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WO1993017670A1 - Reduction des fluctuations apres le repas des concentrations plasmiques de grands acides neutres - Google Patents

Reduction des fluctuations apres le repas des concentrations plasmiques de grands acides neutres Download PDF

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Publication number
WO1993017670A1
WO1993017670A1 PCT/US1993/002651 US9302651W WO9317670A1 WO 1993017670 A1 WO1993017670 A1 WO 1993017670A1 US 9302651 W US9302651 W US 9302651W WO 9317670 A1 WO9317670 A1 WO 9317670A1
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WO
WIPO (PCT)
Prior art keywords
lnaa
protein
approximately
carbohydrate
ratio
Prior art date
Application number
PCT/US1993/002651
Other languages
English (en)
Inventor
Richard J. Wurtman
Judith J. Wurtman
Original Assignee
Interneuron Pharmaceuticals, Inc.
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 Interneuron Pharmaceuticals, Inc. filed Critical Interneuron Pharmaceuticals, Inc.
Priority to JP5516069A priority Critical patent/JPH07507058A/ja
Priority to AU39294/93A priority patent/AU3929493A/en
Priority to KR1019940703100A priority patent/KR950700073A/ko
Priority to EP93908485A priority patent/EP0630238A4/fr
Publication of WO1993017670A1 publication Critical patent/WO1993017670A1/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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • A61K35/16—Blood plasma; Blood serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism

Definitions

  • Treatment of some diseases includes administration of a drug which is a large neutral amino acid ⁇ LNAA) and which must cross the blood-brain barrier to be effective.
  • a drug which is a large neutral amino acid ⁇ LNAA
  • L-dopa, alphamethyldopa (Aldomet) and 5-hydroxytryptophan, which are LNAA can be administered in the treatment of Parkinson's Disease, hypertension or myoclonus.
  • Patients who take such drugs may exhibit variability in their responses to them and may suffer adverse effects, such as L-Dopa induced dyskinesia, from them.
  • the present invention pertains to a method of reducing post-prandial fluctuations in plasma LNAA levels in an individual, particularly for the purpose of reducing variability in the individual's response to treatment with drugs which are themselves LNAA. It further relates to compositions for administration to an individual to reduce fluctuations in plasma concentrations of large neutral amino acids (LNAA) .
  • LNAA includes amino acids which have a single amino group and a single carboxyl group, for example, leucine, isoleucine, tyrosine, valine, phenylalanine and tryptophan.
  • the present composition comprises an appropriate ratio of carbohydrates to protein to reduce fluctuations in plasma LNAA levels, when administered to an individual.
  • the ratio of carbohydrate to protein used can vary from about 3:1 to about 10:1, depending on the individual to whom such a composition is administered, with a ratio 7:1 having been found to be particularly effective. Such characteristics as body weight and plasma amino acid responses will be considered in determining an appropriate carbohydrate to protein ratio for an individual.
  • the present invention also relates to methods of administering foods or compositions which minimize post-prandial fluctuations in plasma LNAA levels. Administration of such compositions or of foods selected to contain a carbohydrate to protein ratio of from about 3:1 to about 10:1 is particularly valuable in minimizing the variability in responses some individuals exhibit to drugs, such as L-dopa, which are themselves LNAA. If an individual wishes to minimize fluctuations in plasma LNAA for only a segment of the twenty-four hour day, the present method can be used to determine the composition of meals and/or snacks consumed during that segment.
  • foods which provide about 80- 500 grams of carbohydrate per day and 7-100 grams of protein per day can be administered to an individual suffering from Parkinson's disease who is being treated with L-dopa and whose response to the drug varies and may be associated with adverse effects, such as dyskinesia.
  • the figures provide graphic representations of the effects of administration of meals in which the ratio (per meal) of carbohydrate to protein was about 4:1 to an individual with Parkinson's Disease who was taking L-dopa. Times at which meals were consumed are indicated by ⁇ .
  • Figure 1 is a graphic representation of L- dopa toxicity, as represented by dyskinesis, the extent to which its administration was associated with dyskinesis at hourly intervals.
  • FIG 2 is a graphic representation of plasma branched-chain amino acid (BCAA) levels (e.g., isoleucine, leucine or valine) at hourly intervals in the individual.
  • BCAA plasma branched-chain amino acid
  • the branched chain amino acids are the most abundant LNAA in the plasma and their levels are most affected by eating carbohydrates or proteins; thus, they are the main determinant of uptake of LNAA drugs into the brain.
  • the ability of the new diet to minimize variations in plasma BCAA level paralleled its damping effects on variations in plasma LNAA.
  • Figure 3 is a graphic representation of plasma DOPA levels (o o) and of the plasma DOPA/LNAA ratio (+ +) at hourly intervals in the individual.
  • the present invention is based on the discovery that fluctuations in plasma LNAA levels, particularly post-prandial fluctuations, can be reduced or controlled and, as a result, that the variability in response in an individual to administration of a drug or drugs which is/are LNAA can also be reduced or controlled.
  • the ability to reduce plasma LNAA level fluctuation and, concomitantly, variation in response to a drug which is a LNAA is of particular value in the management of individuals, such as those with Parkinson's disease, who take such a drug or drugs for treatment of a disease or other condition. It is now possible to improve treatment of individuals taking LNAA because the adverse effects can be ameliorated or eliminated and, as a result, individuals are able to continue to follow their prescribed treatment.
  • Fernstro et al report that plasma leucine was 60 nmoles/ml after a protein-free, high carbohydrate breakfast, and about 240 nmoles/ml after a high protein breakfast.
  • Plasma valine varied from about 100 nmol/ml to 50 nmols/ml under these conditions, and plasma isoleucine ranged from 30 to 60 nmols/ml.
  • a meal rich in carbohydrates elicits the secretion of insulin and facilitates the passage of LNAA out of the blood stream and into peripheral tissues, thus reducing circulating levels.
  • a meal rich in protein tends to increase blood levels of LNAA.
  • LNAA post-prandial changes in plasma LNAA are also important determinants of brain levels of drugs which are themselves LNAA and must compete with other LNAA for transport across the blood-brain barrier.
  • drugs such as L-dopa
  • L-dopa that compete with circulating large neutral amino acids (LNAA) for passage from the blood stream into the brain.
  • L-dopa and such other drugs as alphamethyldopa (Aldomet) and 5- hydroxytryptophan which are themselves LNAA, must enter the brain in order to be effective.
  • L-dopa Brain levels of one such drug, L-dopa, are known to vary with the plasma dopa ratio (i.e., the ratio of plasma dopa concentration to the summed concentrations of the other LNAA) and not with the dopa concentration alone. See Markovitz et al.. Science 197: 1014-1015 (1977). Patients who take such drugs may exhibit variability in response to them, as well as adverse effects, such as dyskinesia.
  • the present invention relates to a method for reducing fluctuations in plasma levels of large neutral amino acids and to compositions and combinations of foods having a selected carbohydrate to protein ratio for use in treating individuals who exhibit variability in responses to drugs, such as L- dopa, which are themselves LNAA, and which must enter the brain in order to be effective.
  • LNAA includes amino acids which comprise a single amino acid and a single carboxyl group such as leucine, isoleucine, valine, tyrosine, phenylalanine, and tryptophan.
  • a composition in which the carbohydrate to protein ratio is approximately 7:1 is administered to a group of individuals.
  • the ratio of carbohydrate to protein can vary from about 3:1 to about 10:1.
  • individuals with reduced insulin sensitivity i.e., secondary to type II diabetes, obesity, or elevated lean body mass
  • foods for meals or snacks can be prepared which provide an effective carbohydrate to protein ratio to minimize post ⁇ prandial fluctuations in plasma concentrations of LNAA.
  • Foods which provide approximately 80-500 grams of carbohydrate per day or 80-116 grams of carbohydrate per meal and approximately 7-100 grams of protein per day or 7-27 grams of protein per meal can be administered to an individual. For example, approximately 250 grams of carbohydrate per day and approximately 35 grams of protein per day will minimize fluctuations in plasma LNAA levels.
  • the actual quantity (or range of quantities) of carbohydrate and of protein to be administered to an individual will be determined empirically, by determining the proportion that elicits the optimal clinical response (i.e., greatest drug response and fewest side effects) .
  • the optimal amounts of carbohydrates and protein can be affirmed by testing their effects on plasma LNAA levels and ratios.
  • LNAA measured are leucine, isoleucine, valine, tyrosine, phenylalanine and tryptophan.
  • the post-prandial changes are measured between 1 and 5 hours after the meal or snack has been consumed.
  • Assessment of values obtained in this manner make it possible to determine an appropriate carbohydrate to protein ratio for an individual (i.e., one effective in reducing or eliminating fluctuations in plasma LNAA levels and, concomitantly, in reducing or eliminating variable responses to a drug, such as L-dopa, which is a LNAA) .
  • the carbohydrates in the foods may be normalized in terms of their ability to trigger insulin release (foods with a high glycemic index include among others potato, starch or sucrose) .
  • a preferred embodiment utilizes a combination of maltodextrin and sucrose.
  • compositions or foods comprising an effective carbohydrate to protein ratio can be administered to individuals to minimize the variability in clinical responses to treatment with drugs which are LNAA.
  • drugs such as L- dopa (levodopa) , Aldomet (alphamethyldopa) , and 5- hydroxytryptophan are LNAA and must compete with other LNAA for transport across the blood-brain barrier.
  • EXEMPLIFICATION I Assessment of post-prandial plasma levels of LNAA and dopa The subject was an otherwise healthy 59-year old with a 12-year history of Parkinson's Disease, which was poorly controlled on Sinimet (i.e., L-dopa and a peripheral decarboxylase inhibitor) plus a dopamine agonist. The subject had experienced difficulty in controlling the marked fluctuations in his symptoms. At one time of day he might be vastly overmedicated, and suffer from very disturbing abnormal movements, or dyskinesis; at another time, not too much later, he would be undermedicated, and suffer from rigidity and tremor. To study plasma levels of dopa and LNAA along with the clinical responses to L-dopa, the subject consumed test meals designed to minimize post-prandial fluctuations in plasma LNAA levels.
  • the subject consumed three meals, each which contained a carbohydrate to protein ratio of approximately 4:1 (87-116 grams of carbohydrate and 20-27 grams of protein for breakfast, lunch and dinner) .
  • LNAA after consumption of a composition with a 7:1 ratio of carbohydrate to protein The subjects were 12 healthy individuals, 6 males and 6 females, between the ages of 56 and 72 years (average age: 67.6 years). Blood was drawn for a determination of the fasting blood levels of LNAA, in each individual, prior to ingestion of a beverage containing a 7:1 ratio of carbohydrate to protein. Blood was then drawn at one (1) hour and three (3) hours post-consumption for determination of LNAA levels.
  • LNAA in Parkinsons patients after consumption of a composition with a 7:1 ratio of carbohydrate to protein The subjects were 7 individuals with Parkinson's Disease, 4 males and 3 females, between the ages of 57 and 79 years (average age: 66.3 years). Blood was drawn for a determination of the fasting blood levels of LNAA, in each individual, prior to ingestion of a beverage containing a 7:1 ratio of carbohydrate to protein. Blood was then drawn at one (1) hour and three (3) hours post-consumption for determination of LNAA levels. As shown in Table III, at one hour after consumption of the 7:1 beverage, the mean level of LNAA for all individuals was 19% higher than the mean fasting level of LNAA. At three hours post- consumption, the mean level was 3% lower than the mean fasting level of LNAA.
  • LNAA in Parkinsons patients after consumption of a composition with a 10:1 ratio of carbohydrate to protein The subjects were 7 individuals with Parkinson's Disease, 4 males and 3 females, between the ages of 57 and 79 years (average age: 66.3 years). Blood was drawn for a determination of the fasting blood levels of LNAA, in each individual, prior to ingestion of a beverage containing a 10:1 ratio of carbohydrate to protein. Blood was then drawn at one (1) hour and three (3) hours post-consumption for determination of LNAA levels.
  • the mean level of LNAA for all individuals was 8% higher than the mean fasting level of LNAA.
  • the mean level was 8% lower than the mean fasting level of LNAA.

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Abstract

L'invention concerne des procédés de réduction des fluctuations après le repas des niveaux dans le plasma de grands acides aminés neutres, ainsi que des compositions utilisées dans ce procédé. Les aliments et compositions ont un rapport hydrate de carbone/protéine compris entre 3:1 environ et 10:1 et, dans un mode spécifique de réalisation, un rapport de 7:1, ce qui a pour résultat de réduire au minimum les variations de réaction que les individus ont envers les médicaments que sont les grands acides aminés neutres.
PCT/US1993/002651 1992-03-11 1993-03-11 Reduction des fluctuations apres le repas des concentrations plasmiques de grands acides neutres WO1993017670A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP5516069A JPH07507058A (ja) 1992-03-11 1993-03-11 大型の中性アミノ酸（ｌｎａａ）の血中濃度の食後変動の低減
AU39294/93A AU3929493A (en) 1992-03-11 1993-03-11 Reducing post-prandial fluctuations in plasma concentrations of large neutral amino acids (lnaa)
KR1019940703100A KR950700073A (ko) 1992-03-11 1993-03-11 거대 중성 아미노산(LNAA)의 혈장농도의 식사후 변이를 감소시키는 방법 및 조성물(Reducing post-prandial fluctuations in plasma concentrations of large neutral amino acide(LNAA)
EP93908485A EP0630238A4 (fr) 1992-03-11 1993-03-11 Reduction des fluctuations apres le repas des concentrations plasmiques de grands acides neutres.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US84924692A 1992-03-11 1992-03-11
US849,246 1992-03-11

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WO1993017670A1 true WO1993017670A1 (fr) 1993-09-16

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PCT/US1993/002651 WO1993017670A1 (fr) 1992-03-11 1993-03-11 Reduction des fluctuations apres le repas des concentrations plasmiques de grands acides neutres

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EP (1) EP0630238A4 (fr)
JP (1) JPH07507058A (fr)
KR (1) KR950700073A (fr)
AU (1) AU3929493A (fr)
CA (1) CA2131801A1 (fr)
WO (1) WO1993017670A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2282048A (en) * 1993-09-13 1995-03-29 Elan Corp Plc Compositions for reducing fluctuations in plasma concentrations of large neutral amino acids
US5432162A (en) * 1989-04-03 1995-07-11 Interneuron Pharmaceuticals, Inc. Reducing post-prandial fluctuations in plasma concentrations of large neutral amino acids (LNAA)
US5698525A (en) * 1989-04-03 1997-12-16 Interneuron Pharmaceuticals, Inc. Reducing post-prandial fluctuations in plasma concentrations of large neutral amino acids (LNAA)
EP1645273A3 (fr) * 2000-03-10 2006-04-19 MERCK PATENT GmbH Nouvelle utilisation de (R)-(-)-2-(5-(4-Fluorophenyl)-3-Pyridylmethylaminomethyl)-chromane et de ses sels physiologiquement acceptables
US7872030B2 (en) 2001-07-26 2011-01-18 Merck Patent Gmbh Use of 2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane and its physiologically acceptable salts

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4210637A (en) * 1978-07-31 1980-07-01 Massachusetts Institute Of Technology Composition and method for suppressing appetite for calories as carbohydrates
US4542123A (en) * 1982-01-11 1985-09-17 Massachusetts Institute Of Technology Composition and method for increasing brain tyrosine levels
US4639465A (en) * 1985-08-30 1987-01-27 Commonwealth Medical Corporation Of America Method and composition for relieving pain
US4687763A (en) * 1985-02-25 1987-08-18 Massachusetts Institute Of Technology Composition and method for increasing levels or release of brain serotonin
US4690820A (en) * 1985-06-07 1987-09-01 The State University Of New York High-caloric, high-fat dietary formula
US4833128A (en) * 1984-12-28 1989-05-23 Neil Solomon Dietary supplement
US4869907A (en) * 1984-04-18 1989-09-26 Toyo Jozo Kabushiki Kaisha Method of enhancing growth and weight gain in swine and block for use therein
US5055446A (en) * 1988-10-21 1991-10-08 University Of Cincinnati Method to improve survival of patients during sepsis by diet composition

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5206218A (en) * 1989-04-03 1993-04-27 Interneuron Pharmaceuticals, Inc. Reducing post-prandial fluctuations in plasma concentrations of large neutral amino acids (lnaa)

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4210637A (en) * 1978-07-31 1980-07-01 Massachusetts Institute Of Technology Composition and method for suppressing appetite for calories as carbohydrates
US4542123A (en) * 1982-01-11 1985-09-17 Massachusetts Institute Of Technology Composition and method for increasing brain tyrosine levels
US4869907A (en) * 1984-04-18 1989-09-26 Toyo Jozo Kabushiki Kaisha Method of enhancing growth and weight gain in swine and block for use therein
US4833128A (en) * 1984-12-28 1989-05-23 Neil Solomon Dietary supplement
US4687763A (en) * 1985-02-25 1987-08-18 Massachusetts Institute Of Technology Composition and method for increasing levels or release of brain serotonin
US4690820A (en) * 1985-06-07 1987-09-01 The State University Of New York High-caloric, high-fat dietary formula
US4639465A (en) * 1985-08-30 1987-01-27 Commonwealth Medical Corporation Of America Method and composition for relieving pain
US5055446A (en) * 1988-10-21 1991-10-08 University Of Cincinnati Method to improve survival of patients during sepsis by diet composition

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
HARRY DAY et al., "The Carbohydrates Chemistry, Biochemistry, Physiology", published 1957 by Academic Press Inc. (N.Y.), see pages 779-817. *
RIVKA BEITNER, "Regulation of Carbohydrate Metabolism", Volume I, published 1985 by CRC Press, Inc. (Boca Raton, Florida), see pages 87-103. *
See also references of EP0630238A4 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5432162A (en) * 1989-04-03 1995-07-11 Interneuron Pharmaceuticals, Inc. Reducing post-prandial fluctuations in plasma concentrations of large neutral amino acids (LNAA)
US5698525A (en) * 1989-04-03 1997-12-16 Interneuron Pharmaceuticals, Inc. Reducing post-prandial fluctuations in plasma concentrations of large neutral amino acids (LNAA)
GB2282048A (en) * 1993-09-13 1995-03-29 Elan Corp Plc Compositions for reducing fluctuations in plasma concentrations of large neutral amino acids
GB2282048B (en) * 1993-09-13 1997-03-19 Elan Corp Plc Compositions for reducing fluctuations in plasma concentrations of large neutral amino acids and use thereof in therapy
EP1645273A3 (fr) * 2000-03-10 2006-04-19 MERCK PATENT GmbH Nouvelle utilisation de (R)-(-)-2-(5-(4-Fluorophenyl)-3-Pyridylmethylaminomethyl)-chromane et de ses sels physiologiquement acceptables
US7928128B2 (en) 2000-03-10 2011-04-19 Merck Patent Gesellschaft Mit Beschrankter Haftung Use of(R)-(−) -2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane and its physiologically acceptable salts
US7872030B2 (en) 2001-07-26 2011-01-18 Merck Patent Gmbh Use of 2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane and its physiologically acceptable salts

Also Published As

Publication number Publication date
EP0630238A4 (fr) 1995-05-24
CA2131801A1 (fr) 1993-09-16
KR950700073A (ko) 1995-01-16
JPH07507058A (ja) 1995-08-03
AU3929493A (en) 1993-10-05
EP0630238A1 (fr) 1994-12-28

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