ANTITHROMBOTIC TREATMENT

Abstract: New antithrombotic antiplatelet aggregatory and anti­ coagulant agents utilizing bisulfite and sulfite ions and use thereof.

Description: DESCRIPTION "Antithrombotic Treatment" Sodium bisulfite (usually shown by formula to be NaHS03) has heretofore been used for many commercial purposes, such as a preservative for prevention of the deterioration of liquids such as food stuffs and pharmaceutical solids, and has been used medically externally for parasitic skin diseases and internally as a gastrointestinal antiseptic. The solid sodium bisulfite of commerce reportedly consists chiefly of sodium metabisulfite, Na2S205, and sodium bisulfite, and, for purposes of this invention, such is believed to possess the same properties as (and to be equivalent to) sodium bisulfite when dissolved in an aqueous solution. Anticoagulants and antithrombotics are a group of compounds with diversified pharmacologic actions which are used in a variety of chemical thrombotic disorders. Thrombotic disorders are generally divided into venous thrombosis and arterial occlusive disorders. Venous thrombosis of the lower extremities is important because it can cause pulmonary embolism which may be fatal. Heparin and warfarin are commonly used in clinical medicine for prevention and treatment of deep venous thrombosis and pulmonary embolism. Their pharmacological actions are in the inhibition of blood coagulation activity (i.e., heparin) or of synthesis of coagulation factors (i.e., warfarin). Platelets play an important part in arterial thrombosis. Drugs that inhibit platelet aggregation are generally regarded as being potentialy useful for prophylactic therapy of arterial thrombotic diorders, including, for example, stroke, myocardial infarction and peripheral vascular disease. Despite the availability of many agents which possess anti-platelet aggregating properties, only a few are currently under clinical trials (for example, aspirin, dipyridamole, sulfinpyrazone). None of these agents exhibit unequivocal efficacy. Compounds with more specific pharmacological action are urgently sought in order to provide better medical care for patients with these serious disorders. An anticoagulant is a substance which inhibits coagulation of the blood. An antiplatelet aggregatory agent is a substance which inhibits platelet aggregation. An antithrombotic agent is a substance which inhibits formation or development of a thrombus (or thrombosis). For present purposes, it will be understood that the term "thrombus" or equivalent includes the subject matter of the term "embolus" unless otherwise specifically indicated. In general, an antithrombotic agent may display in the presence of mammalian blood or appropriately prepared plasma anticoagulant activity and/or anti-platelet aggregatory activity. There has now been discovered a class of active agents, the members of which, when orally ingested and/or injected produce amelioration of a thrombotic condition in mammals (including man) when used in antithrombotically effective amount as taught herein. An active agent of this invention is a compound which furnishes at least one ion selected from the group of ions consisting of bisulfite and sulfite in aqueous solution. Such a compound is characterized by an ability to prolong PT (prothrombin time) in human plasma at least about 1.5 times compared to a control using a final concentration of such compound of 0.5 molar, and by an ability to prolong PTT (blood partial thromboplastin time) in human plasma at least about 2.0 times a control using a final concentration of such compound of 0.5 molar. Unless otherwise indicated herein, plasma is prepared by centrifuging at 2,000 r.p.m. whole blood. Also, as used herein unless otherwise indicated the term "control" in reference to plasma and indicates a PT or PTT time as determined with normal saline solution (equal volume). An active agent of this invention is preferably selected from the following compounds: (A) Inorganic salts of sulfurous acid which display anticoagulant and antithrombotic activity; thus, these agents are selected from the group consisting of alkali metals, alkaline earth metals and ammonium salts of sulfites and bisulfites (including metabisulfites) and mixtures thereof. Alkali metal bisulfites are presently preferred active agents, and sodium bisulfite is a presently most preferred active agent. (B) Lower alkyl amine sulfite compounds represented by the formula: EMI4.1 where: R1 is selected from the group consisting of radicals containing less than 11 carbon atoms each, cycloalkyl radicals containing from 6 to 10 carbon atoms each, and monohydroxyalkyl radicals containing less than 11 carbon atoms each, R2 is selected from the group consisting of alkyl radicals containing less than 11 carbon atoms each, monohydroxyalkyl radicals containing less than 11 carbon atoms each, and hydrogen, R1 and R2 together can constitute a ring selected from the group consisting of morpholine, piperidine, and hexamethyleneimine, provided that each such ring can be substituted on one of its carbon atoms by an alkyl radical containing less than 11 carbon atoms each, R3 is selected from the group consisting of alkyl radicals containing less than 11 carbon atoms each, monohydroxyalkyl radicals containing less than 11 carbon atoms each, hydrogen, and radicals of this formula: EMI5.1 X is selected from the group consisting of -SO3Hm, chloride, bromide, and hydrogen, and R4 is a divalent saturated aliphatic radical containing less than 11 carbon atoms m and n are integers and the sum of m and n is 2, and n is either 0 or 1. Presently preferred such compounds are bisulfite compounds. (C) Quaternary ammonium sulfite and bisulfite compounds of the formula: EMI5.2 where: R1, R2, R3, and R4 are each an independently selected lower alkyl radicals, m plus n is equal to 2, and n is 0 or 1, and compounds of the formula: EMI6.1 wherein, in such formula, R1, R2, R3 and R4 have their above specified respective meanings. Presently preferred such compounds are bisulfite compounds. (D) Salts of carbonyl sulfur dioxide adducts representable by the formula: EMI6.2 where: R is a radical selected from the group consisting of hydrogen and hydroxymethyl, R1 is a radical selected from the group consisting of hydrogen and straight chain alkyl radicals each containing a total of 3, 4, or 5 hydroxylated carbon atoms, X is selected from the group consisting of alkali metals and ammonium. One presently preferred compound of formula (5) is sodium formaldehyde bisulfite. Sodium is presently preferred as X. (E) Aqueous solutions of sulfur dioxide. Examples of suitable alkylamine starting materials for making compounds of formula (1) include methyl amine, dimethyl amine, trimethyl amine, ethyl amine, tripentyl amine, monocyclohexyl amine, dimethylcyclohexyl amine, dimethyl ethyl amine, dimethylcyclohexyl amine, tri-n-butyl amine, and the like. Trimethyl amine salts tend, however, to be undesirable because of a strong associated odor, but with this exception, tri (lower alkyl) amines are one presently preferred class of starting materials for preparation of compounds of formula (1). Another presently preferred class of starting materials for such a preparation comprises monalkyl amines having from 5 through 10 carbon atoms per molecule, such as mono-n-octyl amine, and the like. Examples of suitable diamine starting materials for making compounds of formula 2 include: ethylene diamine, hexamethylene diamine, triethylene diamine (DABCO), 1, 2propylene diamine, tetramethyl ethylene diamine, N-l, N-2 dimethyl ethylene diamine, and the like. Examples of quaternary ammonium bisulfite compounds include: tetramethyl ammonium bisulfite, tetraethyl ammonium bisulfite, tetrabutyl ammonium bisulfite, trimethyl ethyl ammonium bisulfite, tetramethyl ammonium metabisulfite, and the like. Tetra (lower alkyl) ammonium sulfites are also active agents, however. Antithrombotic agents of this invention are believed to be usable in both arterial thrombosis and venal thrombosis. Examples of clinical thrombotic conditions include stroke (as a cerebral vascular thrombosis) myocardial infarction (coronary artery disease), peripheral vascular disease, cardiac valve replacement, deep vein thrombosis, pulmonary embolism, and the like. The mechanism(s) by which the active agents function is presently unknown; however, an inhibition of platelet aggregation and a prolongation of normal blood coagulation time appear to be associated with use thereof in the manner taught by the present invention. In one aspect, the present invention is directed to the use of certain bisulfite and sulfite pharmaceutical compositions as antithrombotic, anticoagulant, and antiplatelet aggregatory agents in mammalian (including human) medicine. In another aspect, the present invention is directed to a method for control of, and/or prevention of, an embolus or a thrombus in man by oral ingestion and/or injection of a pharmaceutically effective amount of compound(s) within the scope of active agents of this invention. In another aspect, the present invention provides symptomatic and objective improvement in a thrombotic (including cardiovascular) disease conditions, such as, for examples, an abnormal coagulation, or an intravascular thrombosis, in man. By the term "symptomatic improvement", as used herein, reference is had to an improvement in a patients subjective symptoms (e.g., as reported by the patient). By the term "objective improvement", as used herein, reference is had to a measurable and objective change in a patient's condition. Other and further aspects, objects, purposes advantage, aims, utilities, features and the like will be apparent to those skilled in the art from a reading of the present specification. More particularly, this invention concerns a process for treating a human or other mammal wherein there is introduced orally and/or by injection into such mammal a pharmaceutically effective amount of active agent of this invention as an antithrombotic. Sulfite and/or bisulfite anions do not normally occur in human tissues or blood, so far as is now known. In medicine, for example, arterial thrombosis is diagnosable by clinical manifestations, by arteriography, and recently, by an Indium 111 platelet labeling technique (see, for example, the article entitled "Differential Effects of Two Doses of Aspirin on Platelet-Vessel Wall Interaction In Vivo" by K.K. Wu et al being published in the Journal of Clinical Investigtion, August, 1981). Also in medicine, for example, a thrombosis is detectable from patient conditions symptomatically perceivable by a skilled medical practitioner and well known to the art of medicine. Objectively various methods, including venography, impederme plethysmography, doppler ultrasound and the 1251-fribrinogen test (see, for example, the article by Kakkar, "Archives of Surgery", 104, page 152 (1972) and Kelton, J. G. et al, Journal of Clinical Investigation, Vol. 62, pgs. 892-895, (1978) are available). The present invention does not contemplate feeding a normal patient (that is, one not suffering from a thrombotic condition) an active agent of this invention at a pharmaceutically effective dosage as indicated herein. By the term "thrombotic condition" as used herein, reference is had both to: (a) an existing thrombus (including an embolus); and/or (b) an incipient thrombus (including an incipient embolus). An "incipient thrombus" or "incipient thrombotic condition", as such a term is used herein, can-exist in a patient who has a predisposed condition for development of a thrombotic condition. For examples, diabetes mellitus, hylipidemia, and the like are conditions which predispose a patient to arterial thrombosis. On the other hand, surgery, trauma, bed rest, and the like, for a few examples, predispose a patient to venal thrombosis. Those skilled in the practice of medicine routinely determine the presence of a thrombotic condition (including an actual thrombus in a patient). Such a condition is determined for the present invention preferably by state of the art techniques. Such determination techniques are known to the prior art and do not at such constitute a part of the present invention. Preferably, to practice this invention in vivo, one introduces into blood of a patient, such as a human, the equivalent of from about 1 to 100 milligrams per kilogram of mammal body weight (including human) per day, though larger and smaller dose rates may be employed, if desired, within the spirit and scope of this invention. The exact amount or dose in any given case is selected to be sufficient and appropriate for achieving a desired antithrombotic effect. In general, to initiate practice of the present invention, such an introduction may be commenced at a dosage rate within the range above indicated as soon as a thrombotic condition (or a thrombus) is found to exist in a patient. Thus, and for example, in a prefered practice of this invention, as a first step, a determination is made that a patient suffers from a thrombotic condition Then, one starts orally feeding and/or injecting such patient with at least one active agent of the present invention at an effective dose rate in the range above indicated. Presently, a more prefered dose rate is believed to be from about 20 to 50 mg/kg per day. Preferably, at least two or three spaced doses per day are employable, each such dose being conveniently administered around meal time. Any convenient dose arrangement can be employed. Not uncommonly, it is desirable or necessary to start treatment immediately upon the discovery of a patient's thrombotic condition to avoid damage, injury, or perhaps even death of the patient, as from an embolus. If oral administration is not convenient or rapid enough for a situation, the active agent can be directly introduced by injection into a patient, if desired, such as intravenously, intramuscularly, subcutaneously, or the like. When an active agent is so directly introduced, it is preferably dissoved in an aquous medium wherein the total amount of active agent introduced into such medium is preferably within the range from about 1 to 11 weight percent (based on the total solution weight). Distilled water is a presently preferred solvent for such a medium. If desired, conventional (standardized) aqueous media can be used as vehicles for such introduction; for example, standard saline solutions can be used as vehicles. A present preference for purposes of evaluating an antithrombotic effect is to withdraw samples of blood from a patient undergoing treatment and to measure platelet aggregation. One method is described in the paper by Born in Nature 194, pp. 927-929 (1962), which may be used for this purpose if desired. After administration has started, the dose rate is preferably adjusted to a value which is sufficient to disrupt platelet function and/or coagulation factors and thereby achieve a desired antithrombotic effect An active agent of this invention, for example, is characteristically capable of exhibiting platelet aggregation both in vitro and in vivo. Also, such an active agent is characteristically capable of lengthening both PT (prothrombin time) and PTT (blood partial thromboplastin time) in vitro. Dose rate of active agent is presently believed to be directly proportional to resulting effects upon blood factors, such as inhibition of platelet aggregation, or the like. Consequently, under this prefered procedure, use of an active agent at a suitable dose for an individual patient ameliorates that patient's thrombotic condition. Selected blood parameters of a patient are preferably determined before dosing with active agent is started, as when time permits. Preferably, a dose rate adjustment is accomplishable after administration of an active agent has commenced and is continuing. The amount of adjustment (or incremental change in dosage) is determinable by comparing a patient's measured values during administration of active agent to desired values (such as the patient's own starting corresponding values, normal species, e.g. human, values, or the like). Inhibition of platelet aggregation can be used for measurements. Then, the deviation, if any, from the patient's such measured values is compared to such desired values (the patients starting values, normal species values, or the like). Then, a change in dose rate may be undertaken to correct for any deviation so determined. For instance, in humans, normal values for platelet aggregation are dependent upon the particular agent used for stimulation. For example, when adosine diphosphate (ADP) at 3 micromolar concentration is employed, platelet aggregation values fall typically in the range between 50% to 100% of light transmission. Other stimulation agents include collagen, epinephrine, arachidonic acid, and the like. Also, for instance, in humans, normal PT values are believed to fall in the range from about 11 to 13 seconds while normal PTT values are believed to fall in the range from about 25 to 41 seconds. If PT values and/or PTT values could be measured in a given patient, as for purposes of achieving a desired antithrombotic effectiveness, it is currently estimated that a lengthening of PTT value of from about 1.5 to 2 times a PTT value in such normal range in a given starting patient is appropriate (suitable) for antithrombotic effectiveness, which is equal to a lengthened PTT value for a given patient of from about 45 to 60 seconds; such an estimate is consistent, for example, with the lengthened PTT values achieved in the human use of heparin, a prior art agent sometimes previously employed as an antithrombotic agent. Similarly, it is currently estimated that a lengthening of PT value of about two times a PT value in such normal range in a given starting patient is appropriate (suitable) for antithrobmotic effectiveness, which is equal to a lengthened PT value for a given patient of from about 22 to 26 seconds; such an estimate is consistent, for example, with the lengthened PT values achieved in the human use of coumidin (warfarin), a prior art agent sometimes previously employed as an antithrombotic agent. The active agents of the present invention, contrary to such prior art agents, appear to affect in vitro both PT and PTT values in a given patient, surprisingly. The mechanism by which the present active agents work is apparently substantially different from, and not comparable to, the prior art agents. Study and evaluation of the active agents of this invention continues. Contrary to such prior agents (like heparin and coumidin), the active agents of the present invention appear to affect both blood coagulation factors and platelet aggregation. Conveniently and preferably, measurements of blood factors are carried out periodically, such as every 3 to 7 days, on a patient undergoing treatment under the practice of this invention. An active agent can be orally consumed in the form of a capsule, a tablet, or the like, or in the form of a solution (e.g. aqueous). Also, an active agent can be injected in the form of an aqueous solution. A particularly presently preferred antithrombotic field of use is in post operative patient treatment, as when arteries or deep veins may be involved in, or threatened by, a thrombotic condition. By way of explanation, as those familiar with mammalian anatomy appreciate, the venous system in the lower extremities consists of superficial and deep veins. Because of the manner in which the deep veins interconnect and supply blood to the heart and lungs, a thrombus occurring in the deep veins, but not in the superficial veins, can become the source of a blood clot which is moved through the veins and becomes lodged in the lungs, resulting in a pulmonary embolus, which can have obvious catastrophic effects (including causing death). Examples of deep veins include the iliac, the femoral, the popliteal, the calf veins, and the like. The prevention of pulmonary emboli following surgery affecting the deep veins in the lower extremities is a significant medical problem. One solution to this problem is to prevent thrombi from occurring and/or developing in deep veins. To achieve this solution, active agents of this invention appear to be well suited. Thus, in one such mode, of this invention, one may achieve a symptomatic and objective improvement of a deep vein thrombotic complication in a patient during post-operative care following surgery, inhibiting intravascular thrombus formation (including embolism). In one preferred mode of using this invention, an aqueous solution of from about 1 to 10 percent by weight of an active agent of this invention, preferably sodium bisulfite, is prepared. Then, such solution is orally consumed by a human or injected at the total (or accumulated) dose rate ranging from about 1.0 to 50 mg per each kg of body weight per day, more preferably in the form of at least two spaced doses per day, and still more preferably in the form of at least three spaced doses per day, such a dose being preferably taken around meal time. Solid or encapsulated active agents may be orally consumed alternatively. Because of a tendency for bisulfites to undergo oxidation when in aqueous solution, it is presently preferred to minimize contact of active agents with oxygen before use. However, compounds of formula (5) appear to be stable towards oxygen. It is presently preferred in practicing this invention with inorganic alkali metal bisulfite to employ a solution which comprises on a 100 percent by weight total solution basis: (a) from about 1 to 10 percent by weight of dissolved inorganic solids, and (b)the balance up to 100 percent by weight of any In such a solution, such dissolved inorganic solids can comprise on a calculated 100 percent by weight dry basis: : (a) at least about 50 and more preferably at least about 90 percent by weight alkali metal bisulfite, and (b)the balance up to 100 percent by weight thereof being inorganic compounds produced or producible by the oxidation of alkali metal bisulfite. The water used in such a solution is preferably purified (e.g., filtered, deionized, distilled, or the like). After preparation, such a solution is preferably stored in a closed container to reduce oxidation. Such an aqueous solution can be directly used in accordance with the teachings of this invention, in which case such a solution can be dispensed dropwise, or such a solution can be encapsulated, or the like, and used as measured dosage units, as desired. For example, an aqueous solution containing 5 weight percent of sodium bisulfite can be injected into a patient, or it can be directly consumed by a patient as drops (e.g., from about 5 to 9 drops per meal for each of the two or three meals eaten by such patient per day, depending upon an individual patient's body weight, or the like). Symptomatic improvement in varicose veins and in hemorrhoids may be observable when using an active agent. A lengthened blood coagulation time in a human using an active agent may be observable. Compounds (active agents) of type (B) and (C) above are conveniently prepared by preparing an aqueous solution (preferably using a purified or distilled water) of a corresponding lower (or corresponding quaternary ammonium hydroxide) alkyl amine compound wherein such compound is present at a specified or calculated concentration, such as 10 weight percent. Then, through this solution is bubbled S 2 gas until the resulting solution increases in weight to an extent sufficient to produce a weight corresponding to the desired sulfite or bisulfite salt. For example, to prepare a product solution which is substantially a bisulfite salt, twice as much weight increase is needed compared to the corresponding sulfite salt. If the starting amine or quaternary ammonium compound is not fully soluble (or fully in a dissolved form) at the start of the sulfur dioxide gas addition (but is partially only dispersed or suspended in the aqueous phase), it becomes completely dissolved as SO2 addition continues. The product solutions made from the various starting corresponding amines appear to exist most conveniently in solution form, although some if desired may be otained as solids, e.g., monoethyl ammonium sulfite. Product solutions may be diluted to about 1 to 10 percent and are preferably stored in closed containers to reduce oxidation. By an alternative synthetic procedure an ion exchange resin in the sulfite form could be used, if desired. Some of the produce solutions made from various starting correspnding quaternary compounds can be, after preparation, subsequently evaporated to dry solid form, such as the tetramethyl ammonium bisulfite; others appear to exist only in solution form. Salts of carbonyl sulfur dioxide adducts can be prepared by any convenient techniques. One presently preferred starting material for making a compound of formula (5) is formaldehyde. A presently preferred class of starting materials is one of monsaccharides having a carbonyl group and which are selected from the group consisting of aldoses and ketoses wherein each ketose has its carbonyl group in the 2-position. More preferred such monosaccharides each contain five os six carbon atms per molecule. Presently preferred aldoses are selected from the group consisting of hexose, gluicose, mannose, ribose, xylose, arabinose, galactose, and the like. A presently preferred ketose is fructose, or the like. Sodium formaldehyde bisulfite may be purchased commercially. One convenient preparation technique is to agitate a saturated queous solution of the desired bisulfite salt with less than a stoichiometric amount of a carbonyl compound which corresponds to the desired carbonyl sulfur dioxide adduct desired. In the case of monosaccharide adducts, one or more equivlanets of the sugar is (are) mixed with an equivalent of the bisulfite compound in aqueous medium to provide a solution of the bisulfite adduct of the sugar. Solutions containing more than about 60 weight percent water are preferred. Other known synthetic methods may be used if desired. Since aqueous solutions, of sulfur dixoide do display a coacity to lengthen PT and PTT values to an extent at least as indicated above, aqueous solutions of sulfur dioxide could be used in combination with (in admixture with) aqueous solutions of compounds of types (A), (B), (C) and (D) above identified. One class of presently preferred compositions for use in practicing the present invention comprises an isotonic aqueous solution of a sugar (such as a 5 weight percent solution of glucose) containing additionally dissolved therein a bisulfite or sulfite (preferably an inorganic bisulfite such as sodium bisulfite) in an amount sufficient to provide a desired therapeutic dose for antithrombotic purposes. Such a composition is useful wherein an active agent of this invention is being utilized by injection (intravenously), as when such an active agent is being utilized at a relatively low dosage rate over an extended period of time. Aqueous solutions of oxygen-sensitive bisulfites with sugar (e.g., glucose) are advantageous because they are less susceptible to autoxidation than such bisulfites alone in aqueous solution. In such solutions, there is a equilibrium mixture of sugar bisulfites, and the reaction products of such sugar and such bisulfites which reaction products are substituted hydroxy methane sulfonic acids. As regards ability of such monosaccharide-containing such solutions to affect PT and/or PTT values, it is surprising and unexpected that such solutions do extend PT and PTT values since investigation has revealed that bisulfite adducts of aliphatic (including cycloaliphatic) and aromatic aldehydes and ketones having more than one carbon atom appear to be substantially without ability to affect PT and PTT values. Preferred such compositions are isotonic (as shown, for example, by an osmolarity machine) because such a solution avoids lysis of red blood cells. A presently most preferred sugar is glucose. A presently most preferred bisulfite is sodium bisulfite. The glucose (sugar) can be present in molar excess relative to the bisulfite. One preferred such aqueous composition is adapted for treatment of a thrombotic condition which is selected from the condition group consisting of (a) deep vein thrombosis, (b) an incipient deep vein thrombosis selected from the groups of conditions consisting of surgery, trauma, prolonged bed rest, and obstretics, (c) arterial thrombosis, and (d) an incipient arterial thrombosis selected from the group of conditions consisting of diabetes mellitus and hyperlipidemia. Such a composition comprising on a 100 weight % starting material basis: (A) from about 4 to 7 weight percent of at least one monosaccharide selected from the group consisting of aldoses and ketoses wherein each ketose has its carbonyl group in the 2-position, each such monosaccharide containing a total of 5 to 7 carbon atoms inclusive, (B) from about 1 to 4 weight percent of at least one compound whicch in water solution produces bisulfite ions and which lengthens PT and PTT values as hereinabove described for active agents of this invention, (C) from about 89 to 95 weight percent water, provided that (A) and (B) combine in said composition at least in part to form their equilibrium reaction product. In a preferred process for treating a thrombotic condition in a mammal (including man) by the present invention, one follows the following steps: (A) determine that a mammal suffers from a thrombotic condition, (B) remove from such mammal a sample of blood which is at least large enough to determine 1. at least one blood coagulation factor selected from the group consisting of prothrombin time and partial thromboplastin time, and 2. platelet aggregation factor and so determining such factors, (C) when such factors are found to fall within normal ranges for such mammal, then administer to such mammal a composition of claim 4 at a dose rate and time sufficient to both (1) lengthen such blood coagulation factor(s) and (2) inhibit such platelet aggregation factor to an extent at least sufficient to inhibit thrombus development in said mammal but which is smaller than an amount which will cause spontaneous internal bleeding in said mammal, (D) further remove from such mammal at periodic intervals during such administering further samples of blood to determine both (1) such so lengthened blood coagulation facotr(s) and (2) such so inhibited platelet aggregation factor, (E) adjust such administering to achieve and maintain in said mammal desired values for (1) such so lengtherened blood coagulation factor(s) and (2) such so inhibited platelet aggregation factors, and (F) continue said steps (C), (D), and (E) until said mammal has recovered from said thrombotic condition. The present invention can also be regarded as a method which can be practiced in vivo or in vitro for inhibiting blood coagulation factors and for inhibiting platelet aggregation involving adding to blood and/or plasma derived from such blood an active agent of this invention. The present invention is further illustrated by reference to the following examples. Those skilled in the art will appreciate that other and further embodiments are obvious and within the spirit and scope of this invention from the teachings of these present examples taken with the accompanying specification. Example A A solution of sodium bisulfite is prepared by dissolving pharmaceutical grade (U.S.P. Grade) powdered sodium bisulfite (sodium metabisulfite) in distilled water at room temperature to form a 1 percent by weight aqueous solution. This solution is then placed into a series of plastic squeeze bottles, each with a volumetric capacity of about 50-52 ml. Each bottle is provided with a cap permitting dropwise dispensing of solution from such bottle at an estimated rate of 15 drops per ml. Example B A solution of sodium bisulfite is prepared by dissolving prepared by dissolving pharmaceutical grade (U.S.P. Grade) powdered sodium bisulfite (sodium metabisulfite)in distilled water at room temperature to form a 2.5 percent by weight aqueous solution. This solution is then placed into a series of plastic squeeze bottles, each with a volumetric capacity of about 50-52 ml. Each bottle is provided with a cap permitting dropwise dispensing of solution from such bottle at a rate estimated to be 15 drops per ml. Example C A solution of sodium bisulfite is prepared by dissolving pharmaceutical grade (U.S.P. Grade) powdered sodium bisulfite to form a 5 percent by weight aqueous solution. This solution is then placed into a series of plastic squeeze bottles, eachwith a volumetric capacity of about 5052 ml. Each bottle is provided with a cap permitting dropwise dispensing of solution from such bottle at an estimated rate of 15 drops per ml. Example D The procedure of Example C above is repeated except that a 7 1/2 percent by weight solution of sodium bisulfite is prepared. Example E The procedure of Example C is repeated except that a 10 percent by weight solution of potassium metabisulfite is prepared. Example F Baker analytical grade sodium bisulfite is placed into gelatin capsules so that each capsule contains 75 mg of sodium bisulfite. Example G Baker analytical grade sodium bisulfite is placed into gelatin capsules so that each capsule contains 50 mg of sodium bisulfite. Example H A 10 weight percent aqueous solution of triethyl amine bisulfite is prepred by bubbling SO2 through an appropriate weight percent solution or dispersion of triethyl amine in water to form the desired aqueous product solution. Example I Using the procedure of Solution H, a .10 weight percent aqueous slution of a diethyl amine bisulfite is prepred from deithyl amine. Example J Using the procedure of Solution H, a 10 weight percent aqueous solution of isobutyl amine bisulfite is prepared from isobutyl amine. Example K Using the procedure of Solution H, a 5 wight pecent aqueous solution of n-octyl amine bisulfite is prepared from n-octyl amine. Example L Using the procedure of Solution H, a 5 weight percent solution of tributyl amine bisulfite from tributyl amine is prepared. Example M Using the procedure of Solution H, a 5 weight percent solution of ethylene diamine bisulfite is prepred from ethylene diamine. Example N Using the procedure of Solution H, a 5 weight percent solution of morpholine bisulfite is prepared from morpholine. Example O Using the procedure of Solution H, a 5 weight percent solution of cyclophexyl amine bisulfite is prepred from cyclohexyl amine. Example P Following the procedure of Solution H a 10 weight percent solution of triethyl amine sulfite is prepared from triethyl amine. One half as much SO2 is consumed as compared to Solution A preparation. Example Q A 10 weight percent aqueous solution of tetramethyl ammonium bisulfite is prepared by bubbling SO2 through a solution of tetramethyl ammonium hydroxide to form the desire aqueous product solution. Example R Using the procedure of Solution Q, a 10 weight percent aqueous solution of tetraethyl ammonium bisulfite is prepared from tetraethyl ammonium hydroxide. Example S Using the procedure of Solution Q, a 10 weight percent aqueous solution of trimethyl ethyl ammonium bisulfite is prepared from trimethyl ammonium hydroxide. Example T Using the procedure of Solution Q, a 5 weight percent solution of tetrabutyl ammonium hydroxide is prepared from tetramethyl ammonium hydroxide. Example U A sample of the tetramethyl ammonium bisulfite (Solution Q) is evaporated in a Buchi rotary evaporator under vacuum to dryness. When the water is all removed, an oil bath heated to 1300C is applied to this flask containing the'solid and heating under vacuum is continued for 4 more hours thereby removing water from this bisulfite to produce the metabisulfite from the starting bisulfite. Example V A 5 weight percent aqueous solution of tetramethyl ammonium sulfite is prepared by bubbling S02 through a solution of tetramethyl ammonium hydroxide to form the desired aqueous product solution. One half as much SO2 is consumed compared to Solution A preparation. Example W A solution of sodium formaldehyde bisulfite is prepared by dissolving commercially available solid sodiumformaldehyde bisulfite in distilled water at room temperature to form a 3 percent by weight aqueous solution. Example X Another solution of sodium formaldehyde bisulfite is preparedby dissolving commercially available solid sodium formaldehyde bisulfite in distilled water at room temperature to form a 10 percent by weight aqueous solution. Example Y A capsule of sodium formaldehyde bisulfite is prepared by charging to each of standard gelatin capsules sufficient sodium formaldehyde bisulfite to make 25 mg of active agent. Example Z The procedure of Example Y is repeated except that 50 mg capsules of active agent are prepared. Example AA A solution to contain 2% by weight of sodium bisulfite equivalent is prepared by dissolving the desired amount of bisulfite with one equivalent of glucose. Example BB The procedure of Example AA is repeated except that four equivalents of glucose are used. Example CC The procedure of Example BB is repeated except that the product is heated on a steam bath (about 900C) for one hour. Example DD The procedure of Example AA is repeated except that in place of glucose, fructose is used. Example EE The procedure of Example AA is repeated except that in place of glucose arabinose is used. Example FF A solution of sulfur dioxide in water is prepared by dissolving (bubbling a purified grade of sulfur dioxide) in distilled water at room temperature to form a 2 percent by weight aqueous solution. The resulting substance is then titrated with alkali using phenolphthalein to verify concentration. Example GG A solution of sodium bisulfite is prepared by dissolving pharmaceutical grade (U.S.P. Grade) powdered sodium bislfite (sodium metabisulfite) in distilled water at room temperature to form a 1 percent by weight aqueous solution. Thereafter, purified S02 gas is bubbled into such solution to give a concentration of SO2 in such solution of 1 percent by weight. Example 1 That sodium bisulfite is an antiplatelet aggregatory agent is shown by using a platelet aggregometer based on the technique of Born (above cited). It is found that this material at a concentration of 1 millimole (mM) abolishes platelet aggregation in human platelet rich plasma included by optimal concentrations of ADP, collogen, epinephrine, and arachidonic acid. A similar effect is observed in rabbit platelet rich plasma except that slightly higher concentrations of this material are required to achieve equivalent effect. This indicates that this material does have significant in vitro inhibitory effect on platelet aggregation. Based on these results, it appears that this material would be suitable for use as an antithrombotic agent. Example 2 Sodium bisulfite is evaluated under in vivo conditions as an antithrombotic agent using the anti-indium 111 platelet labeling technique in rabbits (see the Wu et al article above cited). The material was administered by intravenous injection (72.80 milligram per kilogram of animal body weight). The results indicate that this material reduces platelet thrombus formation on damaged aortic wall significantly (see Table I below). Table I Platelet Accumulation Rabbit I. at damaged vessel wall II. at normal vessel wall cpm/gm * % ** cpm/gm* A 133,986 0.11 98,611 0.08 B 146,630 0.15 83,066 0.08 Control 1,167,820+ 0.44+ 72,140+ 0.03+ (means + 21,310 0.08 39,040 0.02 S.D. of 10 animals) * Count per minute per gram dry weight of tissue. ** % = percentage of injected radioactivity per gram dry weight of tissue. The findings indicate that the active agent reduces accumulation of platelet thrombus at the damaged vessel wall by 70%. Example 3 The alkali metalbisulfites, sodium and potassium, and ammonium bisulfite are found to prolong PT and PTT in a dose-related fashion. When added to human, rabbit, and rat plasma in vitro, both agent significantly prolong PT and PTT at a concentration of 0.5 mg/ml concentration of agent and the effects are found to be dose-related. The results are shown in Table II below. The evaluation procedure used is described in a standard textbook, entitled "Human Blood Coagulation, Haemostasis and Thrombosis", edited by Rosemary Biggs, published by Blackwell Scientific Publications, Oxford, England (2nd edition), pages 670-705, 1976. Example 4 The effect of U.S.P. grade sodium bisulfite on blood coagulation factors is evaluated by standard procedures (Biggs) and the results are shown in Table III below. The work is replicated using chemical grade sodium bisulfite and the results are shown in Table IV below. These results indicate that sodium bisulfite at a concentration of 0.5 mg per ml has a significant inhibitory effect on Factors IX, X, XI, XII, and VII. Factor II and Factor VIII are mildly affected by this agent. The effect iS directly proportional to dose. At 5 mg/ml the coagulation of human plasma is completely disrupted. When this procedure is repeated using rabbit and also rat plasma, similar results were observed except that blood coagulation factors in these species are not as sensitive as respects their response to this agent. When this procedure is repeated using human plasma, TABLE II ACTIVITIES OF VARIOUS ACTIVE AGENTS TEST SEQUENCE A PT (seconds) PTT(seconds) Example Active Exp. 1 Exp. 2 Exp. 1 Exp. 2 Designation Agent (0.5/ml) C A C A C A C A 7 Sodium Metabisulfite 13.4 18.5 14.1 21.9 42.1 76.9 @0.5 80.3 7.2 Sodium Sulfite 13.4 16.2 14.1 17.7 42.1 66.1 @0.5 80.7 7.3 Ammonium Sulfite 13.0 14.7 14.1 16.9 44.7 56.5 50.5 65.2 7.4 Sodium Bisulfite 13.9 22.1 14.1 23.2 53.8 128.2 50.5 121.9 7.5 Potassium Metabisulfite 13.9 18.3 14.1 22.0 53.8 77.6 50.5 111.3 TEST SEQUENCE B 7.6 Sodium Sulfite 13.1 16.8 13.5 17.7 44.0 74.8 44.5 82.1 7.7 Sodium Bisulfite 13.5 25.5 - - 44.0 128.2 44.5 162.6 7.8 Potassium Metabisulfite 13.5 20.4 - - 44.0 91.6 44.5 105.2 C = Control A = Active Agent but employing potassium bisulfite and ammonium bisulfite, similar results are obtained. Example S The anti venous thrombotic effect of sodium bisulfite is evaluated in rabbits by using I125 fibrinogen technique as described in an article in "Archives of Surgery" Vol. 104, pg. 152 (1972). The rabbit was continuously infused with aqueous sodium bisulfite solution at the rate of .001 mg/kg per min. (5.154 gram per hour) (animal body weight 2.3 kg) for a time of five hours. After 5 hours, the animal was sacrificed and the radioactive fibrinogen accumulated in the damaged jugular vein was determined. The radioactivity on the contra-lateral (undamaged) jugular vein was also determined to serve as a control. Concurrently, another rabbit had experienced the same procedure but received only a standard sodium chloride solution as a control. The rabbit from the normal saline solution has seven times as much radioactivity as his counterpart infused with sodium bisulfite. It is concluded that sodium bisulfite shows a definite positive effect of decreasing thrombus formation in the jugular vein. A second rabbit, similarly evaluated along with a control rabbit displays similar results. Other rabbits, similarly evaluated, died before the experiment was completed, apparently because of overdose from using this active agent. TABLE III EFFECTS OF SOLUTION D ON COAGULATION IN VITRO Sodium Bisulfite Concentration (mg/ml) Coagulation Parameters@ Control 0.01 0.05 0.1 0.5 1.0 5.0 PT (sec)@ 34.67 33.37 34.00 34.85 42.73 85.33 > 150 PTT (sec)@ 12.20 12.33 12.43 12.85 15.43 22.63 > 150 TT (sec)@ 12.00 12.07 12.10 12.00 13.97 16.08 34.3 FISRINOGEN (mg%) 218 222 228 217 190 185 130 PROTHROM@IN (%) 87 79 80 72 40 26 5 FACTOR V (%) 75 74 72 80 70 60 54 F VII (%) 73 67 57 51 23 8 1 F VIII (%) 57 62 68 55 58 29 11 F IX (%) 66 60 52 56 4 3 < 1 F X (%) 78 73 68 66 31 11 3 F XI (%) 117 98 81 58 27 4 < 1 F XII (%) 86 94 87 79 17 3 < 1 # values represent mean of 5 determinations in duplicate abbreviations : PT: Prothrombin time; PTT: Partial thromoplastic time; TT: Thrombin time Methods for PT, PTT, TT and FACTOR assay are standard TABLE IV EFFECTS OF CHEMICAL GRADE SODIUM BISULFITE ON BLOOD COAGULATION IN VITRO Coagulation Parameters# Sodium Bisulfite Concentration (mg/ml) Control 0.01 0.05 0.1 0.5 1.0 5.0 PTTS 34.67 32.80 33.77 34.40 44.87 78.46 > 150 PTs 12.20 12.30 12.47 12.90 16.10 22.38 > 150 TTs 12.00 12.20 12.30 12.15 14.53 16.23 35.5 FIBROGEN (mg%) 218 228 245 218 182 184 119 PROTHROMBIN (%) 87 88 82 75 34 25 8 FACTOR V 75 70 68 68 64 66 60 F VII 73 62 63 53 17 7 2 F VIII 57 58 55 56 55 31 13 F IX 66 49 44 40 5 1 < 1 F X 78 80 69 66 22 6 4 F XI 117 83 82 55 24 2 < 1 F XII 86 104 102 75 25 9 < 1 # values represent mean of 5 determinations in duplicate abbreviations: PT: Prothrombin time; PTT: Partial thromboplastic time; TT: Thrombin time Methods for PT, PTT, TT and FACTOR assay are standard Example 6 A variety of agents were coded and evaluated under a code designation. Among these compounds, thiouracil, mercaptosuccinic acid, thiosemicarbazide, phenothiazine and sodium thiosulfate were included to compare sodium bisulfite to certain compounds shown in Renoux et al USP 4, 148, 855. After the determination of PT and PTT values, the coded compounds were decoded. The bisulfite and sulfites showed an in vitro effect and only one other compound (sodium formaldehyde bisulfite) was effective in increasing PT and PTT valves. The results are shown in Table V where mean values of 5 replications in each case are reported. The findings demonstrate the reliability of the test method. This procedure was repeated with some additional compounds on two different days using a different control on each day. The results are shown in Table VI below. These data indicate that the active moieties are probably the bisulfite and sulfite groups. Example 7 Five rats, each in a separate cage, were given a bait containing 0.5 percent by weight of sodium bisulfite. The bait consisted of cracked grains (wheat, corn, millet, and corn meal). The amounts of bait eaten are summarized for an eleven day period. The first day determination of PT showed that three of the rats had an increase of PT values with no TABLE V EFFECTS OF CODED AGENTS (0.5mg/ml) L.C. UNKNOWN REAGENTS No. PT (sec) No. PTT (sec) LAB (code 1) CONTROL 5 12.92# 5 43.38# A2 5 14.60# 5 48.70# Merc@ptosuccinic acid A3 4 14.95# 3 53.00# Dihydroxymalcic acid 2 H2O SO2 5 14.94# 5 49.22# Sodium Formaidehyde sulfoxal@te SO3 5 19.50# 5 58.60# Sodium Formaidehyde bisulfite SO4 5 14.02# 5 49.60# Sodium diethyl dithiocarb@mate SI1 5 19.34# 5 83.84# Pota@@ium metabisulfite SI2 5 16.14# 5 64.62# Sodium sulfite SI4 5 23.06# 5 114.80# Sodium bisulfite CONTROL A1 13.10 44.7 A4 12.70 51.8 L-Ascor@ic acid N1 13.1 47.5 D-(-)-Ascorbic acid N2 12.8 45.4 Thiour@cil N3 12.7 43.9 Carbohydrazide N4 13.0 47.6 Thiosomicarbazide SO1 12.9 45.4 Sodium p-tolu@n@ sulfinate SI3 13.6 43.0 Sodium phosphate SI5 13.4 44.2 Sodium hypophosphite SI6 13.5 42.4 Sodium thiosulfite TABLE VI EFFECTS OF VARIOUS AGENTS (0.5 mg/ml) Reagents No PT (sec) No PTT (sec) exp exp Control 5 13.40# 4 42.6# Na2S2O5 5 19.56# 4 77.75# NaHSO3 5 22.42# 4 120.35# Na Sulfide 5 21.12# 4 78.50# Na2SO3 5 16.38# 4 66.53# (NH4)2SO3 5 16.08# 4 58.80# Na-formaldehyde - HSO3 5 19.68# 3 56.30# K2H2SO5 5 18.76# 4 80.60# Control - 13.40 - 42.10 Na-phosphite 1 12.9 - Na-hydrosulfite 2 14.4 - 45.2 (39.0) mecaptosuccinic acid 1 14.7 1 52.6 Na-thiosulfate 1 13.5 1 46.2 Na2SO4 1 13.6 1 44.2 Na-diethylthiocarbonate 1 13.6 1 48.1 Na-Hypophosphite 1 13.9 1 47.19 (53.8) Na-formaldehyde Sulfoxalate 1 13.8 1 45.1 (53.8) apparent change in PTT (Table VII). To evaluate the effect of sodium bisulfite in human use (this agent being known to be safe for human consumption), certain patients received this agent. The case history and observations are summarized individually below. In each case, each patient is provided with such a bottle of Solution D, unless otherwise noted, and is instructed to dose himself (or herself, as the case may be) from the bottle so provided at the rate of seven drops to be taken orally with each of his (her) three daily meals. When the contents of one such bottle is thus so gradually consumed by an individual patient, another is provided to him (her). Case I A man now age 33, height 5'10", weight 88.8 kgs., had a myocardial infarction at the age of 29, and he had been treated with heparin as an anticoagulant and also with vasodilator agents. It was felt that he had coronary atherosclerosis and hypertension. He was also on a special low salt, low fat diet. This man improved symtomatically in the patient's estimation after about 2 weeks of treatment with Solution D. A gradual lowering of his heparin dose was achieved, and also of his vasodilator medicines. With continuance of the treatment, this man has been enjoying good health for about 3 years. It is reported that after an initial period of use of Solution D as described, this man's dosage rate was increased to 8 drops taken three times a day. Case II A woman, now age 64, height 5'5", weight 86.3 kgs., had a long history of severe varicose veins in her legs, and the right leg had become so swollen that she could scarcely walk. After about 1 month of treatment with Solution D, the swollen leg returned to normal, and her varicose condition improved as demonstrated by reduced size of the avarices. After about 4 years of continuous use of Solution D, no recurrence of her original condition has resulted. Case III A man, age 72 at death, height 6', weight 86.4 kgs., suffered an injury to his leg complicated by an embolus, which apparently had its inception in the leg, moved to the brain, and paralyzed the right side of his body. Subsequently he began to have thrombophlebitis in both his leg. After use of Solution D was started, his phlebitis gradually disappeared. Beneficial results began to be observed in about two weeks. However, his hemiparesis did not regress; he continued to be bed ridden. It is reported that after an initial period of use of Solution D as described, his dosage rate was increased to 9 drops taken TABLE VII FIVE 250g RATS FED BAIT CONTAINING 0.5% SODIUM BISULFITE RAT 1 RAT 2 RAT 3 RAT 4 RAT 5 DAYS g bait eaten g bait eaten g bait eaten g bait eaten g bait eaten 1 day 27.8 25.9 26.7 28.0 27.0 2 days DIED 27.9 17.3 DIED 8.0 days 19.2 19.4 11.4 4 days 18.9 10.1 10.4 9 days 26.8 27.8 25.7 10 days 22.7 26.2 26.3 11 days 23.8 21.0 22.@ FIRST DAY RAT 1 RAT 2 RAT 3 RAT 4 RAT 5 BLOOD PACTOR PT PTT PT PTT PT PTT PT PTT PT PTT 26% 150 24% 150 28% 150 27 70 increase increase increase three times a day. After almost three years of continuously using Solution D, he had not experienced any return of phlebitis to his legs. However, this man died from a kidney infection. Case IV A man, now age 79, height 5'11", weight 82 kgs., had mild hypertension, mild arthritis, mild arrithmia, hemorrhoids, dispepsia, cyanotic fingers and toes, mild diabetes, general malaise, and lassitude. After his gall bladder had been removed at age 66, his digestion deteriorated. His diabetes was acquired shortly before treatment with sodium bisulfite began and has been controlled continuously since with Diabinese (500 mg daily). After oral ingestion of aqueous solutions of sodium bisulfite of various concentrates (Solutions A, B, C, or D) at dose rates varying from to 20 drops per meal, all of the above identified conditions improved (except for diabetes) within 2-3 months. Thereafter they gradually disappeared and never recurred. After about seven years of continuous experimental use, the man remains in good health, and is alert and vigorous with excellent color. After about 3-4 years of use, the man found that he had a prolonged blood clotting time whereupon he reduced his dosage rate somewhat to about 8 drops per meal per day of Solution D and his blood clotting time then normalized. Samples of about 4 cc each of his blood were prepared. To each of these was added about 10 drops of a solution 10 weight percent and sodium bisulfite in distilled water. Each sample was then sealed into a glass vial. After about 2 1/2 years of storage at ambient temperatures, these blood samples have not coagulated. At the time when prolonged clotting time was observed, the man was orally taking about 7 to 10 drops per meal per day of Solution E and his clotting time was estimated to have increased from about 5-9 to 10 minutes to 20 minutes. This same man also, before taking this medication, had had a blood cholesterol value which oscillated between 200 and 220 mg %. After about 5 years of taking this medication as described above, this man was found to have a blood cholesterol value of about 144 mg %, which value this man continues to keep through continued treatment by sodium bisulfite solutions as described above. Case V A man reported to be of average weight, had been in an automobile accident about 20 years previously, as a result of which his pelvis was broken and his legs were broken in many places. Then and now, the man smokes cigarettes heavily. Over a year after the accident, when the man had slowly begun to regain use of his legs without crutches, clotting problems in his leg veins developed. The main vein in his left leg was replaced with a plastic vein which his body rejected. A second plastic vein was implanted and later blood clotting rendered it useless. A third plastic vein was implanted which has been effective for many years down to the present time. His sciatic nerve was damaged during the third vein implant operation. However, his left leg gradually became difficult to use and displayed severe swelling and paresthesia. His right leg also had some swelling problems. Seven years after this third plastic vein had been in place, use of Solution C was started at a rate believed to be about 7 drops with each of three daily meals. Gradually, swelling was reduced to normal in both legs and the parasthesis disappeared. After preliminary treatment with Solution C, Solution D is reported to have been substituted for Solution C at about the dose rate (7 drops with each of three daily meals). Physiotherapy is being used. Use of Solution C has not improved or changed the damage to his sciatic nerve, but walking has become easier. Example 8 The Solution I is found to prolong PT and PTT in a dose related fashion. When added to human and to rabbit plasma in vitro, the agent triethyl ammonium bisulfite is found to significantly prolong PT and PTT values at a concentration of 0.5 mg/ml and the effects are directly propotional to dose. The agent is active in inhibiting various coagulation factors, including factors VII, IX, X, XI, and XII. References for PT, PTT, and assays of all the coagulation factors can be found in a standard textbook, entitled "Human Blood Coagulation, Haemostasis and Thrombosis", edited by Rosemary Biggs, published by Blackwell Scientific Publications, Oxford, England (2nd edition), pages 670-705, 1976. Examples 9 and 10 When Solution I and Solution Q are each further similarly tested as in Example 8, prolongations of PT and PTT values at similar respective concentrations are observed, although somewhat different such values are obtained. Data evaluated by the procedure above described is provided in Tables VIII and IX below. Example 11 To demonstrate that triethylamine sulfite and triethylamine bisulfite have an effect upon blood coagulation factors, the data in Table VIII (below) for fibrinogen, Factor IX and Factor X using Biggs procedure are obtained. The results show a substantial effect on these factors with the bisulfite being more active. Example 12 To demonstrate reproducibility of the Biggs procedure, the work of Example 11 is repeated 5 times and the deviation is summarized and shown in Table IX below. Example 13 A rabbit is injected with about +72 mg/kg of body weight of triethyl amine bisulfite. After a period of 5 hours, a blood sample was withdrawn and centrifuged at 1000 r.p.m. (220 g) for 10 minutes to give a platelet rich plasma. The material was evaluated for platelet aggregation by the method described in Born et al (ref. cited above) and it was found that aggregation of Platelets was markedly decreased in comparison with an untreated rabbit. It is concluded that triethyl amine bisulfite is an agent which inhibits thrombotic condition formation in vivo. Other amine bisulfites such as n-octyl amine bisulfite, and tri-n-butyl amine bisulfite also demonstrate similar inhibition of platelet aggregation when similarly tested. Example 14 Platelet rich plasma from rabbit and men was prepared by the centrugation technique referenced in Example 13. Using ADP (adosine diphosphate) as a stimulus rapid aggregation of platelets occurred. When the so stimulated blood had been treated with each of the agents of Example 13, there was a strong inhibition of platelet aggregation. This procedure is described in the article by Born in Nature, Vol. 194, pgs. 927-929 (1962). The results demonstrate that these agents cause inhibition of platelet Table VIII EFFECT OF AMINE DERIVATIVES ON SELECTED COAG. FACTOR FACTOR: FIBRINOGEN, FACTORS IX AND X AGENT (1) (2) (3) EXP. NO. RESIGNATION FIBRINOGEN (%) FACTOR IX (%) FACTOR X (%) 4.1 CONTROL 205 50 100 4.2 TRIETHYL AMINE BISULFITE 125 14 14 4.3 TRIETHYL AMINE SULFITE 170 19 23 TABLE I FOOTNOTES: (1) Values shown represent mean of two experiments. (2) Value of a single experiment. (3) Mean of three experiments. Table IX EFFECT OF AMINE DERIVATIVES ON COAGULATION EXAMPLE NO. EXPERIMENT NO. MEAN LSD NO. 1 NO. 2 NO. 3 NO. 4 NO. 5 PT(Sec)PTT(Sec) PT(Sec)PTT(Sec) PT(Sec)PTT(Sec) PT(Sec)PTT(Sec) PT(Sec)PTT(Sec) 5.1 CONTROL 12.9 36.7 12.9 36.2 11.4 36.4 12.0 36.0 12.1 38.9 12.3 36.8 #0.6 #1.2 5.2 TRIETHYLAMINE 23.3 24.7 25.3 86.3 18.5 64.2 18.9 71.2 20.4 68.9 21.3 73.1 BISULFITE #3.0 #8.3 5.3 TRIETHYLAMINE 17.0 59.2 18.5 65.1 15.4 54.9 16.6 59.0 16.8 64.0 16.9 60.6 SULFITE #1.1 #4.1 (1) PT = PROTHROMBIN TIME (WHICH MEASURES INTEGRITY OF THE EXTENSIC COAG. PATHWAY). PTT = PARTIAL PROTHROMDIN TIME (WHICH MEASURES INTEGRITY OF THE INTRINSIC PATHWAY). aggregation in vitro. Other stimuli, collagen and arachidonic acid, yielded similar results. Example 15 The procedure of Biggs is repeated for PT and PTT determination using various compounds of formula with multiple replications for accuracy and consistency reasons. Compounds are generally effective in increasing PT and PTT. In general, the bisulfites of Formula are somewhat more effective in increasing PT and PTT values than are the sulfites; the bisulfites of diamine (as compared to monoamines) are effective. Such an increase, indicates an anticoagulation effectiveness in vitro. The dially amine bisulfite is unexpectedly of low activity in increasing PT and PTT valves. The results are shown in Table X below. Even though aromatic amines, such as aniline, form active agents, the aromatic amines are believed to bw excessively toxic for mammalian use in this invention; hence such are not included within the scope of formula (1). The alkanolamine bisulfites are of approximately the same activity as are the lower alkyl amine bisulfites. Example 16 To evaluate whether or not an amine moiety has an effect on blood factors some amines were evaluated as their hydrochlorides (as opposed to corresponding sulfites and TABLE X EFFECT OF AMINE BISULFITES ON BLOOD COAGULATION PTT REPLICATIONS PT REPLICATIONS 1 2 3 1 2 3 7.1 N-METHYL CYCLOHEXYL AMINE 60.6 61.8 61.6 20.5 20.3 20.4 7.2 ALLYL AMINE 47.1 46.9 44.9 16.1 16.0 15.6 7.3 TERT-BUTYL AMINE 68.2 68.9 69.0 21.7 21.8 21.8 7.4 DIALLYL AMINE 38.8 39.@ 39.1 13.4 13.7 13.8 7.5 PYRIDINE 80.0 71.1 5@.@ 29.3 27.8 27.2 7.6 N,N-DIMETHYL CYCLOHEXYL AMINE 60.1 62.1 58.9 18.9 20.4 19.8 7.7 MORPHOLINE 66.8 61.8 51.7 19.3 21.0 17.5 7.8 ANILINE 45.4 44.9 42.9 16.0 16.9 16.0 7.9 ETHANOL AMINE 65.3 66.1 61.1 19.3 20.5 18.4 7.10 CONTROL PLASMA 37.5 39.5 37.8 12.8 12.8 13.1 7.11 4-METHYL MORPHOLINE 63.5 61.3 60.6 21.3 21.5 20.4 7.12 DIET@@NOL AMINE 62.6 58.0 60.6 20.6 19.8 19.7 7.13 TRIETHANOL AMINE 74.2 68.8 73.6 22.9 23.1 23.3 7.14 CONTROL PLASMA 38.2 38.3 39.2 13.1 13.1 13.0 Table XI EFFECT OF AMINE HYDROCHLORIDES ON BLOOD COAGULATION PT PTT 1 2 3 1 2 3 9.1 T@@ETHYL@@INE HYDROCHLORIDE 12.8 12.7 13.5 32.0 31.5 34.5 9.2 CYCLOHEXYL AMINE 13.8 13.6 13.5 32.5 32.7 34.3 HYDROCHLORIDE 9.3 ALLYL AMINE 13.2 13.2 14.4 31.6 30.5 32.4 HYDROCHLORIDE 9.4 DIALLYL AMINE HYDROCHLORIDE 12.8 13.1 13.5 30.5 30.7 30.4 9.5 PYRIDINE HYDROCHLORIDE (CRYSTALS) 12.9 12.8 14.0 31.3 31.1 32.2 9.6 PYRIDINE HYDROCHLORIDE (POWDER) 12.6 12.5 13.8 30.5 30.8 31.1 9.7 CORTROL PLASMA 13.0 12.5 13.5 31.5 31.3 31.2 bisulfites). After their respective preparation the amine salts were evaluated by the Biggs method for their effect on PT and PTT. The data (results) shown in Table XI below shows that these hydrochlorides have no effect upon PT and PTT in vitro. Example 17 A rabbit is continuously infused with aqueous triethyl amine bisulfite solution at a rate of .001 kg per minute (5.514 gram per hour) for a time of five hours. After 5 hours, the animal is sacrificed and the radioactive fibrinogen accumulated on the damgaged jugular vein is determined. The radioactivity on contra-lateral (undamaged) jugular vein is also determined as a control. Concurrently, another rabbit has experienced the same procedure but receives only sodium chloride solution as a control. The rabbit from the normal saline solution had seven times as much radioactivity as his counterpart infused with trimethyul amine bisulfite. It is concluded that triethyl amine bisulfite shows a definite positive antithrombotic effect in the jugular vein. When n-octylamine bisulfite, tributyl amine bisulfite, diethanol amine bisulfite, and triethyl amine sulfite are similarly evaluated, it is concluded that such compounds also show a definite positive antithrombotic effect in the jugular vein. Example 18 In addition the solutions J and K both cause an increase in PT and PTT when added to plasma at 0.5 mg/ml. Example 19 Triethyl amine bisulfite is evaluated under in vivo conditions as an anti-indiumlll platelet labeling technique in rabbits (see Wu et al above cited). The material was administered by intervenous injection (127.39 mg/kg if body weight) equivalent to 0.01 molar concentrations in blood). The active agent effected reduction of about 30% in accumulation of platelet thrombus. Another rabbit so tested died. Example 20 The Solution R is found to prolong PT and PTT in a dose related fashion. When added to human or rabbit plasma in vitro, the agent tetramethyl ammonium bisulfite is found to significantly prolong PT and PTT at a concentration of 0.5 mg/ml and the effects are dose related (proportional). The agent is active in inhibiting various coaguation factors, including VII, IX, X, XI, and XII. References for PT, PTT, and assays in vitro of all the coagulation factors can be found in a standard textbook, entitled "Human Blod Coagulation, Haemostatis and Thrombosis", edited by Rosemary Biggs, published by Blackwell Scientific Publications, Oxford, England (2nd edition), pages 670-705, 1976. Example 21 The procedure of Example 20 is repeated using solution S and similr results are obtained. Example 22 The procedure of Example 20 is repeated using solution T and similar results are obtained. Example 23 Solutions R and w are used according to the procedure of Biggs to determine the effect upon PT and PTT. Data from five replications is shown in Table XII below. (The concentration of active agent employed is 0.5 mg/ml in each instance.) Both solutions are effective for lengthening blod coagulation time but the bisulfite is more active. Example 24 Solutions of R and W are used according to the procedure of Biggs to evaluate their effect upon fibrinogen and Factors IX and X. The data results as shown in Table XIII indicates strong effect upon Factors IX and X and a relative mid effect upon fibrinogen (Factor I). Example 25 Plasma was centrifuged at 1000 r.p.m. (200 g) to prepare a platelet rich plasma. Using adosine diphosphate (ADP) as a stimulous, rapid aggregation of platelets in the plasma was efected. On the other hand, when such plasma is first treatd with (a) tetramethyl ammonium sulfite, (b) tetramethyl ammonium bisuifite, and then (c) tetrabutyl TABLE XII EFFECT OF QUATERNARY AMINE DERIVATIVES ON COAGULATION EXPERIMENT NO. EMI58.1 &num;1 <SEP> &num;2 <SEP> &num;3 <SEP> &num;4 <SEP> &num;5 <SEP> Mean <SEP> LSD <tb> PT <SEP> (1) <SEP> PTT <SEP> PT <SEP> PTT <SEP> PT <SEP> PTT <SEP> PT <SEP> PTT <SEP> PT <SEP> PTT <SEP> PT <SEP> PTT <tb> (Sec) <SEP> (Sec) <SEP> (Sec) <SEP> (Sec) <SEP> (Sec) <SEP> (Sec) <SEP> (Sec) <SEP> (Sec) <SEP> (Sec) <SEP> (Sec) <SEP> (Sec) <SEP> (Sec) <tb> CONTROL <SEP> 12.9 <SEP> 36.7 <SEP> 12.9 <SEP> 36.2 <SEP> 4.4 <SEP> 36.4 <SEP> 12.2 <SEP> 36.0 <SEP> 12.1 <SEP> 38.9 <SEP> 12.3# <SEP> 38.8# <tb> 0.6 <SEP> 1.2 <tb> Tetramethyl- <SEP> 21.7 <SEP> 73.4 <SEP> 23.7 <SEP> 86.7 <SEP> 17.8 <SEP> 66.2 <SEP> 19.1 <SEP> 70.0 <SEP> 20.1 <SEP> 77.0 <SEP> 20.5# <SEP> 74.7# <tb> ammonium <SEP> 2.3 <SEP> 7.8 <tb> bisulfite <tb> Tetramethyl- <SEP> 17.5 <SEP> 59.0 <SEP> 19.2 <SEP> 67.3 <SEP> 16.1 <SEP> 57.9 <SEP> 17.4 <SEP> 61.8 <SEP> 18.2 <SEP> 70.0 <SEP> 17.7# <SEP> 63.2# <tb> ammonium <SEP> 1.1 <SEP> 5.3 <tb> sulfite <tb> (1) PT = Prothrombin time (which measures the integrity of extensic coagulation pathway) PTT = Partial thromboplastin time (which measures the integrity of intrinsi@ pathway) ammonium bisulfite, it is found that platelet aggregation in each instance is inhibited, indicating that each of these compounds is a potent inhibitor of platelet aggregation. Example 26 To demonstrate that it is not the quaternary ammonium group which is affecting blood factors, two tests are run evaluating the effect of tetramethyl ammonium bromide and tetra butyl ammonium bromide (Biggs) in vitro on PT and PTT using human plasma. The data shown in Table XIV indicates that these compounds have little or no effect on PT and PTT when compared to the effect demonstrated by the corresponding bisulfites. Example 27 A rabbit is continuously infused with aqueous tetrabutyl ammonium bisulfite solution at the rate of .001 mg/kg min (5.154 gram per hour) for a time of five hours. After 5 hours, the animal is sacrificed and the radioactive fibrinogen accumulatd in the damaged jugular vein is determined. The radioactivity on the contra-lateral (undamaged) jugular vein is also determined to serve as a control. Concurrently another rabbit experienced the same procecedure but received only a sodium chloride solution as control. The rabbit from the normal saline solution had approximately 7 times as much radioactivity as its counterpart infused with sodium bisulfite. It is concluded that tetrabutyl ammonium bisulfite shows a definite positive TABLE XIII EFFECT OF QUATERNARY AMINE DERIVATIVES ON SELECTED COAGULATION Factors: Fibrogen, Factor IX and Factor X EMI60.1 Fibrinogen <SEP> (%)(1) <SEP> Factor <SEP> IX <SEP> (%) <SEP> (2) <SEP> Factor <SEP> X <SEP> (%)(3) <tb> CONTROL <SEP> 205 <SEP> 50 <SEP> 100 <tb> Tetramethyl- <SEP> 170 <SEP> 12.5 <SEP> 10 <tb> ammonium <tb> bisulfite <tb> Tetramethyl- <SEP> 175 <SEP> 20 <SEP> 25 <tb> ammonium <tb> sulfite <tb> (1) Values shown represent mean of 2 experiments (2) Value of a single experiment (3) Mean of 3 experiments TABLE XIV EFFECT OF TETRA ALLYL AMMONIUM BROMIDE 0.5 mg/ml PT sec. PTT sec Tetramethyl Ammonium Bromide 12.5 38.5 Tetrabutyl Ammonium Bromide 12.4 38.3 Control 12.3 38.1 Tetramethyl Ammonium Bisulfite 21.7 Control 12.9 effect of decreasing thrombus formation in the jugular vein. The same procedure using tetramethylammonium bisulfite produced death of the rabbit. Example 28 In vitro assays of the product of each certain above Examples are conducted for coagulation factors as taught in a standard textbook, entitled: "Human Blood Coagulation, Haemostatis and Thrombosis", edited by Rosemary Biggs, published by Blackwell Scientific Publication, Oxford England (2nd Edition), pages 670-705, 1976. The results are shown in Table XV below. Example 29 Evaluation of the antithrombotic effect of sodium formaldehyde bisulfite was caried out on a rabbit as described in Kelton et al: "Thrombogenic Effect of High Dose Aspirin in Rabbits", Journal of Clinical Investigation", Volume 62, pages 892-895, 1978. When the rabbit was treated with 50 mg/kg of CH2SO3Na (OH) (e.g., sodium formaldehyde bisulfite), the thrombus disappeared more rapidly than in a control animal. Example 30 A rabbit is fed orally by gavage about 50 mg/kg in two spaced doses of sodium formaldehyde bisulfite as the solution of Example X. After a period of 1 day, the animal's blood is analyzed for PT and PTT values, and it is found that both these values have lengthened compared to TABLE XV PT PTT REPLICATIONS REPLICATIONS I II III I II III NaHSO3 in 1/1 glucose 20.9 20.3 19.9 65.5 63.9 65.8 NaHSO3 in 1/4 glucose 21.3 21.9 21.5 68.5 69.0 70.2 NaHSO3 in 1/4 glucose 22.8 21.5 21.0 77.2 70.4 75.6 heated NaHSO3 in water 20.2 20.3 20.0 64.4 63.2 63.9 Control 13.1 13.1 13.0 38.2 38.3 39.2 Sodium formaldehyde 20.5 63.5 Bisulfite Control 14.1 50.5 corresponding values from the blood of an otherwise untreated control rabbit. Example 31 Using the procedure of Example 28, PT and PTT values for sodium formaldehyde bisulfite are obtained as shown in Table XVI below: TABLE XVI PT PTT Control 12.5 33.4 0.01 Molar 54.6 Sodium Formaldehyde Bisulfite 24.4 Example 32 Two jugular veins on a normal, healthy rabbit are exposed and one of the veins is systematically damaged by clamping in two longitudinally spaced places. The rabbit is then continuously infused with aqueous sodium formaldehyde bisulfite at the rate of .001 kg per minute (5.154 gram per hour) (animal body weight 2.3 kg). The rabbit is then injected with fibrinogen labeled with I125. After 5 hours, the damaged jugular vein is evaluated for radioacive count with a Geiger counter. When the amount of radioactivity on the rabbit infused with sodium formaldehyde bisulfite is compared to the count of the jugular vein of a rabbit infused with normal saline solution, the rabbit from the normal saline solution has more radioactivity than his counterpart infused with sodium formaldehyde bisulfite. It is concluded that sodium formaldehyde bisulfite shows a definite positive effect of decreasing thrombus formation as in the jugular vein. This iodine 125 evaluation technique is described by Kakkar in Archieves of Surgery, Vol. 104, pg. 152 (1972) and by Kelton, J.G. et al, Journal of Clinical Investigation, Vol. 62, pgs. 892-895, (1978). Closely similar results were achieved with a second rabbit. Other rabbits, similarly evaluated, died, apparently because of overdose by the infustion technique. Example 33 A rabbit is injected with about 72 mg/kg of body weight of sodium formaldehyde bisulfite. After a period of 5 hours, a blood sample was withdrawn and centrifuged at 1000 r.p.m. (220 g) for 10 minuts to give a platelet rich plasma. The material was evaluated for platelet aggregation by the method described in Wu et al (ref. cited above) and it was found that aggregation of platelets was markedly decreased in comparison with an untreatd rabbit. It is concluded that sodium formaldehyde bisulfite is an agent which inhibits thrombus formation in vivo. Similar test results were achieved with other rabbits so tested. It is estimated that this material is 1000 times less effective than sodium bisulfite. Example 34 Platelet rich plasma from rabbits and men was prepared by the centrugation technique referenced in Example 13. Using ADP (adosine diphosphate) arachidonic acid as a stimulus, rapid aggregation of platelets occurred. When the so stimulated blood had been treated with sodium formaldehyde bisulfite, there was a strong inhibition of platelet aggregation. This procedure is described in the article by Born, Nature, Vol. 194, pgs. 927-929 (1962). The results demonstrate that sodium bisulfite causes inhibition of platelet aggregation in vitro. Example 35 Bisulfite adducts were prepared from acetone, cyclohexane, benzaldhyde and 2-octanome. When evaluated by the Biggs' technique, they had a minimal effect on PT and PTT at 0.5 mg/ml. Example 36 The solution of Example HH is tesed for anticoagulant properties using human blood plasma by measuring PT and PTT values in seconds. For PT, the reagent used is Thromboplastin C from Dade Chemical and for PTT the reagent used is APTT from General Diagnostics. The results are summarized in the following Table XVII: TABLE XVII Number of Repeats PT PTT For Test (seconds) (seconds) 1 37.7 105.9 2 37.3 100.9 3 37.3 102.3 4 37.2 101.7 5 36.7 -- For PT, the mean is 37.3 seconds compared to the PT for the untreated control of 10.5 seconds. For PTT, the mean is 102.7 seconds compared to the PTT for the untreated control of 27.5 seconds. The system appears to be particularly active in inhibiting coagulation factors VII, IX, X, XI and XII. It has a moderate inhibitory effect on factor VII. Its effects on fibrinogen (factor I) and factor V are quite mild. The data thus demonstrates that the solution of Example A demonstrates strong anticoagulant activity. Suitable solvents for SO2 in the practice of this invention are water, ethanol, 2-propanol, l-propanol, acetone, ethyl acetate, ethyl formate, propylene glycol, dipropylene glycol, ethyl propionate and the like. Example 37 Example Gg is a system which when added to human or rabbit plasma in vitro is found to significantly prolong PT and PTT in a dose related fashion. The agent is active in inhibiting various coagulation factors, including VII, IX, X, XI, and XII. References for PT, PTT and assays of all the coagulation factors can be found in a standard textbook, entitled "Human Blood Coagulation, Haemostasis and Thrombosis", edited by Rosemary Biggs, published by Blackwell Scientific Publications, Oxford, England (2nd Edition), pages 670-705, 1976. As is apparent from the foregoing specification, the present invention is susceptible of being embodied with various alterations and modifications which may differ particularly from those that have been described in the preceding specification and description. For this reason, it is to be fully understood that all of the foregoing is intended to be merely illustrative and is not to be construed or interpreted as being restrictive or otherwise limiting of the present invention, excepting as it is set forth in the hereto-appended claims.

Claims: CLAIMS We Claim: 1. A method for treating a thrombotic condition in a mammal comprising administering to said mammal an antithrombotically effective amount of at least one compound which furnishes at least one ion selected from the group of ions consisting of bisulfite and sulfite in aqueous solution, such compound being characterized by an ability to prolong prothrombin time in human plasma at least about 1.5 times compared to a control using a final concentration of such compound of 0.5 molar, and by an ability to prolong blood partial thromboplastin time in human plasma at least about 2.0 times compared to a control likewise using a final concentration of such compound of 0.5 molar. 2. The method of claim 1 wherein said thrombotic condition is selected from the group of conditions consisting of (a) a deep vein thrombosis, (b) an incipient deep vein thrombosis selected from the group of conditions consisting of surgery, trauma, prolonged bed rest, and obstretics, (c) arterial thrombosis, and (d) an incipient arterial thrombosis selected from the group of conditions consisting of diabetes mellitus and hyperlipidemia. 3. The method of claim 1 said compound is selected from the group consisting of: (A) alkali metal, alkaline earth metal, and ammonium salts of sulfites and bisulfites and mixtures thereof: (B) compounds of the formula: EMI70.1 where: R1 is selected from the group consisting of radicals containing less than 11 carbon atoms each, cycloalkyl radicals containing from 6 to 10 atoms each, and monohydroxyalkyl radicals containing less than 11 carbon atoms each, R2 is selected from the group consisting of lower alkyl radicals containing less than 11 carbon atoms each, monohydroxyalkyl radicals containing less than 11 carbon atoms each, and hydrogen, R1 and R2 together can constitute a ring selected from this group consisting of morpholine, piperidine, and hexamethyleneimine, provided that each such ring can be substituted on one of its carbon atoms by a lower alkyl radical containing less than 11 carbon atoms each, R3 is selected from this group consisting of alkyl radicals containing less than 11 carbon atoms each, monohydroxyalkyl radicals containing less than 11 carbon atoms each, hydrogen, and radicals of this formula: EMI71.1 X is selected from the group consisting of -SO3Hn, chloride, bromide, and hydrogen, R4 is a divalent saturated aliphatic radical containing less than 11 carbon atoms, and, m and n are integers and the sum of m and n is 2, and n is either 0 or 1; (C) compounds of the formula: EMI71.2 wherein: R1, R2, R3 and R4 are each an independently selected lower alkyl radical, m + n is equal to 2, and n is 0 or 1, and compounds of the formula: : EMI72.1 wherein R1, R2, R3 and R4 have their specified respective meanings; and (D) compounds of the formula: EMI72.2 where: R is a radical selected from the group consisting of hydrogen and hydroxymethyl, R1 is a radical selected from the group consisting of hydrogen and straight chain alkyl radicals each containing a total of 3, 4 or 5 hydroxylated carbon atoms, and X is selected from the group consisting of alkali metals and ammonium. 4. A pharmaceutical composition for treating a thrombotic condition in a mammal which contains as the active treating agent at least one compound which furnishes at least one ion selected from the group of ions consisting of bisulfite and sulfite in aqueous solution, such compound being characterized by an ability to prolong prothrombin time in human plasma at least about 1.5 times compared to a control using a final cocnentration of such compound of 0.5 molar, and by an ability to prolong blood partial thromboplastin time in human plasma at least about 2.0 times compared to a control likewise using a final concentration of such compound of 0.5 molar. 5. The composition of claim 4 wherein said thrombotic condition is selected from the group of conditions consisting of (a) a deep vein thrombosis, (b) an incipient deep vein thrombosis selected from the group of condtions consisting of surgery, trauma, prolonged bed rest, and obstretics, (c) arterial thrombosis, and (d) an incipient arterial thrombosis slected from the group of conditions consisting of diabetes mellitus and hyperlipidemia. 6. The composition of claim 4 wherein said active treating agent is selected from the group consisting of: (A) alkali metal, alkaline earth metal, and ammonium salts of sulfites and bisulfites and mixtures thereof, (B) compounds of the formula: EMI73.1 where: R1 is selected from the group consisting of radicals containing less than 11 carbon atoms each, cycloalkyl radicals containing from 6 to 10 atoms each, and monohydroxyalkyl radicals containing less than 11 carbon atoms each, R2 is selected from the group consisting of alkyl radicals containing less than 11 carbon atoms each, monohydroxyalkyl radicals containing less than 11 carbon atoms each, and hydrogen, R1 and R2 together can constitute a ring selected from this group consisting of morpholine, piperidine, and hexamethyleneimine, provided that each such ring can be substituted on one of its carbon atoms by an alkyl radical containing less than 11 carbon atoms each, R3 is selected from this group consisting of alkyl radicals containing less than 11 carbon atoms each, monohydroxyalkyl radicals containing less than 11 carbon atoms each, hydrogen and radicals of this formula: EMI74.1 X is selected from the group consisting of -SO3Hn, chloride, bromide, and hydrogen R4 is a divalent saturated aliphatic radical containing less than 11 carbon atoms, and, m and n are integers and the sum of m and n is 2, and n is either 0 or 1. (C) compounds of the formula: EMI75.1 wherein: R1, R2, R3 and R4 are each an independently selected lower alkyl radical, m + n is equal to 2, and n is 0 or 1, and compounds of the formula: EMI75.2 wherein R1, R2 R3, and R4 have their above specified respective meanings; and (D) compounds of the formula: EMI75.3 where: R is a radical selected from the group consisting of hydrogen and hydroxymethyl, R1 is a radical selected from the group consisting of hydrogen and straight chain alkyl radicals each containing a total of 3, 4 or 5 hydroxylated carbon atoms, and X is selected from the group consisting of alkali metals and ammonium 7. A process for treating a thrombotic condition in a mammal comprising the steps of: (A) determining that such mammal suffers from a thrombotic condition, (B) removing from such mammal a sample of blood which is at least large enough to determine 1. at least one blood coagulation factor selected from the group consisting of prothrombin time and partial thromboplastin time and 2. platelet aggregation factor and so determining such factors, (C) when such factors are found to fall within normal ranges for such mammal, then administering to such mammal a composition of claim 4 at a dose rate and time sufficient to both (1) lengthen such blood coagulation factor(s) and (2) inhibit such platelet aggregation factor to an extent at least sufficient o inhibit thrombus development in said mammal but whioch is smaller than an amount which will cause spontaneous internal bleeding in said mammal, (D) further removing from such mammal at periodic intervals during such administering further samples of blood to determine both (1) such so lengthened blood coagulation factor(s) and (2) such so inhibited platelet aggregation factor, (E) adjusting such administering to achieve and maintain in said mammal desired values for (1) such so lengthened blood coagulation factor(s) and (2) such so inhibited platelet aggregation factors, and (F) continuing said steps (C), (D), and (E) until said mammal has recovered from said thrombotic condition. 8. The method of claim 7 wherein said thrombotic condition is selected from the group of conditions consisting of (a) a deep vein thrombosis, (b) an incipient deep vein thrombosis selected from the group of conditions consisting of surgery, trauma, prolonged bed rest, and obstretics, (c) arterial thrombosis, and (d) an incipient arterial thrombosis selected from the group of conditions consisting of diabetes mellitus and hyperlipidemia. 9. A method for inhibiting blood coagulation factors and for inhibiting platelet aggregation comprising adding t blood and/or plasma derived from such blood a composition of claim 4. 10. The composition of claim 4 wherein said active agent is sodium bisulfite. 11. The composition of claim 4 wherein said active agent is trimethylamine bisulfite. 12. The composition of claim 4 wherein said active agent is n-octylamine bisulfite. 13. The ccomposition of claim 4 wherein said active agent is tetrabutyl ammonium bisulfite. 14. The composition of claim 4 wherein said active agent is sodium formaldehyde bisulfite. 15. The composition of claim 4 wherein said active agent is sodium glucose formaldehyde. 16. A pharmaceutical composition comprising on a 100 weight percent starting material basis: (A) from about 4 to 7 weight percent of at least one monosaccharide selected from the group consisting of aldoses and ketoses wherein each ketose has its carbonyl group in the 2-position, each such monosaccharide containing a total of 5 to 7 carbon atoms inclusive, (B) from about 1 to 4 weight percent of at least one compound which in water solution produces bisulfite ions and which lengthens PT and PTT values as hereinabove described for active agents of this invention, (C) from about 89 to 95 weight percent water, provided that (A) and (B) combine in said composition at least in part to form their equilibrium reaction product.

Inventors: ARIAS ALVAREZ, JOSE ANTONIO, THOMPSON, RALPH B., Arias Alvarez, José Antonio
Applicants: T AND R CHEMICALS, INC.
Application year: 1981
Main classification: A61K33
IPC codes: A61K31, C07H11, A61K33