WO1982000250A1 - Procede permettant d'accroitre l'energie et d'ameliorer l'humeur des patients humains normaux - Google Patents

Procede permettant d'accroitre l'energie et d'ameliorer l'humeur des patients humains normaux Download PDF

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Publication number
WO1982000250A1
WO1982000250A1 PCT/US1981/000963 US8100963W WO8200250A1 WO 1982000250 A1 WO1982000250 A1 WO 1982000250A1 US 8100963 W US8100963 W US 8100963W WO 8200250 A1 WO8200250 A1 WO 8200250A1
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WO
WIPO (PCT)
Prior art keywords
tyrosine
phenylalanine
amino acid
brain
acid composition
Prior art date
Application number
PCT/US1981/000963
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English (en)
Inventor
R Wurtman
Original Assignee
R Wurtman
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 R Wurtman filed Critical R Wurtman
Priority to JP50253681A priority Critical patent/JPS58501117A/ja
Publication of WO1982000250A1 publication Critical patent/WO1982000250A1/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
    • A61K31/185—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
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin

Definitions

  • This invention relates to a method and composition for improving vigor in humans increasing the level of a cate- cholamine (norepinephrine, epinephrine, dopamine) in neuronal synapses.
  • DOPA dihydro- xyphenylalanine
  • DOPA has been adminis ⁇ tered to patients ho suffer medical disability resulting from dopamine deficiency in diseases such as Parkinson's
  • DOPA when administered is taken up by cells throughout the body and converted to dopamine and this interferes with the normal metabolic processes in these other cells.
  • DOPA interferes with the body's normal storage of the neurotransmitter serotonin, and lowers brain levels of the compound S-adenosylmethionine. It is believed that these effects contribute to such unwanted side- effects as the "On-Off Phenomenon" and, in some patients, psychotic symptoms.
  • drugs that act by increas- ing dopamine, norepinephrine and epinephrine levels in synapses include the Monoamine Oxidase Inhibitors (which slow the destruction of -these neurotransmitters) and the tricyclic antidepressants; these compounds, which are used in treating diseases like depression, also are relatively non-specific, producing many chemical effects besides increasing synaptic catecholamine levels and thus have a range of unwanted side- effects such as the dangerous increases in blood pressure that occur when people receiving monoamine oxidase inhibitors eat certain foods.
  • Monoamine Oxidase Inhibitors which slow the destruction of -these neurotransmitters
  • tricyclic antidepressants these compounds, which are used in treating diseases like depression, also are relatively non-specific, producing many chemical effects besides increasing synaptic catecholamine levels and thus have a range of unwanted side- effects such as the dangerous increases in blood pressure that occur when people receiving monoamine oxidase inhibitors eat certain foods.
  • Depression in a human patient can be alleviated by administering to the patient tyrosine, phenylalanine or mixtures thereof.
  • tyrosine phenylalanine
  • phenylalanine phenylalanine
  • Human patients afflicted with depression repeat ⁇ edly are afflicted with the following .characteristics : feelings of sadness, diminshed activity, early morning insomnia, inability to take pleasure in outside activity and subjective feeling of lethargy or reduced vigor.
  • normal patients generally are afflicted with one or more of these characteristics only occasionally and not repetitively.
  • the present invention provides a method for treating lack of vigor in human patients associated with a deficiency of cate ⁇ cholamines in synapses.
  • This invention is based upon the dis ⁇ covery that treatments that increase neuronal tyrosine levels can also cause corresponding increases in the amounts of cate ⁇ cholamines released into synapses.
  • the tryosine, and its pre ⁇ cursor, phenylalanine can be administered alone or in ad ⁇ mixture, with other neutral amino acids with or without drugs,
  • OMPI in order to raise brain tyrosine (and phenylalanine) levels, and thereby to improve vigor, the lack of which is associated with deficiency of catecholamines in synapses.
  • tryptophan another amino acid, in the mix- ture, the synthesis and synaptic release of serotonin, another brain neurotransmitter, can similarly be controlled.
  • In ⁇ creased synaptic catecholamine levels are obtained by giving tyrosine regardless of whether the catecholamine-releasing neurons are or are not especially active.
  • Phenylalanine can, in low doses,, be used in place of tyrosine. Tryptophan's proportion in the neutral amino acid mixture can be used to regulate serotonin's release into synapses while increasing catecholamine release as described herein.
  • tyrosine and/or phenylalanine and/or other neutral amino acids is adminis ⁇ tered to a patient, either alone or in combination with one or more drugs thereby to increase the -level of catecholamines like norepinephrine which are released into synapses.
  • Sero ⁇ tonin release also can be controlled at the same time by varying the proportion of tryptophan present in the amino acid mixture. Release of a catecholamine or serotonin into synapses can be increased using amino acid mixtures whether or not the catecholine-releasing or serotonin-releasing neurons are especially active.
  • composition of the amino acid mixture that is utilized depends upon the nature of the illness in the patient that is to be treated.
  • tyrosin and/or phenylalanine
  • trypto ⁇ phan is administered, with or without other amino acids not including serotonis's precursor, trypto ⁇ phan, in doses ranging between 5 mg/kg and 200 mg/kg.
  • OMFI therapy is useful in normal human patients not afflicted with a particular disease or afflication, but who desire to in ⁇ crease their vigor.
  • phenylalanine can be used as a substitute for tyrosine, inasmuch as much of this amino acid is converted to tyrosine in the liver and released into the blood stream for uptake into the brain.
  • plasma phenylalanine levels should be less than about double those of tyrosine, since at the higher levels, phenylalanine competes with tyrosine for uptake into the brain and can in- hibit the enzyme tyrosine hydroxyla ' se.
  • compositions administered also contain tryptophan in addition to tyrosine and/or phenylalanine and other neutral amino acids.
  • Other neutral amino acids that these compositions, can contain in ⁇ clude the branched-chain amino acids (leuchine, isoleucine, valine) as well as methionine, threonine and histidine.
  • the amino acids can be supplied as monomers or as natural or synthetic polymers, e.g., peptides.
  • the pehnylalanine, trypto ⁇ phan and tyrosine will be referred to collectively as "the useful amino acids”.
  • the ratios of the plasma concentrations of tyrosine, phenylalanine and tryptophan to the sum of the other neutral amino acids are normally about 0.08-0.12, 0.07-0.12 and 0.06- 0.14, respectively, depending on the composition of the diet.
  • these ratios are abnormal, causing changes in brain dopamine, norepinephrine, epinephrine and serotonin release.
  • the parti ⁇ cular compositions used in these situations are designed to restore the plasma ratios to normal. To improve vigor, the
  • OMPI goal of amino acid therapy is to raise or lower these ratios above or below their normal ranges, in order to increase the release of a catecholamine, with or without serotonin in ⁇ crease into synapses.
  • the tyrosine, phenylalanine and other neutral amino acids can be administered as free amino acids, esters, salts, natural or synthetic polymers or as constituents of foods.
  • the route of administration can be oral or- parenteral, e.g., intravenous.
  • the following example illustrates the present invention and is not intended to limit the same.
  • Tryosine/Tryp-tophan protocol In the first paradigm, hereafter referred to as the Tryosine/Tryp-tophan protocol, four subjects were tested in a. within subjects design over four test sessions. On each test day subjects ingested a packet containing either tryptophan (50 mg/kg body weight), tyrosine (100 mg/kg), a placebo iden ⁇ tical in appearance to tryptophan, or a placebo identical in appearance to tyrosine. Both placebos consisted of 1 gram of the amino acid valine. Each subject took the substances in a different sequence, in a triple blind design in which neither subject, nor tester, nor data scorer knew what substance had been ingested, and scorer was blind to the subject's overt behavior during the test session.
  • POMS Profile of Mood States
  • the POMS is a self-report mood questionnaire yielding factor analytically derived scales for Tension-Anxiety, Depression-Dejection, Anger-Hostility- Vigor-Activity, Fatique-Inertia, Confusion-Bewilderment.
  • the test consists of 65 5-point adjective rating items, and can be completed easily in 5 minutes. It was developed by McNair, Lorr and Droppel an and is marketed by Educational and Industrial Testing Service, San Diego, California.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Le niveau de catecholamine dans les synapses des neurones est augmente de maniere a accroitre l'energie en administrant une composition neutre d'acide amine a un patient humain de maniere a produire une augmentation du niveau cerebral de catecholamine lorsque la composition contient des quantites accrues de tyrosine et/ou de phenylalamine. Des niveaux cerebraux accrus ou reduits de serotonine sont obtenu lorsque la composition d'acide amine contient des quantites accrues ou reduites de tryptophane. La composition neutre d'acide amine peut etre administree seule ou en meme temps qu'une substance accroissant ou reduisant la neurotransmission catecholaminergique.
PCT/US1981/000963 1980-07-15 1981-07-15 Procede permettant d'accroitre l'energie et d'ameliorer l'humeur des patients humains normaux WO1982000250A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP50253681A JPS58501117A (ja) 1981-07-15 1981-07-15 正常なひと患者における精神賦活剤

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US16900180A 1980-07-15 1980-07-15
US169001800715 1980-07-15

Publications (1)

Publication Number Publication Date
WO1982000250A1 true WO1982000250A1 (fr) 1982-02-04

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Application Number Title Priority Date Filing Date
PCT/US1981/000963 WO1982000250A1 (fr) 1980-07-15 1981-07-15 Procede permettant d'accroitre l'energie et d'ameliorer l'humeur des patients humains normaux

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EP (1) EP0056401A1 (fr)
WO (1) WO1982000250A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0174981A1 (fr) * 1984-03-01 1986-03-26 Vernon Erk Procede de traitement de la depression chez les vertebres.
FR2659236A1 (fr) * 1990-03-06 1991-09-13 Interneuron Pharma Composition pour augmenter l'activite et son utilisation.
CN114377011A (zh) * 2021-12-21 2022-04-22 素密肽(北京)科技有限公司 一种通过雾化吸入补充人体所需神经递质的试剂

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
Biochem. Pharmacology, Vol. 26, pp. 1137-42, published June 1977, GIBSON et al. *
CHEMICAL ABSTRACTS, Vol. 79, entry No. 87422s, published 1973. *
Science, Vol. 185, pp. 183-4, published 12 July 1974, WURTMAN et al. *
Scientific American, pp. 52-6, published December 1957, page. *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0174981A1 (fr) * 1984-03-01 1986-03-26 Vernon Erk Procede de traitement de la depression chez les vertebres.
EP0174981B1 (fr) * 1984-03-01 1995-02-08 ERK, Vernon Procede de traitement de la depression chez les vertebres
FR2659236A1 (fr) * 1990-03-06 1991-09-13 Interneuron Pharma Composition pour augmenter l'activite et son utilisation.
CN114377011A (zh) * 2021-12-21 2022-04-22 素密肽(北京)科技有限公司 一种通过雾化吸入补充人体所需神经递质的试剂

Also Published As

Publication number Publication date
EP0056401A1 (fr) 1982-07-28

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