EP0056401A1 - Process for improving vigor and mood in normal human patients - Google Patents

Process for improving vigor and mood in normal human patients

Info

Publication number
EP0056401A1
EP0056401A1 EP19810902146 EP81902146A EP0056401A1 EP 0056401 A1 EP0056401 A1 EP 0056401A1 EP 19810902146 EP19810902146 EP 19810902146 EP 81902146 A EP81902146 A EP 81902146A EP 0056401 A1 EP0056401 A1 EP 0056401A1
Authority
EP
European Patent Office
Prior art keywords
tyrosine
amino acid
phenylalanine
brain
acid composition
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP19810902146
Other languages
German (de)
French (fr)
Inventor
Richard J. Wurtman
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
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 Individual filed Critical Individual
Publication of EP0056401A1 publication Critical patent/EP0056401A1/en
Withdrawn legal-status Critical Current

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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.

Landscapes

  • 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.The level of catecholamine in the synapses of neurons is increased in order to increase energy by administering a neutral amino acid composition to a human patient in such a way as to produce an increase in the cerebral level of catecholamine when the composition contains increased amounts of tyrosine and / or phenylalamine. Increased or reduced brain levels of serotonin are obtained when the amino acid composition contains increased or reduced amounts of tryptophan. The neutral amino acid composition can be administered alone or in conjunction with a substance that increases or decreases catecholaminergic neurotransmission.

Description

PROCESS FOR IMPROVING VIGOR AND MOOD IN NORMAL HUMAN PATIENTS
Background of the Invention
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.
It is well known that the neurotransmitters dopamine, norepinephrine and epinephrine are derived from dihydro- xyphenylalanine (DOPA]. DOPA is, in turn, produced .in neurons by the enzymatic hydroxylation of the amino acid tyrosine. This process is catalyzed by the enzyme tyrosine hydroxylase. The DOPA is decarboxylated to dopamine by the enzyme aromatic L-amino acid decarboxylase (AAAD) and norepinephrine is pro- duced from dopamine in neurons that also contain the enzyme , ■dopamine beta-hydroxylase. It is also known that within this reaction chain, the rate-limiting step is the conversion of tyrosine to DOPA. For this reason, DOPA has been adminis¬ tered to patients ho suffer medical disability resulting from dopamine deficiency in diseases such as Parkinson's
Disease. Unfortunately, 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. In addition, 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. Other types of 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.
Prior attempts to increase or decrease the catechol¬ amine levels by modifying neuronal tyrosine levels have been deemed unsuccessful because the total amounts of these compounds' in brains and tissues were not noted to change.
It was first observed in Wurtman et al (Science 185:183-184, July 12, 1974) that increases in brain DOPA concentrations, which, under the conditions of the experiments varied in pro¬ portion to the rates at which catecholamines were being syn- thesized, could be obtained by increasing brain ty-rosine concentrations, and that decreases in brain DOPA concentra¬ tions could be produced by giving rats treatments that . decreases brain tyrosine. An example of a treatment that increased brain tyrosine was the administration of tyrosine itself. An example of a treatment that decreased brain tyrosine was the administration of one of the other neutral amino acids, e.g., leucine, that competes with plasma tyrosine for uptake into the brain. Prior to that disclosure, it had been believed that the rate-limiting enzyme, tyrosine hydro- xylase, was so saturated with tyrosine, that increases or decreases. in brain tyrosine levels would not affect tryosine's conversion to DOPA. In neither the above Wurtman et al article nor a subsequent paper by Gibson and Wurtman (Biochem. Pharmacology, 26:1137-1142, June 1977) was it actually shown that such changes in DOPA accumulation were accompanied by changes in brain dopamine, norepinephrine or epinephrine levels. Furthermore, in neither was it shown that changing brain tyrosine levels had any effect on the amounts of catechola ines released into synapses.
Depression in a human patient can be alleviated by administering to the patient tyrosine, phenylalanine or mixtures thereof. In order to regulate blood plasma levels of tyrosine or phenylalanine and thereby to form corres¬ ponding amounts of catecholamines released in synapses in the brain. 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. On the other hand, normal patients generally are afflicted with one or more of these characteristics only occasionally and not repetitively. It would be desirable to provide a means for treating normal patients having occasional reduced vigor, in order to provide relief from such a temporary condition. It would be desirable to provide such a means which is biochemr ically specific and lacks the undesirable side-effects or side-effects associated with administration of presently available drugs which have the effect of increasing cate- cholamine levels released in synapses in the brain. Alterna¬ tively, such a means could be used in combination with presently available drugs to treat lack of vigor, thereby to amplify their therapeutic effects.
Summary of the Invention
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. By varying the proportion of 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.
Detailed Description of Specific Embodiments
In accordance with this invention, 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.
The composition of the amino acid mixture that is utilized depends upon the nature of the illness in the patient that is to be treated. When there is need to increase catecholamine release to increase vigor without increasing that of serotonin, tyrosin (and/or phenylalanine) 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. This
OMFI therapy is useful in normal human patients not afflicted with a particular disease or afflication, but who desire to in¬ crease their vigor. In some situations, 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. However, 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.
In some instances, it may be desirable to also increase brain serotonin levels while increasing catecholamine release since it appears that increasing brain serotonin levels tends to reduce depression. In these instances, the 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. In some diseases, e.g., cirrhosis of the liver leading to coma; diabetes; hyperinsulinism; such catabolic states as starvation, cachexia, disseminated cancer, or severe burns or traumas, 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.
EXAMPLE I A. Tyrosine/Tryptophan/Placebo - Within Subjects
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.
Subjects were normal male college students examined by a physician prior to study entry. On each test morning, one subject ingested the experimental agerft at 8:30 and began a 1-hour test session at 9:15. Another took the substance at 9:30 and began testing for Profile of Mood States (POMS) at 10:15. 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. All sclaes have internal consistency reliabilities in the range of .90. Test-retest reliability over a median period of 20 days ranges between .65 - .74. Although stability is less than would be desired for measurement of a stable personality trait, it is adequate for a more ephemeral characteristic ■ such as mood. Indeed, higher stability might challenge the construct validity of the Scale. The Vigor-Activity subscale of the POMS showed substantial changes over dietary con- ditions and a considerable degree of consistency across sub¬ jects. Scores for each of the four subjects in all four dietary conditions are graphed in Figure 1. As Figure 1 indicates, compared to their own performance on tyrosine* placebo-, all subjects showed a lengthening or slowing of reaction time following ingestion of tryosine. For two subjects, the slowing on tyrosine is similar to that observed on tryptophan or tryptophan placebo, but for two others it is much more pronounced. On the Vigor scale of the POMS, all subjects show some degree of increased vigor after tryosine ingestion as compared to tryosine placebo, and for three, subjective vigor on tryosine is substant-ially greater than vigor following ingestion of tryptophan or tryptophan placebo.
The remaining scales of the POMS showed substantial variability, so that they are difficult to interpret without a greater number of subjects.
OMPI

Claims

1. The process for improving vigor in a human patient which comprises administering to the patient a neutral amino acid composition containing tryosine, phenylalanine or mixtures of tyrosine and phenylalanine in an amount effective to regulate blood plasma levels of tyrosine or phenylalanine to form corresponding amounts of catecholamines released in synapses in the brain.
2. The process of claim 1 wherein the neutral amino acid composition contains tyrosine and tryptophan, the amount of tryptophan being sufficient to increase brain serotonin levels.
3. The process of claim 1 wherein said neutral amino acid composition contains tyrosine and phenylalanine, the amount of phenylalanine being less than that which competes with tryosine for uptake into the brain.
4. The process of claim 1 wherein a drug which induces an increase in catecholaminergic neurotransmission is adminis¬ tered concomitantly with said neutral amino acid composition.
EP19810902146 1980-07-15 1981-07-15 Process for improving vigor and mood in normal human patients Withdrawn EP0056401A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US16900180A 1980-07-15 1980-07-15
US169001 1980-07-15

Publications (1)

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EP0056401A1 true EP0056401A1 (en) 1982-07-28

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Country Status (2)

Country Link
EP (1) EP0056401A1 (en)
WO (1) WO1982000250A1 (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0174981B1 (en) * 1984-03-01 1995-02-08 ERK, Vernon Method of treating depression in vertebrates
US5096712A (en) * 1990-03-06 1992-03-17 Interneuron Pharmaceuticals, Inc. Method for enhancing performance so as to improve vigor and decrease fatigue, confusion, tension, and anxiety
CN114377011A (en) * 2021-12-21 2022-04-22 素密肽(北京)科技有限公司 A preparation for supplementing neurotransmitter required by human body by aerosol inhalation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8200250A1 *

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