine in dosages of 200 mg to 2,000 mg per day.
  • the camosine supplement is available in gel capsule form from Alfa Chem (Kings Point, New York).
  • the camosine supplement can be administered orally several times daily.
  • L-camosine is an amino acid dipeptide (histidine and alanine), that may indirectly affect spike and wave discharges by altering GABA bioavailability or affecting copper and zinc influx at the cellular level.
  • MRI spectroscopy has recently demonstrated that brain homocamosine levels may correlate with seizure control.
  • camosine ingestion would modulate homocamosine in the brain, causing spike and wave activity to decrease and seizure control to improve.
  • L-carnosine is a useful add-on medication for intractable seizure disorders with encephalopathic EEG changes or generalized epileptiform activity. Although the exact mechanism is unknown, L-camosine is believed to bind with GABA to form homo-camosine, and may also modulate copper and zinc influx into the neurons decreasing the after-discharges of spike-wave discharges. Further investigation of the effects and exact mechanisms of L-Camosine is warranted.
  • the following protocol was designed to target the purported brain region of dysfunction in ASD, via supplementation with a naturally-occurring amino acid which is believed to act upon frontal lobe systems or GABA receptors.
  • Camosine is the first dietary supplement that may alter the neuronal function in children with ASD that has been substantiated by a double-blind controlled study. Further study is needed to investigate the mechanism of camosine supplementation on brain biochemistry.
  • the purpose of this example is to demonstrate the benefits of treating attention deficit or attention deficit hyperactivity disorder (ADD/ADHD) using carnosine.
  • Patients having been diagnosed with ADD/ ADHD using DSMIVR criteria, are divided into two groups.
  • One group is given a placebo, and the other is given camosine (e.g., a composition comprising camosine, zinc and vitamin E). Both placebo and active substance are identical in encapsulated or powdered appearance, without taste or smell. All pills are contained by a gelatin capsule, and when powder is used, patients or parents of patients are instructed to mix the powder with either food or drink. Dosage of camosine will be 400mg by mouth, twice a day.
  • the experiment will last twelve weeks, and every four weeks, the patients will be examined based on the following criteria: common rating scale, parental diary, teaching reports, etc.
  • Statistical analysis will be conducted on the resulting data using a SSPS program, ANOVA t-tests or student t-tests.
  • Improvements are evaluated for statistical significance. Significant improvement over any parameter used to assess treatment for ADD/ ⁇ DHD provides an indication that the camosine composition is a beneficial therapy (or adjuct therapy for subjects on medication during the study). Improvements seen in subjects that are receiving ADD/ ADHD medications during the study provide an indication to formulate such medications with camosine and/or to package unit doses for patients that include their medication in combination with carnosine.
  • EXAMPLE 6 CARNOSINE AND APRAXIAS The purpose of this example is to demonstrate the benefits of treating apraxias with camosine. The study is conducted in a manner substantially identical to that described in example 5, except that the patients will have been diagnosed with an apraxia and the patients will be evaluated using criteria relevant to the particular apraxia. EXAMPLE 7
  • the purpose of this example is to demonstrate the benefits of treating Tourette's Syndrome with carnosine.
  • the study is conducted in a manner substantially identical to that described in example 5, except that the patients will have been diagnosed with Tourette's and the patients will be evaluated using criteria relevant to Tourette's. Diagnosis is based on clinical history and criteria meeting DSMIYR standards. A tic severity scale such as the Yale Tic Inventory Scale is used. Achenbach and Aberrant Behavorial Checklist is performed. Camosine is added and evaluated for effect on mood, attention, and tic frequency. Dosage of 400 mg b.i.d. for children under 10 years of age, 800 mg b.i.d. for children 10-16 years of age is used.
  • the purpose of this example is to demonstrate the benefits of treating dyslexia with camosine.
  • the study is conducted in a manner substantially identical to that described in example 5, except that the patients will have been diagnosed with dyslexia and the patients will be evaluated using criteria relevant to dyslexia. Patients diagnosed using standard pscychometric testing and by meeting clinical criteria for dyslexia are included in the study.
  • the purpose of this example is to demonstrate the benefits of treating mild depression with camosine.
  • the study is conducted in a manner substantially identical to that described in example 5, except that the patients will have been diagnosed with mild depression and the patients will be evaluated using criteria relevant to mild depression.
  • the dosage for those ages twelve years old and older is 400 mg b.i.d., titrated up to 800 mg b.i.d.. Patients are followed for four months with monthly visits to assess progress.
  • DSMIVR criteria, Aberrant Behavior Checklist, and an appropriate depression inventory scale can all be used to assess progress.
  • EXAMPLE 11 VARIATIONS ON CARNOSINE TREATMENT EXAMPLES Examples 1 through 10 describe studies designed to study camosine's beneficial ability to treat various neurological disorders. Variations of these studies that are also contemplated include using a camosine analog in addition to or substitution of carnosine itself. For example, one of the various Formula I compounds besides camosine is employed EXAMPLE 12
  • This example's purpose is to exhibit the beneficial effect of camosine or other Formula I compound to increase the efficacy of an anticovulsant (AED).
  • AED anticovulsant
  • the study population is paired to match patients undergoing similar pharmaceutical therapy for the neurological condition under study. In half of the patients (control), medication is supplemented with placebo. In the test population, medications are supplemented with varying dosages of camosine (e.g , 400mg, 800 mg, or 1000 mg delivered orally, twice daily) or other compounds described herein.
  • a composition containing camosine e.g. carnosine with vitamin E and zinc.
  • child epilepsy patients are pair-matched by the single or combination anticonvulsant therapies they are receiving. If population study permits, the matching is further refined by other parameters such as age, sex, and/or similarity of clinical symptoms of epilepsy, as well as by seizure type (i.e., one study will be of generalized epilepsy, one of myoclonic epilepsy, and one of partial complex seizures.
  • seizure type i.e., one study will be of generalized epilepsy, one of myoclonic epilepsy, and one of partial complex seizures.
  • One member of each pair continues to receive their current anticonvulsant therapy plus placebo, and the other member of the pair receive their current therapy in combination with the camosine compound.
  • matched patients are evaluated to determine if combination therapy with their anticonvulsant medication and camosine (or other compounds described herein) permits reduction in their dosage of anticonvulsant medication without detrimental clinical effect.
  • camosine or other compounds to permit medicine dosage reductions is scored as increasing efficacy and is highly beneficial, since many neurological medications are more expensive and have greater side-effects than camosine.
  • This example's purpose is to exhibit the beneficial effect of camosine or other Formula I compound to increase the efficacy of a selective serotonin reuptake inhibitor.
  • the study is performed with patients diagnosed with depression, and randomized to camosine and selective serotonin reuptake inhibitor medication together, and selective serotonin reuptake inhibitor medication alone. After six and twelve weeks of treatment, methods appropriate for assessing the effectiveness of selective serotonin reuptake inhibitor medication are employed. Specifically, the severity of depression in the two groups will be compared.
  • acetylcholinesterase inhibitor donepezil hydrochloride (Aricept)
  • This example's purpose is to exhibit the beneficial effect of camosine or other Formula I compounds to increase the efficacy of an acetylcholinesterase inhibitor in the treatment of Alzheimer's Disease.
  • the study is performed in patients with Alzheimer's Disease requiring an acetylcholinesterase inhibitor.
  • One group of patients is given both carnosine and an acetylcholinesterase inhibitor.
  • Another group of patients is given an acetylcholinesterase inhibitor alone.
  • Tests appropriate for assessing the cognitive state of Alzheimer's Disease patients are used to track the progress of the patients, and to compare the progress of the two groups.
  • Participation in the study was voluntary and no compensation for participation was given.
  • the study coordinators obtained written informed consent approved by the Lake Forest Hospital Institutional Review Board from one parent at the baseline visit. Procedures: At the baseline visit, patients were randomized into two groups, group one receiving 2.5 milligrams of DH and group two receiving placebo. The standard donepezil dosage recommendation of 5 milligrams was halved in accordance with pediatric protocols to arrive at a quantity of 2.5 milligrams. The duration of the double-blind, parallel trial was six weeks, at which time all subjects entered open-label treatment for an additional six weeks.
  • Medication Placebo and DH were identical in appearance in capsule (sprinkle) form to allow for easy oral administration. The dose was lowered to 1.25 milligrams or discontinued throughout the 12-week trial if adverse events persisted for more than one week (e.g., irritability, hyperactivity, or gastrointestinal problems). The maximum daily dose was 2.5 milligrams. The medication was adjusted by halving the dose (1.25 mg) if parents noted their children to have tolerable yet persistent gastrointestinal distress, hyperactivity, or irritability. Medication was discontinued if GI intolerability or changes in behavior were considered to be an adverse event (i.e., persisted for more than one day). Medication was administered at dinnertime, unless restlessness occurred in sleep, in which case administration was changed to an earlier time in the day. Dinnertime was selected as the preferred administration time in an attempt to alleviate gastrointestinal side effects observed in the dementia population.
  • the Expressive One- Word Picture Vocabulary Test - Revised can be used as a tool to determine auditory-visual-verbal association ability as well as. expressive language functioning in young children ages two through 12. Gardner, M.F. Expressive One- Word Picture Vocabulary Test (Revised): EOWPVT-R. Novato, CA: Academic Therapy Publications 1990.
  • the test was developed to address general concrete concepts, grouping, abstract concepts, and descriptive concepts. Participants are shown a black-and-white picture and asked to identify it verbally. The test is completed when the child makes six consecutive errors.
  • the Childhood Autism Rating Scale was used to assess changes in autistic features. Schopler, E., Reichler, R.J., Renner, B.R. The Childhood Autism Rating Scale: CARS. Los Angeles, CA: Western Psychological Sciences 1988. It was designed as a rating system for identification of behavioral symptoms and for classification purposes by replacing subjective clinical judgments with objective and quantifiable ratings based upon direct behavioral observation. We adapted the interview-based clinician assessment to a parental rating report that was completed together with the research coordinator at the time of the 6 and 12-week clinic appointments. We asked that the same parent complete the CARS scale each time for the sake of consistency and homogeneity in assessment. The study coordinators asked the parent to form an impression of the child from the last six weeks when completing the CARS at each visit.
  • the CARS is divided into 15 subcategories, each scored by increments of 0.5 points on a scale of one through four, which are cumulatively added resulting in a total score ranging from 15 to 60.
  • the rating scale for total scores is then divided into three classifications: Non-autistic (15-30), Mildly/Moderately Autistic (30.5-36), and Severely Autistic (36.5-60). A lower total score, therefore, designates a less severe rating.
  • Group I and Group II were statistically equivalent at baseline (See Table 1.), all / .05.
  • Improvements in speech and language were apparent at 6 weeks, and improvements were stable through week 12 when compared to baseline. Improvements in CARS scores are indicated by lowered scores, which were most pronounced by week 12.
  • Table 3 shows the changes in speech and behavior for children administered placebo for the first six weeks, followed by six weeks of DH. Table 3. Changes in speech and autistic behaviors for children in Group II
  • Table 4 shows the results of combining the six week treatment data for the two groups. The results of the first six weeks from Group I were combined with the six weeks of treatment for Group II. It is important to note that this combined group therefore contains the data from subjects who were both blinded (Group 1) and unblinded (Group 2) to control for any expectancy effects. Statistically significant changes were observed across all three domains.
  • This example's purpose is to exhibit the beneficial effect of camosine or other Formula I compound to increase the efficacy of an acetylcholinesterase inhibitor in patients with Autistic spectrum disorders.
  • One group of patients is given both camosine and an acetylcholinesterase inhibitor.
  • Another group of patients is given an acetylcholinesterase inhibitor alone.
  • Tests appropriate for assessing the cognitive function of Autistic spectmm disorder children are used to track the " progress of the patients, and to compare the progress of the two groups, as described in detail in Example 15. The study can similarly be repeated in individuals with Tourette's Syndrome, ADD/ ADHD and Down's Syndrome with appropriate modifications in testing when necessary.
  • This example's purpose is to exhibit the beneficial effect of camosine or other Formula I compound to increase the efficacy of an ADD/ ADHD medication.
  • the study is performed in a manner substantially identical to that described in example 12, with the substitution of ADD/ ADHD medication in place of anticonvulsant medication, and the use of tests appropriate for assessing the effectiveness of ADD/ ADHD medication. Specifically, common rating scales, teacher reports and parental diaries are employed.
  • This example's purpose is to exhibit the beneficial effect of camosine or other Formula I compound to increase the efficacy of a pervasive developmental disorder medication.
  • the study is performed in a manner substantially identical to that described in example 12, with the substitution of medications if necessary, and the use of parameters appropriate for assessing the effectiveness of pervasive developmental disorder medication.
  • Examples 12 through 19 describe studies designed to study camosine's beneficial ability to increase the efficacy of various types of medications. Variations of these studies that are also contemplated include using a camosine analog in addition or substitution of camosine itself. For example, one of the various Formula I compounds besides camosine is employed.

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Abstract

La présente invention concerne des substances et des procédés pour le traitement de maladies et de troubles neurologiques, y compris, entre autres, l'épilepsie et l'autisme, ainsi que de problèmes cognitifs généraux.
PCT/US2002/022341 2001-08-08 2002-07-15 Amelioration des fonctions neurologiques WO2003013514A1 (fr)

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WO2005027968A1 (fr) * 2003-09-19 2005-03-31 Eisai Co., Ltd. Medicament contre le syndrome de down
US8729067B2 (en) * 2006-05-22 2014-05-20 The Board Of Trustees Of The Leland Stanford Junior University Pharmacological treatment of cognitive impairment
US10172825B2 (en) 2006-05-22 2019-01-08 The Board Of Trustees Of The Leland Stanford Junior University Pharmacological treatment of cognitive impairment
US9649297B2 (en) 2007-02-07 2017-05-16 Gosforth Centre (Holdings) Pty Ltd. Treatment of ADHD
WO2008095221A1 (fr) * 2007-02-07 2008-08-14 Gosforth Centre (Holdings) Pty Ltd Traitement du syndrome hypercinétique
US8957099B2 (en) 2007-02-07 2015-02-17 Gosforth Centre (Holdings) Pty Ltd. Treatment of ADHD
US10028971B2 (en) 2008-08-06 2018-07-24 Gosforth Centre (Holdings) Pty Ltd. Compositions and methods for treating psychiatric disorders
US9789119B2 (en) 2010-12-17 2017-10-17 The Board Of Trustees Of The Leland Stanford Junior University Cognitive function
US8946206B2 (en) 2010-12-17 2015-02-03 The Board Of Trustees Of The Leland Stanford Junior University Methods for improving cognitive function
JP2022118233A (ja) * 2014-03-28 2022-08-12 国立大学法人 東京大学 イミダゾールジペプチドを含む剤
JP2015193582A (ja) * 2014-03-28 2015-11-05 国立大学法人 東京大学 イミダゾールジペプチドを含む剤
US20180140655A1 (en) * 2014-03-28 2018-05-24 The University Of Tokyo Agent containing imidazole dipeptide
WO2015146522A1 (fr) * 2014-03-28 2015-10-01 国立大学法人 東京大学 Agent comprenant un dipeptide d'imidazole
CN106413733A (zh) * 2014-03-28 2017-02-15 国立大学法人东京大学 包含咪唑二肽的试剂
JP2016102068A (ja) * 2014-11-27 2016-06-02 Ｓｈｉｏｄａライフサイエンス株式会社 鯨筋肉抽出物からなる中長期記憶障害予防改善剤
CN108366999A (zh) * 2015-09-09 2018-08-03 奥维德医疗公司 使用哌苯甲醇治疗发育障碍的方法
KR20190010602A (ko) * 2016-05-19 2019-01-30 시에이치알. 한센 에이/에스 우유-응고 특성이 개선된 키모신 변이체
KR102448390B1 (ko) 2016-05-19 2022-09-28 시에이치알. 한센 에이/에스 우유-응고 특성이 개선된 키모신 변이체
CN108578678A (zh) * 2018-03-13 2018-09-28 孟斯琴 一种抗癫痫药物组合物及其制备方法
JP2021017402A (ja) * 2019-07-17 2021-02-15 東海物産株式会社 軽度認知障害改善用組成物及びこの組成物を用いた軽度認知障害の改善方法
JP7321017B2 (ja) 2019-07-17 2023-08-04 東海物産株式会社 機能性食品

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