WO2010130869A1 - Utilización de extractos de hojas de olivo en una composición farmacéutica para inducir angiogénesis y vasculogénesis - Google Patents
Utilización de extractos de hojas de olivo en una composición farmacéutica para inducir angiogénesis y vasculogénesis Download PDFInfo
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- WO2010130869A1 WO2010130869A1 PCT/ES2010/070327 ES2010070327W WO2010130869A1 WO 2010130869 A1 WO2010130869 A1 WO 2010130869A1 ES 2010070327 W ES2010070327 W ES 2010070327W WO 2010130869 A1 WO2010130869 A1 WO 2010130869A1
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- pharmaceutical composition
- olive leaf
- angiogenesis
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- endothelial
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Classifications
-
- 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)
- A61K36/63—Oleaceae (Olive family), e.g. jasmine, lilac or ash tree
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/28—Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
-
- 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
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- 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
-
- 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 falls within the medical-pharmaceutical sector and specifically in the technical field of the promotion of angiogenesis and vascularization, endothelial repair and the treatment of wounds and ulcers.
- the object of the present invention is the use of olive leaf extracts for the preparation of a pharmaceutical composition capable of inducing angiogenesis and vascularization.
- This composition can be used in general for therapeutic applications in which it is desired to promote the differentiation of stem cells to progenitor endothelial cells (EPCs) and / or mature endothelial cells, as well as the induction of vessel formation from those endothelial cells.
- EPCs progenitor endothelial cells
- / or mature endothelial cells as well as the induction of vessel formation from those endothelial cells.
- cardiovascular diseases, ischemic processes in general, ulcers and wound healing are pathologies to which this angiogenic and vascularization-inducing composition will be directed both in the field of medicine and in the veterinarian.
- Vasculogenesis consists in the formation of new blood vessels from endothelial precursor cells (EPCs) that migrate and differentiate to endothelial cells in those places where Ia vascularization
- EPCs endothelial precursor cells
- Angiogenesis consists in the formation of new branches of capillaries from existing blood vessels.
- Arteriogenesis meanwhile, refers to the remodeling of an existing artery as a result of its adaptation to blood flow. The arteriogenesis differs from that of the angiogenesis in its mechanism.
- the organism regulates angiogenesis, through a series of mechanisms that act as "on” and “ofl” switches.
- the "on” switches are known as angiogenic growth factors, while the “ofl” are known as endogenous angiogenic inhibitors.
- pathologies such as cancer, atherosclerosis and diabetic retinopathy can develop, among others. While a decrease in angiogenesis favors the development of cardiovascular diseases, ischemic processes in general, ulcers and difficulty in wound healing, etc ...
- the treatment of pathologies associated with a lower angiogenesis includes the use of growth factors that promote the formation of vessels, such as endothelial growth factor (EGF), vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), hypoxia inducible factor-1 alpha (HIF-1 ⁇ ), FGF -4, hepatocyte growth factor (HGF), kallikrein tissue peptide (TK), activators of proteinase activated receptors (PAR-activators), thrombin, "frizzled-A” protein and nitric oxide [Madeddu , P. (2005). "Therapeutic angiogenesis and vasculogenesis for tissue regeneration.” Exp Phvsiol 90 (3): 315-26], between others.
- EGF endothelial growth factor
- VEGF vascular endothelial growth factor
- FGF fibroblast growth factor
- HGF hepatocyte growth factor
- TK kallikrein tissue peptide
- PAR-activators activators of
- stem cells Due to their plasticity, stem cells can be differentiated into vascular and non-vascular elements, so they can regenerate the part damaged by ischemia. Thus, for example, in the case of myocardial infarction, said cells can also be differentiated into myocytes, recovering damaged tissue.
- the strategy of the use of cell therapy presents the problem of the loss of functionality of the EPCs within a few hours after the transplant. To reduce this phenomenon, it has been proposed: 1) a local release of cells instead of systemic, 2) administration of chemokines that promote the mobilization of EPCs, 3) enrichment and expansion of EPCs cultures and 4) increase of Ia functionality of EPCs by genetic modification [Madeddu, P. (2005).
- an additional angiogenesis is induced by the increase of VEGF in the damaged tissue, with a maximum at several days after the damage [Karayiannakis AJ, Zbar A, Polychronidis A, Simopoulos C. Serum and drainage fluid vascular endothelial growth factor levéis in early surgical wounds. Eur Surg Res 2003; 35, 492-6], thus, in the process of wound healing and repair, angiogenesis and related factors are essential.
- VEGF factor in certain concentrations, in the culture medium of mesenchymal stem cells (MSCs) is the cause of the differentiation of these cells towards endothelial cells
- MSCs mesenchymal stem cells
- the object of the present invention constitutes a pharmaceutical composition containing olive leaf extracts, which meet the definition of Olive leaf extract published in Pharmeuropa Olive [(2007) Leaf dry extract Pharmeuropa 19 (3): 510-511] for its use in the induction of angiogenesis and vasculogenesis.
- the present invention relates to the use of olive leaf extracts for the preparation of a pharmaceutical composition.
- the present invention relates to the use of olive leaf extracts for the preparation of a pharmaceutical composition for the induction of angiogenesis and vasculogenesis and related biological processes such as scarring, endothelial repair, ischemic processes etc.
- the pharmaceutical composition used is presented in the form of a cream, ointment, balm, solution, emulsion or ointment for topical administration.
- the pharmaceutical composition comprises a concentration of less than 30% olive leaf extract. In another preferred embodiment, the pharmaceutical composition comprises between 10 ⁇ 1 and 10 ⁇ 10 M of oleuropein contained in the olive leaf extract.
- the pharmaceutical composition is applied between 1 and 8 times a day.
- the pharmaceutical composition is applied together with another product.
- the pharmaceutical composition is applied for the first time up to 14 days after the appearance of the damage.
- the pharmaceutical composition is applied by means of a transdermal patch.
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising extracts of olive leaves enriched in polyphenols and / or stimulating factors of angiogenesis and vasculogenesis.
- the pharmaceutical composition also comprises mesenchymal stem cells.
- the pharmaceutical composition is presented in the form of a cream, ointment, balm, solution, emulsion or ointment for topical administration.
- the pharmaceutical composition comprises an olive leaf extract concentration of less than 30%. In another preferred embodiment, the pharmaceutical composition is applied between 1 and 8 times a day.
- the pharmaceutical composition is applied together with another product.
- the pharmaceutical composition is applied by means of a transdermal patch.
- the pharmaceutical composition is applied for the first time up to 14 days after the appearance of the damage.
- the present invention relates to a method of treatment and / or prevention of wounds or ulcers comprising the application of a pharmaceutical composition as described above.
- composition containing olive leaf extracts can be used, alone or in association with other substances, in the formation of endothelial cells derived from mesenchymal stem cells and also in the formation of vessels from endothelial cells.
- Vascular endothelial growth factor (VEGF, Vascular Endothelial Growth Factor) is a signaling protein involved in vasculogenesis (de novo formation of the circulatory system) and in angiogenesis (blood vessel growth from preexisting vessels).
- VEGF Vascular Endothelial growth factor
- the actions of VEGF have been studied in vascular endothelial cells, although it also has effects on other cell types (for example, it stimulates the migration of monocytes / macrophages, neurons, renal epithelial cells and tumor cells). In vitro, it has been shown that VEGF stimulates the division and migration of endothelial cells.
- VEGF is also a vasodilator and increases vascular permeability; Originally it was called vascular permeability factor.
- the olive leaf extract used in the present invention has the ability to stimulate the synthesis of VEGF and with this the vasculogenesis and angiogenesis. These processes are the first step for tissue recovery, so that olive leaf extract is capable of promoting wound healing and ulcers, especially those that appear in diabetic and / or elderly patients.
- composition is prepared for oral, rectal, parenteral, intraperitoneal, intradermal, transdermal, topical, intratracheal, intramuscular, intravenous or inhalation administration.
- Figure 1 A and B compares two optical microscopy images of mesenchymal stem cells.
- Cells treated with olive leaf extract, image B form tubular structures typical of the angiogenic process.
- Those same cells without the treatment with olive leaf extract are not capable of forming such structures, image A.
- FIG. 1 Images obtained with optical microscopy comparing the formation of tubular structures in HUVECs cells in endothelial medium without treatment (figure 2A), treated with VEGF (figure 2B) and treated with olive leaf extract (figure 2C) on matrigel.
- Figure 3 It is shown in A, the results of the treatments performed with the leaf extract and in B, the results of the treatments with pure oleuropein. The evolution of the wounds that have received the treatment directly, are shown in the graphs on the right, while the evolution of those that have not received treatment is shown in the graphs on the left.
- Figure 4. Shows the response in wounds of an animal to which 10 ⁇ 7 M oleuropein was administered.
- Figure 5 Shows the response in the wounds of an animal to which the olive leaf extract containing 10 ⁇ 5 M of oleuropein was administered.
- Figure 6. Shows the evolution of the ulcer of a patient to whom the composition of the invention was applied, from day 0 (6.A) to day 1 1 (6.B).
- Phenotypic evidence After 15-28 days of culturing mesenchymal stem cells with olive leaf extracts, typical endothelial cell structures such as microvessels are formed. 2) Evidence of expression of membrane markers: Treatment with olive leaf extracts causes an increase of cells with surface markers CD144 and VEGFR2 3) Evidence of expression of genes involved in endothelial differentiation: VEGF, PCAM, PDGFR and VEGFRI
- mesenchymal stem cells Mesenchymal stem cells obtained from human bone marrow were expanded and grown in essential medium minimum alpha modification ( ⁇ -MEM) supplemented with 10% fetal bovine serum, 2mM Ultraglutamine and with antibiotics. When the cells were close to the confluence, they were treated with olive leaf extracts. As controls, part of the crops were not treated.
- ⁇ -MEM essential medium minimum alpha modification
- Endothelial cells The established line of endothelial cells obtained from human umbilical vein (HUVE) was supplied by Lonza Group, Ltd. Switzerland, these cells were expanded in a bottle with basic endothelial medium (EBM, Lonza) supplemented with antibiotics and fetal bovine serum. When the cells reached the confluence they were subcultured. The medium was changed every 3 days. To carry out these experiments cells 2nd and 3rd pass was used. The treatments that received these cells were: 1.- Leaf extract at various concentrations 2.- VEGF 10 ⁇ g / mL 3.- Control, without treatment
- Flow cytometry assays were performed for the study and analysis of cell membrane markers.
- the cells were washed with PBS + 3% fetal bovine serum, anti-human monoclonal antibodies Conjugates, CD144-FITC and VEGFR2-PE were incubated for 30 minutes at room temperature.
- the labeled cells were washed three times, resuspended in 0.5 ml of PBS and analyzed the tide with a FACScan Caliber flow cytometer (Benton-Dickinson).
- RT-PCR Real time polymerase chain reaction
- RNA of the cells was obtained using the Tri Reagent reagent (Sigma Aldrich) and following the manufacturer's instructions.
- the cDNA was synthesized from a microgram of total RNA, which had previously been treated with DNAsal (Sigma Aldrich), using the Biorad iSCript TMcDNA Synthesis Kit.
- the real-time PCR used to quantify the analyzed mRNAs was carried out. in a Light-Cycler (Roche) system using SYBR®Green.
- the Endothelial Tube Formation Assay kit, CeII Biolab Inc. was used to perform the In Vitro angiogenesis assays. The test conditions are as indicated in the supplier's instructions.
- the media used were basic endothelial medium supplemented untreated (negative control) and treated with VEGF (positive control) or with olive leaf extract.
- the structures formed were labeled by an antibody conjugated with calcein AM supplied in the kit, specific for the tubules. Results obtained in the differentiation of mesenchymal stem cells to endothelial cells
- Cytometry analysis of the characteristic surface markers of endothelial cells showed that these are found in MSCs treated with olive leaf extract and in all cases analyzed the percentage of these endothelial markers in the treated cells with the extracts they show significant differences with respect to the control culture).
- angiogenesis begins with tissue damage, which causes the activation of The proliferation of endothelial cells and their assembly in tubular structures around which the new vessel walls will be formed [Karamysheva AF. Mechanisms of angiogenesis 2008 Biochemistry]; The results presented here with olive leaf extracts allow the application of these as an angiogenic factor, due to their ability to differentiate stem cells to endothelial cells capable of forming tubular structures.
- Vascular endothelial growth factor-165 gene therapy promotes cardiomyogenesis in reperfused myocardial infarction. J Interv Cardiol 21 (3): 242-51]; [Michaels, J. T., M. Dobryansky, et al. (2005). "Topical vascular endothelial growth factor reverses delayed wound healing secondary to angiogenesis inhibitor administration.” Wound Repair Regen 13 (5): 506-12]; [Galiano, R. D., O. M. Tepper, et al. (2004). "Topical vascular endothelial growth factor accelerates diabetic wound healing through increased angiogenesis and by mobilizing and recruiting bone marrow-derived cells.” Am J Pathol 164 (6): 1935-47].
- Term Amniotic membrane is a high throughput source for multipotent Mesenchymal Stem CeIIs with the ability to differentiate into endothelial cells in vitro.
- BMC Dev Biol 7: 11 The results obtained both in the gene expression of endothelial markers and in the analysis of surface markers of mesenchymal stem cells differentiated to endothelial with leaf extracts and VEGF show that the inductive effect that these extracts have on them is comparable VEGF, recognized inducer of the differentiation of these cells to endothelial
- mice female aged 10 to 12 weeks were used. They were obtained through Charles River Laboratories (Spain), the average weight of the animals at the reception of them was 35.64g. Throughout the study, the animals were kept in animals specially designed to allow control of the animals' environmental environment, such as relative humidity (30-70%), temperature (22 ⁇ 2 ° C), air pressure, number of renovations and photoperiod (12/12 hours of light / dark). Accessibility to water was "ad libitum" and the diet was a standard for dry and pelleted rats supplied by PanLab (Barcelona, Spain).
- mice After the acclimatization period, a random distribution of the mice in the different study groups was performed.
- rhVegf Sigma Aldrich
- a placebo group was used all the compounds used in this study were dissolved in PBS. The concentrations used in this test are detailed in Table 1.
- Table 1 Compositions administered to the different study groups and their respective concentrations
- the formulation of the invention to be applied to humans can be prepared in its simplest or elemental form by dissolving the corresponding olive leaf extract containing a known concentration of oleuropein, in concentrations ranging from 10 ⁇ 2 M to 10 "7 M, in a mixture with water gel, or common commercial moisturizers, to give them consistency and facilitate local application on the affected area of the skin.
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Abstract
Description
Claims
Priority Applications (15)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP10774593.7A EP2431046B1 (en) | 2009-05-14 | 2010-05-14 | Use of olive leaf extracts in a pharmaceutical composition for inducing angiogenesis and vasculogenesis |
SI201030920T SI2431046T1 (sl) | 2009-05-14 | 2010-05-14 | Uporaba izvlečka lista olive v farmacevtskem sestavku za induciranje angiogeneze in vaskulogeneze |
MX2011011970A MX2011011970A (es) | 2009-05-14 | 2010-05-14 | Utilizacion de extractos de hojas de olivo en una composicion farmaceutica para inducir angiogenesis y vasculogenesis. |
PL10774593T PL2431046T3 (pl) | 2009-05-14 | 2010-05-14 | Zastosowanie ekstraktów z liścia oliwnego w farmaceutycznej kompozycji do indukcji angiogenezy i waskulogenezy |
ES10774593.7T ES2535758T3 (es) | 2009-05-14 | 2010-05-14 | Utilización de extractos de hojas de olivo en una composición farmacéutica para inducir angiogénesis y vasculogénesis |
DK10774593.7T DK2431046T3 (en) | 2009-05-14 | 2010-05-14 | Application of olive leaf extract in a pharmaceutical composition for inducing angiogenesis and vasculogenesis |
US13/320,180 US20120141435A1 (en) | 2009-05-14 | 2010-05-14 | Use of olive leaf extracts in a pharmaceutical composition for inducing angiogenesis and vasculogenesis |
BRPI1007728-6A BRPI1007728B1 (pt) | 2009-05-14 | 2010-05-14 | uso de uma composição farmacêutica |
PT107745937T PT2431046E (pt) | 2009-05-14 | 2010-05-14 | Uso de extratos de folhas de oliveira, composição farmacêutica e método de tratamento e/ou prevenção de feridas ou úlceras |
LTEP11743251.8T LT2570124T (lt) | 2009-05-14 | 2011-05-13 | Oleuropeino kompozicijos, skirtos pagyvenusių žmonių ir (arba) diabetu sergančių žaizdų ir opų gydymui |
ES11743251.8T ES2613950T3 (es) | 2009-05-14 | 2011-05-13 | Composiciones de Oleuropeína para cicatrización de heridas y úlceras en ancianos y/o diabéticos |
RS20170111A RS55672B1 (sr) | 2009-05-14 | 2011-05-13 | Supstance oleuropeina za lečenje rana i čireva kod starijih ljudi i/ili dijabetičara |
EP11743251.8A EP2570124B1 (en) | 2010-05-14 | 2011-05-13 | Oleuropein compositions for healing wounds and ulcers in elderly people and/or diabetics |
PCT/ES2011/070343 WO2011141611A1 (es) | 2010-05-14 | 2011-05-13 | Composiciones de oleuropeína para cicatrización de heridas y úlceras en ancianos y/o diabéticos |
HRP20150455TT HRP20150455T1 (hr) | 2009-05-14 | 2015-04-28 | Upotreba ekstrakata lista masline u farmaceutskom pripravku za induciranje angiogeneze i vaskulogeneze |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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ESP200901296 | 2009-05-14 | ||
ES200901296A ES2349976B1 (es) | 2009-05-14 | 2009-05-14 | Utilizacion de extractos de hojas de olivo en una composicion farmaceutica para inducir angiogenesis y vasculogenesis. |
Publications (1)
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WO2010130869A1 true WO2010130869A1 (es) | 2010-11-18 |
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PCT/ES2010/070327 WO2010130869A1 (es) | 2009-05-14 | 2010-05-14 | Utilización de extractos de hojas de olivo en una composición farmacéutica para inducir angiogénesis y vasculogénesis |
Country Status (14)
Country | Link |
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US (1) | US20120141435A1 (es) |
EP (1) | EP2431046B1 (es) |
BR (1) | BRPI1007728B1 (es) |
CY (1) | CY1116447T1 (es) |
DK (1) | DK2431046T3 (es) |
ES (3) | ES2349976B1 (es) |
HR (1) | HRP20150455T1 (es) |
LT (1) | LT2570124T (es) |
MX (1) | MX2011011970A (es) |
PL (1) | PL2431046T3 (es) |
PT (1) | PT2431046E (es) |
RS (1) | RS55672B1 (es) |
SI (1) | SI2431046T1 (es) |
WO (1) | WO2010130869A1 (es) |
Cited By (1)
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WO2011141611A1 (es) * | 2010-05-14 | 2011-11-17 | Sanidad Y Residencias 21, S.A., | Composiciones de oleuropeína para cicatrización de heridas y úlceras en ancianos y/o diabéticos |
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ES2395539B1 (es) * | 2011-06-16 | 2014-01-20 | Agencia Pública Empresarial Sanitaria Hospital Alto Guadalquivir | Uso del aceite de oliva en la prevención y el tratamiento de las enfermedades que cursan con un proceso isquémico |
CN116920069B (zh) * | 2023-07-06 | 2024-05-17 | 廊坊康宝汇泰生物技术有限公司 | 一种中药提取液及其在促进脐带干细胞分泌vegf中的应用 |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011141611A1 (es) * | 2010-05-14 | 2011-11-17 | Sanidad Y Residencias 21, S.A., | Composiciones de oleuropeína para cicatrización de heridas y úlceras en ancianos y/o diabéticos |
Also Published As
Publication number | Publication date |
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PT2431046E (pt) | 2015-05-28 |
BRPI1007728A2 (pt) | 2016-12-27 |
RS55672B1 (sr) | 2017-06-30 |
MX2011011970A (es) | 2012-07-17 |
EP2431046A4 (en) | 2013-07-31 |
DK2431046T3 (en) | 2015-05-11 |
ES2613950T3 (es) | 2017-05-29 |
HRP20150455T1 (hr) | 2015-08-14 |
SI2431046T1 (sl) | 2015-07-31 |
PL2431046T3 (pl) | 2015-07-31 |
CY1116447T1 (el) | 2017-02-08 |
EP2431046A1 (en) | 2012-03-21 |
BRPI1007728A8 (pt) | 2018-06-12 |
LT2570124T (lt) | 2017-02-27 |
ES2349976B1 (es) | 2011-11-10 |
US20120141435A1 (en) | 2012-06-07 |
ES2349976A1 (es) | 2011-01-13 |
BRPI1007728B1 (pt) | 2021-06-08 |
EP2431046B1 (en) | 2015-02-18 |
ES2535758T3 (es) | 2015-05-14 |
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