WO2009121687A1 - L-citrulline for treating endothelial dysfunction and erectile dysfunction - Google Patents
L-citrulline for treating endothelial dysfunction and erectile dysfunction Download PDFInfo
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- WO2009121687A1 WO2009121687A1 PCT/EP2009/052799 EP2009052799W WO2009121687A1 WO 2009121687 A1 WO2009121687 A1 WO 2009121687A1 EP 2009052799 W EP2009052799 W EP 2009052799W WO 2009121687 A1 WO2009121687 A1 WO 2009121687A1
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- Prior art keywords
- citrulline
- dysfunction
- arginine
- erectile dysfunction
- nitric oxide
- Prior art date
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- RHGKLRLOHDJJDR-BYPYZUCNSA-N L-citrulline Chemical compound NC(=O)NCCC[C@H]([NH3+])C([O-])=O RHGKLRLOHDJJDR-BYPYZUCNSA-N 0.000 title claims abstract description 94
- 229960002173 citrulline Drugs 0.000 title claims abstract description 48
- 208000010228 Erectile Dysfunction Diseases 0.000 title claims abstract description 28
- 201000001881 impotence Diseases 0.000 title claims abstract description 28
- 206010048554 Endothelial dysfunction Diseases 0.000 title claims abstract description 25
- 230000008694 endothelial dysfunction Effects 0.000 title claims abstract description 24
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 claims abstract description 20
- 229920002770 condensed tannin Polymers 0.000 claims abstract description 13
- 239000000203 mixture Substances 0.000 claims abstract description 13
- 235000018192 pine bark supplement Nutrition 0.000 claims abstract description 13
- 229940106796 pycnogenol Drugs 0.000 claims abstract description 13
- 239000000126 substance Substances 0.000 claims abstract description 12
- 241000221013 Viscum album Species 0.000 claims abstract description 11
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000011724 folic acid Substances 0.000 claims abstract description 10
- 229960000304 folic acid Drugs 0.000 claims abstract description 10
- 235000019152 folic acid Nutrition 0.000 claims abstract description 10
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 claims abstract description 10
- FNKQXYHWGSIFBK-RPDRRWSUSA-N sapropterin Chemical compound N1=C(N)NC(=O)C2=C1NC[C@H]([C@@H](O)[C@@H](O)C)N2 FNKQXYHWGSIFBK-RPDRRWSUSA-N 0.000 claims abstract description 10
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- 239000006286 aqueous extract Substances 0.000 claims abstract description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
- ACFIXJIJDZMPPO-NNYOXOHSSA-N NADPH Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](OP(O)(O)=O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 ACFIXJIJDZMPPO-NNYOXOHSSA-N 0.000 claims abstract 3
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 claims description 39
- 235000014852 L-arginine Nutrition 0.000 claims description 36
- 229930064664 L-arginine Natural products 0.000 claims description 36
- 108010021487 Nitric Oxide Synthase Proteins 0.000 claims description 17
- 102000008299 Nitric Oxide Synthase Human genes 0.000 claims description 17
- 102000004190 Enzymes Human genes 0.000 claims description 13
- 108090000790 Enzymes Proteins 0.000 claims description 13
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- XJLXINKUBYWONI-NNYOXOHSSA-N NADP zwitterion Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-NNYOXOHSSA-N 0.000 description 9
- 230000003511 endothelial effect Effects 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 8
- ZOOGRGPOEVQQDX-KHLHZJAASA-N cyclic guanosine monophosphate Chemical compound C([C@H]1O2)O[P@](O)(=O)O[C@@H]1[C@H](O)[C@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-KHLHZJAASA-N 0.000 description 7
- 241000196324 Embryophyta Species 0.000 description 6
- YDGMGEXADBMOMJ-LURJTMIESA-N N(g)-dimethylarginine Chemical compound CN(C)C(\N)=N\CCC[C@H](N)C(O)=O YDGMGEXADBMOMJ-LURJTMIESA-N 0.000 description 6
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- FFFHZYDWPBMWHY-VKHMYHEASA-N L-homocysteine Chemical compound OC(=O)[C@@H](N)CCS FFFHZYDWPBMWHY-VKHMYHEASA-N 0.000 description 5
- YDGMGEXADBMOMJ-UHFFFAOYSA-N asymmetrical dimethylarginine Natural products CN(C)C(N)=NCCCC(N)C(O)=O YDGMGEXADBMOMJ-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
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- 101001124309 Homo sapiens Nitric oxide synthase, endothelial Proteins 0.000 description 3
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- KDZOASGQNOPSCU-WDSKDSINSA-N Argininosuccinic acid Chemical compound OC(=O)[C@@H](N)CCC\N=C(/N)N[C@H](C(O)=O)CC(O)=O KDZOASGQNOPSCU-WDSKDSINSA-N 0.000 description 2
- 101001128158 Homo sapiens Nanos homolog 2 Proteins 0.000 description 2
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- RHGKLRLOHDJJDR-UHFFFAOYSA-N Ndelta-carbamoyl-DL-ornithine Natural products OC(=O)C(N)CCCNC(N)=O RHGKLRLOHDJJDR-UHFFFAOYSA-N 0.000 description 2
- 102100029438 Nitric oxide synthase, inducible Human genes 0.000 description 2
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- 230000009986 erectile function Effects 0.000 description 2
- 229930003935 flavonoid Natural products 0.000 description 2
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- JPFCOVZKLAXXOE-XBNSMERZSA-N (3r)-2-(3,5-dihydroxy-4-methoxyphenyl)-8-[(2r,3r,4r)-3,5,7-trihydroxy-2-(4-hydroxyphenyl)-3,4-dihydro-2h-chromen-4-yl]-3,4-dihydro-2h-chromene-3,5,7-triol Chemical compound C1=C(O)C(OC)=C(O)C=C1C1[C@H](O)CC(C(O)=CC(O)=C2[C@H]3C4=C(O)C=C(O)C=C4O[C@@H]([C@@H]3O)C=3C=CC(O)=CC=3)=C2O1 JPFCOVZKLAXXOE-XBNSMERZSA-N 0.000 description 1
- 102000004452 Arginase Human genes 0.000 description 1
- 108700024123 Arginases Proteins 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 241001444063 Aronia Species 0.000 description 1
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- 101710090055 Nitric oxide synthase, endothelial Proteins 0.000 description 1
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- 241000700159 Rattus Species 0.000 description 1
- 235000012300 Rhipsalis cassutha Nutrition 0.000 description 1
- 235000001466 Ribes nigrum Nutrition 0.000 description 1
- 241001312569 Ribes nigrum Species 0.000 description 1
- 241000221012 Viscum Species 0.000 description 1
- 235000014787 Vitis vinifera Nutrition 0.000 description 1
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- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000009697 arginine Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000004706 cardiovascular dysfunction Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
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- 210000002889 endothelial cell Anatomy 0.000 description 1
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- 230000001856 erectile effect Effects 0.000 description 1
- 235000020776 essential amino acid Nutrition 0.000 description 1
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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
- 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 or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7084—Compounds having two nucleosides or nucleotides, e.g. nicotinamide-adenine dinucleotide, flavine-adenine dinucleotide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
-
- 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
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Definitions
- the present invention relates to a compound and a pharmaceutical composition for treating endothelial dysfunction and in particular erectile dysfunction.
- endothelial dysfunction an alteration of the normal biochemical processes normally performed by endothelial tissue which causes several vascular disorders and particularly male erectile dysfunction, is due to the reduced local bioavailability of nitric oxide (NO), the quintessential endogenous vasodilatory substance.
- NO nitric oxide
- NOS nitric oxide synthase
- Nitric oxide once produced, enters the smooth muscle cell, where it activates a particular enzyme known as soluble guanylyl cyclase (sGC), with a consequent increase in the quantity of intracellular cyclic guanosine monophosphate (cGMP), reduction in the concentration of Ca 2+ ion, and consequent vasodilation.
- sGC soluble guanylyl cyclase
- nitric oxide bioavailability increase the bioavailability of the nitric oxide precursor, i.e., L-arginine; increase the activity of NOS enzymes; and increase the concentration of intracellular cGMP.
- L-arginine The semi-essential amino acid L-arginine is derived mostly from food and only for 5-15% from de novo synthesis.
- Another limitation to oral administration of high doses of L-arginine is the presence of endogenous inhibitors of the reaction for conversion of L-arginine into nitric oxide by NOS. These inhibitors push the activity curve of the enzyme reaction toward higher levels of L-arginine than those administered, an effect acknowledged scientifically as a "paradox effect”.
- ADMA Asymmetric dimethylarginine
- NOS NOS isoforms
- ADMA normally circulates in blood at low dosages, but a conspicuous increase thereof is observed in subjects affected by endothelial dysfunction and in particular by erectile dysfunction or in subjects receiving excessive administration of L-arginine. It has been demonstrated scientifically that the ratio between L-arginine and ADMA is one of the key factors in the production of nitric oxide by NOS.
- oral administration of L-arginine is unable to increase endogenous production of nitric oxide due to the low absorption of this amino acid caused by: the intense catabolism to which it is subjected in the intestine; its short half-life; and difficulty in modifying the L- arginine/ADMA ratio.
- erectile dysfunction therapy is based substantially on oral administration of phosphodiesterase-5 (PDE5) inhibitors.
- Drugs containing active ingredients capable of inhibiting PDE5 act by increasing the bioavailability of cGMP at the smooth muscle cell level, inhibiting its catabolism operated by PDE5.
- these drags are actually unable to increase nitric oxide synthesis and are therefore considered "on demand" drugs, which lead to a temporary increase in erectile functionality.
- the aim of the present invention is to provide a drug that can cure endothelial dysfunction wherever it occurs by means of an increase in the endogenous production of nitric oxide and does not require ad hoc administration to obtain a momentary increase in nitric oxide.
- an object of the invention is to provide a drug that is capable of acting in a differentiated but simultaneous manner on the normal biochemical processes that regulate endogenous synthesis of nitric oxide.
- NOS nitric oxide synthase
- an object of the present invention is to provide a drug that can increase the penetration of L-arginine at the endothelial intracellular level.
- L-citrulline for the treatment of endothelial dysfunction or of erectile dysfunction.
- the aim and objects of the invention are also achieved by a pharmaceutical composition comprising L-citrulline in combination with one or more substances selected from the group consisting of pycnogenol, aqueous extract of Visciim album, nicotinamide adenine dinucleotide phosphate (NADPH), tetrahydrobiopterin, folic acid, and mixtures thereof.
- L-citrulline in the treatment of endothelial dysfunction is due to the fact that this non-essential amino acid does not undergo pre-systemic elimination. It is in fact believed that L- citrulline undergoes systemic metabolism, during which it is converted by the L-argininosuccinate synthase enzyme into L-argininosuccinate, which in turn is broken down by the L-argininosuccinase enzyme to yield L-arginine. From this point of view, L-citrulline can be considered as the natural precursor of L-arginine. L-citrulline in fact allows indirectly to increase the bioavailability and plasma half-life of L-arginine, since differently from L- arginine it does not undergo intense intestinal catabolism.
- L-citrulline known until now only in the treatment of cardiovascular dysfunctions, is capable of curing endothelial dysfunction wherever it occurs and in particular in the case of erectile dysfunction.
- Another embodiment of the present invention consists of the further combination of L-citrulline for the treatment of endothelial dysfunction or of erectile dysfunction with a substance selected from the group consisting of pycnogenol, aqueous extract of Viscum album, and mixtures thereof.
- Pycnogenol is a plant-derived flavonoid, also known as proanthocyanidin. This substance is contained naturally in many plants, including Vitis vinifera, Vaccinus myrtillus, Ribes nigrum, Cornelia sinensis, plants of the genus Aronia and other plants generally known to contain flavonoids.
- pycnogenol is capable of increasing the activity of the NOS3 (endothelial NOS) enzyme at the sperm cell level.
- Viscum album is a plant known by the more common name of mistletoe.
- the aqueous extract of this plant has proved to be capable of inducing an overexpression of NOS2 and NOS3 enzymes at the level of muscle cells of the Guinea pigs to which it has been administered.
- Another embodiment of the present invention also consists of the further combination of L-citrulline for the treatment of endothelial dysfunction or of erectile dysfunction with one or more enzyme cofactors selected from the group consisting of nicotinamide adenine dinucleotide phosphate (NADPH), tetrahydrobiopterin, folic acid and mixtures thereof.
- enzyme cofactors are substances whose presence is required for the optimum biochemical activity of some enzymes.
- NOS enzymes use NADPH and tetrahydrobiopterin as essential cofactors.
- the inventor of the present invention has discovered that resorting to a combination of L-citrulline with NADPH and/or tetrahydrobiopterin allows to favor the activity of NOS and accordingly the production of nitric oxide.
- the inventor of the present invention has discovered that resorting to a combination of L-citrulline with folic acid allows to increase endothelial penetration of L-arginine by way of the reduction of homocysteine levels. In turn, this allows a higher inflow of the nitric oxide precursor, L-arginine, at the level of the tissues involved in endothelial and erectile dysfunction.
- L-citrulline on its own or in combination with one or more substances selected from the group consisting of pycnogenol, aqueous extract of Viscum album, NADPH, tetrahydrobiopterin, folic acid, and mixtures thereof can be characterized in that the treatment of the endothelial dysfunction or of the erectile dysfunction occurs by means of the simultaneous increase in the levels of L-arginine and nitric oxide synthase (NOS).
- NOS nitric oxide synthase
- L-citrulline may be administered preferably in a quantity equal to 6 grams/day.
- daily administration of L-citrulline may be split into two doses of 3 grams each or three doses of 2 grams each.
- L-citrulline for treating endothelial dysfunction or erectile dysfunction may be used also in combination with other drugs already known for treatment of erectile dysfunction, for example drugs containing PDE5 inhibitors.
- the present invention relates also to a pharmaceutical composition characterized in that it comprises L-citrulline in combination with one or more substances selected from the group consisting of pycnogenol, aqueous extract of Viscum album, NADPH, tetrahydrobiopterin, folic acid and mixtures thereof.
- composition of the present invention may further comprise one or more excipients generally used in pharmaceutical practice.
- composition may assume any formulation suitable for its administration to a patient affected by endothelial dysfunction or erectile dysfunction.
- the composition according to the invention may be in the form of powder, capsules or sachets.
- the inventor of the present invention has discovered that the pharmaceutical composition described herein is effective particularly in the treatment of endothelial dysfunction and of erectile dysfunction, and therefore in a preferred embodiment the pharmaceutical composition according to the invention may be used in the treatment of endothelial dysfunction or of erectile dysfunction.
- the present invention also relates to a method for treating endothelial dysfunction or erectile dysfunction by administering L-citrulline to a patient, optionally in combination with one or more substances selected from the group consisting of pycnogenol, aqueous extract of Viscum album,
- NADPH tetrahydrobiopterin
- folic acid NADPH, tetrahydrobiopterin, folic acid and mixtures thereof.
- the method according to the invention may provide for oral administration of L-citrulline.
- L-citrulline may be administered in an amount equal to 6 grams/day.
- the daily administration of L-citrulline may be split into two doses of 3 grams each or three doses of 2 grams each.
- L-citrulline in the treatment of erectile dysfunction has been verified by conducting a randomized prospective study on 20 patients, during which L-citrulline was administered orally with a dosage of 6 grams/day, in two separate 3-gram doses, to patients affected by erectile dysfunction.
- a second group of patients received an administration of L-arginine equal to 3 grams/day, split into two 1.5-gram doses.
- the effects of the administration were then tested at the biochemical level by studying the following parameters:
- L-citrulline for treating endothelial dysfunction or erectile dysfunction fully achieves the intended aim, since the administration of L-citrulline alone modifies positively and in a statistically significant way the biochemical and clinical parameters linked to erectile dysfunction, thus indicating that the endogenous capacity of tissues to synthesize nitric oxide has been restored.
- L-citrulline also thanks to combination with other substances such as pycnogenol, extract of Viscum album and enzyme cofactors, allows to act in a differentiated but simultaneous manner on the normal biochemical processes that regulate endogenous synthesis of nitric oxide.
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- Natural Medicines & Medicinal Plants (AREA)
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- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Botany (AREA)
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- Microbiology (AREA)
- Mycology (AREA)
- Biotechnology (AREA)
- Alternative & Traditional Medicine (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
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Abstract
L-citrulline for treatment of endothelial dysfunction and in particular of erectile dysfunction and a pharmaceutical composition comprising L-citrulline in combination with one or more substances selected from the group consisting of pycnogenol, aqueous extract of Viscum album, NADPH, tetrahydrobiopterin, folic acid and mixtures thereof.
Description
L-CITRULLINE FOR TREATING ENDOTHELIAL DYSFUNCTION
AND ERECTILE DYSFUNCTION
Technical field
The present invention relates to a compound and a pharmaceutical composition for treating endothelial dysfunction and in particular erectile dysfunction.
Background art
It is now universally acknowledged that endothelial dysfunction, an alteration of the normal biochemical processes normally performed by endothelial tissue which causes several vascular disorders and particularly male erectile dysfunction, is due to the reduced local bioavailability of nitric oxide (NO), the quintessential endogenous vasodilatory substance.
Production of nitric oxide occurs starting from a semi-essential amino acid, L-arginine, which is converted into nitric oxide and citrulline by the nitric oxide synthase (NOS) enzyme. There are three isoforms of this enzyme, designated respectively by the acronyms NOSl (neuronal), NOS2
(inducible) and NOS3 (endothelial).
Nitric oxide, once produced, enters the smooth muscle cell, where it activates a particular enzyme known as soluble guanylyl cyclase (sGC), with a consequent increase in the quantity of intracellular cyclic guanosine monophosphate (cGMP), reduction in the concentration of Ca2+ ion, and consequent vasodilation.
In view of the above, there are three hypothetical ways to act on the decrease in nitric oxide bioavailability: increase the bioavailability of the nitric oxide precursor, i.e., L-arginine; increase the activity of NOS enzymes; and increase the concentration of intracellular cGMP.
The semi-essential amino acid L-arginine is derived mostly from food and only for 5-15% from de novo synthesis. Several metabolic studies have shown that after oral administration, L-arginine is subjected to massive systemic and pre-systemic elimination by intestinal bacteria and by the
arginases present in the intestine and liver. A recent experimental study, in which a radioactive isotope of L-arginine was administered, showed that only 1% of the administered dosage is used as a precursor by NOS, mostly due to intense intestinal metabolism. Moreover, it has been demonstrated scientifically that the administration of L-arginine produces blood levels of this amino acid that are characterized by a short half-life, a factor which severely limits the possibility of L-arginine to perform a satisfactory therapeutic effect. Another limitation to oral administration of high doses of L-arginine is the presence of endogenous inhibitors of the reaction for conversion of L-arginine into nitric oxide by NOS. These inhibitors push the activity curve of the enzyme reaction toward higher levels of L-arginine than those administered, an effect acknowledged scientifically as a "paradox effect".
Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of all three NOS isoforms. ADMA normally circulates in blood at low dosages, but a conspicuous increase thereof is observed in subjects affected by endothelial dysfunction and in particular by erectile dysfunction or in subjects receiving excessive administration of L-arginine. It has been demonstrated scientifically that the ratio between L-arginine and ADMA is one of the key factors in the production of nitric oxide by NOS.
Accordingly, oral administration of L-arginine is unable to increase endogenous production of nitric oxide due to the low absorption of this amino acid caused by: the intense catabolism to which it is subjected in the intestine; its short half-life; and difficulty in modifying the L- arginine/ADMA ratio.
Currently, erectile dysfunction therapy is based substantially on oral administration of phosphodiesterase-5 (PDE5) inhibitors. Drugs containing active ingredients capable of inhibiting PDE5 act by increasing the bioavailability of cGMP at the smooth muscle cell level, inhibiting its catabolism operated by PDE5. However, these drags are actually unable to
increase nitric oxide synthesis and are therefore considered "on demand" drugs, which lead to a temporary increase in erectile functionality.
As an alternative, therapies are being tested for treating erectile dysfunction by direct insertion of the NOS gene at the penile endothelial cell level. This gene therapy procedure uses bacterial vectors to transfer the NOS gene and up to now has proved to be valid in improving erectile function in rats. However, such a method has not yet been developed sufficiently for use in humans; moreover, resorting to gene therapy procedures, and in particular the use of bacterial vectors, is an approach that might be more difficult to accept for a patient with respect to the administration of a drug.
There is, therefore, the need for a drug that can cure endothelial dysfunction and the disorders linked to it by increasing the amount of nitric oxide produced by the body. Disclosure of the Invention
The aim of the present invention is to provide a drug that can cure endothelial dysfunction wherever it occurs by means of an increase in the endogenous production of nitric oxide and does not require ad hoc administration to obtain a momentary increase in nitric oxide. Within this aim, an object of the invention is to provide a drug that is capable of acting in a differentiated but simultaneous manner on the normal biochemical processes that regulate endogenous synthesis of nitric oxide.
Another object, of the invention is to provide a drug that leads to an increase in the bioavailability of L-arginine. Still another object of the present invention is to provide a drug that can induce nitric oxide synthase (NOS) activity.
Finally, an object of the present invention is to provide a drug that can increase the penetration of L-arginine at the endothelial intracellular level. Other objects, characteristics and advantages of the invention will be
described in the foregoing detailed description.
This aim and these and other objects that will become better apparent hereinafter are achieved by L-citrulline for the treatment of endothelial dysfunction or of erectile dysfunction. The aim and objects of the invention are also achieved by a pharmaceutical composition comprising L-citrulline in combination with one or more substances selected from the group consisting of pycnogenol, aqueous extract of Visciim album, nicotinamide adenine dinucleotide phosphate (NADPH), tetrahydrobiopterin, folic acid, and mixtures thereof. Ways of carrying out the invention
Without intending to be bound to any theory in particular, it is believed that the therapeutic action of L-citrulline in the treatment of endothelial dysfunction is due to the fact that this non-essential amino acid does not undergo pre-systemic elimination. It is in fact believed that L- citrulline undergoes systemic metabolism, during which it is converted by the L-argininosuccinate synthase enzyme into L-argininosuccinate, which in turn is broken down by the L-argininosuccinase enzyme to yield L-arginine. From this point of view, L-citrulline can be considered as the natural precursor of L-arginine. L-citrulline in fact allows indirectly to increase the bioavailability and plasma half-life of L-arginine, since differently from L- arginine it does not undergo intense intestinal catabolism.
The inventor of the present invention has thus discovered that the administration of L-citrulline, known until now only in the treatment of cardiovascular dysfunctions, is capable of curing endothelial dysfunction wherever it occurs and in particular in the case of erectile dysfunction.
Another embodiment of the present invention consists of the further combination of L-citrulline for the treatment of endothelial dysfunction or of erectile dysfunction with a substance selected from the group consisting of pycnogenol, aqueous extract of Viscum album, and mixtures thereof. Pycnogenol is a plant-derived flavonoid, also known as
proanthocyanidin. This substance is contained naturally in many plants, including Vitis vinifera, Vaccinus myrtillus, Ribes nigrum, Cornelia sinensis, plants of the genus Aronia and other plants generally known to contain flavonoids. In particular, it has been observed that pycnogenol is capable of increasing the activity of the NOS3 (endothelial NOS) enzyme at the sperm cell level.
Viscum album is a plant known by the more common name of mistletoe. The aqueous extract of this plant has proved to be capable of inducing an overexpression of NOS2 and NOS3 enzymes at the level of muscle cells of the Guinea pigs to which it has been administered.
The inventor of the present invention has discovered that resorting to a combination of L-citrulline with pycnogenol and/or with Viscum album extract allows to increase the quantity and activity of endogenous NOS, with a consequent higher production of nitric oxide. Another embodiment of the present invention also consists of the further combination of L-citrulline for the treatment of endothelial dysfunction or of erectile dysfunction with one or more enzyme cofactors selected from the group consisting of nicotinamide adenine dinucleotide phosphate (NADPH), tetrahydrobiopterin, folic acid and mixtures thereof. Enzyme cofactors are substances whose presence is required for the optimum biochemical activity of some enzymes. In particular, in the case of the reaction for production of nitric oxide from L-arginine, NOS enzymes use NADPH and tetrahydrobiopterin as essential cofactors.
The inventor of the present invention has discovered that resorting to a combination of L-citrulline with NADPH and/or tetrahydrobiopterin allows to favor the activity of NOS and accordingly the production of nitric oxide.
Moreover, it is known that the rise of blood levels of homocysteine reduces endothelial penetration of L-arginine and that in a patient with endothelial dysfunction, and particularly with erectile dysfunction, blood
levels of homocysteine increase. Folic acid, a cofactor of the enzymes involved in the synthesis of homocysteine, has a specific action in lowering the values of homocysteine.
The inventor of the present invention has discovered that resorting to a combination of L-citrulline with folic acid allows to increase endothelial penetration of L-arginine by way of the reduction of homocysteine levels. In turn, this allows a higher inflow of the nitric oxide precursor, L-arginine, at the level of the tissues involved in endothelial and erectile dysfunction.
Therefore, in an embodiment of the present invention, L-citrulline on its own or in combination with one or more substances selected from the group consisting of pycnogenol, aqueous extract of Viscum album, NADPH, tetrahydrobiopterin, folic acid, and mixtures thereof can be characterized in that the treatment of the endothelial dysfunction or of the erectile dysfunction occurs by means of the simultaneous increase in the levels of L-arginine and nitric oxide synthase (NOS).
In an embodiment of the present invention, L-citrulline may be administered preferably in a quantity equal to 6 grams/day. For example, daily administration of L-citrulline may be split into two doses of 3 grams each or three doses of 2 grams each. Moreover, L-citrulline for treating endothelial dysfunction or erectile dysfunction may be used also in combination with other drugs already known for treatment of erectile dysfunction, for example drugs containing PDE5 inhibitors.
In another aspect, the present invention relates also to a pharmaceutical composition characterized in that it comprises L-citrulline in combination with one or more substances selected from the group consisting of pycnogenol, aqueous extract of Viscum album, NADPH, tetrahydrobiopterin, folic acid and mixtures thereof.
Of course, the pharmaceutical composition of the present invention may further comprise one or more excipients generally used in
pharmaceutical practice.
Moreover, the composition may assume any formulation suitable for its administration to a patient affected by endothelial dysfunction or erectile dysfunction. For example, the composition according to the invention may be in the form of powder, capsules or sachets.
The inventor of the present invention has discovered that the pharmaceutical composition described herein is effective particularly in the treatment of endothelial dysfunction and of erectile dysfunction, and therefore in a preferred embodiment the pharmaceutical composition according to the invention may be used in the treatment of endothelial dysfunction or of erectile dysfunction.
The present invention also relates to a method for treating endothelial dysfunction or erectile dysfunction by administering L-citrulline to a patient, optionally in combination with one or more substances selected from the group consisting of pycnogenol, aqueous extract of Viscum album,
NADPH, tetrahydrobiopterin, folic acid and mixtures thereof.
Preferably, the method according to the invention may provide for oral administration of L-citrulline.
Moreover, in the method according to the invention L-citrulline may be administered in an amount equal to 6 grams/day. For example, the daily administration of L-citrulline may be split into two doses of 3 grams each or three doses of 2 grams each.
The effectiveness of the administration of L-citrulline in the treatment of erectile dysfunction has been verified by conducting a randomized prospective study on 20 patients, during which L-citrulline was administered orally with a dosage of 6 grams/day, in two separate 3-gram doses, to patients affected by erectile dysfunction. As a comparison, a second group of patients received an administration of L-arginine equal to 3 grams/day, split into two 1.5-gram doses. The effects of the administration were then tested at the biochemical
level by studying the following parameters:
1. plasma levels of L-arginine;
2. blood modification of L-arginine/ ADMA ratio;
3. urinary excretion of nitrates; 4. urinary excretion of cGMP.
Moreover, the effects at the clinical level were also tested by administering the "Erectile function assessment card" (IIF-5 questionnaire) to the patients and by measuring flow-mediated vasodilation of the cavernous arteries before and after therapy. The data related to the above cited biochemical parameters were acquired for patients subjected to the test 7 days after the beginning of the administration of the drug and are shown below in Table 1, Table 2, Table 3 and Table 4.
Table 1
Plasma levels of L-arginine (μmol/1)
Drug Max plasma concentration
L-arginine 89 ± 10
L-citrulline 172 ± 25
Table 2
L-arginine/ ADMA ratio
Drug baseline after administration
L-arginine 186 ± 7 189 ± 10
L-citrulline 183 ± 8 290 ± 15
Table 3 Urinary excretion of nitrates (nmol/mmol creatinine)
Drug baseline after administration
L-arginine 91 ± 10 93 ± 12
L-citrulline 89 ± 9 133 ± 16
Table 4 Urinary excretion of cGMP (nmol/mmol creatinine)
Drug baseline after administration
L-arginine 38 ± 3.1 39 ± 4.5
L-citrulline 40 ± 2.8 55 ± 3.8
The data shown in Tables 1 to 4 allow to observe that oral administration of L-citrulline, with respect to the administration of L- arginine, is able to produce statistically higher plasma levels of arginine and to lead to a statistically longer plasma half-life of L-arginine. Moreover, it should be noted that the administration of L-citrulline also leads to a higher excretion of nitrates and cGMP (measured in terms of nmol/mmol of creatinine), a sign of actual production of nitric oxide by endothelial tissues.
Moreover, from a clinical standpoint, it has been observed that administration of L-citrulline leads to a modification of the IIF-5 questionnaire by patients at the level of the components related to achieving and maintaining erection. Also from a clinical standpoint, a statistically higher increase in flow-mediated vasodilation at the level of the cavernous arteries was also observed with administration of L-citrulline.
In practice it has been found that L-citrulline for treating endothelial dysfunction or erectile dysfunction according to the invention fully achieves
the intended aim, since the administration of L-citrulline alone modifies positively and in a statistically significant way the biochemical and clinical parameters linked to erectile dysfunction, thus indicating that the endogenous capacity of tissues to synthesize nitric oxide has been restored. Moreover, it has been observed that L-citrulline, also thanks to combination with other substances such as pycnogenol, extract of Viscum album and enzyme cofactors, allows to act in a differentiated but simultaneous manner on the normal biochemical processes that regulate endogenous synthesis of nitric oxide. It has in fact been observed that L-citrulline alone or in combination with pycnogenol, extract of Viscum album and/or enzyme cofactors allows to increase the bioavailability of L-arginine, induce the activity of NOS enzymes and increase the penetration of L-arginine at the endothelial intracellular level. The disclosures in Italian Patent Application no. MI2008A000567, from which this application claims priority, are incorporated herein by reference.
Claims
1. L-citrulline for the treatment of endothelial dysfunction or erectile dysfunction.
2. L-citrulline according to claim 1, wherein the L-citrulline is in combination with a substance selected from the group consisting of pycnogenol, aqueous extract of Viscum album, and mixtures thereof.
3. L-citrulline according to claim 1 or 2, wherein the L-citrulline is in combination with one or more enzyme cofactors selected from the group consisting of NADPH, tetrahydrobiopterin, folic acid and mixtures thereof.
4. L-citrulline according to one or more of the preceding claims, wherein the L-citrulline is administered with a dosage equal to 6 grams/day.
5. L-citrulline according to one or more of the preceding claims, wherein the treatment of endothelial dysfunction or of erectile dysfunction occurs by means of the simultaneous increase in the levels of L-arginine and of nitric oxide synthase (NOS).
6. A pharmaceutical composition comprising L-citrulline in combination with one or more substances selected from the group consisting of pycnogenol, aqueous extract of Viscum album, NADPH, tetrahydrobiopterin, folic acid and mixtures thereof.
7. The pharmaceutical composition according to claim 6 for the treatment of endothelial dysfunction or of erectile dysfunction.
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PL09728678T PL2257283T3 (en) | 2008-04-02 | 2009-03-10 | L-citrulline for treating erectile dysfunction |
ES09728678T ES2378656T3 (en) | 2008-04-02 | 2009-03-10 | L-citrulline to treat erectile dysfunction |
US12/935,782 US8802162B2 (en) | 2008-04-02 | 2009-03-10 | L-citrulline for treating endothelial dysfunction and erectile dysfunction |
DK09728678.5T DK2257283T3 (en) | 2008-04-02 | 2009-03-10 | L-citrulline for the treatment of erectile dysfunction |
EP09728678A EP2257283B9 (en) | 2008-04-02 | 2009-03-10 | L-citrulline for treating erectile dysfunction |
AT09728678T ATE536179T1 (en) | 2008-04-02 | 2009-03-10 | L-CITRULLINE FOR THE TREATMENT OF ERECTILE DYSFUNCTION |
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IT000567A ITMI20080567A1 (en) | 2008-04-02 | 2008-04-02 | L-CITRULLIN FOR THE TREATMENT OF ENDOTHELIAL DYSFUNCTION AND ERECTILE DYSFUNCTION. |
ITMI2008A000567 | 2008-04-02 |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012067745A1 (en) * | 2010-10-19 | 2012-05-24 | K.L.R.M., Llc | Compositions and methods for treating erectile dysfunction |
WO2022027122A1 (en) * | 2020-08-06 | 2022-02-10 | Ramade & Cia Holding Corp. | Compositions with cannabinoids of cannabis sativa for treating erectile and sexual dysfunction |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
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AU2013219258B2 (en) * | 2012-02-15 | 2017-05-25 | Kyowa Hakko Bio Co., Ltd. | Agent for preventing or ameliorating vascular endothelial malfunction |
US9572848B1 (en) | 2014-03-26 | 2017-02-21 | Aemes Research L.L.L.P. | Composition of matter for sexual dysfunction |
WO2019084540A1 (en) | 2017-10-27 | 2019-05-02 | Zeta Biolongevity, Inc. | Compositions and methods for treating and preventing proteinuria and endothelial erosion |
US12064409B2 (en) * | 2021-06-22 | 2024-08-20 | Vanderbilt University | Action of L-citrulline to prevent or treat endothelial dysfunction |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006002096A2 (en) | 2004-06-18 | 2006-01-05 | Vivo Therapeutics, Inc. | Low doses of l-citrulline for treating diseases |
WO2006113389A1 (en) * | 2005-04-13 | 2006-10-26 | The General Hospital Corporation | High dose folic acid compositions for vascular dysfunction |
WO2007114903A2 (en) * | 2006-04-04 | 2007-10-11 | Nestec S.A. | Treatments using citrulline |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE4341000A1 (en) | 1993-12-02 | 1995-06-08 | Beiersdorf Ag | Use of L-arginine, L-ornithine or L-citrulline and topical preparations with these substances |
WO2005107735A2 (en) | 2004-04-30 | 2005-11-17 | Pump Formulations, Ltd. | Nutritional composition for enhancing lean muscle stimulus, growth, strength and recovery, creating and prolonging intense muscle pumps, supporting endurance, strength, performance, size and stamina, providing a transducer effect for nitric oxide, incresing nutrient delivery and/or promoting increased vascular response in a |
-
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006002096A2 (en) | 2004-06-18 | 2006-01-05 | Vivo Therapeutics, Inc. | Low doses of l-citrulline for treating diseases |
WO2006113389A1 (en) * | 2005-04-13 | 2006-10-26 | The General Hospital Corporation | High dose folic acid compositions for vascular dysfunction |
WO2007114903A2 (en) * | 2006-04-04 | 2007-10-11 | Nestec S.A. | Treatments using citrulline |
Non-Patent Citations (7)
Title |
---|
DREWES S E ET AL: "Recent findings on natural products with erectile-dysfunction activity", PHYTOCHEMISTRY, PERGAMON PRESS, GB, vol. 62, no. 7, 1 April 2003 (2003-04-01), pages 1019 - 1025, XP004410106, ISSN: 0031-9422 * |
DUMITRESCU CRISTIAN ET AL: "Tetrahydrobiopterin and NADPH treatment reverses endothelial dysfunction in post-ischemic hearts", CIRCULATION; 77TH SCIENTIFIC MEETING OF THE AMERICAN-HEART-ASSOCIATI ON, NOVEMBER 07-10, 2004, LIPPINCOTT WILLIAMS & WILKINS, US; NEW ORLEANS, LA, USA, vol. 110, no. 17, suppl. S, 26 October 2004 (2004-10-26), pages 206, XP008107792, ISSN: 0009-7322 * |
DURACKOVA Z ET AL: "Lipid metabolism and erectile function improvement by Pycnogenol, extract from the Pinus pinaster in patients suffering from erectile dysfunction-a pilot study", NUTRITION RESEARCH, ELSEVIER INC, XX, vol. 23, no. 9, 1 September 2003 (2003-09-01), pages 1189 - 1198, XP002983608, ISSN: 0271-5317 * |
SOMMER F ET AL: "Evaluation of tetrahydrobiopterin (BH4) as a potential therapeutic agent to treat erectile dysfunction", ASIAN JOURNAL OF ANDROLOGY, SCIENCE PRESS, SHANGHAI, CN, vol. 8, no. 2, 1 March 2006 (2006-03-01), pages 159 - 167, XP008107947, ISSN: 1008-682X * |
SULLIVAN M E ET AL: "Nitric oxide and penile erection: is erectile dysfunction another manifestation of vascular disease?", CARDIOVASCULAR RESEARCH 15 AUG 1999, vol. 43, no. 3, 15 August 1999 (1999-08-15), pages 658 - 665, XP002535884, ISSN: 0008-6363 * |
TENORIO F A ET AL: "Vasodilator activity of the aqueous extract of Viscum album", FITOTERAPIA, IDB HOLDING, MILAN, IT, vol. 76, no. 2, 1 March 2005 (2005-03-01), pages 204 - 209, XP025264959, ISSN: 0367-326X, [retrieved on 20050301] * |
TODA N ET AL: "Nitric oxide and penile erectile function", PHARMACOLOGY AND THERAPEUTICS, ELSEVIER, GB, vol. 106, no. 2, 1 May 2005 (2005-05-01), pages 233 - 266, XP004870345, ISSN: 0163-7258 * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012067745A1 (en) * | 2010-10-19 | 2012-05-24 | K.L.R.M., Llc | Compositions and methods for treating erectile dysfunction |
CN103402530A (en) * | 2010-10-19 | 2013-11-20 | K.L.R.M.公司 | Compositions and methods for treating erectile dysfunction |
KR101853851B1 (en) * | 2010-10-19 | 2018-05-02 | 케이.엘.알.엠., 엘엘씨 | Compositions and methods for treating erectile dysfunction |
US10406196B2 (en) | 2010-10-19 | 2019-09-10 | K.L.R.M., Llc | Compositions and methods for treating, inhibiting the onset, and slowing the progression of erectile dysfunction including naturally occurring age related erectile dysfunction |
WO2022027122A1 (en) * | 2020-08-06 | 2022-02-10 | Ramade & Cia Holding Corp. | Compositions with cannabinoids of cannabis sativa for treating erectile and sexual dysfunction |
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EP2257283A1 (en) | 2010-12-08 |
ITMI20080567A1 (en) | 2009-10-03 |
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US8802162B2 (en) | 2014-08-12 |
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