US20130237577A1 - Compositions comprising amino acids for prevention and/or treatment of renal disorders - Google Patents

Compositions comprising amino acids for prevention and/or treatment of renal disorders Download PDF

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US20130237577A1
US20130237577A1 US13/521,937 US201113521937A US2013237577A1 US 20130237577 A1 US20130237577 A1 US 20130237577A1 US 201113521937 A US201113521937 A US 201113521937A US 2013237577 A1 US2013237577 A1 US 2013237577A1
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composition
leucine
composition according
isoleucine
valine
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Franco Conti
Francesco Saverio Dioguardi
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Determinants of Metabolism Research Laboratory SRL
MELLA ISABELLA ARBORIO
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Determinants of Metabolism Research Laboratory SRL
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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
    • A61K31/33—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
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/175—Amino acids
    • 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
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
    • A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
    • 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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4172—Imidazole-alkanecarboxylic acids, e.g. histidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the present invention regards compositions for prevention and/or treatment of renal disorders in mammals. More specifically, the present invention concerns the use of compositions for prevention and/or treatment of renal disorders comprising natural and non-natural amino acids preferably in an elderly subject.
  • kidneys age better than other fundamental organs, such as the heart and brain, their decline in structure and function increases the susceptibility of healthy subjects as well as those with chronic disease to drugs and electrolyte abnormalities during stressful conditions.
  • Chronic kidney diseases CKD
  • ESRD end-stage renal disease
  • LPD low
  • VLPD very low
  • Restricting protein in the diet of pregnant mice results in reduced numbers of nephrons in newborn animals greater than 30%.
  • Low (LPD) or very low (VLPD) protein diets have been widely used, first for treating uremia and then to prevent the progression of CKD, but recently, a meta-analysis of existing data concluded that there is no evidence that LPD or VLPD diets have any effect in reducing the progression of kidney disease in diabetic nephropathy, and very often some degree of dangerous protein malnutrition occurs in these patients.
  • the present invention has the aim of providing new compositions for a prophylactic and therapeutic treatment, preferably but not exclusively intended for elderly subjects, of renal disorders.
  • the composition described herein is particularly useful in the prophylactic and therapeutic treatment of renal disorders, and comprises a mixture of amino acids in free form suitable for use over a long period of time.
  • such mixture improves renal filtration, particularly in elderly subjects.
  • the present invention regards compositions based on amino acids for preventing and/or treating renal diseases in mammals having—as main active ingredients—the branched chain amino acid leucine in combination with at least one of, and preferably both, the branched chain amino acids isoleucine and valine.
  • the present invention concerns compositions comprising—as main active ingredients—the branched chain amino acids leucine, isoleucine and valine in combination with at least one of, and preferably both, threonine and lysine.
  • compositions described herein lie in the high tolerability of the composition, which can be administered chronically.
  • administration may occur over a period of time sufficiently long to allow at least partial recovery of renal function.
  • compositions subject of the invention are preferably produced, with or without excipients, according to known production, in formulations suitable for oral administration.
  • the compositions described herein have a pH in aqueous solution comprised between 6.5 and 8.5, with or without excipients suitable for preparing tablets, capsules, powders, etcetera, through which a pharmacological performance suitable for oral administration is intended to be obtained.
  • amino acids compositions produced, still according to per se known production techniques, for other types of administration shall be deemed comprised in the scope of the invention.
  • An advantage linked to the use of the composition described herein lies in the fact that the use of amino acids in free form allows producing such compositions at a comparatively extremely low cost with respect to proteins and growth factors synthesis, through per se known production processes and widely used in the field of preparing compositions based on free amino acids.
  • the field of application of the invention may however also be extended to amino acids obtained through genetic engineering or any other artificial method.
  • FIG. 1 A) Density of glomeruli (Nglo/mm 2 ) and B) ratio between glomerular area and total area (Aglo/Atot) in the 3 experimental groups. * P ⁇ 0.05 versus young; ° P ⁇ 0.05 versus M-aged, Student-Newman-Keuls test.
  • FIG. 2 VEGF immunohistochemistry (counterstained with hematoxylin). The M-aged animals expressed much less VEGF than young animals. After EAA supplementation, the VEGF immunostaining increased inside the glomerulus and inside the cells of Bowman's capsule. Scale bar, 100 ⁇ m.
  • FIG. 3 eNOS immunohistochemistry (counterstained with hematoxylin). Young animals strongly expressed eNOS inside the tubular cells, whereas the expression decreased strongly in the M-aged animals. EAA supplementation restored the immunostaining in the tubular compartment to a level similar to that in the young group. Immunostaining was absent or very faint inside the glomeruli. Scale bar, 100 ⁇ m.
  • FIG. 4 iNOS immunohistochemistry (counterstained with hematoxylin). Young and EAA-fed M-aged animals showed intense iNOS expression only in some cells of distal tubules (star). The M-aged animals fed a standard diet showed intense immunostaining inside glomeruli and in the tubular compartment. Scale bar, 100 ⁇ m.
  • compositions according to the invention comprise—as main active ingredients—the branched amino acid leucine in combination with at least one of, and preferably both, the branched amino acids isoleucine and valine.
  • the preferred molar ratios of isoleucine and valine, with respect to one mole of leucine, are as follows:
  • the inventor ascertained that the activity of the mixtures grew after adding at least one of, and preferably both, the amino acids threonine and lysine to the branched chain amino acids. More in detail, the preferred molar ratios of these amino acids, with respect to one mole of leucine, are as follows:
  • compositions are those in which, considering the sum of leucine, isoleucine and valine equal to 1, in the abovementioned stoichiometric ratio, then the sum of threonine and lysine is comprised between 0.10 and 0.50 (i.e. 1:0.10-0.50), still according to the molar weight, preferably between 0.25 and 0.45 (i.e. 1:0.25-0.45).
  • compositions are more active in presence of further one or more essential amino acids selected from histidine, phenylalanine, methionine and tryptophan.
  • further one or more essential amino acids selected from histidine, phenylalanine, methionine and tryptophan.
  • the overall amount of the further essential amino acids may vary between 0.02 to 0.25 (i.e. 1:0.02-0.25), preferably from 0.05 to 0.15 (i.e. 1:0.05-0.15), still intended as the molar ratio.
  • the sum of the amount of threonine and lysine, still on the basis of the molecular weight, is preferably lower with respect to the sum of the single amounts of branched amino acids used, but greater with respect to the sum of the amount of the further essential amino acids used in the mixture. Furthermore, still preferably and on a molecular weight basis:
  • the activity of the mixtures may be further enhanced by also providing for the insertion of the non-essential amino acid cystine (and/or cysteine) into the composition, in an amount of moles at least equivalent to that of methionine, and preferably comprised between 150 and 350% of methionine.
  • the AA-compositions described herein may also comprise the non-essential amino acid tyrosine, whose ideal amount shall be comprised between 15 and 50%, preferably between 20 and 35%, of the amount of phenylalanine in moles.
  • the AA-compositions may possibly comprise other amino acids with respect to the ones described above, the overall amount of said other amino acids shall not exceed 20% of the total of the active ingredients, and/or not exceed 10% per each single said other amino acid (still in molar weight).
  • the amino acids serine, proline, glycine, alanine, glutamic acid and, above all, arginine are preferably avoided, given that they can be counterproductive or even harmful in some concentrations or stoichiometric ratios with the said formulation.
  • amino acids used in the experimentation that led to the identification of the indicated ratios are those of the levogyrous type, corresponding to those present in nature and which are thus to be considered the preferred active form.
  • the inventor ascertained that also the racemic form may perform the same activity, though in a lower manner proportional to the d-form percentage.
  • active derivatives of the indicated amino acids, in particular the salts thereof, shall obviously be deemed falling within the scope of the present invention.
  • the ratios indicated are applicable, in general terms, also in case of calculation according to the weight in grams of the various amino acids indicated (however bearing in mind that the amount of lysine, expressed in grams, may then be greater with respect to the single amounts of isoleucine and valine).
  • the present inventor demonstrated in the instant description that in M-aged rats chronic AA-composition supplementation prevents the onset of morphological changes during the early stages of senescence.
  • reduced glomerular tufts was detected in the M-aged group that were restored after AA-composition supplementation to the form in younger rats.
  • AA-composition supplementation in the diet is a new strategy for maintaining a healthy renal status to prevent renal disorders and improve the quality of life.
  • the experimental protocol was approved and conducted in accordance with the Italian Ministry of Health and complied with the The National Animal Protection Guidelines . Seventeen male Wistar rats were used: 5 young (2-month-old) animals, and 12 middle-aged (M-aged; 18-month-old) animals.
  • the rats were fed a standard diet ad libitum (18.8% protein content; Dottori Piccioni, Gessate, Milan, Italy) with water ad libitum (control M-aged and young groups) or a diet supplemented with AA-composition in the form of a solution (M-aged+AA group) that provided 1.5 g/kg per day of AA-compositions in the drinking water for 90 days.
  • the concentration of the AA-composition in the drinking water was adjusted to the average daily water consumption of the rats (about 25 mL) and mimicked the recommended daily dose for humans (1).
  • the composition of AA-composition used in the present experiments is shown in Table 1. The body weight and water or AA-composition consumption of each animal were monitored daily.
  • composition of AA-composition used in the present experiments is shown in Table 1.
  • the weight ratios between leucine, isoleucine and valine are preferably equivalent to 2:1:1.
  • Table 1 and Table 2 also show that the single amounts (weight in grams or moles) of histidine, phenylalanine, methionine and tryptophan are preferably decreasing (i.e. the amount of histidine is greater than phenylalanine, which is greater than methionine, which is greater than tryptophan) and the amount (weight in grams or moles) of cystine (and/or cysteine) is preferably greater than tyrosine.
  • the present inventor performed a study—during a period of 20 months—directed to assess the renal function as blood urea nitrogen (BUN) by the Reflotron test (Roche Diagnostics, Indianapolis). Blood samples of control rats (control group) and rats supplemented with AA-composition (AA-treated group) for BUN determination were collected at different time intervals after cisplatin injection. BUN levels exceeding 30 mg/dl were considered abnormal.
  • Rats were from Charles River, Italy and the treatment was performed in accordance with the international guidelines. Male rats of 4 months were caged separately and divided in 2 groups (control and AA-composition treated group) of 40 animals each.
  • the rats were fed a standard diet ad libitum (18.8% protein content; Dottori Piccioni, Gessate, Milan, Italy) with water ad libitum (control group) or a diet supplemented with AA-composition in the form of a solution (AA-treated group) that provided 1 g/kg/day of AA-composition in the drinking water for 20 months.
  • the composition of AA-composition used in the present experiment is shown in Table 1. The body weight and water or AA-composition consumption of each animal were monitored daily.
  • kidneys from each animal were removed, fixed with 3% glutaraldehyde in PBS (pH 7.4, 0.1M), and postfixed for 1 hour with 1% OsO 4 in the same buffer.
  • the samples were processed with standard procedures for embedding in Araldite (Sigma Chemical Co, Milan, Italy). Thick sections (about 1 ⁇ m) were stained with toluidine blue. Ultrathin sections (70 nm) were stained with a saturated aqueous solution of uranyl acetate and lead citrate and examined with a Philips CM10 electron microscope.
  • Collagen deposition and fibrosis were evaluated by a Sirius Red staining method using a modified picrosirius procedure as previously described (4). Briefly, the sections were deparaffinized, rehydrated in distilled water, and immersed in 1% phosphomolybdic acid (Sigma-Aldrich, St. Louis, Mo., USA) for 5 min and then covered with 0.1% (w/v) Sirius Red F3B (C.I.35780 Science Lab, Huston, Tex., USA) in saturated picric acid solution for 1 h at room temperature. The sections were then washed in water and rapidly dehydrated, cleared in xylene, and mounted.
  • 1% phosphomolybdic acid Sigma-Aldrich, St. Louis, Mo., USA
  • Sirius Red F3B C.I.35780 Science Lab, Huston, Tex., USA
  • Sections were incubated overnight with primary anti-iNOS (NOS2-N20-sc651), anti-eNOS (N053-C20-sc654), or anti-VEGF (C-1-sc7269) polyclonal antibodies from Santa Cruz Biotechnology Inc. (Santa Cruz, Calif., USA) diluted 1:100 with PBS.
  • the sections were processed in accordance with the manufacturers' protocols, visualized with a rabbit ABC-peroxidase staining system kit (Santa Cruz Biotechnology), and mounted with DPX.
  • the reaction product was visualized using 0.3% H 2 O 2 and DAB at room temperature.
  • the immunohistochemistry control was performed by omitting the primary antibody in the presence of isotype-matched IgGs.
  • the present inventor also carried out experiments using the peroxidase-anti-peroxidase detection system, but obtained similar results. Each set of experiments was done in triplicate, with each replicate always carried out under the same experimental conditions.
  • the staining intensity on both histochemical and immunohistochemical slides was evaluated using an optical Olympus BX50 microscope equipped with an image analysis program (Image Pro Plus, Immagini e Computer, Milano, Italy) and analyzed quantitatively.
  • the integrated optical density (IOD) was calculated for arbitrary areas, by measuring 10 fields for each sample using a 40 ⁇ objective. Data were pooled to obtain a mean value, and a statistical analysis was applied to compare the results obtained from different experimental groups.
  • Morphometric data are expressed as mean ⁇ SD unless otherwise stated. The statistical significance of the differences between means was assessed with one-way ANOVA followed by the Student-Newman-Keuls test or with a Student t-test. A probability of less than 5% (P ⁇ 0.05) was considered significant.
  • the present inventor did not observe any significant differences of glomerular number (Nglo/mm 2 ) among groups. However, M-aged rats had significantly smaller glomeruli (Aglo), reflected in a reduction in Aglo/Atot of about 40% relative to young rats. Animals in the M-aged+AA group were not statistically different from young animals on these measures ( FIG. 1 ).
  • the M-aged animals occasionally showed signs of interstitial fibrosis and glomerulosclerosis of moderate intensity.
  • the M-aged animals supplemented with AA-composition of table 1 did not show these morphological signs of incipient senescence.
  • VEGF Vascular Marker
  • M-aged animals showed significantly lower VEGF expression relative to young animals.
  • the glomerular endothelia and Bowman's capsule cells of M-aged animals did not show VEGF expression.
  • the animals supplemented with AA-composition of table 1 showed intense VEGF expression mainly in glomeruli and to a lesser extent inside the Bowman's capsule cells ( FIG. 2 ).
  • Endothelial Nitric Oxide Synthase eNOS
  • the present inventor observed a decrease of renal function of the control group during the 20 month period of treatment (t 0 to t 4 ), i.e. an increase of BUN, while the AA-treated group surprisingly maintained renal function within the limits (BUN ⁇ 30 mg/dl).
  • the data (expressed an mean ⁇ SD) are reported in table 5. At the end of the treatments, the animals were 24 months-old.
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CN113304243A (zh) * 2021-04-23 2021-08-27 南方医科大学南方医院 一种人发提取生物活性肽在制备改善慢性肾脏病蛋白代谢治疗药物中的应用及药物
IT202000021664A1 (it) * 2020-09-14 2022-03-14 Iaf Network S P A Formulazione amminoacidica bilanciata

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US10653720B2 (en) 2017-11-03 2020-05-19 Lysulin, Inc. Prevention of protein glycation using lysine/zinc supplements
US11255838B2 (en) 2017-11-03 2022-02-22 Lysulin, Inc. Levels, functions, and resistances related to chronic conditions by using lysine-based supplements
US10610544B2 (en) 2017-11-03 2020-04-07 Lysulin, Inc. Insulin resistance and beta cell function using lysine-based supplements
US10656166B2 (en) 2017-11-03 2020-05-19 Lysulin, Inc. Inhibiting chronic blood and nephrological disorders using lysine-based supplements

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EP3967304A1 (en) * 2020-09-14 2022-03-16 IAF Network S.p.A. Balanced amino acid formulation
CN113304243A (zh) * 2021-04-23 2021-08-27 南方医科大学南方医院 一种人发提取生物活性肽在制备改善慢性肾脏病蛋白代谢治疗药物中的应用及药物

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WO2011086507A1 (en) 2011-07-21
CA2786764A1 (en) 2011-07-21
ITTO20100012A1 (it) 2011-07-13
IT1397446B1 (it) 2013-01-10
US9421190B2 (en) 2016-08-23
WO2011086507A8 (en) 2011-09-29

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