WO2008075117A1 - Apovincaminic acid or its ethyl ester derivative for the treatment of microangiopathies - Google Patents
Apovincaminic acid or its ethyl ester derivative for the treatment of microangiopathies Download PDFInfo
- Publication number
- WO2008075117A1 WO2008075117A1 PCT/HU2007/000125 HU2007000125W WO2008075117A1 WO 2008075117 A1 WO2008075117 A1 WO 2008075117A1 HU 2007000125 W HU2007000125 W HU 2007000125W WO 2008075117 A1 WO2008075117 A1 WO 2008075117A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- apovincaminic acid
- ethyl ester
- treatment
- microangiopathies
- pharmaceutical composition
- Prior art date
Links
- 206010062198 microangiopathy Diseases 0.000 title claims abstract description 14
- ZFCQLDAGNBFMJQ-QUCCMNQESA-N apovincaminic acid Chemical compound C1=CC=C2C(CCN3CCC4)=C5[C@@H]3[C@]4(CC)C=C(C(O)=O)N5C2=C1 ZFCQLDAGNBFMJQ-QUCCMNQESA-N 0.000 title claims abstract description 12
- 125000004494 ethyl ester group Chemical group 0.000 title abstract description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 12
- DDNCQMVWWZOMLN-IRLDBZIGSA-N Vinpocetine Chemical compound C1=CC=C2C(CCN3CCC4)=C5[C@@H]3[C@]4(CC)C=C(C(=O)OCC)N5C2=C1 DDNCQMVWWZOMLN-IRLDBZIGSA-N 0.000 claims abstract description 10
- 230000002265 prevention Effects 0.000 claims abstract description 10
- 229960000744 vinpocetine Drugs 0.000 claims abstract description 10
- 230000001575 pathological effect Effects 0.000 claims abstract description 8
- 238000002360 preparation method Methods 0.000 claims abstract description 7
- 238000007911 parenteral administration Methods 0.000 claims description 3
- 210000004027 cell Anatomy 0.000 description 21
- 206010021143 Hypoxia Diseases 0.000 description 18
- 230000007954 hypoxia Effects 0.000 description 13
- 230000000694 effects Effects 0.000 description 10
- 238000002474 experimental method Methods 0.000 description 10
- 150000001875 compounds Chemical class 0.000 description 9
- 210000001519 tissue Anatomy 0.000 description 8
- PLXBWHJQWKZRKG-UHFFFAOYSA-N Resazurin Chemical compound C1=CC(=O)C=C2OC3=CC(O)=CC=C3[N+]([O-])=C21 PLXBWHJQWKZRKG-UHFFFAOYSA-N 0.000 description 7
- 201000010099 disease Diseases 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 238000011161 development Methods 0.000 description 6
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- 206010059245 Angiopathy Diseases 0.000 description 5
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 5
- 230000001146 hypoxic effect Effects 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
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- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- 108010078791 Carrier Proteins Proteins 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 206010054805 Macroangiopathy Diseases 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
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- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- TYNSUEXNGLNQSS-UHFFFAOYSA-N 6-carbamoyl-5-hydroxy-4-methoxy-7,8-dihydro-3h-pyrrolo[3,2-e]indole-2-carboxylic acid Chemical compound C1=2C=C(C(O)=O)NC=2C(OC)=C(O)C2=C1CCN2C(N)=O TYNSUEXNGLNQSS-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
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- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical class CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 1
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000009857 Microaneurysm Diseases 0.000 description 1
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- 208000017442 Retinal disease Diseases 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- 108010052164 Sodium Channels Proteins 0.000 description 1
- 102000018674 Sodium Channels Human genes 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 229940089973 Sodium channel antagonist Drugs 0.000 description 1
- 239000004133 Sodium thiosulphate Substances 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 241000863480 Vinca Species 0.000 description 1
- 241000863486 Vinca minor Species 0.000 description 1
- MMAKJMJXJYHDDQ-UHFFFAOYSA-N [Cl].CCCCO Chemical compound [Cl].CCCCO MMAKJMJXJYHDDQ-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
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- 238000003556 assay Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
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- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 201000009101 diabetic angiopathy Diseases 0.000 description 1
- 201000002249 diabetic peripheral angiopathy Diseases 0.000 description 1
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- 238000003028 enzyme activity measurement method Methods 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- HXQVQGWHFRNKMS-UHFFFAOYSA-M ethylmercurithiosalicylic acid Chemical compound CC[Hg]SC1=CC=CC=C1C(O)=O HXQVQGWHFRNKMS-UHFFFAOYSA-M 0.000 description 1
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- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
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- 230000006883 memory enhancing effect Effects 0.000 description 1
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- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
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- 230000004089 microcirculation Effects 0.000 description 1
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- 229940067107 phenylethyl alcohol Drugs 0.000 description 1
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- 150000004760 silicates Chemical class 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 239000004289 sodium hydrogen sulphite Substances 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
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- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 238000005199 ultracentrifugation Methods 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
-
- 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
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
Definitions
- C-AVA cis-apovincaminic acid
- VPA ethyl ester
Abstract
The present invention relates to the use of cis-apovincaminic acid of formula (I) ((3α, 16α)- apovincaminic acid) (I) or its ethyl ester derivative of formula (II) ((3α, 16α)-apovincaminic acid ethyl ester, vinpocetine)) (ii) for the preparation of a pharmaceutical composition for the treatment and prevention of pathological conditions accompanied by microangiopathies.
Description
APOVINCAMINIC ACID OR ITS ETHYL ESTER DERIVATIVE FOR THE TREATMENT OF MICROANGIOPATHIES
The present invention relates to the use of cis-apovincaminic acid of formula (I) ((3α, 16α)- apovincaminic acid) or cis-apovincaminic acid ethyl ester of formula (II) ((3α, 16α)- apovincaminic acid ethyl ester)
II
for the preparation of a pharmaceutical composition for the treatment and prevention of pathological conditions accompanied by microangiopathies.
The damages of small and large arteries are called angiopathy. According to the size of the injured vessels, macroangiopathy - the disease of large and medium sized arteries, and microangiopathy - the disease of the walls of small vessels and capillaries, can be defined. Thickening of the basal membrane of the vessels and the increased permeability, followed by protein leakage, occur in the development of the microangiopathy, hi time microscopic size dilatations, i.e. microaneurysms appear on the capillaries. The blood tends to clot at these dilated sites as well as in the pathologically altered capillaries. Therefore, the capillaries become obliterated and ischemic condition develops in the supplied tissue, which is, induces the development of new capillaries (neovascularization). Because of the pathological metabolism leading to the microangiopathy these newly developed micro vessels also will be altered accordingly they will not fulfill their function. The disease of the vasculature of the fundus of the eye (retinopathy), the alteration of the renal microcirculation (nephropathy) and the neuropathies developed on the basis of the disease of the supplying capillaries of the nerves are the most studied microangiopathies. However, the myocardial, pulmonal, and gallbladder angiopathies are also important. The development of the angiopathy may lead to different diseases:
- the amyloid angiopathy in the brain may play role in the development of Alzheimer's disease.
- the diabetic angiopathy that can be divided into the types (micro- and macroangiopathy) which frequently accompanied by hypertension. Currently the prevention of the diabetes and hypertension is the only effective way to avoid the development of the microangiopathies. There is no known prevention strategy or curative therapy targeting the micro vessel's endothelium.
The role of the endothelium in the vessel's wall: The cells that form the inner lining of the vessel's wall are called endothelial cells. Those endothelial cells that build the capillary wall are particularly important. The double membranes of the endothelial cells are regulating the traffic between the blood and the tissues. The transport across the membranes is active with the exception of water. The water flow between the cells, through the 7 nm pores is driven by the osmotic equalization. Sodium and chlorine cotransporters and sodium channels regulate the transport of ions. Amino acid transport takes place through the proper transporters from the blood toward the tissues. For example, such mechanism carries the neurotransmitter precursor L-DOPA from the blood to the nervous tissue. The glucose crosses the luminal as well as the basal membranes via the GIuT transporters. The intact sate of the endothelium is an important condition for the normal function of the adjacent tissues.
It is well known that the alkaloid of the periwinkle (Vinca minor) both its natural and synthetic form has beneficial effect in different diseases. The known derivative cis- apovincaminic acid ethyl ester of formula (II) ((3α, 16α)-apovincaminic acid ethyl ester, vinpocetine) is efficient PDE I inhibitor (Beavo J.A.: Physiol Rev 1995:725-748), as well as sodium and calcium channel's antagonist (Bonoczk P, et al: Brain Res Bull. 2000 Oct;53(3):245-54). As it stimulates brain circulation, it can be applied in the post-treatment of stroke (Bereczki D., Fekete L: Eur J Clin Pharmacol 1999; 55:349-352). It is also widely applied in the treatment of the neurodegenerative diseases with dementia (Thai LJ, Salmon DP, Lasker B, et al.: J Am Geriatr Soc 1989; 37:515-520). It has memory enhancing effect.
The aim of our invention was the preparation of a pharmaceutical product that prevents and treats diseases accompanied with microangiopathy via the protection of endothelium.
In the course of our experiments we have surprisingly found, that the cis-apovincaminic acid (C-AVA), and its ethyl ester (vinpocetine) derivative was able to protect the endothelial cells in hypoxic circumstances effectively.
Both compounds prevented the damage of the endothelial cells, the development of the pathological conditions with angiopathy as well as the damage of the circumvented cells and tissues.
According to the above, the object of the present invention is the use of cis-apovincaminic acid of formula (I) ((3α, 16α)-apovincaminic acid) for the preparation of a pharmaceutical composition for the prevention and treatment of pathological conditions accompanied by microangiopathy.
Another object of the present invention is the use of cis-apovincaminic acid ethyl ester of formula (II) ((3α, 16α)-apovincaminic acid ethyl ester) for the preparation of a pharmaceutical composition for the prevention and treatment of pathological conditions accompanied by microangiopathy.
In the preferred embodiment of the invention the pharmaceutical composition is for oral or parenteral administration.
In case of oral administration, the pharmaceutical composition can be formulated as tablet or capsule. The tablet can be formulated with any solid form of formulating vehicle. The vehicle can be for example magnesium stearate, starch, lactose, sacharose, cellulose and so on.
A composition in the solid form of capsule can be prepared using routine encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carriers, for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
Typical parenteral composition consists of a solution or suspension of the compound of formula I or formula II thereof in a sterile aqueous carrier or in a parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilized and then reconstituted with a suitable solvent just prior to administration. Furthermore, any aqueous solution of the active ingredient can be applied of which concentration is physiological and properly buffered respectively.
Other non-aqueous solvent system can also be applied which is physiologically acceptable and suitable as a solvent of the active substance. Such solvents are ethanol, propylene glycol, organic oils of animal or plant origin, as well as their aqueous blends and suspensions.
Other additives that do not affect the effectiveness of the active ingredient also can be applied for example buffering, absorption aiding agents and preservatives. Sodium bisulphite, sodium bisulphate, sodium thiosulphate, benzalconium chloride, chlorine butanol, thiomerosal, methylparaben, polyvinyl alcohol, phenyl ethyl alcohol and other water-soluble preservatives can be applied. The concentration of these additives must be in the range of 0,001 and 5 m/m %. Sodium carbonate, sodium borate, sodium phosphate, sodium acetate, sodium bicarbonate etc. can be applied as water-soluble buffering agents. The concentration of these additives must not exceed 5 m/m % related to the active ingredient.
In our experiments the cytoprotective effect of vinpocetine and C-AVA was studied on human brain endothelial cells (HBEC). The optimal hypoxia/deoxygenating time have been determined in preliminary experiments via AlamarBlue® (Biosource) staining with ELISA in the presence of test compounds.
The HBEC were isolated by ultracentrifugation on Percoll (Pharmacia) gradient and freeze-stored in liquid nitrogen until use. The reconstituted cells were grown in Dulbecco's Modified Eagle's Medium (DMEM; Sigma) supplemented with 10% heat-inactivated fetal calf serum (FCS; Gibco) in Petri dishes (d: 9.4 mm; Greiner) until 90% confluence. The cell cultures were starved for 18-20 h in complete DMEM with 2% FCS then they were replaced to complete DMEM/F12 (Gibco) under hypoxia. Then the FCS-containing medium was washed off thoroughly the cells were collected and stored in cryotubes in liquid nitrogen. The forwarding was made on dry ice. The hypoxia was maintained in Argon-filled airtight chamber placed in a 37 0C thermostat. The partial oxygen tension was controlled during the
process. After 30 minutes po2 was 50 Hgmm, after 60 minutes po2 was 40 Hgmm and after 90 minutes it dropped under 40 Hgmm. The pH value of the culture medium was less the 8 following hypoxia.
The compounds were added in the final concentration indicated later following the hypoxic treatment with DMEM/F12 supplemented with 10% FCS. In the experiments 69 well microplate (Greiner) was used for culturing and photometric analysis as well.
The endothel-protective effect was measured with AlamarBlue solution. The AlamarBlue (Biosource) solution was added in a volume of 1 to 10 according to the supplier's instruction. The absorbance is monitored at 550 and 620 nm. The reductive capacity of the cells was characterized by the calculated reduction index. The fluorescent and colorimetric signal generated from the assay is proportional to the number of living cells in the sample. Reduction related to growth causes the REDOX indicator to change from the oxidized (no fluorescent, purple color) form to the reduced (fluorescent, red color) form. The absorbance data detected at the two wavelengths were corrected for AlamarBlue. Data from two independent experiments (n=12) were compared by groups (Student's t-test). hi the AlamarBlue proliferation assay the controls of the system were TC=tissue culture (cells in the medium, background) and TC+AB=tissue culture plus AlamarBlue. Further wells contained the compound-treated cells (cell+TC+AB+compound). Values in the tables indicating the activity of the cells in increasing scale.
The hypoxia/reoxygenation experiments were carried out in argon gas-filled hypoxic chamber. Hypoxia for 0,5, 1 and 1,5 h were applied for measurement of activity. The activity of the cells was higher in normoxic environment then in hypoxia/reoxygenation conditions. According to the data, a medium density (50-70 000 cell/well) and 1 h hypoxia was chosen for the enzyme activity measurements. The cell activities were measured for 21 h in 4 time points.
The further experiments were carried out in reoxygenated conditions following 60 min of hypoxia. The obtained data were compared to the normoxic cell activity values. In this setup the compounds and the AlamarBlue were present already during the hypoxia. Our results are summarized in table 1.
Table 1.
σ>
OO
In the second series of experiments, the compounds were added following 2 h hypoxia i.e. following the damage of the cells. The results are shown in table 2.
Table 2.
The effect of the examined compouns on the activity of the cells in normoxic and reoxygenation followed 2 h hypoxic conditions
CO
N>
The reductive capacity of the cell is characteristic to the cell's metabolic activity. We can conclude form the first series of experiments that the significantly raised activity appeared 4 h following hypoxia in the 10'7 M vinpocetine- (p<0,005) and C-AVA- (p<0,001) treated cells. Both examined compounds had a significant activating effect in the long reoxygenation period. This was a preventive-like effect.
We can conclude from the second series of experiments that both vinpocetine and C-AVA significantly raised the reduction index that is raised the cells vitality in hypoxic conditions in the therapeutic range.
hi summary, we can conclude that
• in normoxic conditions C-AVA proved to be active that is points to its effectiveness in prevention,
• in hypoxia/reoxygenation conditions, both C-AVA and vinpocetine proved to be active in the prevention of the late-type cell damage.
Claims
1. Use of cis-apovincaminic acid of formula (I)
I
((3α, 16α)-apovincaminic acid) for the preparation of a pharmaceutical composition for the treatment and prevention of pathological conditions accompanied by microangiopathies.
2. The use according to claim 1, characterized in that the pharmaceutical composition is for oral administration.
3. The use according to claim 1, characterized in that the pharmaceutical composition is for parenteral administration.
4. Use of cis-apovincaminic acid ethyl ester of formula (II)
((3α, 16α)-apovincaminic acid ethyl ester) for the preparation of a pharmaceutical composition for the treatment and prevention of pathological conditions accompanied by microangiopathies.
5. The use according to claim 4, characterized in that the pharmaceutical composition is for oral administration.
6. The use according to claim 1, characterized in that the pharmaceutical composition is for parenteral administration.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HUP0600917 | 2006-12-18 | ||
| HU0600917A HUP0600917A2 (en) | 2006-12-18 | 2006-12-18 | Pharmaceutical composition for influencing endothelial cells containing aporincaminic acid or rinpocetine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2008075117A1 true WO2008075117A1 (en) | 2008-06-26 |
Family
ID=89987197
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/HU2007/000125 WO2008075117A1 (en) | 2006-12-18 | 2007-12-18 | Apovincaminic acid or its ethyl ester derivative for the treatment of microangiopathies |
Country Status (2)
| Country | Link |
|---|---|
| HU (1) | HUP0600917A2 (en) |
| WO (1) | WO2008075117A1 (en) |
-
2006
- 2006-12-18 HU HU0600917A patent/HUP0600917A2/en unknown
-
2007
- 2007-12-18 WO PCT/HU2007/000125 patent/WO2008075117A1/en active Application Filing
Non-Patent Citations (3)
| Title |
|---|
| BODA J ET AL: "Examination of Cavinton effect in elderly diabetic patients", THERAPIA HUNGARICA, BUDAPEST, HU, vol. 37, no. 3, 1989, pages 176 - 180, XP009096317, ISSN: 0133-3909 * |
| BONOCZK P ET AL: "Vinpocetine increases cerebral blood flow and oxygenation in stroke patients: A near infrared spectroscopy and transcranial Doppler study", EUROPEAN JOURNAL OF ULTRASOUND 2002 IRELAND, vol. 15, no. 1-2, 2002, pages 85 - 91, XP002470650, ISSN: 0929-8266 * |
| YAMADA S ET AL: "Cerebral protective effects of VA-045, a novel apovincaminic acid derivative, in mice", RESEARCH COMMUNICATIONS IN CHEMICAL PATHOLOGY AND PHARMACOLOGY, PJD PUBLICATIONS LTD., WESTBURY, NY, US, vol. 86, no. 1, 1994, pages 83 - 91, XP009096331, ISSN: 0034-5164 * |
Also Published As
| Publication number | Publication date |
|---|---|
| HUP0600917A2 (en) | 2008-08-28 |
| HU0600917D0 (en) | 2007-02-28 |
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