GB2078516A - Pharmaceutical compositions containing arginine and lysine - Google Patents

Pharmaceutical compositions containing arginine and lysine Download PDF

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Publication number
GB2078516A
GB2078516A GB8110839A GB8110839A GB2078516A GB 2078516 A GB2078516 A GB 2078516A GB 8110839 A GB8110839 A GB 8110839A GB 8110839 A GB8110839 A GB 8110839A GB 2078516 A GB2078516 A GB 2078516A
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United Kingdom
Prior art keywords
lysine
arginine
pharmaceutical composition
composition
present
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GB8110839A
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GB2078516B (en
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Laboratori Baldacci SpA
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Laboratori Baldacci SpA
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    • 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
    • A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/18—Iodine; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/58—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Inorganic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Oral pharmaceutical compositions comprise arginine and lysine, or pharmaceutically acceptable salts thereof, optionally together with a carrier and/or other pharmaceutical or nutritive materials. The arginine may be present as the pyrrolidone-carboxylate or aspartate salt; the lysine may be as its hydrochloride or aspartate. The composition may also contain fructose, sucrose and/or potassium iodide. The compositions are said to stimulate secretion of insulin and growth hormone.

Description

SPECIFICATION Pharmaceutical composition for therapeutical and diagnostic use and useful as feed integrator The present invention relates to a novel composition having therapeutical activity, which is furthermore useful both for diagnostics and for the integration of diets.
More specifically the present invention relatesto a composition comprising a combination of active principles capable of promoting the release of human growth hormone and of insuline, whereby it finds therapeutical use for the stimulation of the body growth and ofthe weight increase. Furthermore the composition of the present invention is useful for the diagnostic control of the hypophysis functionality.
It is known that after the intravenous adminstration of 30 g of arginine (Floyd J. C. et al, Clin. Res., 322, 1965; Merimee Thomas et al, "Effect of Arginine on Serum Levels of Human Growth-Hormone" The Lancet, 668, 1965) an increase of the insulinemy and of the human growth hormone occurs.
Subsequent research studies (Penny R. et al, "Sequential Study of Arg inine Monochloride and Normal Saline as Stimuli to Growth Hormone Release", Methabolism, 19(2), 165, 1970) confirmed that the intravenous administration of 0.5 glkg of Arginine causes a significant increase of the human growth hormone and an insuline release.
It is lastly known that the human growth hormone and the insuline, together with the thyroid hormones, are responsible of the maturation of the central nervous system, (Roger J. L., "Evidence for Tyroxine. Growth Hormone Interaction during Brain Development", Nature, 282,414, 1979), as it is demonstrated by the increased synthesis of the polyamines, whereby the therapeutical contribution of the present invention is evident under this specific point of view.
Lastly, as regard the diagnostic feature, the intravenous injection of arginine is used as a diagnostic test, especially in paediatrics, to assess the hypophysis functionality.
The arginine, as the hydrochloride or the aspartate, together with other aminoacids and vitamins, and the lysine, in combination with vitamins, are since some time used in the therapy of the physical and phsychic overting, of anorexic states and of protein lack states.
The main purpose of the present invention is that of providing a composition capable of stimulating the incretion of human growth hormone and of insuline.
Another purpose of the present invention is that of providing a composition, as above stated, which can be orally administered and is capable of stimulating the release of human growth hormone and of insuline, both for therapeutical use and for the integration of the diet of human beings and of domestic animals.
A further purpose of the present invention is that of providing a composition of the aforesaid type which is equally useful in the diagnostic field.
These purposes are achieved by means of a pharmaceutical composition for oral use, characterized in that it contains in combination arginine and lysine, either as such or as non toxic, pharmacologically acceptable salts thereof.
According to the preferred embodiment of the composition of the present invention, it is in form of a fructose based syrup containing as a solution arginine pyrrolidon-carboxylate and lysine hydrochloride, further ingredients being possibly added, as for instance iodine, capable of an interaction with the thyroid functionality and consequently capable of an interaction with other factors influencing the growth, particularly those having an activity with respect to the nervous system.
The activity of the composition comprising arginine and lysine according to the invention is highly surprising if it is compared with that of the single active ingredients, as regards the effect on the human growth hormone after the oral administration.
In the enclosed drawings: fig. 1 shows, as a function of the time from the administration, the plasma levels of growth hormone in the human being: the plots A and D relate to the arginine adminstration (1,200 and 2,400 mg respectively; the plot B relates to the adminstration of lysine (1,200 mg) and the plot C relates to the administration of the composition of the present invention (containing 1,200 mg of arginine and 1,200 mg of lysine).
From the fig. 1 the synergic effect of the two aminoacids is evident as regards the stimulation of the release of growth hormone, whereas it is evident as well that both lysine and mainly arginine, at the dose of 1,200 and 2,400 mg, do not cause significant modifications of the growth hormone release.
As regards the stimulation of the insuline release, fig. 2 shows the plot of the plasma levels of insuline (RIA assay method) in response to the administration of arginine 1,2 - pyrrolidon - 5 - carboxylate (1,200 mg), L-aspartic acid (200 mg), and L-lysine hydrochloride (1,200 mg) respectively to normal adult patients (both male and female).
As it is kell known, insulin is one of the most important growth factors, and the action thereof adds to the specific activity with respect to the growth hormon, the latter being further stimulated by the hypoglycemia originating from the insulinemic peak.
Lastly, fig. 3 shows the somatomedinic activity of the serum of patients after the oral administration of the same composition used for the test reported in fig. 2.
These date, reported as absolute Asm values, indicate a good plasmatic somatomedinic activity. It seems thus confirmed that the oral administration of the composition according to the invention causes the release, apart from the immuno-reactive insulin, of a somatotropinic molecule which is biologically active on the components of the somatomedinic system.
Also in vitro, with a substrate of lynphocytes in a monolayer culture, it has been demonstrated that the composition of the present invention induces the release from the hypophysis of the biologically active hormone.
According to the present invention and with refer ence both to the use and to the administration modes, several formulations and dosages are fore seen, namely: a) granule preparation to be solved in water, containing: Lysine HCI 1,200 mg arginine L-2-pyrrolidon-carboxylate 1,200 mg fructose 12 g b) Oral small bottles containing a 4% solution of fructose and 600 mg of lysine HCI and arginine L 2-pyrrolidoncarboxylate per each 15 ml dose.
In the case of the formulation (b), for the human use also preparations are foreseen in which the dosage or arginine pyrrolidoncarboxylate is higher, since the pyrrolidon-carboxylic acid seems to be able to promote the transport through the cell membranes and the utilization of some am inoacids.
Iodine can be further present, in form of potassium iodine for the previously mentioned purpose.
With respectto the latter formulation, namely 15 ml small bottles of a 40% fructose solution containing: arginine pyrrolidon-carboxylate 1 g lysine HCI 0.06 g potassium iodide 0.0005 g the acute toxicity (per os and i.p.) in the rat and in the mouse as well as the chronic toxicity in the rat (after 180 days) and in the minipig (after 90 days) has been studied.
As a result, the composition, at the dose of 1600 mg/kg for 180 days in the rat and for 90 days in the minipig neither caused appreciable modifications of the behaviour nor gave place to suffering signs. On the contratry it was found that the body weight increased both in the rats and in the minipgs undergoing the treatment.
The necroscopic and histomorphological anaylses, the hematochemical, enzimatic and hematologic parameters did not show significant dif ferenceswith respect to the controls and were always within the normal percent limits.
The administration of the composition, before the copulation and during the organogenetic period of the pregnancy does not influence in the rat the reproduction function, the course of the gestation and the foetal and neonatal growth, as doses of 1.6 gperkg.
In the rabbitthe oral administration of 1.6 g per kg does not influence the course of the gestation and has no teratogenic effect. As regards the weight increase the treatment shows a relevent stimulating influence on the body growth of the animals at already the dose foreseen for the therapeutical use in the chimical field.
The action of the aminoacid composition has been tested as regards the weight increase of rats sub jected to a lysine lacking diet.
From these experiments it resulted that, with respect to the negative effects as regards the weight increase as caused by a lysine lacking diet, the administration of the lysine-arginine composition is able to correct the deficicency of the essential aminoacid and to promote the growth of the animals in a decisely better manner in comparison with the administration of the lacking aminoacid alone.
The stimulation of the incretion of growth hormone and of the insulinemia, as shown in the human being by oral admistering the arginine and lysine composition, is capeble of promoting the weight increase of the rats and of the minipigs.
The arginine-lysinecomposition, as it has been assessed, is capable of stimulating the tonic and constant release, aftereach oral administration, of growth hormone and of insulin and seems to be the medium more akin to the physiological way to obtain the optimum promotion of the stature growth and of the weight increase.
In fact, it is known that the incretion of the growth hormones is critic and periodic in the 24 hours range.
As regards the diagnostic use of the compositions of the present invention, it is evident the advantage, especially in the paediatric field, of the use of an orally administerable composition, at a dose of only 40 mg/kg (namely 2,400 mg per 60 kg) ofthecom- position, instead of having recourse to the administration of 500 mg/kg (30 g per 60 kg) by intravenous route.
Only by example and without any limiting purpose, some examples of pharmaceutical composition fortherapeuctical use, for diagnostic use and as feed integrators for the man and the animals, shall be hereinafter given.
Examples ofdiagnostic compositions 1) 30 ml syrup small bottles containing 1,200 mg of arginine pyrrolidon-carboxylate and 1,200 mg of Iysine HCI as a solution.
2) Small envelopes containing 1,200 mg of arginine, 1,200 mg of lysine and 30 g of fructose and saccharose.
Examples of pharmaceutical compositions 1) One-dose small bottles of 15 ml of syrup containing: - 600 mg of arginine pyrrolidon-carboxylate - 600 mg of lysine HCI.
2) Small envelopes containing: - 600 mg of arginine pyrrolidon-carboxylate - 600 mg of lysine HCI - sugarorfructoseq.b.to 10g.
3) One-dose small bottles of 1 S ml of syrup containing: - I g of arginine pyrrolidoncarboxylate - 0.69 of lysineHCI - 0.0005 9 of potassium iodide.
Examples of compositions for both pharmaceutical and diagnostic use 1)30 ml small bottles of a fructose solution of 1,200 mg of arginine and1,200 mg of lysine.
2) Envelopes containing 1,200 mg of arginine, 1,200 mg of lysine and saccharose upto 15 g.
Lastly it is to be pointed out that, for the purposes of the present invention, the possibility of supplementing the two essential active ingredients with other components having auxiliary or different functions or purposes should not be excluded.

Claims (8)

1. Oral pharmaceutical composition for the stimu lation ofthe release of growth hormone and of insulin, characterized by containing arginine and lysine in combination.
2. Pharmaceutical composition according to claim 1, characterized in that the arginine is present as pyrrolidon-carboxylate or aspartate.
3. Pharmaceutical composition according to claim 1 characterized in that the lysine is present as hydrochloride or aspartate.
4. Pharmaceutical composition according to claim 1, characterized in that arginine and lysine are contained at the doses of 1,200 mg.
5. Pharmaceutical composition for the stimula- tion of the stature growth and of the weight increase, characterized in that it contains arginine and lysine, is in form of a fructose solution syrup and further comprises potassium iodide.
6. Oral diagnostic composition for the assessment of the hypophysis functionality, characterized by containing arginine and lysine.
7. Diagnostic composition according to claim 6, characterized by containing 1,200 mg of arginine and 1,200 mg of lysine.
8. A composition for the feed integration, for human and veterinary use, characterised by containing arginine and lysine, in free form or as pharmacologically acceptable non toxic salts.
GB8110839A 1980-06-30 1981-04-07 Pharmaceutical compositions containing arginine and lysine Expired GB2078516B (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
IT23101/80A IT1131854B (en) 1980-06-30 1980-06-30 PHARMACEUTICAL COMPOSITION FOR THERAPEUTIC USE, FOR DIAGNOSTIC USE AND AS A FOOD SUPPLEMENT

Publications (2)

Publication Number Publication Date
GB2078516A true GB2078516A (en) 1982-01-13
GB2078516B GB2078516B (en) 1985-02-27

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ID=11203787

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GB8110839A Expired GB2078516B (en) 1980-06-30 1981-04-07 Pharmaceutical compositions containing arginine and lysine

Country Status (9)

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JP (1) JPS5714530A (en)
AU (1) AU560450B2 (en)
CH (1) CH649222A5 (en)
DE (1) DE3115322A1 (en)
FR (1) FR2485371A1 (en)
GB (1) GB2078516B (en)
IT (1) IT1131854B (en)
PT (1) PT73286B (en)
ZA (1) ZA814430B (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5077313A (en) * 1988-11-25 1991-12-31 Gert Lubec Process for inhibiting pathological collagen cross-linking in diabetes patients
WO2000045651A1 (en) * 1999-02-02 2000-08-10 Novartis Nutrition Ag Oral arginine and insulin secretion

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3314079A1 (en) * 1982-04-19 1983-12-22 Papst Motoren Gmbh & Co Kg Multi-shaft mechanism for signal carriers in cassette form
DE3242501C1 (en) * 1982-11-18 1984-03-29 Degussa Ag, 6000 Frankfurt Use of aqueous L-lysine solutions to supplement feed with L-lysine
FR2568124B1 (en) * 1984-07-24 1988-12-09 Cortial MEDICINE FOR TREATING HYPOTROPHIC CONDITIONS BY ADMINISTRATION OF ARGININE ASPARTATE
AT393080B (en) * 1988-11-25 1991-08-12 Lubec Gert Pharmaceutical use of arginine (salts)
AT393079B (en) * 1989-03-06 1991-08-12 Lubec Gert Pharmaceutical use of agmatine

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR6588M (en) * 1967-10-11 1968-12-30

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5077313A (en) * 1988-11-25 1991-12-31 Gert Lubec Process for inhibiting pathological collagen cross-linking in diabetes patients
WO2000045651A1 (en) * 1999-02-02 2000-08-10 Novartis Nutrition Ag Oral arginine and insulin secretion
US6143786A (en) * 1999-02-02 2000-11-07 Novartis Nutrition Ag Oral arginine and insulin secretion

Also Published As

Publication number Publication date
CH649222A5 (en) 1985-05-15
GB2078516B (en) 1985-02-27
IT8023101A0 (en) 1980-06-30
IT1131854B (en) 1986-06-25
PT73286A (en) 1981-07-01
DE3115322A1 (en) 1982-04-08
ZA814430B (en) 1982-09-29
FR2485371B1 (en) 1985-04-12
JPS5714530A (en) 1982-01-25
PT73286B (en) 1982-07-22
FR2485371A1 (en) 1981-12-31
AU7233681A (en) 1982-01-14
AU560450B2 (en) 1987-04-09

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PCNP Patent ceased through non-payment of renewal fee