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
  • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
  • A61K31/385—Heterocyclic compounds having sulfur as a ring hetero atom having two or more sulfur atoms in the same ring
• • 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
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4415—Pyridoxine, i.e. Vitamin B6
• • 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
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • 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
  • A61K36/16—Ginkgophyta, e.g. Ginkgoaceae (Ginkgo family)
• • 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)
  • A61K36/19—Acanthaceae (Acanthus family)
• • 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)
  • A61K36/23—Apiaceae or Umbelliferae (Carrot family), e.g. dill, chervil, coriander or cumin
• • 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)
  • A61K36/77—Sapindaceae (Soapberry family), e.g. lychee or soapberry
• • 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)
  • A61K36/87—Vitaceae or Ampelidaceae (Vine or Grape family), e.g. wine grapes, muscadine or peppervine
• • 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)
  • A61K36/88—Liliopsida (monocotyledons)
  • A61K36/896—Liliaceae (Lily family), e.g. daylily, plantain lily, Hyacinth or narcissus
  • A61K36/8962—Allium, e.g. garden onion, leek, garlic or chives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

• This invention concerns a compound for use in sclerotherapy treatment, venous insufficiency, circulation and microcirculation disorders.
• This procedure which is called three-dimensional regenerative sclerotherapy, uses a buffered salicylate glycerin solution, known by its brand name BISCLERO, which is described in the European patent No. 0572963.
• BISCLERO buffered salicylate glycerin solution
• the propagation of the regenerative therapeutic action throughout the vessels of the superficial and perforating circulation increases the risk of thrombophlebitis. Although it can also occur spontaneously in susceptible individuals, thrombophlebitis must be avoided during sclerotherapy; indeed, if it is deep and located in the thigh, it is likely to extend to femoral and iliac veins. This may give rise to potentially lethal pulmonary embolisms, thereby leading to serious medical-legal problems.
• platelet aggregation inhibitors In order to obviate this risk, platelet aggregation inhibitors must be administered to the patient. Diapedesis of red blood cells across vessel micro-fissures is another drawback in sclerotherapy treatment, venous insufficiency, circulation and microcirculation disorders. Small amounts of hemoglobin are released by these red blood cells.
• the bivalent iron ion contained in hemoglobin may cause inflammation and cell damage through the production of free radicals; in the brain, the bivalent iron ion can cause endothelial damage and produce oxidative metabolites that are toxic to the neurons. Furthermore, iron stimulates melanosis, and, hence, the onset of post-sclerotherapy pigmentation or, more generally, post-inflammation pigmentation.
• Another metal contained in the blood and involved in melanogenesis is copper. Copper acts as a catalyst in the enzymatic oxidation chain, producing melanine, which is responsible for post-sclerotherapy pigmentation.
• a sclerosing solution When a sclerosing solution is injected into a telangiectasia, it usually generates a vasospasm of the unaffected capillary network, which disappears after a few seconds. In some instances, when the sclerosing solution penetrates into arterial capillaries through arterial-venous shunts or because of excessive retrograde pressure, the vasospasm lasts longer, and may result in skin necrosis.
• Another problem that may arise during sclerotherapy is that of elevated serum homocysteine levels. In addition to being linked to degenerative endothelial cell damage, which promotes vessel occlusion, a high level of homocysteine has recently been included among conventional biochemical risks for cardiovascular mortality and morbidity. Finally, thrombophlebitis is known to be due not only to the slowing down of blood flow, but also to vessel wall damage or to disorders in blood components on which clotting depends.
• thrombophlebitis may occur even without evident trauma.
• the traditional way to obviate this risk is to administer 50 or 100 mg of acetylsalicylic acid per day.
• acetylsalicylic acid may trigger allergic reactions, gastritis even haemorrhagic and bleeding. Many patients are therefore reluctant to take this drug.
• acetylsalicylic acid has no chelating or anti- edematogenic action, nor does it stimulate the microcirculation.
• Another conventional method is to administer ticlopidine, which selectively inhibits thromboxane A2 synthesis, and, at the same time, promotes prostacycline - PGI - synthesis, which, as well as inhibiting platelet aggregation, also has a vasodilatory effect.
• the main side-effects reported in the literature are nausea, vomiting, diarrhea, skin rashes, leukopenia, agranulocytosis, sometimes even lethal, and thrombocytopenia. Patients undergoing this treatment must take a blood test every 15 days. Both ticlopidine and acetylsalicylic acid are ineffective in preventing restenosis after angioplasty.
• Another well-known method in the therapy of venous insufficiency, circulation and microcirculation disorders involves the use of plant extracts which contain one or, occasionally, two extracts with inhibiting platelet aggregation activity.
• the main drawback to this method lies in the fact that each plant extract acts on a specific site of the platelet aggregation chain. If only one or, less commonly, two plant extracts are used, a large quantity will have to be administered in order to obtain effective inhibition platelet aggregation, which will in turn totally inhibit their specific action sites. This total inhibition may cause hemorrhages, such as in the case of Ginkgo Biloba, when administered in effective doses as a platelet aggregation inhibitor.
• the aim of this invention was to formulate a compound that would combine the various effects of all its constituent substances and act differentially to eliminate or reduce the various thrombotic risk factors; a compound that could be administered chronically, without complications and without requiring blood tests.
• the resulting compound consists of folic acid (vitamin B9), piridoxine (vitamin B6), lipoic acid, and six different plant extracts: Ginkgo Biloba, Andrographis, Garlic (allium sativum), Centella Asiatica (Gotu Kola), Grape seeds and Horse Chestnut.
• Ginkgo Biloba Garlic (allium sativum), Andrographis and Grape seeds act as platelet aggregation inhibitors. All the plant extracts and lipoic acid exert an anti-inflammatory and anti-free radical action. Lipoic acid, Garlic (allium sativum), and Grape seeds also have a metal chelating action. Lipoic acid, Garlic, Andrographis and Ginkgo Biloba also exert a vasodilatory action. Horse Chestnut, Andrographis, Grape seeds and Centella Asiatica (Gotu Kola) promote vessel wall trophism. Folic acid (vitamin B9) and Ginkgo Biloba have a more marked trophic action on endothelia.
• Folic acid (vitamin B9) and piridoxine (vitamin B6) have anti-thrombotic properties.
• the first of the many advantages offered by the present invention is its platelet aggregation inhibition, since platelet aggregation is the first step in thrombophlebitis and thrombosis.
• four plant extracts are used in small doses: Ginkgo Biloba, Garlic (allium sativum), Andrographis, and Grape seeds.
• Each of these extracts acts at different sites along the platelet aggregation chain, thus inhibiting platelet aggregation in different ways.
• Effective platelet aggregation inibition activity is therefore achieved with less risk of bleeding than if one or two plant extracts with the same action are used at higher doses.
• acetylsalicylic acid and ticlopidine which engender risks of allergies and negative effects on blood chemistry, no longer need to be administered.
• Another particularly important benefit of using the compound described is linked to its iron and copper chelating action.
• both metals are involved in melanogenesis, in that they facilitate inflammation and the production of free radicals, thereby promoting the subsequent onset of post-sclerotherapy pigmentation. The reduced presence of these metals therefore slows down pigmentation, with less damage caused by these metals.
• chelation of the bivalent iron ion which is mainly bound in storage molecules like haptoglobin and ferritin, helps to accelerate the disappearance of post-sclerotherapy ecchymoses and improve microcirculation.
• Vasodilation is another particularly beneficial effect obtained through the use of this compound during sclerotherapy.
• Vasoconstriction is prevented, or at least limited, by lipoic acid, which inhibits endothelin, a powerful vasoconstrictor.
• Garlic (allium sativum), Andrographis and Ginkgo Biloba also exert a vasodilatory action, which, in the case of Ginkgo Biloba, is partially mediated by the nitric oxide system.
• Garlic (allium sativum) and Ginkgo Biloba also help to reduce blood viscosity by increasing the flexibility of red blood cells.
• Another advantage of this invention stems from the fibrinolytic action of Garlic (allium sativum), which is especially useful in dissolving the small superficial thromboses that frequently occur following sclerotherapy. Finally, this compound is able to pharmacologically lower elevated homocysteine serum levels, through the action of folic acid (vitamin B9) and piridoxine (vitamin B6).
• folic acid modifies the risk factor related both to genotype and phenotype conditions, and to special local, even iatrogenic, stress events to the body, such as sclerosing injections.
• Folic acid lowers the activity of vitamin K-dependent factors, and exerts a favorable action on platelets by reducing their activation induced by the intake of oral oestroprogestogen contraceptives.
• Piridoxine helps folic acid to reduce plasma homocysteine levels. It has a neutrophic action, especially on axons, and may exert an anti-inflammatory action on the skin.
• Lipoic acid is one of the most effective anti-oxidants. It is water- and lipo- soluble. It is able to replenish depleted levels of glutathione, which is a powerful detoxicant and inflammation modulator, since it lowers Interleukine 1 (IL-1) and alpha (TNF-alpha) Tumor Necrosis Factor production; it exerts a chelating action on metals - particularly iron and copper - through both thiolic (-SH) and carboxylic (-COOH) groups.
• IL-1 Interleukine 1
• TNF-alpha alpha
• Tumor Necrosis Factor production it exerts a chelating action on metals - particularly iron and copper - through both thiolic (-SH) and carboxylic (-COOH) groups.
• Lipoic acid inhibits both the activation of NF-KB inflammation factor in the cell cytoplasm and the production of endothelin, a very potent vasoconstrictor. This latter property is also useful in the case of sclerotherapy-induced inflammation or ischemia.
• lipoic acid is used in a 99% concentration.
• Ginkgo Biloba extract exerts a protective action on the vascular endothelium of the brain, and inhibits neuronal toxicity induced by glutammate and by monoamine-oxidase metabolites. It is also effective against serum and/or tissue factors involved in platelet aggregation. The most important of these factors is PAF (platelet activating factor), since it induces both platelet aggregation and inflammation, in particular edemas caused by increased capillary and venular permeability.
• PAF platelet activating factor
• Ginkgo Biloba The platelet aggregation inhibition promoted by Ginkgo Biloba is based on a marked PAF inhibition; phosphodiesterasis is also inhibited, which is thought to mitigate the calcium ion-mediated action between endothelial cells and platelets.
• Ginkgo Biloba also reduces the production of nitric oxide by macrophages, thus limiting tissue damage and, at the same time, promoting its protective action on the endothelium.
• Ginkgo Biloba also has a vasodilatory effect, which significantly increases regional blood flow; this effect is rendered even more beneficial by the reduction in blood viscosity.
• Ginkgo Biloba also reduces free radicals and fibrinogen.
• Ginkgo Biloba The most active Ginkgo Biloba group of substances involved in achieving the objective described in this invention is that of Ginkgo flavonoid glycosides, also called Ginkgo etherosides. For this reason, this plant extract is generally stated as having a 24% content of these substances.
• a pharmacological activity is also exerted by other substances, such as proantocyanidin, some terpene molecules - like Ginkgolides and Bilobalide, which account for 6% of the extract - and some organic acids, which increase the solubility of flavonoids and of the terpene components in the extract, thus enhancing their availability.
• Ginko Biloba also inhibits cognitive degeneration in the elderly. Andrographis inhibits platelet aggregation in two ways.
• Andrographis In addition to its platelet aggregation inibiting and vasodilatory activity, Andrographis modulates the inter-endothelial junction and exerts an anti-inflammatory action. With regard to prophylaxis and therapy, the most active substance in Andrographis is thought to be Andrographolide, which has pharmacodynamic properties. For this reason, it is partially useful to emply Andrographis with a high Andrographolide content (e.g. 95%). Garlic (allium sativum) is a platelet aggregation inhibitor.
• IL-1 Interleukin 1
• TNF Tumor Necrosis Factor
• Centella Asiatica which limits edema formation, develops endothelia and promotes the proliferation and deposition of collagen, thus promoting venous wall regeneration.
• Centella Asiatica the most active substance contained in Centella Asiatica is Asiaticoside, hence its declared content is 10%.
• Other substances are asiatic and madecassic acids; volatile substances, such as vallerine, camphor and cyneol; sterols such as sitosterol, campesterol and stigmasterol; flavonoids such as kampferol and quercetin with their glycosites, and tannins.
• Centella Asiatica is also used in the therapy of so-called cellulitis and lymphedema. Grape seeds are another component.
• Proantocyanidines which are generally bound together to form dimers, trimers, and tetramers, when available in esterified form with gallic acid, enhance the plant extract's ability to scavenge free radicals.
• their content in Grape seeds used in this invention is stated to amount to 95%.
• Grape seed is also an antioxidant, exerting a protective action on endothelia and reducing inflammation-related tissue damage. Owing to its ability to chelate some metal ions, it protects against the damaging effects of free radicals.
• iron is transformed from Fe— to Fe ⁇ with release of one unpaired electron.
• the chelating effect of Grape seeds on different metal ions derives from the establishment of salification bonds by -OH hydroxyl groups and/or oxygen atoms that are located on the carbon atom rings of polyphenols, also with regard to 'electron dative bonds' or mono/bivalent bond redundancy.
• the anti-inflammatory properties of grape seeds are also due to resveratrol - another substance contained in grape seeds - which inhibits the expression of proteases, including hyaluronidase, elastase and metalloproteases (MMPs). In this way, collagen is not only stabilized, but also generated anew.
• Grape seeds also inhibit platelet aggregation by lowering the production of A 2 thromboxane, which also acts as a vasoconstrictor.
• This platelet aggregation inhibition is primarily based on the marked ability to lower the production of free radicals, which stimulate platelet activation. Secondly, this compound interferes with the pro-aggregating effect of thrombin exposure.
• Horse Chestnut which is generally used in the seed extract form, inhibits vessel permeability, especially of venules and capillaries. In this way, edema development is reduced, even when the edema is caused by damage to the endothelium by a blood clot.
• escin the main substance contained in the extract
• the horse Chestnut extract also contains cumarinic substances, such as flavonoids, incuding quercetin, rutin and saponinic glycosides, which, like kampferol, promote endothelial vessel integrity and lysosome enzyme stability.
• Centella asiatica with 10% asiaticoside 21.881 g
• Horse chestnut with 24% escin 21.881 g
• Extract concentration may vary depending on the availability of the components and on the latest extraction techniques.
• Each dose, which is administered in soft gelatine capsules, capsules, tablets and drops, may vary according to therapeutic indications and needs.
• other plant extracts that have a very high concentration of active principle can also be mixed into the compound, together with the same extracts that have a low concentration of active principle.
• the doses of individual components can be varied, in order to favour particular pharmacodynamic aspects.
• the components will be lyophilised, compacted, or extracted depending on whether the compound is to be prepared in the form of capsules, soft gelatine capsules, tablets, or in the form of liquid extract. Each preparation can be provided in a form that does not irritate the stomach.
• the soft gelatine capsules will be two-coloured, one half red and the other half blue, to symbolize the action of the compound on both the venous and arterial circulation.
• the present invention comprises all modifications of details and variations which may appear obvious to a specialist in the field, also with regard to its pharmaceutical form, which do not lie outside the scope of the present invention, and which are understood to fall within the scope of the attached claims. Similarly, different concentrations of the main active substance of each extract are covered by this invention.

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Cited By (9)

Citations (4)

• 2002
  • 2002-03-25 IT IT2002GE000026A patent/ITGE20020026A1/it unknown
• 2003
  • 2003-03-24 AU AU2003223978A patent/AU2003223978A1/en not_active Abandoned
  • 2003-03-24 WO PCT/EP2003/003036 patent/WO2003080062A1/en not_active Application Discontinuation

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