Title of Invention

A PHARMACEUTICAL ANTITHROMBOTIC COMBINATION

Abstract

The present invention relates to a pharmaceutical anti thrombotic combination comprising as component (A) a therapeutic effective amount of a therapeutically antjthrombotic agent causing at least one haemorrhagic side effect selected from a group consisting of antiaggregants, an anti vitamin k, fibrinolytics, thrombin inhibitors, anticoagulants, and mixtures thereof and (B) a therapeutic effective amount of compound of formula (CH<sub>3</sub>)<sub>3</sub>N<sup>+</sup>(CH<sub>2</sub>)<sub>n</sub>COO. with n an integer from 1 to 5, or a pharmaceutically acceptable salt thereof, or mixtures thereof, for preventing or reducing 'the haemorrhagic side effect or for potentialising the therapeutic (antithrombotic) effect of said active agent with the proviso that the said active' pharmaceutical antithrombic combination is not for topical application.

Full Text

FIELD OF THE INVENTION This invention relates to the use of glycine betaine to eliminate phystopathological vascular attacks. The invention relates to the curative and preventive activity of glycine betaine in the pathogenesis of thromboembolic and haemostatic diseases of arterial or venous origin. Glycine betaine exhibits preventive activity while preventing the formation of thrombi and exhibits a curative activity which prevents the proliferation of thrombi while destroying them. The significance of the present invention is based on the fact that the use of glycine betaine does not result in any risk of haemorrhage or allergy in opposition to the molecules and treatments currently used. PRIOR ART Vascular thromboses are a response of the organism which is facing attack on a vessel wall and on the content of cells and plasma thereof. Thrombosis is a localised activation of coagulation with the formation of a thrombus. The interest to which this pathology has been subjected in recent years has enabled several causative factors to be identified: - the vessel, the vascular wall and the endothelial cells, - the role of elements which occur in blood - the coagulation and fibrinolysis systems, and inhibitors thereof. Several types of thromboses exist which can occur in arteries, in veins, in the micro¬circulation of the organs, in the cavities of the heart ami at artificial surfaces m contact with blood. Vascular thromboses are a response to the attack on the vessel wall and on its content of cells and plasma. A thrombosis is an organised mass of blood elements (platelets, red corpuscles and while corpuscles), of fibrin and of other plasma proteins, which are deposited at the surface or which obstruct the free passage of the vascular system. The mechanisms of thrombosis resemble those of haemostatis, but are pathological due to their abnormal intravascular location. Thromboses and embolisms are the main reasons for clinical complications associated with cardiovascular diseases and atherosclerosis. According to Virchow, at least three types of thrombogenetic factors determine the location, the extent and the regression of a thrombosis: haemodynamic and Theological factors; endothelial lesion; activation of the constituents of blood, particularly of platelets, and of coagulation which results in the formation of thrombin. Thromboembolic disease of arterial or venous origin remains one of the main reasons of death in developed countries. Arterial thrombosis is often due to a rupture of the atherosclerotic plaque, whereas venous thrombosis results from a deficit of a coagulation inhibitor (AT III) or from a deficit of a fibrinolysis activator (S protein and/or C protein) or more frequently from stasis. In fact, both of these result from an interaction between blood and the vascular wall, from the formation of a venous thrombosis and/or from a haemostatic anomaly. Arterial thrombosis is more often secondary to a parietal anomaly and mainly involves blood platelets. It contributes to a wide variety of clinical pictures depending on the arterial layers involved in the interruption of vascularisation. Thrombosis is mainly capable of affecting the cardiac arteries (coronary), and the arteries of the lower, cerebral or digestive organs. Thus arterial disease favours the formation of the thrombus itself which is responsible for the majority of terminal vascular occlusions. Moreover, participation of haemostatic disorders and of the thrombus formed at other vascular lesions is evident: aggravation of the lesions of the vascular wall, ischemia and problems in the micro-circulation. Three therapeutic strategies can be distinguished for the prevention of accidents associated with thromboses: Anticoagulants. These constitute the major element in the treatment of a patient exhibiting a thrombo-emboiic disorder. Heparin and derivatives thereof arc currently used. However, the use of heparins can give rise to two major complications, namely haemorrhage or throrobopenia. K antivitamins (KAV). Prescribed for long-term treatment, these cannot be used in an emergency and cannot be prescribed simultaneously with other anti-aggregants, since they potentiate the haemorrahgic effect thereof. Platelet antiaggregants. Prescribed to prevent arterial thrombosis associated with atherosclerosis. The main inhibitors of platelet functioning which are currently prescribed are: aspirin, ticlopidine, dipyridamole, and certain non-steroid anti¬inflammatory agents such as flurbiprofen and prostacyclin. These treatments are really effective, but have undesirable effects on patients subject to allergies or haemorrhage. Despite their efficacy, all these treatments necessitate special precautions in use, such ^s the administration of antidotes, overdose problems and unwanted side effects. These treatments make it necessary to monitor patients, due in particular to haemorrhage-related problems which can arise during; or after medication, as well as possible incompatibility with other drugs. It was therefore of interest to identify a molecule having a high antithrombotic potential without undesirable effects. Most surprisingly, glycine betaine has been identified as possessing a high therapeutic potential for in the treatment of thromboses. Glycine betaine, or betaine of formula (CHj^N* - (CK2) - COO', is a molecule known for its osmo-protective properties and for its cosmetic and pharmaceutical uses. Various pharmaceutical uses of betaine are known, particularly the use of betaine for the treatment of homocistinuria, which causes cardiovascular problems (L. & B. Wilken, J. Inner. Metab. Dis. 1997}. Thus patients suffering from homocistinuria, which is a genetic anomaly, exhibit premature atherosclerotic and thrombo-embolic disorders (S.H. Mudd et al., The metabolism and molecular bases of inherited disease, 1995), and of cardiovascular diseases (McCully, Atherosclerosis Rev. 11, 1983). Homocistinuria is a hereditary deficiency, the homozygotic form of which is rare, ft is estimated that the prevalence of this homozygotic form corresponds to 1 in 200 in the general population. Homocystinuria is due to elevated levels of homocysteine in the plasma of the affected patient The administration of betaine enables the concentration of homocysteine in the blood to be reduced. Publication WO 951 157 50 proposes the use of ingredients comprising betaine in order to prevent vascular disorders in homocistinuric patients. Publication WO 98 /19690 also relates to patients suffering from an elevated homocysteine level in their blood. The use of betaine amongst other ingredients is intended to reduce the level of homocysteine in the blood, it having been established that homocysteine is a positive factor of risk in the occurrence of cardiovascular diseases, as well as in Alzheimer's disease. Publication EP 0 347 864 describes the use of betaine together with other ingredients in order to combat the increase in sulfhydryl groups, which are due to cysteine and to homocysteine, in human plasma, and thus to inhibit the formation of atherosclerotic plaques. This ami-atherosclerotic effect is known and is extensivety documented. These publications relate to the effect of betaine on the metabolism of lipids (Zapadnyuk et al. Biol. Med. 1987), and on that of cholesterol (Panteleimonova et al„ Farmakol. Toksikol, Moscow 1983). Publication WO 97 38685 describes the use of betaine and taurine for the treatment of complications resulting from ischemia in some organs. Ischemia is a localised stoppage of the bloodstream and only represents one of the pathologies due to thrombosis. Publication EP 0 781 554 comprises examples which describe experiments on enucleated hearts, i.e. on hearts which have been extracted and isolated from the vascular system. The use of betaine for its known osmoprotective and antiradical properties enables the inventors to claim a protective action thereof on the cardiac muscle. Other forms of betaine have been proposed (WO 91106795), but have not hitherto equaled the potency and performance of glycine betaine. None of these publications discloses the potency of glycine betaine with respect to venous and/or arterial thrombosis, nor its anti-aggregant and anticoagulant potency. WO 0051596 of applicant, the scope of which is incorporated by reference, discloses the use of betaine for the treatment of thrombosis not induced by homocystinuria. In examples, said application discloses the combination of glycine betaine with a contrast agent. thereof, precursors thereof, precursors thereof; precursors thereof, and mixtures thereof; - A controlled release pharmaceutical system for releasing an effective therapeutically amount of at least a compound selected from the group consisting of betaines or an effective amount of a compound of formula (CHj)3N+(CH2)nCOO" with n an integer from 1 to 5, pharmaceutically acceptable salts thereof, esters thereof, precursors thereof, precursors thereof, precursors thereof, and mixtures thereof, for treating or preventing blood flow disturbances. BRIEF PESCBIPTTON OF THE INVENTION niycine hetaine. as well as betairte compounds of the general formula (CHs^N* - (CHj),, - COO', with n varying from 1 to 5 (preferably equal to 1) in the context of the present invention can be used for various clinical applications, such as: coronary thromboses and venous thromboses thromboses and re occlusion of the vascular system following a thrombolysis or an angioplasty infarct, angina pectoris, aneurysm, pulmonary embolism, phlebitis cerebral embolism post-traumatic shock, whether or not of surgical origin prevention of accidents of microcirculation in the following cases: haemophilia, chemotherapy, ageing, oral contraception using oestrogens, obesity, tobacco addiction, prosthesis, diabetes. prevention of the risks associated with the administration of contrasting ionic and non ionic products. The extracorporal circulation and the haemodialysis procedures. The blood in contact with artificial surfaces of patients subject to an extracorporal circulation has a risk of formation of platelet nails, of thrombi and embolism. These risks can be prevented by administering the cotnpound(s) of the invention before and/or during and/or after these procedures. Inflammation phenomena. When binding it with integrine of Mac-1 receptor of the leukocytes and by reducing the expression of mitogenes and pro inflammation cytokines. When acting on the Mac-1 receptor, the compounds of the invention reduce the'adhesive and migration properties of the leukocytes reducing thereby the tissue aggression. Haemostatic glues. By allowing, in function of pathologies, the gel time of the glues, while reducing secondary effects due to their uses. Stings and bites of venomous animais. Experimental data show that the injection of compounds of the invention to rats to which a venom lethal dose is injected, delays the death thereof. The compounds of the invention are therefore suitable for entering into antidote composition for venom, possibly in combination with other antivenomous compound(s). Prevention of blood circulation problems due to contact with artificial surfaces, such as biomaterial elements, prosthesis, etc. {cardiac valves, balloons, catheters, hip prosthesis, stents etc .). When using these elements with betaine, the secondary effects are reduced Moreover costing these exougeuous materials with betaine avoid problems BS reocclusion, rethrombosis and restJnosis. Metastasis Prevention of cancerous ceils. This anti tumoral activity is bound to the fact that cancerous cells released from tumours are transported by the micro thrombi inside the vascular system. These cancerous cells are undetectable by the immune system able to destroy them. Moreover, their incorporation in the micro thrombi facilitates their binding to the vascular system or in the organs, and creates then new cancerous colonies. As the formation of thrombi is function to the adhesion of fibrinogen to glycoprotein lib Ilia site on the activated platelets, an antagonist of fibrinogen adhesion has an anthnetastasis activity by permitting the immune system to detect the cancerous ceils during their migration, and by removing the vehicle (thrombus) enabling their transport and their binding. The compounds of the invention can be administered alone or with other anticancerous compounds (simultaneous administration or not) so as to improve their efficiency and the process of angiogenesis during malignant melanomas. Process for detecting and localizing thrombi by binding compounds of the invention to a portion detectable in vivo and/or in vitro. Process for avoiding thrombo-embolic problems correlated to air trips. In view of its very low toxicity and its blood fluidifying characteristics, the betaine can be administered in the form of patch, sweets, confectioneries, cookies, drinks, meais, candies, etc. so as to prevent thromboembolic events for airplane /flight passengers. Sweetener for diabetes, the betaine being or not associated with another sweetener. As Betaine is a residue of sugar production, betaine has some sweetening properties which can be used for the preparation of sweetener with anti aggregation properties. Said sweetener, while avoiding circulation problems bound to diabetes, could improve the efficiency of insulins. It has been demonstrated that the activation of vitronectin receptors facilitates the cell migration and provides the necessary signals for the regulation and proliferation of cells, and potentialises the insulin effect (Ruoslahti, Kidney Int., 1997,51, 1413-1417) Process for individualizing cells in culture in vitro As anti bacterial and anti infectious Use of a compound of the invention ( compound of the general formula (CHJ)JNT -(CHiJn - COO", with n an integer from 1 to 5, preferably equal to 1, or a mixture of such compounds or one or more pharmaceutically acceptable salts, for the preparation of a pharmaceutical composition for the treatment or for the prevention of troubles hound to one or more glycoproteins, especially to the receptor of one or more glycoproteins, preferably to the receptor of glycoprotein lib Ilia. Use of a compound of the invention ( compound of the general formula (CHjJjN* -{CH2\ - COO", with n an integer from 1 to 5, preferably equal to l,.or a mixture of such compounds or one or more pharmaceutically acceptable salts for potentializing the therapeutical effect of a pharmaceutical active agent. Platelet aggregation is an essential event in the formation of blood clot and thrombus. In normal conditions, following a vascular lesion, blood clots prevent blood losses by closing the opening. However, in some pathological instances, the formation of a blood clot can reduce partly or completely the blood circulation, with the consequence of a cellular necrosis. For example, the platelet aggregation and thus the thrombosis at the level of the artherosclerosis plaques is an important factor for the genesis of conditions such as angina pectoris, myocardus infarct, vessel occlusion following a thrombolysis or an angioplasty. Patients suffering a heart attack are treated with thrombolytic agents such as plasmin activators and the streptokinases which dissolve the fibrin from the clots. A major complication of this therapy is the reocclusion of vessels due to platelet aggregation, which can lead to irreversible damages to the heart, the brain or other organs. Thrombosis starts with the adhesion of platelets at the vascular lesion sites.The platelet adhesion is initiated by the receptor located at the surface of the platelets which bind to proteins of the extracellular cellular matrix of the exposed endothelium, such as fibrinogen, fibronectin. Von Willebrand factor, as well as other adhesive proteins such as vibronectin, collagen and laminin. Therefor, the activation of platelets is a reply to agonists such as epinephrine, ADP, collagen, the arachidonic acid or die thrombin. This activation leads to the activation of the glycoprotein lb receptor (GP lb) and/or of the glycoprotein nb Ilia receptor (GP lib Hla) at the surface of the platelets. This receptors) (GP lb and/or GP lib Ilia) is/are then available for its/their binding to fibrinogen and the platelet aggregation. The adhesion of the receptor (GP lib Ilia) to other adhesive proteins such as the Von Willebrand factor also leads the attachment of platelets between them and their aggregation. The adhesion of molecules such as fibrinogen or the Von Willebrand factor to the receptor (GP lib Ula) leading the platelet aggregation is art essential step in the formation of the thrombus. The receptor (GP lib Ilia ) is thus a privileged target for die new therapy treating thrombosis and ihromboembolitic pathologies. Furthermore, the use of antagonists of the glycoprotein lib ma'receptor inhibits the platelet aggregation, while respecting the other hemostasia mechanisms, is highly desirable in the new therapies bound to thrombosis. Several molecules having this antagonist property are marketed with usage restrictions due to immunoreactivity problems, toxicity, allergy or hyperseiwibiiity reactions for some patients. A subject natter of the present invention is to propose a molecule, especially a wsU-known and osed molecule of vegetal origin, having this antagonist activity for the glycoprotein lib Ilia receptor, while not having toxic characteristics. It is also known that the activation of the vitronectin receptor improves the cell migration and provides regulating signals of the cell proliferation and cell differentiation, and activates the effects of insulin (Ruoslahti, Kidney Int., 1997, 51, 1413-1417). The regulation of the vitronectin receptor is associated with pathological conditions, such as vascular restinosis (Clemetson and Clemetson, Cell.Mot. Life Sci., 1998,54,502-513), bone excess resorbtion (Rodan and Rodan, J. Endocrinol., 1997, 154 Suppl, S47-56), and the angiogenesis process during the malignant melanomas (Cheresh, Cancer Metastasis Rev., 1991,10,3-10). Surprisingly, it has now been found that betaines of formula (CH&N* - (CH:)„ -COO', with n an integer from 1 to 5, and their pharmaceutically acceptable salts, have an antagonist activity for one or more glycoprotein^) receptors, such as the glycoprotein lb receptor and the glycoprotein Hb Ufa receptor, by inhibiting the platelet aggregation induced by various agonists. This antagonist activity is not restricted to the glycoprotein site Tib Ilia but to all glycoprotein sites implicated in the cell adhesion of various origins, there between. Platelets are activated by some agonists, whereby their forms, as well as their secretions of their granules can be modified, and whereby the aggregation thereof can be induced and the formation of clots and thrombi can be produced. Several endogenous agonists, such as ADP (adenosine-5-djphosphate), serotinine, arachidonic acid, epinephrine, adrenaline, thrombin, collagen, ristocetaie are known. 12 Recently a mechanism of action of these agonists has been identified, namely the activation of the glycoproteic site GP lib Ilia which causes the adhesion of the circulating fibrinogen (Thromb. Res. 1993, 72, 231-245) and therefore the consolidation ofplateiets groups and the formation of clot. (Drug of the future, 1994, 19(2), 135-159) The actually used platelet aggregation inhibitors are acting only on a single agonist. For example, aspirin is active against the arachidonic acid, ticlopidin is active against ADP, hirudin is active against thrombin. The hetaines of the general formula of the invention disclosed here before are actives against various agonisu, as well as on fibrinogen, fibronectin, Von WiUebrand factor and other adhesive proteins such as vitronectin, collagen, iaminin. This is a major improvement for their efficiency, while preserving the hemostasis mechanism so as to avoid haemorrahgic or bleeding events. Due to their activity by oral administration, said compounds are excellent candidates for pathologies with adhesion of cells between them. In view of its very low toxicity and its efficiency, the best results have been obtained with glycine betaine (compound of the general formula with n = 1). None of the publications to which reference is made in the present specification teach the antagonist activity of the betaine with respect to glycoprotein lib Ilia receptor, nor its activity with respect to adhesive proteins. This antagonist activity is not only limited to the site of glycoprotein lib Ilia, but also to all the other glycoproteic sites acting in the adhesion of cells of various origins there between. In the present specification, pharmaceutically acceptable salts are salts of betaine which can be administered, such as salts of betaine with hydrochloric acid, sulfuric acid, sulfonic acid, organic acids such as acetic acid, citric acid, tartaric acid, formic acid, etc., as well as the monohydrate radical. Betaines, preferably glycine betaine, is advantageously administered orally, parenteraHy, sub cutaneously, by suppositories, tables, capsules, syrup, etc. Administered doses can vary from O.OOlg to 10 g per kg live body, for example from 0.0O5 g to 5 g, in particular from 0.01 g to 3 g per kg life body. Examples of administration forms are : tablets, capsules, patches, injectable forms, releasing forms, sublingual administration form, powder (for example for inhalation therapy, buccal inhalation), syrup, solution (nebulization, for example for inhalation therapy, buccal inhalation). As preferred administration forms, subcutaneous injectable dosage form, patches (to be applied on the skin) and entero soluble oral dosage form, such as gastro insoluble tablets or capsules, etc. provided with an entero soluble coating or matrix or system. As the pH of an aqueous glycine betaine solution is comprised between about 6 and about 7, an injectable solution (preferably for a subcutaneous injection) can be prepared by mixing solid glycine betaine with water (sterilized and possibly demineralized), The glycine betaine can be in the form of a powder (lyophilized powder) placed in a vial, water is then added to said vial for the preparation of the solution to be injected. If necessary, some acid (such as hydrochloric ) can be added to the solution or to the water to be mixed with the powder. The injectable dosage form can be a pressurized dosage form, such as an air pressurized dosage form. Subcutaneous injectable forms of glycine betaine, such as intravenous injectable forms, are preferred. Glycine betaine injectable forms are for example aqueous solution containing 0.1 to 50% by weight glycine betaine, advantageously from 0-5 to 30%, preferably from 10 to 20%. The injectable form has a pH for example comprised between 5 and 8.5, advantageously from 6 to 7.5, preferably from 6 to 6.5. When the injectable form is prepared by mixing glycine betaine (as a solid form or as a powder form), the pH of the solution is about 6-6.5. When the glycine betaine is administered by injection, the glycine betaine can be present in a solution of a flexible bag (baxter), for example a flexible bag (baxter) for intravenous administration of a saline solution, or a physiological solution, or a blood transfusion baxter. The invention relate thus also to a bag (flexible bag or baxter) for subcutaneous administration (preferably intravenous administration) containing a solution suitable for subcutaneous administration. As more specific example, the bag or baxter contains blood or a blood derivative or a blood portion and glycine betaine for subcutaneous administration. Another subject matter of the invention is a pharmaceutical composition (such as a tablet) containing insulin and betaine, a phannaceutical composition (such as a tablet) containing an antibiotic and betaine, a phannaceutical composition (such as a tablet) containing an anti cancerous agent and betaine, a pharmaceutical composition (such as a tablet) containing aspirin and betaine, etc. A subject matter of the invention is thus a pharmaceutical combination comprising an effective amount of betaine (preferably glycine betaine) and an effective amount of another active agent for the prevention or treatment of troubles. Advantageously, the pharmaceutical combination comprises an effective amount of an active agent for the treatment and/or prevention of a trouble, said active agent having at least one side effect selected among the group consisting of haemorrahgic events, coagulation troubles, thromboses and associations thereof, and ari effective amount of a compound of formula (CHJJJN^CHIIVCOO", with n an integer from 1 to 5, preferably equal to 1, for preventing at least 50%, advantageously at least 75%, preferably at least 90%, most preferably substantially completely said troubles and/or for reducing the seriousness of said side effect, advantageously of a factor of at least 50%, preferably of at least 75%, most preferably of at least 90%, especially substantially completely. Betaine is preferably used as anti haemorrahgic agent in said combination. Betaine is preferably used as an antitode to an haemorrahgic agent in said combination. The pharmaceutical combination can be in the form of a kit, so as to prepare the combination before administration or during the administration. Side effect is defined as being events observed more than 2% for the patients in treatment with the active agent.' By combining said active agent with betaine, it is possible to reduce drastically said events, for example to less than 2%, as well as the importance or gravity of said events. The active agent with possible side effect is advantageously selected among the group consisting of contrast agents, anti inflammatory agents, anti aggregation agents, anti coagulation agents, anti thrombotic agents, thrombolytic agents, Tpa agents, anti cholesterol agents, anti vitamin K and mixtures thereof. Specific examples of such agents are glycoaminoglycans, heparins (such unfiractioned heparin, standard heparin, low molecular heparins, heparinoid, and mixtures thereof), heparin-like molecules (such as heparinoid, danaparoid, orgaran, fragmin, dalteparin, enoxaparine, lovenox, ardeparin, normiflo and mixtures thereof), thrombin inhibitor (such as argatroban, novastan, and mixtures thereof), aspirin, anti inflammatory agents (such as non steroid anti inflammatory agents), anti aggregation agents, anti coagulation agents, antiplatelet agents (such as dextrans, dipryridamole, sulfinpyrazone, ticlodipine, abcximab, tirofiban, mixtures thereof), anti thrombotic agents, thrombolytic agents (such as human recombinant activated protein, tissue plasminogen activator, urokinase, streptokinase, anistreplase/APSAC, and mixtures thereof), anti cholesterol agents, anti vitamin K, Tpa agents (tissue plasminogen activator), glycoaminoglycans, heparinoid agents, hirudins, anti vitamin K, warfarins, Coumadin, coumarin, agents of the statin family, riclopidine, statin agents, cerivastatine, simvastatin, lovastatin, agents of the statin family, cerivastatine (Bayco!), simvastatin, lovastatin, etc. The invention relates also to the use of a compound of formula (CH})jN*(CHj)nCOO' with n an integer from 1 to 5, preferably glycine betaine or a pharmaceutically acceptable salt thereof, esters thereof, precursors thereof, precursors thereof, precursors thereof, and mixtures thereof, as active antidote agent for the preparation of an antidote composition, for example for combating haemorrahgic troubles, such as haemorrahgic troubles caused by one or more agents selected from the group consisting of: contrast agents, ami inflammatory agents, anti aggregation agents, anti coagulation agents, anti thrombotic agents, thrombolytic agents, Tpa agents, anti cholesterol agents, anti vitamin K and mixtures thereof. Specific examples of such agents are glycoaminoglycans, heparins (such unfractioned heparin, standard heparin, low molecular heparin, heparinoid, and mixtures thereof), heparin-like molecules (such as heparinoid, danaparoid, orgaran, fragmin, dalteparin, enoxaparine, lovenox, ardeparin, normiflo and mixtures thereof), thrombin inhibitor (such as argatroban, novastan, and mixtures thereof), aspirin, anti inflammatory agents (such as non steroid anti inflammatory agents), anti aggregation agents, anti eradiation agents, antiplatelet agents (such as dextrans, dipryridamole, sulfinpyrazone, ticlodiptne, abcximab, tirofiban, mixtures thereof), anti thrombotic agents, thrombolytic agents (such as human recombinant activated protein, tissue plasminogen activator, urokinase, streptokinase, anistreplase/APSAC, and mixtures thereof), anti cholesterol agents, anti vitamin K, Tpa agents (tissue plasminogen activator), glycoaminoglycans, heparinoid agents, hirudins, anti vitamin K, warfarins, Coumadin, coumarin, agents of the statin family, ticlopidine, statin agents, cenvastatine, simvastatin, lovsstatin, agents of the statin family, cenvastatine (Baycol), simvastatin, lovastatin, etc. Examples of antithrombotic and/or non haemorrahgic formutations in the scope of the present invention can be a combination of therapeutically effective amount of compoundfs) of formula (CHjfeN^CHzJnOOO" with n an integer from 1 to 5, pharmaceutically acceptable salts thereof, esters thereof, precursors thereof and mixtures thereof, and therapeutically effective amount of one or more compound(s), pharmaceuticaHy acceptable salts thereof, esters thereof, precursors thereof and mixtures thereof, selected from the group consisting of: anti aggregants as abciximab, acetylsalicylate basic aluminium, acetylsalicylate carbonate sodium, acetylsalicylate lysine^ acetylsalicylic acid, aloxiprine, anagreli chlorydrate, bencyclane fiiramate, carbasalate calcium, ciopidogrel sulfate, epoprostenol sodium, epifibati, hydroxychloroquine sulfate, iloprost, nicergoline, nifepidine, pyricarbate, sulfinpyrazone, ticlopidine chlorhydrate, tirofiban chlorhydrate, verapamil chlorhydrate, and compounds structurally similar to one of the preceding anti aggregant compounds, and/ or anticoagulants as acenocoumarol, anisindione, biscoumacetate ethyl, bromindione, coumetarot, dalteparine sodium, sirudine, xtran sulfate, enoxaparine sodium, fluindione, heparinate magnesium, heparin calcium, heparine sodium, lepirudine nadroparine calcium, oxazidione, pentosane polyester sulfuric, phenjndione, phenprocoumone, reviparine sodium, tinzaparine sodium, tioclomarol, warfarine sodium, and compounds structurally similar to one of the preceding anti coagulant compounds, and/ or fibrinolytics as altepase, anistreplase, atorvastatine calcium, bromelaines, ciprofibrate, defibroudc, fluvastatine sodium, glicazide, lovastatine, lys-plasminogene, phenformine, pravastatine sodium, reteplsse, simvastatine, streptokinase, urokinase, and compounds structurally similar to one of the preceding fibrinolytic compounds. These antithrombotic and/or non haemorrahgjc formulations can be preparations for oral, rectal, parenteral, transdermal, extracorporal, intracorporal administration. For example, for said combinations, the weight ratio between [compound(s) of formula (CH3ht^(CH2%COO: with n an integer from 1 to 5, pharmaceutically acceptable salts thereof, esters thereof, precursors thereof and mixtures thereof] / [anti aggregants agents and /or anticoagulant agents and/or fibrinolytic agents and/or mixture there of J is comprise between 50/1 and 1/50, advantageously between 25/1 and 1/2, preferably between 10/1 and 1/1. In one embodiment of the present invention, betaine due to its antithrombotic properties may be used to ameliorate die antithrombotic effect of the cited above anti aggregants and/or anticoagulant and/or fibrinolytic agents. The combined pharmaceutical form of antidote can be a combination of anti coagulant antagonists (such as protamine, vitamjne Kl, mixtures thereof), and/or thrombolytic agent antagonists ( amiocaproic acid, tranexamic acid^and mixtures thereof) and a compound of fonnula (CH^jN^CH^COO' with n an integer from I to 5, phamutceutically acceptable salts thereof, esters thereof, precursors thereof and mixtures thereof. These combined form antidote can be preparations for oral, rectal, parenteral,transdermal, extracorporal, intracorporal administration. The antithrombotic and/or non haemorrahgic formulations as described above can be combined to the combined pharmaceutical form of antidote as described above. In one embodiment of the present invention, a compound of formula (CHJ)JN*(CH2),COO" with n an integer from 1 to 5, pharmaceaiically acceptable salts thereof, esters thereof, precursors thereof, and mixtures thereof due to its anti haemorrahgic properties may be used to treat haemophilia. In one embodiment of the present invention, a compound of formula (CHJ^N^CHIXCOO' with n an integer from 1 to 5 due to it's anti haemorrahgic properties may be used in combination to ameliorate the anti haemophilia drugs potency. The combined pharmaceutical form can be a form in which die active agent and the betaine are administered simultaneously or successively, using the same administration way or different administration ways. As specific examples, when using different administration ways, the betaine is administered ir. the form of a patch Or by subcutaneous injection, while the other active agent is administered by oral way or by injection (subcutaneous, venous). When the combined pharmaceutical form is administered using the same administration way, the dosage form is advantageously an injectable form (such as a venous injectable form), but is preferably a oral dosage form, most preferably a solid or semi-solid dosage form. When using a dosage form, the active agent is advantageously in the form of pellets or micropellets or particles which are coated with a betaine containing layer. The coated particles or pellets can be further be coated with an enlerosoluble coating which is gastric insoluble or placed in a matrix or capsule which is enterosoluble and gastric insoluble. Preferably, at least the glycine betaine is in a form suitable for subcutaneous injection (preferably intra venous injection) or in a form adapted for the preparation of a form suitable for subcutaneous injection (preferably intravenous injection). The invention further relates to a process of treatment of a patient in need or for preventing troubles for a patient, by administering to said patient a therapeutic effective amount of an therapeutic active agent having at least one side effect selected among ihe group consisting of haemorrahgic events, coagulation troubles, thromboses and associations thereof, in which before and/or during anaVor after said administration (preferably before and/or during) said patient is administered a therapeutic effective amount of a compound of formula (CHj^tT-CCHiVCOO", with n an integer from 1 to S, preferably equal to 1, for preventing at least 50%, advantageously at least 75%, preferably at least 90%, most preferably substantially completely said troubles and/or for reducing the seriousness of said side effect, advantageously of a factor of at least 50%, preferably of at least 75%, most preferably of at least 90%, especially substantially completely. Glycine betaine is preferably subcutaneous injected (most preferably intravenous injection) The present invention relates to a controlled release preparation or device of betaine and, to processes for its preparation and to its medical use. In particular, the invention relates to a controlled release preparation comprising betaine, preferably glycine betaine or a pharmaceuticaUy acceptable salt thereof. Betaine is a compound of formula (CHi)i N* (CH2) n COO' with n being advantageously an integer of 1 to 5. Conventional preparations in the form of syrup, or powder have been commercially available for many years for use in the treatment of homocystinuria. Such preparations, however, do not provide a controlled release of the betaines. Moreover, despite 's long-standing use, controlled release preparations for oral, rectal, parenteral, transdermal, extracorporal, intracorporal administration containing as active ingredient a betaine have not even previously been described, nor suggested in the literature. It is an object of the present invention to provide an oral, rectal, parenteral, transdermal, extracorporal, intracorporal controlled release of a betaine, preferably glycine betaine preparation suitable for at least 5 minutes, such as for at least 10 minutes, ...twelve-hourly (e.g. up to twenty-four hourly or even more, such as for a week, two weeks, one month, three months ) administration for the treatment of a mammalian. The present invention therefore provides a controlled release preparation and/or device comprising betainc, preferably glycine betaine or a pharmaceutically acceptable salt thereof or ester thereof for body (oral, rectal, parenteral, transdermal, extracorporal, intracorporal, etc.) administration. Suitable pharmaceutically acceptable salts of betaine, preferably glycine betaine for use according to the present invention are those conventionally known in the art such as pharmaceutically acceptable acid addition salts. The anhydrous salt is particularly preferred. The invention relates to a controlled release pharmaceutical system suitable for delivering in a controlled manner to the bloodstream of a mammalian a betaine or an effective amount of a compound of formula (CHjfcN^CHj^COO" with n aa integer from 1 to 5, preferably glycine betaine or a pharmaceutically acceptable salt thereof, esters thereof, precursors thereof, precursors thereof, precursors thereof, and mixtures thereof, and/or to a controlled release pharmaceutical system suitable for delivering in a controlled manner to the bloodstream of a mammalian as active ingredient at least a compound selected from the group consisting of betacnes or an effective amount of a compound of formula (CH3)3N*(CHi)nCOO" with n an integer from 1 to 5, pharmaceutical^ acceptable salts thereof, esters thereof, precursors thereof, precursors thereof, precursors thereof, and mixtures thereof. The system of the invention is an oral controlled release preparation or device and/or a transdermal controlled release preparation and/oral transdermal controlled release device a parenteral controlled release preparation and/or an extracorporal controlled release device arid/or an intracorporal controlled release device or preparation and/or is a rectal controlled release preparation and/or a rectal controlled release device and/or a mucous controlled release preparation or device and/or a pulmonary controlled release preparation or device and/or an ocular controlled release preparation or device. According to an embodiment, the system combines at least two systems selected from the group consisting of: oral controlled release preparations, oral controlled release device, transdermal controlled release preparations, transdermal controlled release devices, parenteral controlled release preparations, parenteral controlled release devices, extracorporal controlled release preparations, extracorporal controlled release devices, intracorporal controlled release preparations, intracorporal controlled release devices, rectal controlled release preparations, rectal controlled release device, a mucous controlled release preparations, mucous controlled release devices, pulmonary controlled release preparations, pulmonary controlled release devices, ocular controlled release preparations and ocular controlled release devices. In the system of the invention the active ingredient is preferably glycine betaine. The invention relates also to a controlled release pharmaceutical system for releasing an effective therapeutically amount of at least a compound selected from the group consisting of betaines or an effective amount of a compound of formula (CHj)jN*{CHj)nCOO' with « an integer from 1 to 5, pharmaceutically acceptable salts thereof, esters thereof, precursors thereof, precursors thereof, precursors thereof, and mixtures thereof, for treating or preventing blood flow disturbances, and to a controlled release pharmaceutical system for releasing an effective therapeutic amount of at least a compound selected from the group consisting of betaines, pharmaceutically acceptable salts thereof, esters thereof, precursors thereof, precursors thereof, precursors thereof, and mixtures thereof, for treating or preventing thrombosis and/or thromboembolic disorders. The system of the invention is advantageously a system controlling at least for 10 minutes, advantageously at least for IS minutes, preferably at least for 30 minutes, the release of at least & compound selected from the group consisting of betaines or an effective amount of a compound of formula (CHj)jN'XCHi)nCOO* with n an integer from 1 to 5„ pharmaceutically acceptable salts thereof, esters thereof, precursors thereof, precursors thereof, precursors thereof, and mixtures thereof, Preferably, the system controls at least for 60 minutes, advantageously at least for 90 minutes, preferably at least for 120 minutes, the release of at feast a compound selected from the group consisting of betaines or an effective amount of a compound of formula (CH3)JN+(CH2)aCOO' with n an integer from 1 to 5„ pharmaceutically acceptable salts thereof, esters thereof, precursors thereof, precursors thereof, precursors thereof, and mixtures thereof. Most preferably the system controls at least for 180 minutes, advantageously at least for 240 minutes, preferably at least for 360 minutes, most preferably at least for 1440 minutes {for example for 1 week, for two weeks, for one month), the release of at least a compound selected from the group consisting of betaines or an effective amount of a compound of formula (CHih^(CH{iDCOO' with n an integer from 1 to 5„ pharmaceutically acceptable salts thereof, esters thereof, precursors thereof, precursors thereof, precursors thereof, and mixtures thereof. According to a possible embodiment, the system and/or the device of the invention comprises one or more electronic device or chips controlling one or more releasing system or device, such as s micro pump(s), a syringe, a balloon, etc. The invention further relates to the use of betaine, a compound of formula (CH3)3N+(CHI)nCOO" with n an integer from 1 to 5„ pharmaceuticaiiy acceptable salts thereof, esters thereof, precursors thereof, precursors thereof, precursors thereof, and mixtures thereof, for the preparation of a system of the invention and/or to a method for treating or preventing a blood flow disturbance, in which a betaine or a compound of formula (CHjJjN^CtynCOO" with n an integer from 1 to 5, pharmaceuticaiiy acceptable salts thereof, esters thereof, precursors thereof, precursors thereof, precursors thereof, and mixtures thereof is administered in a controlled manner to the blood stream of a mammalian, and/or to a method for for treating or preventing thrombosis and/oc iircmboemboJic disorders, in which a betaine or a compound of formula (CHs^N^CfyXCOO" with n an integer from 1 to 5, pharmaceuticaiiy acceptable salts thereof, esters thereof, precursors thereof, precursors thereof, precursors thereof, and mixtures thereof is administered in a controlled manner to the blood stream of a mammalian. An example of oral controlled release preparation according to the present invention is one that achieves slow release of a drug ovef an extended period of time, thereby extending the duration of drug action over that achieved by conventional delivery. Preferably such a preparation maintains a drug concentration in the blood within the therapeutic range for 12 hours or more, most preferably for 24 hours or more. The present inventor has found that in order to allow for controlled release betaine, preferably glycine betaine over at least a twelve hour period following oral administration, the in vitro release rate preferably corresponds to the following % rate of betaine, preferably glycine betaine released: TABLE 1 TIME (H) % RELEASED 1 0-50 2 0-75 4 3-95 8 10-100 12 20-100 16 30-100 24 50-100 36 >80 Another preferred preparation especially suited for twice-a-day dosin? has an in vitro release rate corresponding to the following % rate of betaine, preferably glycine betaine released: TABLE 2 TIME (H) % RELEASED 1 20-50 2 40-75 4 60-95 8 80-100 12 90-100 Yet another preferred preparation particularly suited for once-a-day dosing has an in-vitro release rate corresponding to the following % rate of betaine, preferably glycine betaine released: TABLE 3 TIME (H) % RELEASED 1 0-50 2 0-75 4 10-95 8 35-100 12 55-100 16 70-100 24 >90 A still farther preferred preparation in accordance with the invention also particularly suited for once-a-day dosing has an in vitro release rate corrssponding to the following % rate of betaine, preferably glycine betaine released. TABLE 4 TIME(H) % RELEASED 1 0-30 2 0-40 4 3-55 8 10-65 12 20-75 16 30-88 24 50-100 36 >80 More preferably a preparation for once-a-day dosing has an in vitro release rate substantially as follows; TIME (H) % BETAINE, PREFERABLY GLYCINE BETAINE RELEASED 1 15-25 2 25-35 4 30-45 8 40-60 12 55-70 16 60-75 \nother preferred dissolution rate in vitro upon release of the controlled release reparation for administration twice daily according to the invention, is between 5 uid 50% (by weight) betaine, preferably glycine betaine released after 1 hour, between 10 and 75% (by weight) betaine, preferably glycine betaine released after 2 hours, between 20 and 95% (by weight) betaine, preferably glycine betaine released after 4 hours, between 40 and 100% (by weight) betaine, preferably glycine betaine released after 8 hours, more than 50% (by weight) betaine, preferably glycine betaine released after 12 hours, more than 70% (by weight) released after 18 hours and more than 80% (by weight) betaine, preferably glycine betaine released after 24 hours. Furthermore, it is preferred in the case of a controlled release preparation for administration twice daily that after 8 hours following oral administration between 70 and 95% (by weight) betaine, preferably glycine betaine is absorbed in vivo, between 77 and 97% (by weight) betaine, preferably glycine betaine is absorbed after 10 hours and between 80 and 100% (by weight) betaine, preferably glycine betaine is absorbed after 12 hours. A formulation in accordance with the invention suitable for twicc-a-day dosing may have a tmax of 1.5 to 8 hours, preferably 2 to 7 hours, and a W.sub.50 value in the range 7 to 16 hours. A formulation in accordance with the invention suitable for once-a-day dosing may have a tmax in the range of 3 to 6 hours, preferably 4 to 5 hours and a W.sub.50 value in the range of 10 to 36 hours. The W.sub.S0 parameter defines the width of the plasma profile at 50% Cmax, i.e. the duration over which the plasma concentrations are equal to or greater than 50% of the peak concentration. The parameter is determined by linear interpolation of the observed data and represents the difference in time between the first (or only) upslope crossing and the last (or only) downslope crossing in the plasma profile. The in vitro release rates mentioned herein can be are, except where otherwise specified, those obtained by measurement using the Ph. Eur. Paddle Method, at 100 -rpm in 900 ml 0. IN hydrochloric acid at 37.degree. C. and using ary suitable method for detecting the betaine or glycine betaine (such as HPLC, UV detection, etc.,). The in vivo absorption rate is determined from measurement of plasma concentration against time using the deconvolution technique. A conventional release betaine, preferably glycine betaine drop preparation (Tramal (trade mark), Grunenthal) was used as the weighting-functiorj and the elimination half life of betaine, preferably glycine betaine was taken as 7.8 hours. The controlled release preparation according to the invention preferably contains an effective amount of betaine, preferably glycine betaine or r, pharmaceutical^ acceptable salt or esters thereof, precursors thereof, precursors thereof, conveniently in the range of from 50 to 8000 mg, especially 100, 200, 300, 400 to 600, 800 to 1000, 1500 to 5000 mg (calculated as betaine, preferably glycine betaine anhydrous) per dosage unit. The controlled release preparation according to the invention may be presented, for example, as granules, spheroids, pellets, multiparticulates, capsules, tablets, sachets, controlled release suspensions, or in any other suitable dosage form incorporating such granules, spheroids, pellets or multiparticulates. The active ingredient in the preparation according to the invention may suitably he incorporated in a matrix. This may be any matrix that affords controlled release betaine, preferably glycine betaine over at least a twelve hour period and preferably that affords in-vitro dissolution rates and in vivo absorption rates of betaine, preferably gfycine betaine within the ranges specified above. Preferably the matrix is a controlled release matrix. Alternatively, normal release matrices having a coating which provides for controlled release of the active ingredient may be used. Suitable materials for inclusion in a controlled release matrix include (a) Hydrophilic or hydrophobic polymers, such as gums, cellulose ethers, acrylic resins and protein derived materials. Of these polymers, the cellulose ethers, especially alkylcelluloses are preferred. The preparation may conveniently contain between 1% and 80% (by weight) of one or more hydrophilic or hydrophobic polymers. (b) Digestible, long chain (Cg -C50, especially Cn -C«o), substituted or unsubstituted hydrocarbons, such as fatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral and vegetable oils and waxes. Hydrocarbons having a melting point of between 25 .degree, and 90.degree. C. are preferred. Of these long chain hydrocarbon materials, fetty (aliphatic) alcohols are preferred. The preparation may conveniently contain up to 60% (by weight) of at least one digestible, long chain hydrocarbon. (c) Polyalkylene glycols. The preparation may suitably contain up to 60% (by weight) of one or more polyalkylene glycols. One particularly suitable controlled release matrix comprises one or more alkylcelluloses and one or more Cn -C36 aliphatic alcohols. The alkylcellulose is preferably C\ -C5 alicyl cellulose, especially ethyl ceHulose. The controlled release preparation according to the invention preferably contains from 1 to 20% (by weight), especially from 2 to 15% (by weight) of one or more alkylcelluloses. Hie aliphatic alcohol may conveniently be lauryl alcohol, myristyl alcohol or stearyl alcohol but is preferably cetyl alcohol or more preferably cetostearyl alcohol. The controlled release preparation suitably contains from 5 to 30% (by weight) of aliphatic alcohol, especially from 10 to 25% (by weight) of aliphatic alcohol. Optionally the controlled release matrix may also contain other pharmaceutically acceptable ingredients which are conventional in the pharmaceutical art such as diluents, lubricants, binders, granulating aids, colorants, flavorants, surfactants, pH adjusters, anti-adherents and gildants, e.g. dibutyl sebacate, ammonium hydroxide, oleic acid and colloidal silica. The controlled release preparation according to the invention may conveniently be film coated using any film coating material conventional in the pharmaceutical art. Preferably an aqueous film coating is used. Alternatively, die controlled release preparation according 10 the invention may comprise a normal release matrix having a controlled release coating. Preferably the preparation comprises film coated spheroids containing the active ingredient and a spheronising agent The spheronising agent may be any suitable pharmaceutically f^csptable material which may be spheronised together with the active ingredient to form spheroids. A preferred spheronising agent is microcrystaUine cellulose. The microcrystalline cellulose used may suitably be, for example, Avicel PH 101 orAvicelPH 102 (Trade Marks, FMC Corporation). Optionally the spheroids may contain other pharmaceuticaily acceptable ingredients conventional in the pharmaceutical art such as binders, bulking agents and colorants. Suitable binders include water soluble polymers, water soluble hydroxyalkyl celluloses such as hydroxypropylcellulose or water insoluble polymers (which may also contribute controlled release properties) such as acrylic polymers or copolymers for example etbylcellulose. Suitable bulking agents include lactose. The spheroids are coated with a material which permits release of the active ingredient at a controlled rate in an aqueous medium. Suitable controlled release coating materials include water insoluble waxes and polymers such as polymethacrylates (for example Eudragit polymers. Trade Mark) or^tater insoluble celluloses, particularly ethylcellulose. Optionally, water soluble polymers such as polyvinylpyrrolidone or water soluble celluloses such as hydroxypropylmethylceliulose or hydroxypropylcelluloac may be included. Optionally other water soluble agents such as polysorbate 80 may be added. Alternatively the drag may be coated onto inert non-paretl beads and the drug loaded beads coated with a material which permits control of the release of the active ingredient into the aqueous medium. In a further aspect the present invention provides a process for preparing a controlled release preparation according to the present invention comprising incorporating betaine, preferably glycine betaine or a pharmaceuticaily acceptable salt thereof in a controlled release matrix: (a) granulating a mixture comprising betaine, preferably glycine betaine or a pharmaceuticaily acceptable salt thereof and one or more alkylcelluloses, (b) mixing the alkylcellulose containing granules with one or more C.sub.12-36 aliphatic alcohols; and optionally (c) shaping and compressing the granules, and film coating, if desireri; or (d) granulating a mixture comprising betaine, preferably glycine betaine or a pharmaceutically acceptable salt thereof, lactose and one or more alkylcelluioses with one or more C.sub. 1 2-36 aliphatic alcohol; and, optionally, (e) shaping and compressing the granules, and film coating, if desired. The controlled release preparation according to the invention may also be prepared in the form of film coated spheroids by granulating the mixture comprising betaine, preferably glycine betaine or a pharmaceutically acceptable salt thereof and a spheronising agent; extruding the granulated mixture to give an extrudate; spheronising the extrudate until spheroids are formed; and coating the spheroids with a film coat. One preferred form of unit dose form in accordance with the inveutirn comprises a capsule filled with controlled release particles essentially comprising the active ingredient, a hydrophobic fusible carrier or diluent and optionally a hydrophilic release modifier. In particular, the controlled release particles are preferably prepared by a process which comprises forming a mixture of dry active ingredient and fusible release control matemis followed by mechanically working the mixture in a high speed mixer with an energy input sufficient to melt or soften tiie fusible material whereby it forms particles with the active ingredient. The resultant particles, after cooling, are suitably sieved to give particles having a size range from 0.1 to 3.0 min, preferably 0.25 to 2.0 mm. An example according to the invention is described below which is suitable for the commercial production of dosage units. When using such a processing technique it has been found that, in order most readily to achieve the desired release characteristics (both in vivo and in vitro as discussed After the particles have been fanned they are cooled or allowed to cool, and may then be sieved to remove any over or undersized material. The resulting particles may be used to prepare dosage units in accordance with the invention in the form of e.g. tablets or capsules in manners known per se. The inventor have also found that particles containing betaine, preferably glycine betaine or a salt thereof produced by a melt processing as described in application PCT/SE93/00225 and the process described and claimed in our prior unpublished UK application No, 9324045.5 filed on 23 Nov. 1993 as well as the process described herein are particularly useful for processing into the form of tablets. The inventor found that by suitable selection of the materials used in forming the particles and in die tabletting and the proportions in which they ys us-jd, enables a significant degree of control in the ultimate dissolution and release rates of the betaine, preferably glycine betaine or salt thereof from the compressed tablets. Usually, to form a tablet in accordance with the invention, partirtes prepared as described above will be admixed with facetting excipienls e.g. cze sr more or the standard excipienls such as diluents, lubricants, binding agents, flow aids, disintegrating agents, surface active agents or water soluble polymeric materials. Suitable diluents are e.g. microcrystalline cellulose, lactose and dicalrium phosphate. Suitable lubricants are e.g. magnesium stearate and sodium £tearyl fumarate. Suitable binding agents are e.g. hydroxypropyl methyl cellulose, polyvidone and methyl cellulose. Suitable disintegrating agents are starch, sodium starch glycolate, crospovidone and croscarmatose sodium. Suitable surface active are Poloxamer 188.RTM., polysorbate SO and sodium lauryl sulfate. Suitable flow aids are talc colloidal anhydrous silica. Suitable water soluble polymers are PEG with molecular weights in the range 1000 to 6000. To produce tablets in accordance with the invention, particles produced in accordance with the invention may be mixed or blended with the desired excipient(s), if any, using conventional procedures, e.g. using a Y-Cone or bin-blender and the resulting mixture compressed according to conventional tabletting procedure using a suitable size tabletting mold. Tablets can be produced using convention;:! tabletting machines, and in the embodiments described below were produced on standard single punch F3 Manesty machine or Kilian RLE15 rotary tablet machine. Generally speaking I find that even with such a highly water soluble active agent as betaine, preferably glycine betaine or salt thereof tablets formed by compression according to standard methods give very low release rates of the active ingredient e.g. corresponding to release over a period of greater than 24 hours, say more than 36. The inventor found that the release profile can be adjusted in a number of ways. For instance a higher loading of the drug will be associated with increased release rates; the use of larger proportions of the water soluble fusible material in the particles or surface active agent in the tabletting formulation will .Uso je associated with a higher release rate of the active ingredient. By controlling the relative amounts of these ingredients it is possible to adjust the release profile of the betaine, preferably glycine betaine or salt thereof. The following examples illustrate various aspects of the present invention, they are not to be construed to limit the claims in any manner whatsoever. APPARATUS AND METHOD MATERIAL Betaine anhydrous, BETAFIN ® ( Finnsugar Bioproducts, CULTOR, Helinski) Rats Wistar, males, weight between 250 and 300 grams Sodium Thiopental Aggregometer CHRONOLOG COULTRONIC S.A. France ADP & coliagen Laboratoires Stago France METHODS The aggregation is made in accordance to the methods Cardinai & Flower. Pharmacol. Method. 1980 . and to American Journal of Clinical Pathology, 1989; 92: 676-679. Sureney. JD. Whole Blood aggregometry. After a keeping period of 8 days, the rats are subjected to a fasting for 12 hours. Betaine is subcutaneous injected one hour before blood sampling. The rats are then anaesthetised with sodium Thiopental administered at a dose of 20Qmg/Kg and the blood samples are taken by intracardiac puncture on a trisodium citrate solution ( 1 volume of solution at 3,8 % citrate for9 volumes of blood). Agtisated PtagnJaiion Oias. I. kaolin} This test explores the intrinsic coagulation pathway. One hour after sub cutaneous administration of die betaine, 0.8 mi total blood by intracardiac way is injected in a container HR, HemoTec. These tubes contain the kaolin activator. ( Method HemoTec, automated coagulation timer manufactured by MEDTRONIC HEMOTEC Inc., Englewood, CO., USA). induced haernorrah,gic time IHT (E. Dejana. Bleeding time in rats . Thrombosis. Rech. 1982 ) Blood samples are made before the test The tail of anaesthetised rat, is dipped for 5 minutes in a water bath at 37°C so as to provoke a dilatation of the peripheral vessels which are removed and cut at the end, the chronometer being siartsd. The IHT is defined as being the time period comprised between the cutting of end tail and the end of the haemorrhage or bleeding. The end of haemorrhage is defined as the time where the last drop of biood is removed from the taif and no other drop is seen during ISO seconds. The substances were subcutaneously administrated 60 minutes prior to the ml cut. t A/ Principle of laser-induced thrombosis (Seiffge D. et aL, 1989; Weichter W. et il., 1983) In this model, lesion of the vascular wall is induced by a laser beam. This beam causes a limited lesion of the vascular endothelium (only 1 to 2 cell': are destroyed). This laying bare of the sub-endothelium, which is a thrombogenetic surface, results in the adherence of platelets via glycoprotein II. This adherence of platelets is followed by the activation thereof. They form pseudopods and secrete the content of their granules. This activation results in the appearance of glycoproteins Ilb-IIIa which are necessary for the aggregation of the platelets between them. This lesion is induced in the mesenteric microcirculation of tbe rat. Il is immediately followed by the formation of a thrombus (in a few seconds). This thrombus, which rapidly enlarges under the influence of the flow of blood, emboiises before being formed again. By this manes, the assessment of the effect of glycine betaine was conducted pharmacologically in conjunction with the study of two active molecules used as a reference; namely acetylsalicylic acid and heparin (of low molecular weight). The assessment also involved the activity of glycine betalne in relation to the prothrombotic effects induced by contrasting products. B / Stasis-induced thrombosis A laparotomy was performed to open the lower vena cava, on which a ligature was placed at To, followed by subcutaneous injection of glycine betaine at To + 2 hours, followed by withdrawal of the clot and blood samples at T0 + 6 heirs. CI Experimental procedure Male Wisfar rats were used for these tests. They weighed between 200 and 250 grams. After an 8-day stabilisation period, the rats were subjected to fasting for 12 hours. They were than anaesthetised, glycine betaine wzs administered subcutaneous!]/, and the mesentery (laser) or vena cava (stasis) was opened at the end of the experiments. It should be noted that, under the same experimental conditions for the preservation of blood, glycine betaine appeared to possess a high anti¬coagulant capacity compared with tubes containing heparin or EDTA. The effective dose of glycine betaine appeared to be between 3 and 5 mg per haemolysis tube. This experimental result demonstrates the high anticoagulant potential of glycine betaine. It can thus be claimed that glycine betaine can be used as an anticoagulant both for the treatment of the human body in vivo and for the preservation of blood ex vivo. Evaluation of the activity of glycine betaine compared with that of contrasting products In the context of our research on the anti-mrombotic effects, and in order to complement our preliminary work on the efficacy of glycine betaine, we evaluated the effect of glycine betaine on the increase of the thrombo-embolic risk associated with the use of contrasting products known for their prothrombotic capacities. The significance of this model is that it enables a direct observation to be made of the formation of a thrombus at the site of the vascular lesion. These results explain the occurrence of thrombotic occlusions during angioplasty, especially amongst patients whose endothelium is already damaged or injured. Coronary angioplasty causes a stripping of the endothelium, exposing collagen, elastin and the smooth muscle cells of the circulating blood, analogously to the experimental thrombosis model employed. Thus, there is a higher incidence of new thrombi amongst patients who have bad a recent coronary thrombosis or who have an eccentric coronary plaque. The administration of contrasting products reduces the number of white corpuscles, the number of red corpuscles and the number of platelets. Contrasting products interact with leukocytes, induce the liberation of leukotrienes, increase vascular permeability and exert a chemotactic effect. Moreover, contrasting products act to control the expression of P-selectin and cause the adherence of white corpuscles to the vascular endothelium. It has been shown that the use of contrasting products is associated with the occurrence of thrombi in variable amounts depending on the product used. to the administration procedures themselves. Glycine betaine remedies these undesirable effects. CONCLUSION Glycine betaine possesses the same, or even better, therapeutic features as those of the anticoagulants and anti-aggregants investigated (acetylsalicylic acid and heparin), whilst exhibiting no undesirable effects. The superior performance as regards therapeutic efficacy of glycine betaine in relation to these two molecules (acetyisalicylic acid and heparin) is an incentive for the formulation of a drug containing glycine betaine as a therapeutically active ingredient, said drug being intended for the treatment of thromboses and thrombo-embolic diseases. According the results presented above, this drug also exhibits anticoagulant, anti-aggregant and fibrinolytic indications. The demonstrated innocuousness of this molecule enables long-term treatments to be considered which do not necessitate biological monitoring. Interest in dw use of glycine betaine is based on the fact that it acts at several levels of haemostatis, i.e. it acts on platelet aggregation, coagulation and fibrinolysis. This activity is durable and prevents repeated administration, which constitutes a considerable improvement in ^elation to existing treatments. The administration of betaine does not induce any haemorrahgic 25 risk or other side effects (e.g. hepariu-induced thrombopenia), which constitutes a major advance in antithrombotic therapy. The dose effect is confirmed in all the studied parameters. The antagonist activity at the glycoprotein lib Ilia site for the compounds of the invention also applies to other agonists, such as serotinin, arachidonic acid, epinephrine, adrenaline, ristocetine and thrombin. Eyaiqple 32; Human in vivo tflrt Two volunteers (with a weight of about 70-75 kg), considered as heavy smokers (smoking more than 10 cigarettes / day) have oraliy taken capsules (gastro soluble) containing 5g anhydrous glycine betaine/ day during 7 days. Before administration of the betaine, the aggregations induced by ADP, by collagen, by epinephrine, by adrenaline, by thrombin, by ristocetine and by arachidonic acid were determined. After one week treatment, the same platelet aggregations were measured. It appears from said tests that all the induced platelet aggregations were reduced for all said endogenous agonists of at least 30%. Better results are expected when using oral dosage form with controlled release, such as gastro insoluble, but entero soluble form. Example 23 : antS-haemnrrahgic activity t Rats have been used in this test. Some rats received an active agent with haemorrabgic side effect, while other rats received said active agent together with a dose of betaine. The following products were administered to rats for determining whether glycine betaine has an anti-haemorrahgic effect: 100 mg aspirin per kg life body 100 mg aspirin + 50 mg glycine betaine per kg life body 2 mg heparin 2 mg heparin + 50 mg glycine betaine 2 mg heparin + 10 mg glycine betaine 2 mg heparin + 2 mg glycine betaine When inducing a haemorrhage, it was observed that the bleeding time was reduced when glycine betaine was administered. It means therefore that glycine betaine has anti-haemorrahgic properties. In view of the above specification, the invention relates thus also to . - the use of a. compound of formula (CHj^N4- - (CHz)n - COO~ with n an integer from 1 to 5, preferably equal to 1, or a mixture of such compounds or one or more pharmaceutical^ acceptable salts thereof for the preparation of a pharmaceutical composition for the treatment or the prevention of troubles bound to one or more glycoproteins, especially to receptor of one or more glycoproteins, preferably to receptor of glycoprotein Ufa Ilia, - the use of a compound of formula (CHOJN* - (CHi)„ - COO" with n an integer from 1 to 5, preferably equal to L, or a mixture of such compounds or one or more phannaceuticsHy acceptable salts thereof for the preparation of a pharmaceutical composition for the treatment or the prevention of troubles bound to one or more glycoproteins, especially to receptor of one or more glycoproteins, preferably to receptor of glycoprotein lib Ilia for inhibiting the platelet aggregation, - the use of a compound of formula (CHJJJN* - (CH3)„ - COO' with n an integer from 1 to 5, preferably equal to 1, or a mixture of such compounds or one or more pharmaceutically acceptable salts thereof for the preparation of a pharmaceutical composition for the treatment or the prevention of troubles bound to one or more glycoproteins, especially to receptor of one or more glycoproteins, preferably to receptor of glycoprotein lib Ilia for avoiding the adhesion of cells there between - Pharmaceutical composition comprising insulin and at least a compound of formula (CHj)3N*(CHj)nCOO" with n an integer from I to S, preferably equal to 1, or a mixture of such compounds or one or more pharmaceutical ly acceptable salts thereof - Pharmaceutical composition comprising an anticancerous agent and at least a compound of formula (CH3)jNT(CH^)nCOO" with n an integer from 1 to 5, preferably equal to 1, or a mixture of such compounds or one or more pharmaceutically acceptable salts thereof - Pharmaceutical composition comprising an antibiotic ?nd tt least a compound of formula (CH3))N+(CH2)nCOO" with n an integer from 1 to 5, preferably equal to 1, or a mixture of such compounds or one or more pharmaceutically acceptable salts thereof - Use of a compound of formula (CHjJjN^CHiJnCOO' with n an integer from I to 5, preferably equal to 1, or a mixture of such compounds or one or more pharmaceutically acceptable salts thereof, as glycoproteic antagonist agent, in particular as antagonist of the glycoprotein lib Ilia, for the preparation of a pharmaceutical composition - Use of a compound of formula (CH3)3N*(CHi)nCOCr with n an integer from 1 to 5, preferably equal to 1, or a mixture of such compound or one or more pharmaceutically acceptable salts thereof, as therapeutic active agent for the preparation of a pharmaceutical composition for the treatment or the prevention or the stabilization of troubles bound to cancer, in particular to the metastasis of cancerous cells - Use of a compound of formula (CH3)j>r{CHi)nCOO' with n an integer from 1 to 5, preferably equal to 1, or a mixture of such compounds or one or more pharmaceutically acceptable salts thereof, as therapeutic active agent for the preparation of a pharmaceutical composition for the treatment or the prevention or the stabilization of troubles bound to blood circulation, in particular to the blood microcirculation - Use of a compound of formula (CHsbN^CH^COO" with n an integer from 1 to 5, preferably equal to I, or a mixture of such compounds or one or more pharmaceutically acceptable salts thereof, as therapeutic active agent for the preparation of a pharmaceutical composition for the treatment or the prevention or the stabilization of troubles bound to nicotine addiction - Use of a compound of formula (CHj>3N*(CHi)nCOO" with n an integer from 1 to 5, preferably equal to 1* or a mixture of such compounds or one or more pharmaceutically acceptable salts thereof, as therapeutic active agent for the preparation of a pharmaceutical composition for the treatment or the prevention or the stabilization of troubles bound to obesity - Use of a compound of formula (CHs^N^CHiVCOO* with n an integer from I to 5, preferably equal to 1, or a mixture of such compounds or one or more pharmaceutically acceptable salts thereof, as therapeutically active agent for the preparation of a pharmaceutical composition for the treatment or the prevention or the stabilization of troubles bound to hemophilia - Use of a compound of formula - Use of a compound of formula (CH3>3N*(CH1)nCOO" with n an integer from 1 to 5, preferably equal to 1, or a mixture of such compounds or one or more pharmaceutically acceptable salts thereof, as therapeutic active agent for the preparation of a pharmaceutical composition for the treatment or the prevention or the stabilization of diabetic troubles - Use of a compound of formula (CHj^N^Cr^nCOO" with n an integer from 1 to 5, preferably equal to 1, or a mixture of such compounds or one or more pharmaceutically acceptable salts, thereof, as uie.-apeutic active agent for the preparation of a pharmaceutical composition for the treatment or the prevention or the stabilization of troubles bound to aging - Use of a compound of formula (CH3)jN*(CHi)nCOO" with n an integer from 1 to 5, preferably equal to 1, or a mixture of such compounds or one or more pharmaceutically acceptable salts thereof, as therapeutic active agent for the preparation of a pharmaceutical composition for the treatment or the prevention or the stabilization of troubles bound to oestrogen oral contraception - Use of a compound of formula (CH])]N*(CH2)nCOO' with s an integer from 1 to 5, preferably equal to 1, or a mixture of such compounds or one or more pharmaceuticaily acceptable salts thereof, as therapeutically active agent for the preparation of a pharmaceutical composition for the treatment or the prevention or the stabilization of troubles bound to extracorporal blood circulation, in particular to troubles bound to dialysis and to hemodialysis - Use of a compound of formula (CHj)3N+(CH2)nCOO* with n an integer from 1 to 5, preferably equal to 1, or a mixture of such compounds or one or more pharmaceuticaily acceptable salts thereof, as therapeutic active agent for the preparation of a pharmaceutical composition for the treatment or the prevention or the stabilization of troubles bound to inflammation, in particular internal inflammation troubles - Use of a compound of formula (CFfchN^CHjJnCOO' with n an integer from 1 to 5, preferably equal to 1, or a mixture of such compounds or one or more pharmaceuticaily acceptable salts thereof, as therapeutic active agent for the preparation of a pharmaceutical composition for the treatment or the prevention or the stabilization of troubles bound to biuj, m oarticular to bites of venomous animals, - Use of a compound of formula (CH3)jN+(CH2)nCOO" with n an integer from I to 5, preferably equal to 1, or a mixture of such compounds or one or more pharmaceuticaily acceptable salts thereof, as therapeutic active agent for the preparation of a pharmaceutical composition for the treatment or the prevention or the stabilization of troubles bound to post traumatic shock or post surgical shock, - Use of a compound of formula (CH3)jN*(CH2)nCOO" with n an integer from 1 to S, preferably equal to t, or a mixture of such compounds or one or more pharmaceuticaily acceptable salts thereof, as therapeutic active agent for the preparation of a pharmaceutical composition for the treatment or the prevention or the stabilization of troubles bound to septic shocks, - Use of a compound of formula (CHj)3N+(CH2)nCOO" with n an integer from 1 to 5, preferably equal to 1, or a mixture of such compounds or one or more pharmaceittically acceptable salts thereof, as therapeutic active agent for the preparation of a pharmaceutical composition for the treatment or the prevention or the stabilization of troubles bound to hemorrhage, in particular to internal hemorrhage, such as a cerebral hemorrhage, - Use of a compound of formula (CH3)jN*(CH2)nCOO' with n an integer from 1 to 5, preferably equal to 1, or a mixture of such compoi^ids or one or more pharmaceutically acceptable salts thereof, as therapeutic active agent for the preparation of a pharmaceutical composition for the treatment or the prevention or the stabilization of troubles bound to embolism, in particular to cerebral embolism and/or pulmonary embolism - Use of a compound of formula (CHi)iN*(CHt)BCOO' with n an integer from 1 to 5, preferably equal to 1, or a mixture of suet compounds or one or more pharmaceutically acceptable salts thereof, as therapeutic active agent for the preparation of a pharmaceutical composition for the treatment or the prevention or the stabilization of troubles bound to an infract - Use of a compound of formula (CH3)3N+{CH2),,CO ■ Use of a compound of formula (CHj^N^CH^COO" with n an integer from 1 to 5, preferably equal to I, or a mixture of such compounds or one or more pharmaceutically acceptable salts thereof, as therapeutic active agent for the preparation of a pharmaceutical composition for the treatment or the prevention or the stabilization of troubles bound to phlebitis - Use of a compound of formula (CH^jN^CHOnCOO' with n an integer from 1 to 5, preferably equal to 1, or a mixture of such compounds or one or note pharmaceutically acceptable salts thereof, as therapeutic active agent ;or the preparation of a pharmaceutical composition for the treatment or the irevenrion or the stabilization of troubles bound to angina pectoris ■ Use of a compound of formula (CHj)jN*{CH3)nCOO' with n an integer from 1 to 5, preferably equal to 1, or a mixture of such compounds or one or more pharmaceutically acceptable salts thereof, as therapeutic active agent for the preparation of a pharmaceutical composition for the treatment or the prevention or the stabilization of thromboses troubles, in particular troubles bound to reocciusion of the vascular system and/or to thrombolysis and/or to angioplasty - Use of a compound of formula (CH^N^CHj^COO- with n an integer from 1 to 5, preferably equal to 1, or a mixture of such compounds or one or more pharmaceutically acceptable salts thereof, as therapeutic active agent for the preparation of a pharmaceutical composition for die treatment or the prevention or the stabilizatian of troubles bound K> the use of I: emoplastic or hemostatic glues, in particular fibrinogen glue, fibrin glue, coLagen glue, thrombin glue - Use of a compound of formula (CH3)3N+(CH2)llCOO" with n an integer from 1 to 5, preferably equal to 1, or a mixture of such compounds or one or more pharmaceutically acceptable salts thereof, as therapeutic active agent for the preparation of a pharmaceutical composition for th^ tres /incut or the prevention or the stabilization of troubles bound to pregnancy - Use of a compound of formula (CH&N'XCH^nCOO" with n an integer from 3 to 5, preferably equal to 1, or a mixture of such compounds or one or more pharmaceutically acceptable salts thereof, as therapeutic aptive agent for the preparation of a pharmaceutical composition for the tfeatment or the prevention or the stabilization of thromboses troubles, in particular coronary thrombosis and/or venous thrombosis - Use of a compound of formula (CFT^NTCCHi^COO* with n an integer from 1 to 5, preferably equal to 1, or a mixture of such compounds or one or more pharmaceutically acceptable salts thereof, as therapeutic active agent for the preparation of a pharmaceutical composition for the treatment or the prevention or the stabiiization of troubles bound to trip or travel, in particular travel in airplane, buses, trains, racket, space shuttle, preferably travel at speed of more than 200 km/h - Use of a compound of formula (CH^jN^CHz^COO" with n an integer from 1 to 5, preferably equal to 1, or a mixture of such compound:- or one or more pharmaceutical)}' acceptable salts thereof, as therapeutic active agent for the preparation of a pharmaceutical composition for the treatment or the prevention or the stabilization of troubles bound to travel, in particular to travel in pressurized environment - Use of a compound of formula (CHj)jNt'(CHi\COO~ with n an integer from 1 to 5, preferably equal to 1, or a mixture of such compounds or one or more pharmaceutically acceptable salts thereof, as therapeutic active agent for the preparation of a pharmaceutical composition for the treatment or the prevention or the stabilization of bacterial troubles and/or infectious troubles and/or troubles due to virus and/or troubles due to fongus - Use of a compound of formula (CHi)jN*(CH2)nCC>0' w:± r. an integer from 1 to 5, preferably equal to 1, or a mixture of such compounds or one or more pharmaceutically acceptable salts thereof, as therapeutic active agent for the preparation of a pharmaceutical composition for the treatment or the prevention or the stabilization of asthmatic troubles - Use of a compound of formula (CHj)3N+(CH2)nCOO' with n an integer from I to 5, preferably equal to I, or a mixture of such compounds or one or more pharmaceutically acceptable salts thereof, as therapeutic active agent for the preparation of a pharmaceutical composition for the treatment or the prevention or the stabilization of troubles bound to osteoporosis - Use of a compound of formula (CH3)}N*(CHj)nCOO" with n an integer from I to 5, preferably equal to 1, or a mixture of such compounds or one or more pharmaceutically acceptable salts thereof, as therapeutic active agent for the preparation of a pharmaceutical composition for the treatment or the prevention or the stabilization of troubJes bound to graft of*skin srvd/or tissue and/or bone and/or cells - Use of a compound of formula (CHj^K^CHz^COO" with n an integer from 1 to 5, preferably equal to 1, or a mixture of such compounds or one or more pharmaceutically acceptable salts thereof, as antagonist agent for serotinin and/or arachidonic acid and/or epinephrine and/or adrenaline and/or thrombin and/or ristocetine for the preparation of a pharmaceutical composition - Uses as disclosed here before for the preparation of a pharmaceutical form, possibly as a kit, containing an active agent different from compound of formula (CHjJjN^CHiJpCOO' with n an integer from 1 to 5, preferably equal to 1, or a mixture of such compounds or one or more pharmaceutically acceptable salts thereof, for the administration (simultaneous or successive, with the same or different administration path) of said other therapeutic active agent and of a compound of formula (CHj^N^Crfc^COO" with n an integer from 3 to 5, preferably equal to J, or a mixture of such compounds or one or more pharmaceutically acceptable salts thereof - Sweetening composition containing at least a sweetener and at least a compound of formula (CH3)]N*(CHjJ„COO' with n an integer from 1 to 5, preferably equal to 1, or a mixture of such compounds or one or more pharmaceutically acceptable salts thereof - Sweetening composition containing at least a compound of formula (CHi)3N*(CH2)nCOO" with n an integer from 1 to 5, preferably equal to 1, or a mixture of such compounds or one or more pharmaceutically acceptable salts thereof - Use of a compound of formula (CH^N^Ctb^COO" with n an integer from 1 to 5, preferably equal to 1, or a mixture of such compounds or one or more pharmaceutically acceptable salts thereof, as agent for improving the sweetening property of a sweetener, in particular of a synthetic sweetener - Process for detecting and/or localising and/or separating thrombi in vitro and/or in vivo, possibly in an extra corporal loop or circuit, in which blood is mixed or added with at least a compound of formula {CH3)3.V(CH2)nCOO" with n an integer from 1 to 5, preferably equal to 1, or a mixture of such compounds or one or more pharmaceutical!)1 acceptable salts thereof - Preserving process for cells and/or platelets in a medium, in particular in a blood medium or a fraction thereof, in which said medium is added or mixed with compound of formula (CHj^N^CHi^COO* with a an integer from 1 to 5, preferably equal to 1, or a mixture of such compounds ur ore or more pharmaceutical^ acceptable salts thereof - Process for the isolation and/or individualisation of cells and/or platelets in a medium, in particular in a blood medium or a fraction thereof, in which said medium is added or mixed with at least a compound of formula (CHjbN^CHz^COO" with n an integer from 1 to 5, preferably equal to 1, or a mixture of such compounds or one or more pharmaceutically acceptable salts thereof - Platelet rich plasma (blood plasma) or platelet poor plasma, said plasma containing at least a compound of formula (CHJ>JN+(CH2)1,COO" with n an integer from I to 5, preferably equal to I, or a mixture of such compounds or one or more pharmaceutically acceptable salts mereof ^ - Process tor the culture of cells in a medium or on a support or in a bioreactor, in particular in a blood medium or a fraction thereof, in which said medium is added or mixed with at least a compound of formula (CH3)JN+(CHi)BCOO" with n an integer from 1 to 5, preferably equal to I, or a mixture of such compounds or one or more pharmaceutically acceptable salts thereof - Process for the preparation of fibrin and/or collagen by reaction of fibrinogen or collagen in presence of at least a compound of formula (CH])jNt(CH2)nCOO' with n an integer from I to 5, preferably equal to 3, or a mixture of such compounds or one or more pharmaceutically acceptable salts thereof - glue (such as a hemostatic glue) containing at least a compound of formula (CHj)iN*(CH2)nCOO" with n an integer from 1 to 5, preferably equal to 1, or a mixture of such compounds or one or more pharmaceutical^ acceptable salts thereof - Device with a surface in contact with fibrin and/or fibrinogen and/or collagen, said surface being made of and being treated with a composition containing at least a compound of formula (CHJ)jN*(CH2)nCOO" with n an integer from 1 to 5, preferably equal to 1, or a mixture of such compounds or one or more pharmaceutical!;/ acceptable salts thereof - Composition containing at least fibrinogen and at least a compound of formula (CH3)3N+(CH2)„COO' with n an integer from 1 to 5, preferably equal to 1, or a mixture of such compounds or one or more pharmaceutically acceptable salts thereof • ^ - Composition containing at least collagen and at least a Compound of formula (CHabN^CHiJnCOO' with n an integer from 1 to 5, preferably equal to I, or a mixture of such compounds or one or more pharmaceutically acceptable salts thereof - Process for die treatment of blood or a fraction thereof by osmosis and/or reverse osmosis, is which , before and/or during and/or after the osmosis or reverse osmosis, said blood is added or mixed with at least a compound of formula (CHa^N^CH^CQO" with n an integer from 1 to 5, preferably equal to 1, or a mixture of such compounds or one or more pharmaceutically acceptable salts thereof - Process for the treatment of blood or a fraction thereof tjy centrifugation, in which , before and/or during and/or after the centrifugation, said blood is added or mixed with at least a compound of formula (CHiJjT-TfCHa^COO" with n an integer from 1 to 5, preferably equal to I, or a mixture of such compounds or one or more pharmaceutically acceptable salts thereof - Use of a compound of formula (CH3)3N*(CH2)nCOO" with u tn integer from 1 to 5, preferably equal to 1, or a mixture of such compounds or one or more pharmaceutically acceptable salts thereof for the preparation of a pharmaceutical or cosmetic composition for the treatment or prevention or stabilization of hair troubles, in particular troubles due to hair losses - Biological material or synthetic material for implant purposes, especially for bone implant, said materia! being treated with a compound of formula (CHj)jKf(CH2)nCOO" with n an integer from 1 to 5, preferably equal to 1, or a mixture of such compounds or one or more pharmaceutically acceptable salts thereof, and/or a composition containing such a compound - Process of treatment of a patient suffering of a trouble cited hereabove in this specification, in which an effective amount of a compound of formula (CH3)JN*{CHI)I,COO' with n an integer from 1 to 5, preferably epual to 1, or a mixture of such compounds or one or more pharmaceuticaUy acceptable salts thereof* is administered to said patient, so as to treat and/or stabilize said trouble - Process for preventing a patient to suffer a trouble cited hereabove in this specification, in which an effective amount of a compound of formula (CH3)}N*{CHi)nCO0- with n an integer from I to 5, preferably equal to 1, or a mixture of such compounds or one or more pharmaceutically acceptable salts thereof is administered to said patient, so as to prevent said trouble, - Use of a compound of formula (CHi)3N*(CH2)nCOO" with n an integer from 1 to 5, preferably equal to 1, or a mixture of such compounds or one or more pharmaceutically acceptable salts thereof, as antiagglutinant agent, for the preparation of a pharmaceutical composition - Use of a compound of formula (CH3)JN+(CH2)nCOO" with n an integer from 1 to 5, preferably equal to 1, or a mixture of such compounds or one or more pharmaceutically acceptable salts thereof, as blood fluidifying agent, for the preparation of a pharmaceutical composition. Beiaine, preferably glycine beiaine anhydrous (100 mg) and lactose (68 mg) were granulated, transferred to a fluid bed granulator and sprayed with ethylcellulose (15 mg) and water. The granules were teen dried at 60.degree. C. and passed through a 1 mm screen. To the wanned bctsine, preferably glycine betaine containing granules was added molten cetostearyl alcohol (42 mg) and the whole was mixed thoroughly. The granules were allowed to cool and sieved through a 1-6 mm screen. Purified talc and magnesium stearate were added and mixed with the granules. The granules were then compressed into tablets. EXAMPLES 27 and 28 Panicles having the formulations given in Table II below, were prepared by the steps of: i. Placing the ingredients (a) and (c) (total batch weight 0.7 kg) in the bowl of a 10 liter capacity Coltette Gral Mixer (or equivalent) equipped with variable speed mixing and granulating blades; ii. Mixing the ingredients at about 150-1000 rpm whilst applying heat until the contents of the bowl are agglomerated, iii. Classifying the agglomerated material by passage through a Comil and/or Jackson Crockatt to obtain controlled release seeds. iv. Wanning end mixing the classified materia! in the bowl of a 10 liter Collette Gral, until uniform multiparticulates of the desired pre-determined size range are formed in yield of greater than 80%. This takes approximately 5 minutes. v. Discharging the multiparticulates from the mixer and sieving them to separate out the multiparticulates collected between 0.5 and 2 mm aperture sieves. EXAMPLES? Samples of the particles from Example 4 were blended with magnesium stearate and purified talc using a Y-Cone or bin-blender. The blended mixture was then compressed using either (1) 14.times.6 mm, (2) I6.trmes.7 mm or (3) i8.6.times.7.5 mm capsule shaped tooling on a single punch F3 Manesty tablettmg machine to give tablets giving 200, 300 and 400 mg of betaine, preferably glycine betaine anhydrous. The ingredients per dosage unit amounted to the following: These results show that by increasing the loading of the highly water soluble ' etainc, preferably glycine betaine anhydrous (75% wAv in this example ompsred with 5096 w/w in Example 29) a significantly faster release rate of he active ingredient can be achieved. The examples provided above are not meant to be exclusive. Many other variation of the present invention would be obvious to those skilled in the art, and are contemplated to be within the scope of the appended claims. The man skilled in the art can adjust the release rate of a patch so as to have an adapted betaine concentration in the blood, for a period of for example 6 hours, 12 hours, 24 hours, etc. The patch structure can be as taught in US 4,911,916, US4,917,676, US 5,536,503 and US 5,486,362, the scope of which is incorporated by reference. In said patch structure, a betaine of formula (CH3)jN*(CHi)riCOO' with n an integer from 1 to 5, preferably glycine betaine or a pharmaceutical^ acceptable salt thereof, esters thereof, precursors thereof, and mixtures thereof is used as active agent instead of the proposed active agent- The drawings of said patents (especially figures 2 and 3 of t/S 5536503) are incorporated by reference for teaching the possible form and structure of the patch. Transdermal patches have a variety of advantages including avoidance of the ■ gastro-intestinal tract, sustained action which readily can be adjusted, self-administration and the ability to immediately discontinue dosage. The term transdermal patch is intended to include patches capable of being affixed to the skin of an individual and having a part or component capable of delivering an active agent (a betaine of formula (CH3)3N+(CHI)BCOO" with n an integer from 1 to 5, preferably glycine betaine or a phartnaceutically acceptable salt thereof, esters thereof, precursors thereof, mixtures thereof), in a controlled sustained release manner. Examples of types of patches useful in this invention include those having a diffusion layer matrix andVor multicompartmental type patches. These will be described below for glycine betaine as active agent. There are many transdermal patches known to those of ordinary skill in the art and well described in the prior art. One such patch useful involves a diffusion matrix layer that uses a reticulated macroporous polymeric foam as a framework for holding a viscoelastic glycine betaine-polymer mixture. The patch is for example a multi (4 or more)-layer, laminated composite that is adapted to be adhered to the skin. The outermost layer, backing layer, fiinctions as the primary structural element of the device as well as serving as a protective covering to prevent the glycine betaine from being transmitted from the device via the outermost surface. Backing layer preferably is made of a sheet or film of a resilient elastomer of about 10-75 microns thick. Examples of such elastomers include polyether block amide copolymers, polyethylene methacrylate block copolymers, poiyurethanes, silicon elastomers and the like. The glycine betaine-containing matrix layer functions as a reservoir for glycine betaine (possibly an enhancer), and optionally a pressure sensitive adhesive. The framework of the matrix is a reticulated macroporous polymeric foam. Preferably the network is essentially completely open pores (90% or greater). The pore rating of the reticulated foam will normally be in the range of about 10-40 pores per linear centimeter and the density (unfilled) will typically be in the range of about 0.01 to 0.5 g/cm3. Suitable polymers from which such foam frameworks may be manufactured include polyurethanes and polyethylenes. A pressure sensitive adhesive layer covers the exposed face of the matrix layer and a release liner covers the pressure sensitive adhesive. The pressure sensitive adhesive layer is a medical grade adhesive composition having a thickness normally between about 25 and 100 microns. An example of such an adhesive is polydimethylsiloxane {Dow Coming 355 medical grade adhesive). The pores of the foam are wholly or partly filled with a viscoelastic hydrophobic betaine-permeable polymer (and an enhancer if present)- The polymer acts as a carrier for the glycine betaine, while the enhancer acts to control the solubility of the glycine betaine in the polymer and/or absorption of the drug into the skin. The hydrophobic polymer renders the device water-resistant and prevents liquid water from being absorbed by the device, thereby increasing its functionality and wearabiiity. Examples of such polymers are polysiloxanes (silicone polymers), hydrophobic polyacrylates, polyurethanes, plasticized ethylene-vinyl acetate copolymers and the like. An example of a useful enhancer includes Azone. TM.. Another example of a useful dermal permeation enhancer includes transcutol. The mixture including the glycine betaine optionally includes an anti-pruritic agent. Devices of the foregoing nature are generally described in U.S. Pat. No. 4,911,916, entitled "Diffusion Matrix for Transdermal Drug Administration and Transdermal Drug Delivery Devices Including Same", issued Mar. 27, 1990, the entire disclosure of which is incorporated herein by reference. Such patches may be configured to contain sufficient glycine betaine to release from about five milligrams to 5 grams of glycine betaine, such as from 100 to 500 milligrams per day. Preferably such patches are configured to hold sufficient betaine to release from about five to about 500 milligrams per day for seven days, such that a single patch may be worn for one week. The optimum dose range, i.e., the range of doses with which die drug exhibits maximum therapeutic effect (and minimum adverse side effects for die other drug or therapeutic agent of die combination, when the patch is used in such a combination) can be determined empirically. The patch or other delivery system is configured and formulated to contain sufficient glycine betaine to release a dose within the optimum dose range for the desired period of time. Another patch useful is a 4-layer composite defining at least two separate compartments. One compartment contains glycine betaine, and the other compartment contains a delivery substance that when mixed with glycine betaine permits the delivery of the glycine betaine transdermally. The patch has a backing layer sealed to a rate controlling membrane in a manner to create two chambers, betaine containing chamber and a delivery substance containing chamber. An adhesive layer covers the rate controlling membrane and a release sheet covers the adhesive layer. To form the device, a silanized polyester (or other suitable material treated with a releasing agent) approximately 75 microns thick, is used as a release sheet 34. The adhesive layer 32 is cast onto the release sheet, and may be for example polyisobiitylene. The adhesive layer then is laminated to the rate controlling membrane 26, which may be about 100 microns thick. Ethylene-vinyt acetate may be employed for the control membrane. Next, the materials which will become the contents of the betaine containing chamber and delivery substance chamber are placed in separate areas on the rate controlling membrane. The material for the betaine containing chamber may be betaine free base and the material for the delivery substance containing chamber may be an alcoholic or aqueous/alcohofic solution or water. Finally, a suitable backing having a heat sealable coating on one surface is placed over the two areas which are to become the two chambers, and the device is heat sealed around the perimeter and between the two areas to form the two chambers. The heat seal between the two chambers should be less secure than the heat seal about the perimeter, so that the seal between the chambers will selectivefy buret under pressure applied by the user. In this manner, pressure may be applied to either one of the chambers to burst the seal between the chambers, thereby mixing the solution and the betaine and dissolving the glycine betaine (anhydrous). The betaine then is in a form which is capable of passing through the rate controlling membrane for delivery to the skin of the user. As with the patch disclosed in the first embodiment, the chambers may include enhancers or retarder for affecting uptake of the betaine across the skin. Preferred forms of the foregoing patch are shown in greater detail in U.S, Pat. No. 4,917,676, issued Apr. 17, 1990 and entitle* "User-Activated Transdermal Therapeutic System", the entire disclosure of which is incorporated herein by reference. Such patches should contain sufficient lobeline to release from about five to about 500 milligrams of glycine betaine per day (from 2 to 10 mg/kg), and such patches are suitable to provide individual, daily patches. Example 32 In said example parenteral (especially subcutaneous) solutions containing heparin and glycine betaine have been prepared. For example, the solutions of heparin sodium sold by CHOAY® (25000 fU/ml, aqueous solution), sold by LEO® and sold by ROCHE® were mixed with glycine betaine as a powder or as an aqueous solution, so as to prepare injectable solutions containing 25000 IU, 5000 It! and 2500 IU heparin (corresponding to 5 ml injectable solutions containing 5 mg /ml heparin and 100 mg/ml glycine betaine, injectable solutions containing 1 mg/ml heparin and 20 mg/ml glycine betaine, and injectable solutions containing 0,5 mg/ml heparin and ] 0 mg/ml glycine betaine). Example 33 In said example oral formulations containing aspirin ( acid acetylsalicylic) and glycine betaine have been prepared. A) acid acetylsalicylic 500 mg + 500 mg betaine + excipient B) acid acetylsalicylic 300 mg + 200 mg betaine + excipient C) acid acetylsalicylic 300 mg +■ 400 mg betaine + excipient A, B and C being possibly coated with an enterosoluble or controlled release layer, such as tablet or pellet. Or A, B and C being possibly placed in a capsule with an enterosoluble or controlled release layer. D) a syrup containing acid acetylsalicylic + betaine. Example 34 fnduced haemorrahgic time THT (E. Dejana. Bleeding time in rats. Thrombosis. Rech. 1982 ) Male Wistar rats were used for these tests. They weighed between 240 and 260 grams. The effect of various solutions ( NaCl 0,9%, betaine anhydrous 10 mg/kg, heparin sodium CHOAY® 5 mg/ kg, combination betaine 85 * anhydrous 10 mg/kg + heparin CHOAY® 5 mg/ kg ) on the (IHT) or induced haemorrahgic time was tested. The tail of anaesthetised rat, is dipped for 5 minutes in a water bath at 37°C, so as to provoke a dilatation of the peripheral vessels, which are removed and cut at the end ( 6 to 10 mm from the end of the tail), the chronometer being started. The IHT is defined as being the time period comprised between the cutting of end tail and the end of the haemorrhage or bleeding. The end of haemorrhage is defined as the time where the last drop of blood is removed from the tail and where no other drop is seen during 180 seconds. The substances were subcutaneously administrated 60 minutes prior to the tail cut In the combination test betaine 10 mg/ kg and heparin 5 mg/ kg were simultaneously administrated. not measured (no haemorrhage 3 minutes after cutting the end tail ) This test shows cJeariy that the combined use of heparin with betaine prevent rid reduces drastically the haemorrahgic side effect due to heparin. The imultaneous administration of betaine with heparin reduced in a statistically ignificant manner the volume of blood loss comparatively to the group /here heparin was administrated alone, It was noted a reduction by more ian 3 folds of blood loss in the combination group comparatively to the roup where heparin was administrated alone. "he combinations as described in examples may be useful in human clinic, larticularly to natural haemonahgic events linked to thrombosis and ardiovascular diseases or linked to drugs administration side effects bllowing various diseases I CLAIM: 1. A pharmaceutical antithrombotic combination comprising as component (A) a therapeutic effective amount of a therapeutically antithrombotic agent causing at least one haemorrhagic side effect selected from a group consisting of (vii) antiaggregants (viii) an anti vitamin k (be) fibrinolytics (x) thrombin inhibitors (xi) anticoagulants and (xii) mixtures thereof and (B) a therapeutic effective amount of compound of formula (CH3)3N+(CH2)nCOO" with n an integer from 1 to 5, or a pharmaceutical^ acceptable salt thereof, or mixtures thereof, for preventing or reducing the haemorrhagic side effect or for potentialising the therapeutic (antithrombotic) effect of said active agent. wherein antiaggregant is selected from a group consisting of abciximab, acetylsalicylate basic aluminium, acetylsalicylate carbonate sodium, acetylsalicylate lysine, acetylsalicylic acid, aloxiprine, anagreli chlorydrate, bencyclane furamate, carbasalate calcium, clopidogrel sulfate, epoprostenol sodium, epifibati, hydroxychloroquine sulfate, iloprost, nicergoline, nifepidine, pyricarbate, sulfinpyrazone, ticlopidine chlorhydrate, tirofiban chlorhydrate, verapamil chlorhydrate, and mixtures thereof. wherein anti vitamin k is selected from a group consisting of acenocoumarol, anisindione, biscoumacetate ethyl, bromindione, coumetarol, sirudine, oxazidione, phenindione, phenprocoumone, tioclomarol, warfarine sodium, and mixtures thereof, wherein fibrynolitic is selected from a group consisting of altepase, anistreplase, atorvastatine calcium, brornelaines, ciprofibrate, defibrotide, fluvastatine sodium, glicazide, lovastatine, lys-plasminogene, phenformine, pravastatine sodium, reteplase, simvastatine, streptokinase, urokinase, and mixtures thereof, wherein thrombin inhibitor is selected from a group consisting of argatroban, novastan, and mixtures thereof, wherein anticoagulant is selected from a group consisting of dalteparine sodium, sirudine, xtran sulfate, enoxaparine sodium, fluindione, heparinate magnesium, heparin calcium, heparine sodium, lepirudine nadroparine calcium, pentosane polyester sulfuric, reviparine sodium, tinzaparine sodium, glycoaminoglycans, heparins, unfractioned heparin, standard heparin, low molecular heparins, heparinoids, heparin-like molecules, and mixtures thereof with the proviso that the said pharmaceutical antithrombic combination is not for topical application. The pharmaceutical combination as claimed in claim 1, in which the compound of formula (CH3)3N+(CH2)nCOO" is glycine betaine, with n=l. The pharmaceutical combination as claimed in claims 1 or 2, in which glycine betaine is in a form suitable for subcutaneous injection orin a form suitable for the preparation of a form for subcutaneous injection.

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1198-chenp-2003 claims-duplicate.pdf

1198-chenp-2003 claims.pdf

1198-chenp-2003 correspondence-others.pdf

1198-chenp-2003 correspondence-po.pdf

1198-chenp-2003 descripition(completed)-duplicate.pdf

1198-chenp-2003 descripition(completed).pdf

1198-chenp-2003 form-1.pdf

1198-chenp-2003 form-18.pdf

1198-chenp-2003 form-26.pdf

1198-chenp-2003 form-3.pdf

1198-chenp-2003 form-5.pdf

1198-chenp-2003 pct search report.pdf

1198-chenp-2003 pct.pdf

1198-chenp-2003 petition.pdf