MXPA98006518A - Zwitterionic compositions and methods as modifiers of biological response - Google Patents

Abstract

A method for treating a disease in a mammal by administering a therapeutically effective amount of an amphoteric zwitterionic compound as an active ingredient. A pharmaceutical composition comprising an amphoteric zwitterionic compound as an active ingredient in combination with a carrier and other auxiliary pharmaceutical agents

Description

ZWITTERIONIC COMPOSITIONS AND METHODS AS BIOLOGICAL RESPONSE MODIFIERS BACKGROUND OF THE INVENTION In the world population, the incidence of cancer is very significant. It is estimated that one in four people will develop cancer at some time in their life. Half of all people who develop cancer will die from it. The incidence of deaths due to cancer has doubled every thirty years in the United States of America. There are many factors associated with the increasing incidence of the disease. Many people live longer and the incidence may increase due to a geriatric population. Environmental toxins and / or genetic changes may also play a role in the increase. There has also been an increase in the incidence of infectious diseases, particularly infections, viral. Now many virulent strains have been observed. Virus-mediated infections, such as hepatitis (A, B, and C) and HIV-like infections have had a significant impact on the population Some cancers, such as Kaposi's sarcoma, are associated with viral infections. associated with P1470 / 98MX autoimmune disorder. Rheumatoid arthritis and myasthenia gravis are some examples. The etiology of many autoimmune diseases is not clear. The genetic and / or environmental aspects contribute in various ways to alter hemopoietic and immune responses. Certain drugs can activate autoimmune responses as well as induce immunosuppressed states. There are four basic approaches to cancer treatment. These approaches are sometimes combined in the form of multimodality therapies. The basic approaches are surgical resection, chemotherapy, radiation and immunotherapy. Alternative approaches include naturopathy, herbal treatments and acupuncture. The therapies for autoimmune disease have been limited. Mainly, the use of spheroids has been the main support. Advanced cases of diseases, such as rheumatoid arthritis and myasthenia gravis, rarely respond well. The therapies of infectious diseases have had many advances with the use of antibiotics. Few antiviral compounds have been developed. Its use is limited to a few types of infection. HIV is yet to respond to any significant therapy. Immunotherapies have had limited success in the P1470 / 98MX hepatitis. During the last fifty years, there has been a slow development of several immunotherapies. These have included the use of specific cytokines, chemokines, lymphokines and other immunological substances derived from cell culture research and cloning. In the past, it has been shown that certain fractions of cell cultures have produced specialized responses in tumors. The chemotherapeutic agents and the radiation have generated some responses of the tumors, but they have high toxicity. The need to develop agents and compositions that effectively treat cancer, pain from cancer, immunologically mediated diseases and certain infectious diseases continues to be very important.

SUMMARY OF THE. INVENTION The present invention relates to a method for the treatment of diseases in mammals, by the administration of zwitterionic compositions, as biological response modifiers, safe and effective. It also relates to the zwitterionic compositions used and to the preparation of those zwitterionic compositions for use in the treatment.

P1470 / 98MX The present invention demonstrates that zwitterionic molecules have a definitive effect as a biological response modifier (BRM Biological Response Modifier). Zwitterionic compositions are substances that do not have a negative or positive charge. Zwitterions are compounds that have a net charge on the molecule that is zero and that has positive or negative groups that are equally ionized in the molecule and are bipolar molecules that contain, for example, hydroxy groups and amino groups and also acidic groups, such as phosphoric, carboxylic or sulphonic acid groups and, for example, generally have a pKa in the range of 6.15 to 8.4. Various zwitterionic compounds can be used in the treatment of diseases in mammals, as active ingredients, either alone or in various combinations and, typically, in combination with one or more pharmaceutically acceptable carrier or solid carrier materials. Many of these zwitterionic compounds are recognized and used as buffers and are not used or recognized as active ingredients in the treatment of diseases such as HEPES, PIPES, etc., compounds and salts thereof.

P1470 / 98MX Structure Name P a? PKa / ° C Solution Binding constants No. Proposed to Saturated metal-shock absorber 20 ° to 0 ° (M) Log KM Mg ++ Ca ++ Mn ++ Cu ++ MES 6.15 -0.011 0.65 0.8 0.7 0.7 Negl ADA 6.6 -0.011 2.5+ 4.0+ 4.9+ 9.7+ III NaO SCH C H t NH CH CH SO PIPES 6.8 -0.0085 Negl Negl Negl Negl Ul IV H NCOCH NH CH CH SO - ACES 6.9 -0.020 0.22 0.4 0.4 Negl 4.6 2 2 2 2 2 3 V (CH. > -N-CH "CH.NH" C1- ioride of 7.1 -0.027 .2+ Negl Negl Negl Negl 3 colamine VI (HOCH2CH2) 2 = NHCH2CH S03- BES 7.15 -0.016 3.2 Negl Negl Negl 3.5 VII (HOCH2) 2 = NHCH2CH2SO - TES 7.5 -0.020 2.6 Negl Negl Negl 3.2 VIII HEPES 7.55 -0.014 2.25 Negl Negl Negl Negl (Continuation of Table) No. Structure Name PKa? PKa / ° C Solution Connection constants Proposed to Saturated metal-shock absorber 20 ° to 0 ° (M) Log KM Mg ++ Ca ++ Mn ++ Cu IX H Acetamido- 7.7? - Very 2NCOCH2NH2CH2COO-long glycine X (HOCH) = CNH CH COO- Tricine 8.15 -0.021 0.8 1.2 2.4 2.7 7.3 2 2 2 2 XI H 2NCOCH2NH3 Glycinamide 8.2 -0.029 4.6 XII (HOCH2) 2 = CNH2 Tris 8.3 -0.031 2.4 Negl Negl Negl XII I (HOCH CH) = HCH COO- Bicin 8.35 -0.018 1.1 1.5 2.8 3.1 8.1 2 2 2 2 XIV H NCH CONHCH CO-Glycylglycine 8.4 -0.028 1.1 0.8 0.8 1.7 5.8 2 2 2 * Data from Schwarzenbach et al. (nineteen ninety five) . + As the hydrochloride The zwitterionic compounds in the table are characterized by one or two nitrogen-carbon bonds, either as heterocyclic, aliphatic or aliphatic compounds usually with an acid group (COO- or S03-) and an alkaline group (OH or N +, NH and NH2). A group of preferred zwitterionic compounds, such as PIPES and HEPES, comprises six-membered heterocyclic rings with two nitrogen atoms at each end and connected with divalent alkylidenes, such as the divalent radical -CH2-, while the MES is a heterocyclic compound with as much oxygen as nitrogen in the ring, with the NH group connected by (CH2) n? _3 to an acid group. In this way, the group of useful zwitterionic compounds, such as HEPES, MES and PIPES, as an example, would have the structural formula.

H i acid group, wherein Rx and R2 represent a (CH2) n1_3, or Rt is a nitrogen or oxygen atom as a part of a 5-6 membered heterocyclic ring with N or N * H as part of the ring, or where Rx includes a nitrogen directly connected to (CH2) n1_3, alkylidene which is connected to an alkaline group, such as the NH2 group or OH group.

P1470 / 98MX The zwitterionic compounds may include unsaturated nitrogen and carbon groups, such as N = C and N = C ie ethylenic or acetylenic NC unsaturation, with CH2OH or CH2CH2OH or NH2 forming an alkaline end of the compound and CH2S03 or CH2CH2S03 forming the other acid end of the compound. The zwitterionic compounds and their respective pharmaceutically acceptable salts that are preferred include: HEPES, PIPES, MES, ADA and ACES, alone or in therapeutic combinations. The zwitterionic or amphoteric compounds can be used as active diluents with other active diluents, as well as other components and carriers typically used in pharmaceutical compositions as, but not limited to: buffers, stabilizers, dyes, antioxidants, dispersing agents, bulking agents, surfactants, silicones, bulking agents, pigments, salts, human or animal cells (natural or synthetic) and cellular components, antibiotics, drugs, vitamins, amino acids, proteins, serum and various other compounds and combinations thereof in various amounts. The use of the zwitterionic compounds in the pharmaceutical compositions used in the treatment as an active ingredient have already been shown; for example, HEPES and PIPES, which provide macrophage infiltration P1470 / 98MX of cancer tumors in dogs and, in this way, to provide an anti-tumor effect in the treatment of several diseases, and also demonstrate immune stimulation capabilities as evidenced in the tests for the production of giant platelets and histiocytes. It has been shown that in tests, in animals, no evidence of toxicity is shown at doses up to 500 mg / kg. Some animals have received this dose three times in a twenty-four hour period. The dose schedule of the zwitterionic compounds as biological response modifiers may vary depending on the disease and condition, but the treatment may vary from about 0.1 mg / kg to 5000 mg / kg. The effects of immune stimulation of zwitterionic compounds have been demonstrated in animals. Tests show that at specific dose levels, all animals demonstrate the presence of giant platelets and histiocytes in peripheral smears. The following results were found with HEPES in all test animals. 1) all treated dogs had rapid resolution of the bruises at the injection sites; 2) no animal in the treated group had a respiratory infection while it was being treated, many untreated groups had it; 3) all the dogs came to calm down after the injections; P1470 / 98MX and 4) there was strong evidence of improved vascular integrity in the treated groups. There is evidence of marked diuresis in certain dosages that suggest an effect on renal function and / or antidiuretic hormone (ADH). A zwitterionic, amphoteric compound useful in the invention, alone or with other compounds, zwitterionic compounds or as other active ingredients or cell cultures in a therapeutic amount, comprises zwitterionic compounds of piperazine inhibited, such as, for example, non-exclusively, an acid N-2-hydroxyl or amino-alkyl-piperazine-N-2 alkane, such as carboxylic acid, phosphoric or sulfonic acid and their effective non-toxic salts, and derivatives and substituents. In particular, the invention is directed to the use of a zwitterion known as HEPES and its acid salts and is particularly effective therewith; for example, sodium or potassium, known as N-2-hydroxyethylpiperazine-N'-2-ethane sulfonic acid, formula weight 238 (ie, C2H18N204S) (HEPES). It has been routinely used in cell cultures as a buffer and, to date, it was not suspected to have any effect on cells, on physiological pathways or on disease processes. It is now shown that HEPES and other zwitterionic compounds are true biological response modifiers (BRM). Its positive effect changes in cancer, P1470 / 98MX cancer pain, autoimmune disease and viral infections and toxic syndromes. They can be used alone and / or in combination with mammalian serum and / or in combination with cell culture supernatants using mammalian serum. There seems to be a possible interaction with serum and / or cell culture supernatants. The bioactive routes can be affected by various compositions of zwitterionic molecules. It is clear that they can play a role as a biologic response modifier alone or in combinations. These molecules induce antitumor activity, cause a reduction in volume and size of the tumor, induce necrosis and / or lysis of the tumor, reduce pain due to cancer, induce reduction of autoimmune activity in the autoimmune-mediated disease, reduce inflammatory processes and they have antiviral activity. The mechanisms of action can be simple or multiple, comprising physiological, pathophysiological and immunological routes. They may have effects of activation and / or stimulation and / or blocking of specialized routes and / or specialized receptor sites. There is a positive effect on the hemopoietic system. There seem to be effects on the secretion of cellular products in many ways. These effects may be beyond the buffer capacity as evidenced P1470 / 98MX for the effect on disease processes. There may be additional effects at the ionic level as well as different effects on the stability and permeability of the membrane. The stabilization of the membrane can play an important role in causing the abnormal division or function of the cells to normalize, either by external physiogenic factors or internal cellular functions, or both. In any case, this first description of the unique capabilities of HEPES as a zwitterionic molecule and the effect on disease processes is presented. The present invention relates to methods and compositions for inducing antitumor activity, reducing tumor volume, reducing pain in cancer patients, inducing anti-inflammatory response in the autoimmune mediated disease, reducing the activity and progress of immunologically mediated diseases, induction of regression of tumor growth, induction of regression of autoimmune activity in immunologically mediated disease and antiviral effects. The invention shows a unique capacity to induce certain biochemical, physiological and immunological responses that cause the lysis and / or necrosis of tumors and the delay of the progress of diseases, including cancer, autoimmune disease and diseases.

P1470 / 98 X caused by viral infection. In particular, the use of HEPES (N-2-hydroxyethylpiperazine-N'-2-ethane-sulfonic acid), a zwitterionic molecule generally used as a buffer in salts or cell cultures, has shown effects that are antitumorigenic, analgesic, anti -inflammatory, reduction and / or progression of autoimmune diseases, and antiviral activity when used in certain compositions, alone or in conjunction with cell cultures. Additionally, HEPES seems to have an effect on the immunological characteristics of cell cultures, since they are unique and do not relate solely to their buffering capacity. The present invention provides an effective treatment that is relatively non-toxic and safe. His individual singularity is shown in many ways. For years, HEPES, a zwitterionic molecule, has been used as a buffer in mammalian cell culture. It was not believed to have any specialized effect on the cells. Certainly, it has not been seen as a dependent agent to treat cancer, pain from cancer, autoimmune disease or certain infectious states. It is now shown that HEPES (C5H16N2042S) (N-2-hydroxyethylpiperazine-N'-2-ethane-sulfonic acid) and its homologues and analogs may have, in certain preparations, antitumorigenic effects with growth P1470 / 98MX of the tumor, volume reduction, tumor activity and cancer pain. It also has an effect in reducing or reversing certain autoimmune diseases. Additionally, it seems to have antiviral effects. HEPES has been used as a buffer in cell culture technology. The invention becomes apparent when use is made of HEPES and human serum without cell culture as a control in patients who were proposed to receive certain supernatants of cell cultures for the experimental treatment of cancer, cancer pain and autoimmune disease and infections. viral All of the above effects can be demonstrated when HEPES is used alone or in combination with other biological compositions where the effect can be enhanced through specialized physiological, biochemical and immunological actions. It can boost. the production of known and unknown substances in the cultures of mammalian cells, the combinations of which may render the compositions more active, nevertheless, the individual effects of the substance. In addition, it is pointed out that the aspects described are clearly demonstrated outside the technology of cell cultures. In this way, for example, HEPES is an immune activator by itself. This classifies HEPES as a true biological response modifier P1470 / 98MX (BRM). The present invention provides a method for preparing zwitterionic compositions for administration to a subject, and the use of the same compositions for the treatment of cancer, cancer pain, autoimmune diseases and infectious diseases. Compositions used for administration comprise: a) preparing certain concentrations of HEPES in solutions, alone and / or with amino acids and / or L-glutamine and / or with bicarbonate; b) preparing certain concentrations of HEPES in solutions with amino acids and / or glutamine and / or bicarbonate and / or human serum; and c) preparing certain concentrations of HEPES in solutions with amino acids and / or L-glutamine and / or bicarbonate and / or human serum and combining them with cultures of mammalian cells, if the same cells in the culture are transformed or untransformed , and using the supernatant and / or fractions of the supernatant alone or in combination to enhance cellular production of immunological substances that are effective in acting as biological response modifiers, alone or in P1470 / 98MX combination with zwitterionic compounds.

A biological response modifier, individual or in composition, is also provided, produced by the previous methods. The invention also provides a method for activating the immune system of a subject, which comprises the above compositions when they are delivered in an amount of the claimed compositions such that the immune system is activated. The "activation" may include the activation, for example, of some stimulator or blocker of the immune activity. A method is further provided for increasing the CD2, CD3, CD8 and CD20 beads and increasing the production of stem cells in healthy or immunosuppressed subjects, comprising the administration of a zwitterionic molecule, such as HEPES, in compositions such as those described, which increase certain hemopoietic mechanisms. A method for reducing the size and / or volume of the tumor is also provided, which comprises administering to the subject a composition containing HEPES, a zwitterionic molecule in an amount capable of reducing the tumor, compositions such that the volume of the tumor is reduced and / or the size of the tumor. In addition, it is said that the induction of P1470 / 98MX Tumor lysis and / or necrosis occurs due to the biological response modifying effect of HEPES as a zwitterionic compound. The present invention provides a method for treating autoimmune diseases in a subject, comprising administering to the subject a quantity of the compositions containing HEPES or a zwitterionic molecule, such that the progression of the autoimmune disease is delayed and / or reversed, the effect of the which is due to HEPES as a biological response modifier. Methods for treating pain due to inflammation and / or tumor activity and / or activity of the autoimmune disease are also provided, including administering to the subject an amount and certain compositions containing a zwitterionic molecule, such as HEPES or PIPES. Additionally, methods are provided for treating viral infections in a subject, by administering a quantity of the zwitterionic compositions as an active ingredient, resulting in a decrease in viral activity. Methods for treating immunosuppressed and / or immunosuppressed subjects whose pathophysiological status may have been induced by drugs, toxins, radiation or environmental factors are also provided when administering P1470 / 98MX a number of HEPES alone or in compositions. The present invention provides methods for preparing solutions containing zwitterionic, amphoteric compounds, such as HEPES, such as: a) the active ingredient in solutions with HEPES and / or amino acids and / or L-glutamine and / or bicarbonate; b) the active and / or activating agent in solutions containing HEPES and / or amino acids and / or L-glutamine and / or bicarbonate and / or mammalian serum (human); and c) HEPES and / or amino acids and / or L-glutamine and / or bicarbonate and / or human serum and / or human serum (mammal) in cell culture. The cells used in the preparations of the cell cultures were human B lymphoid cells, from a healthy donor. The cells have been transformed or activated prior to exposure to Epstein-Barr virus (EBV) which is confirmed by the presence of the Epstein-Barr virus (EBNA) nucleic antigen. Approximately sixty percent (60%) of the human population is positive to the nucleic antigen. Epstein-Barr virus. There are other methods for cellular activation, such as endotoxin stimulation and protein activation stimulation (PAS) techniques, which are known to those skilled in the art. In addition, the cells used are IgM secretion, and this is not considered a limiting factor. Preparations containing HEPES in the cell culture are P1470 / 98MX may additionally be combined by the presence of HEPES in terms of the effects of activation and / or stimulation and / or blocking in an immunological manner, of other substances secreted by the cells. The effects on cancer, pain from cancer, autoimmune diseases and viral infections can be further increased by HEPES. It may be that the action of HEPES as a biological response modifier can be improved by the presence of certain substances secreted by the cells in culture and / or HEPES or the substances may have synergism in activity and / or activate certain immunological pathways , simulated or blocked when HEPES is added to cell cultures, due to one or more actions of the immunophysiological pathways. It is also known that the same mechanisms and / or additional mechanisms are present when HEPES is combined with human serum. The serum may contain certain immunologically active substances which, when combined with HEPES, are potentiated and / or certain substances when combined with HEPES cause activation and / or stimulation and / or blockage of specialized routes. Additionally, HEPES, a biological response modifier, used alone or in various compositions, or other zwitterionic molecules, has shown efficiency by positive indicators, such as, for example, lysis and / or P1470 / 98MX tumor necrosis, decrease in the number and / or distribution of lesions; decrease in tumor size and / or volume; decrease in tumor markers; decrease in pain and / or analgesic use; increase in immunological and hemopoietic markers; decrease in inflammation and markers associated with inflammatory processes; decrease in the total viral loads and decreases in the autoproduction of antibodies in the immune-mediated disease. The present invention provides a method for activating or enhancing the immune system by stimulating and / or blocking and / or other effects of immunophysiological pathways consistent with a BRM, which comprises administering to a subject an amount of a zwitterionic compound, such as HEPES. or PIPES, in the exposed compositions. The indicators consist of increases in the production of stem cells, the counts of CD2, CD3, CD8 and / or CD20. Other markers may include decreased antibody titers, rheumatoid factor (RF), antinuclear antibodies (ANA), and anti-acetylcholine antibody. Positive changes in certain immunological substances secreted by the cells include, but are not limited to, cytokines, chemokines, kinases, immunoglobulins and other known biological response modifiers. The improvement in subjects with P1470 / 98MX rheumatoid arthritis and myasthenia gravis. The hemopoietic indicators show the positive forces for immunosuppressed and immunosuppressed states due to drugs, chemotherapy, radiation, toxins and / or environmental effects. Additional, spoiled hemopoietic indicators related to immunosuppressed, virally induced states, in addition to the determinants of clusters and stem cells include P-24 antigen and beta-microglobulin levels. This invention contemplates all previous and additional modalities. It has been found that HEPES or other zwitterionic molecules and / or compositions produce giant platelets and histiocytes in the blood, demonstrating an immune stimulation capacity of the zwitterionic molecules, and additionally, shows stimulation of the bone marrow. Zwitterionic compositions, administered in mammals, produce macrocytic invasion of tumors demonstrating antitumor activity. The invention further demonstrates that a zwitterionic molecule is shown to be a biological response modifier when HEPES, or other zwitterionic compositions are used, alone or in combination, and is administered to the subject, and results in reductions in size and / or volume of the tumor and the lysis and / or necrosis of the tumor. The size, volume and necrosis of the tumor can be P1470 / 98MX detect and inspect with methods using computerized axial tomography (CAT) and / or nuclear magnetic resonance imaging (MRI) and / or nuclear medicine scans, as known to those skilled in the art. Any tumor that is reduced or undergoes necrosis or this methods using HEPES or other zwitterionic molecules in the described compositions can be treated by this method, for example, tumors of ectodermal, mesodermal and endodermal origin, such as tumors associated with non-Hodgkins lymphoma , adenocarcinomas, mesothelioma, squamous cell carcinoma, embryonic testicular carcinoma; breast carcinoma, prostate carcinoma, ovarian carcinoma; gallbladder carcinoma, including those of the stamp cell type; Colangitic carcinoma,. esophageal carcinoma, malignant melanoma; carcinoma of the lung, hepatoma; multiple myeloma; Kaposi's sarcoma; seminoma, brain tumor, including astrocytoma and glioblastoma, hepatoma, among many others, and also, that the tumor may be primary or metastatic as exemplified by the examples. It has been found that zwitterionic compounds provide a method for inducing a diuretic effect in mammals. The diuretic effect includes the ability of the zwitterionic molecules to effect renal function and effect the activity of the P1470 / 98MX antidiuretic hormone (ADH). The ADH method improves respiratory function and / or increases oxygen efficiency and / or improves oxygen-carbon dioxide exchange in the lung tissue and includes favorable responses in emphysema, cystic fibrosis, and asthma. Also provided with the invention is a method for treating autoimmune diseases in a subject, which comprises administering to the subject an amount of HEPES, alone, or other zwitterionic molecules, in the described compositions such that the progression of the activity is delayed, retained or reversed. pathology and / or pathophysiology autoinmue. For example, the method can stop attrition, decrease antibody titers, increase appetite, improve sleep, and increase energy. The preferred method of the composition using HEPES alone or other zwitterionic molecules, alone or in compositions as previously described. Any autoimmune disease that responds favorably to this method, as can be proven, as taught herein, can be treated by this method, such as the acquired immunodeficiency syndrome (AIDS), rheumatoid arthritis, myasthenia gravis; psoriasis; glomerulonephritis; thyroiditis; systemic erythromatosis lupus; multiple sclerosis; • amyotrophic lateral sclerosis (AML); diabetes; aphthous stomatitis; lichen planus syndrome and chronic fatigue.

P1470 / 98MX The present invention also provides a method for reducing a lesion caused by a virus in a subject, which comprises administering a quantity of HEPES alone or other zwitterionic molecules, in the compositions described, such that the lesion is reduced. The preferred methods of the composition are as previously described. The progression and involvement of the lesion can be inspected by normal methods by those skilled in the art, for example, blood tests, antibody titers, measurement of the lesions, as well as other evaluation techniques known to those skilled in the art. Lesions produced or induced by any virus that are reduced by this method are included in this invention; as can be proved by the methods in the present, for example, Kaposi's sarcoma; herpes simplex, herpes zoster and genital herpes. The invention further provides a method for reducing the intensity and duration of a viral infection in a subject, which comprises administering to the subject a quantity of HEPES or other zwitterionic molecules in the compositions described, such that the intensity and duration of the infection is reduced. viral. The preferred method of treatment uses the methods of the compositions described previously. The method can be used for any viral infection, the intensity of the duration of the P1470 / 98MX which is reduced by administration in a composition of the present invention, by the claimed method, as can be proved by the methods herein. These viral infections are exemplified by the examples and may include, for example, infection by influenza virus, rotavirus, adenovirus; herpes virus, immunodeficiency virus and Coxsackie virus. The use of zwitterionic compounds provides a method for effecting changes directly and / or indirectly in the production and activity of serotonin and acetylcholine. The method includes a membrane stabilizing effect that results in anti-arrhythmia effects, anticonvulsant effects and improved survival in traumatocidal or physiologically damaged cells. It results in reduced tissue damage in vascular and cerebral accidents and myocardial infarction. Other such effects include reduced damage to nerve cells and / or regeneration of nerve cells. A method for reducing pain and / or inflammation in a subject is further provided by this invention; which comprises administering to the subject a quantity of HEPES, alone or with other zwitterionic molecules in the compositions described, such that pain and / or inflammation is thereby reduced. A P1470 / 98MX preferred method of treatment uses the methods of the compositions as previously described. The remission of pain may include the remission of pain from a decrease in the size and / or volume of the tumor, or in lesions that occupy space, thereby decreasing the pressure and compression of organs of anatomical structures (ie, nerves, vessels and other organs), as well as any pain remission not associated with a decrease in tumor size or volume or capsular lengthening or a decrease in lesions, such as bone pain and other pain that occurs before it occurs a significant decrease in the size or volume of the tumor or lesion. This reduction in pain may also be due to '' the remission or reduction of inflammatory processes such as in rheumatoid arthritis or other inflammatory and / or anti-immune diseases. The remission of pain may also be due to changes in other physiological, pathophysiological and pathophysiological immune enhancements, such as: changes in the production of endorphins and similar biochemicals; changes in the activity of the nervous system and changes in ionic conditions and / or stability in the membrane of a cellular levels or physiological routes. A method is also provided for reducing the effects of mental depression in a subject, which comprises administering to the subject a quantity of HEPES alone, or other P1470 / 98 X zwitterionic molecules in the compositions described, such that the effects of mental depression are reduced. A preferred method of treatment uses the methods of the compositions as previously described. The effects that are within this invention are those that can be reduced by this method, as can be proved by the methods taught herein and by standard protocols for measuring these effects. Examples of effects that can be reduced by this method include insomnia, weight loss, sadness / melancholy, clinical depression and feelings of isolation. The same results of this method include increased appetite, feeling good, reduced anxiety, calm and improved mood, and improved sleep quality. A method for treating cancer in a subject is also provided, which comprises administering a quantity of HEPES alone or other zwitterionic molecules in the disclosed compositions, such that the progression of the cancer is delayed, stopped or reversed. A preferred method in the treatment utilizes the methods of compositions as previously described. The cancers included in these methods are those that are reduced by this method as can be proven given the teachings herein. Examples of cancers include breast cancer, prostate cancer, non-Hodgkins lymphoma, colangitic cancer P1470 / 98MX (including those of seal cell type), glioblastoma and others as previously noted. Cancers can be primary or metastatic. All cancers of ectodermal, mesodermal and endodermal origin are included. The invention comprises a method for improving visual perception of color, increased visual precision, improved depth perception, improved hearing and improved taste. Other cellular effects include promotion of hair growth. The method includes the treatment of toxic syndromes, such as the Gulf War syndrome and / or toxicity by the agent orange and / or other syndromes such as those related to the disease induced by organic phosphate, disease derivations and / or polyneuropathies. A method for treating hepatitis in a subject is further provided herein, which comprises administering to the subject a quantity of HEPES alone or other zwitterionic molecules in the compositions described, such that the pathological and pathophysiological activity of hepatitis is reduced. These pathological and pathophysiological activities are reduced by this method, and include elevated levels of bilirubin and hepatosplenomegaly. A preferred method of treatment uses the methods of the composition described previously. By "hepatitis", it means that it includes, for example, P1470 / 98MX hepatitis A, hepatitis B, hepatitis C (previously, not A, not B), and alcoholic hepatitis. A method for reducing the side effects of chemotherapy and radiation therapy in a subject is also provided herein, which comprises administering to the subject a quantity of HEPES alone or other zwitterionic molecules in the described compositions, such that the Lateral effects of chemotherapy and radiation therapy. A preferred method of treatment uses the compositions previously described. Side effects that can be reduced include nausea, vomiting and hair loss. The administration of the zwitterionic, amphoteric compound has also been shown to produce anti-spasmodic effect (affects the muscle, smooth and striated), activity and promote hair growth in animals. The invention also comprises a method for treating blood coagulation disorders by effecting changes in fibrin and fibrinogen activity. These pathological activities include, for example, hypercoagulable and / or hypocoagulable states as can be seen in genetic disorders and / or certain pathophysiological states, including sepsis and / or drug-induced coagulation disorders and / or other metabolic disturbances.

P1470 / 98MX The present invention also provides a method for detecting infection in a subject, which comprises administering HEPES alone or other zwitterionic molecules in the compositions described to the subject and inspecting the development in a reaction, such as fever, chills, diaphoresis and / or rigidity for the subject, this development indicates the presence of an infection in the subject. A rapid search for infection can be achieved if this infection is clinical or subclinical with the etiology that is bacterial, fungal or viral. It is further contemplated that the reactions of fever, chills and rigidity can be mediated immunologically and, therefore, tested in vitro for immunological substances using the controls against the blood of the subjects and / or cells that would develop. This may include measuring the cytokines (possibly IL-3 or other), chemokines, kinases and other products secreted by the cells. Also provided herein is a method for treating Alzheimer's disease, senile dementia and Creutzfeldt-Jakob disease, in a subject, which comprises administering to the subject a quantity of HEPE? alone or other zwitterionic molecules in the compositions described, such that pathological and / or pathophysiological activities are delayed and / or reversed. These P1470 / 98MX pathological and pathophysiological activities that are delayed or reversed by this method, for example, improved memory, improved coordination, decreased agitation and improved quality of life. A preferred method of treatment uses the methods in the composition described previously. The compositions can be administered parenterally; for example, sublingually; intratacheally, intravenously, intramuscularly; subcutaneously and the like. It shows that oral preparations and topical preparations are effective. The exact amount of a required composition will vary from subject to subject, depending on the species, age, weight, general condition of the subject, the safety of the disease being treated, the mode of administration used and the like. In this way, it is not possible to indicate an exact amount. In general, doses of 1000 mg or more, in the compositions described can be given intravenously daily. Doses of 35 mg intravenously daily have been given with the indicated responses in some diseases. There have been complaints of migraine and fatigue in a few subjects at high doses (< 10%). Toxicity studies have not shown toxic effects at response levels of 500 mg / kg for each disease. The dose may vary from less than 0.1 mg / kg to more than 1 gram / kg daily, intravenously, orally, P1470 / 98MX sublingual, intratracheal or topical way. The duration of the therapy will still be determined. Depending on the proposed mode of administration, the compositions may be in pharmaceutical compositions in solid, semisolid or liquid forms. The total effect of a biological response modifier depends on many variables, including compositions which, as described, may have increased effects, depending on the type of disease and pharmaceutical form. As described, the compositions may have HEPES alone or other zwitterionic molecules, alone or with mammalian serum, or with supernatants or fractions of supernatants, filtered or unfiltered, each having different bioactivity and biological response modifier capacity in different disorders and diseases. In addition, depending on the mode of administration and the composition, the composition can be provided with pharmaceutically acceptable carriers and can further include other medicinal agents, pharmaceutical agents, vehicles, adjuvants, diluents, etc., which do not interfere with the activity of the composition, for example, salt solutions. The present invention is described more particularly in the following examples which are proposed as illustrative only, since they will be apparent to P1470 / 98 X those skilled in the art have numerous modifications and variations herein. The zwitterionic molecular compounds useful in the treatment may vary in therapeutic, effective concentrations, depending on the disease and condition of the mammal. However, in general, effective therapeutic concentrations range from about a little less than 0.001 mg / kg to a little more than 5000 mg / kg, such as 500 mg / kg, or more. Several dose response ranges are, for example, non-exclusive: for reduction in pain from 1 mg / kg to 20 mg / kg and for the generation of platelets, effects of immune stimulation and anti-effects of more than 10 mg / kg, such as from 20 mg / kg to 100 mg / kg. The zwitterionic compounds are used alone or in combination with other representative pharmaceutical carrier compounds, such as saline solution volume agents, stabilizers, inert ingredients, or other active ingredients, such as amino acid compounds, in a non-exclusive manner, such as the following: amines of carbohydrates, such as L-glutamine, in varying amounts, for example, from 0.01 mg / kg to 1 gram / kg. Other amino acids for use with HEPES include L-alanine; L-araline-HCl; L-asparagine-H20; L-aspartic acid; L-cystine-2HCl; L-glutamic acid; glycine; L-Histidine-HCl-H20; L-isoleucine; L-leucine; L- P1470 / 98MX lysine-HCl; L-methionine; L-phenylalanine; L-proline; L-serine; L-tryptophan; L-tyrosine-2Na; L-valine; as well as vitamins including d-biotin; D-Ca pantothenate; Choline chloride; folic acid; i-inositol; nicotinamide; pyridoxine-HCl; riboflavin; thiamine-HCl and vitamin B12. Typically, the zwitterionic molecular compositions are employed in the sterile liquid form of saline solutions, such as in syringes or intravenous containers or bags, and contain a buffering agent, such as phosphate or bicarbonate or other buffers, such as sodium and potassium, in solution saline. The zwitterionic piperazine compounds of the invention include the z-witterionic piperazine compounds with a hydroxyl group and a sulfonic acid group, such as those groups having the structural formula: H í «? - R5 / \ flLC CH, H2C CH, «To R i-) wherein Rx is a linking group N, such as an alkyl group, P1470 / 98MX as alkyl of 1 to 6 carbon atoms; R2 is a hydroxyl or amine; R3 is an N-linking group, such as an alkane, such as from 1 to 6 carbon atoms; and R4 is an acid or substituted acid, such as citrate, adipic, carboxylic (COOH); phosphoric (P04OH) or sulfonic acid (S02OH) and the salts of the zwitterionic compound. The molecular, zwitterionic compositions also useful contain only in human in effective amounts and carriers, such as human sera A, 0, B and particularly AB, certified as being negative for bacteria, microplasmas, hepatitis, TB, HTLVI and II and other agents infectious or components. Some representative compositions prepared in the invention are: Compositions of Type A Zwetthermal Molecular Compounds 100-300 mg of ultra pure HEPES 1.6 ce of L-glutamine Amino Acids Bicarbonate buffer Type B 100-300 of ultra pure HEPES 1.6cc of L-glutamine 0.8 c of AB human serum Amino Acids Shock Absorber of bicarbonate P1470 / 98MX Type C 100-300 mg of HEPES 1.66 ce of L-glutamine 0.8 cc-l.Occ of human AB serum The normal administration was in 50 c of normal saline (0.9% saline) given intravenously for 15-30 minutes.

DESCRIPTION OF THE MODALITIES The present invention can be more readily understood by reference to the following detailed description of the specific embodiments and the examples included herein.

Examples Subject One A sixty-five-year-old white man with a five-year history of prostate cancer. The patient had multiple metastases to bone sites. His pain was intense. He received 400 mg of morphine, 6 tablets of Dilaudid and 3 tablets of Darvocet-N daily. The patient was given a composition of 300 mg of HEPES, 1 ce of human serum, and 1 ml of L-glutamine with amino acids and bicarbonate combined with a supernatant P1470 / 98MX from the culture of human cells (intravenously with normal saline) daily for one month. At the end of the month, the patient had a significant reduction in pain. He did not require narcotics and took occasional non-spheroidal anti-inflammatory medication for occasional discomfort. His prostate specific antigen (PSA) had declined 50% from baseline.

Subject Two A sixty-two-year-old Korean man with a two-year history of pancreatic carcinoma with documented extension, the patient had severe pain with duct obstruction and was dying. He was unable to eat or drink fluids orally. He received 35 mg of Demerol per hour intravenously. The patient was given 100 mg of HEPES, 0.8 ce of human serum, 1.6 ce of L-glutamine with amino acids in normal saline (50 ce) twice daily for two weeks (without cell culture). At the end of the five days, his Demerol IV was reduced to 15 mg per hour. After seven days, I had received 5 mg per hour. He was able to take soft and fluid solids. I could stand without assistance. After two weeks, she required only oral Demerol and was more comfortable and functional. His marker of tumer CA 19-9 had decreased more than 25% of P1470 / 98MX the baseline.

Subject Three A sixty-five-year-old white male with gallbladder cell carcinoma with extensive retroperitoneal involvement. He was unable to eat. Its carcinogenic embryonic antigen (CEA) level was 1300. Its liver functions showed an alkaline phosphatase > 450 mg / ml, SGOT > 100, SGPT > 60, LDH > 200. He took morphine for pain. The patient was given 300 mg of HEPES, 0.8 ce of human serum, 1.6 ce of L-glutamine with amino acids (without culture supernatant) intravenously in 50 oc of normal saline daily for four weeks. After four weeks, her CEA level dropped to 600. Her liver function TG0S, TGPS and LDH were normal. The alkaline phosphatase was < 200. He was essentially free of pain. He was able to drink liquids and soft solids. • Subject Four A fifty-eight-year-old woman with a history of more than five years of rheumatoid arthritis ~ severe oid. She had severe pain. He had failed to respond to therapy with gold and methotrexate. He was given 300 mg of HEPES, 1.6 ce of L- P1470 / 98MX glutamine (without human sera in cell culture) in 50 cc of normal saline for two weeks. After two weeks, he had no significant pain. Non-steroidal anti-inflammatories (NSAIDs) were the only medication needed to be mobile and comfortable. Its erythrocyte sedimentation rate (ESR) was 50% of the baseline. The rheumatoid factor and the ANA were decreased.

Subject Five A seventy-two-year-old man with a ten-year history of recurrent Kaposi's sarcoma. Everything was previously removed. There is no evidence of internal malignancy. The patient has a recurrence in the right foot. The patient was given 300 mg of HEPES, 1.6 ce of L-glutamine, 0.8 ce of human serum with amino acids in 50 ce of normal saline IV three times a week; He also received 30 mg of HEPES, 0.1 ce of human serum, 0.2 ce of L-glutamine with amino acids as an intralesional injection three times a week (total volume of 5 ce). After four weeks, the lesions disappeared and did not return. Kaposi's sarcoma is a tumor mediated by viruses. It is discovered that zwitterionic compounds, P1470 / 98MX such as HEPES, decreases the production of alkaline phosphatase in mammals. The concentration is approximately 12 mg / kg the effect seems to start, while concentrations in excess of 100 mg / kg to 500 mg / kg or higher, the alkaline phosphatase phase line levels fall by a factor of two or more , and in some cases, it is not possible to measure by normal laboratory methods. In one example, five healthy canines were administered up to 500 mg / kg of HEPES. At these doses, serum alkaline phosphatase was not detected by normal laboratory methods in all canines. To date, more than thirty-five patients have been treated with 300 mg / kg to 1000 mg / kg of HEPES (or any other agent or additional compositions). All patients with cancer pain have recovered with pain reduction. All cancer patients have had a reduction of twenty-five to fifty percent (25% -50%) in tumor volume and / or tumor activity. All patients with rheumatoid arthritis and myasthenia gravis have had a reduction of twenty-five to fifty percent (25% -50%) in the activity of the disease.

P1470 / 98MX

Claims (22)

1. NOVELTY OF THE INVENTION Having described the present invention, it is considered as a novelty and, therefore, the content of the following CLAIMS is claimed as property: 1. A method for the treatment of diseases in a mammal, the method comprises administering to the sick mammal, as a biological response modifier, an effective therapeutic amount, in one or more treatments, of a zwitterion composition consisting essentially of an amphoteric zwitterionic compound, as an active ingredient, having acid and alkali groups and one or more nitrogen atoms. The method according to claim 1, wherein the acid is selected from the group consisting of the sulfonic acid and carboxylic acid groups. 3. The method according to claim 1, wherein the alkaline group is selected from the group consisting of the hydroxyl group and amino groups. The method according to claim 1, wherein the zwitterionic compound comprises a six-membered heterocyclic ring with a nitrogen atom as a part of the ring. 5. The method according to claim 4, in P1470 / 98MX wherein the heterocyclic ring comprises two nitrogen atoms at each end of the ring and with an acid group and an alkali group connected by at least one group -CH2- to the acid group and the alkali group. 6. The method according to claim 5, wherein the zwitterionic compound comprises the structural formula: < «) Alkaline acid - < z? n-l-j M - * CH2 * fi -? - 3 7. The method according to claim 1, wherein the zwitterionic compound is selected from the group consisting of PIPES, MES, ACES, HEPES, and combinations thereof. The method according to claim 1, which includes administering from about 0.1 mg / kg to about 5000 mg / kg of the zwitterionic compound per body weight of the mammal. The method according to claim 1, which includes the treatment of a disease that contains a cancer tumor, by infiltration of macrophages and shrinkage of the tumor. The method according to claim 1, wherein the zwitterionic composition comprises an amino acid and serum of human. P1470 / 98MX 11. The method according to claim 1, which includes the treatment of diseases to produce giant platelets and histiocytes. The method according to claim 1, which includes the treatment of liver disease. The method according to claim 1, which includes the treatment of solvents of blood coagulation, by effecting changes in the activity of fibrin and fibrinogen. The method according to claim 1, which includes the treatment of autoimmune diseases. The method according to claim 1, which includes the pain reduction treatment. 16. The method according to claim 1, which includes the reduction treatment of viral activity. 17. The method according to claim 1, which includes the treatment of performing diuresis. 18. The method according to claim 1, which includes the treatment of tumor cancer. 19. The method according to claim 1, which treatment includes reducing the level of alkaline phosphatase in a mammal. 20. A zwitterionic composition adapted for use for treatment in a diseased mammal, the composition comprising: P1470 / 98MX a) an effective therapeutic amount of a zwitterionic compound having acidic and alkaline groups as an active ingredient and having at least one nitrogen atom and the pharmaceutically acceptable salts thereof; b) a pharmaceutically acceptable carrier for the zwitterionic compound; and c) a selected compound consisting of: amino acid, human serum, antibiotics and vitamins, and combinations thereof. The method according to claim 20, adapted for use as an anti-tumor composition for mammals, wherein the zwitterionic compound is selected from the group consisting of HEPES, PIPES, MES and ACES, and combinations thereof. 22. The composition according to claim 20, wherein the zwitterionic compound is present in an amount from about 0.1 mg / kg to about 5000 mg / kg of the zwitterionic compound per the body weight of the mammal to be treated. P1470 / 98MX