• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    The present invention relates to a method for treating and / or preventing liver tissue and cell damage caused by reactive oxygen species in a mammal. More specifically, the present invention relates to preventing and / or reducing damage to liver tissues and cells by administration of histamine and histamine-associated compounds.
    公开号:KR20040058192A
    申请号:KR10-2004-7004884
    申请日:2002-10-11
    公开日:2004-07-03
    发明作者:커트 알. 겔슨；타피오 에스. 케이. 하파란타；스테펜 씨. 혼약
    申请人:맥심 파마수티컬즈 인크.；
    IPC主号:
    专利说明:

    Use of Histamine to Treat Liver Disease {Use of Histamine to Treat Liver Disease}
    [2] Oxidative stress, ie the toxicity caused by reactive oxygen species (ROS), is recognized as a systemic phenomenon in liver disease, the extent of which appears to correlate with the severity and stage of the disease. Mechanisms of action associated with cellular damage caused by oxidative stress have been implicated in many diseases, including hepatitis, and are associated with direct damage to liver cells. A researcher has tested the role of oxidative stress in the development of hyperdynamic circulation in portal hypertension. However, Bomzon and Ljubuncic pointed out that it is imperative to conclude that oxidative stress itself affects at least the smooth muscle cell function of blood vessels in liver disease. Pharmacol Ther., 89 (3): 295-308 (2001).
    [3] The theory that oxidative stress could play a role in liver disease is not surprising. This is because oxidative stress has been suggested to be involved in the state of immunosuppression in malignant tumor sites and chronic viral infections. (See US Pat. Nos. 5,728,378, 6,000,516 and 6,155,266). Lymphocytes in or adjacent to the tumor show signs of oxidative damage, including greater degrees of cell death and defective transmembraneous signaling. Oxidative stress at the site of tumor growth is likely transmitted by ROS produced by adjacent phagocytes (monocytes / macrophages (MO) or neutrophil granulocytes (GR)). Histamine, an inhibitor of ROS production in phagocytes, is currently used as an adjuvant of lymphocyte-activated cytokines (IL-2 and IFN-alpha) for the purpose of enhancing the efficacy of cytokines.
    [4] Rubin et al. Have described the use of histamine and other compounds that act as "primers" for the treatment of cancer, including liver cancer. (See US Pat. No. 6,303,660). The starting compound is believed to act by increasing intracellular levels of cyclic adenosine monophosphate (cAMP) in normal connective tissue cells in solid tumors. Topical administration of a starting agent to the tumor containing area is believed to provide a result of lowering epilepsy pressure. This drop in epilepsy pressure is also believed to promote absorption of anticancer drugs.
    [5] With the devastating consequences of liver disease and the treatments in use today being only partially successful, there is a constant need for improved methods for treating liver disease and reducing liver cell damage.
    [6] Summary of the Invention
    [7] The present invention relates to a method for treating and / or preventing liver tissue and cell damage caused by reactive oxygen species in a mammal. More specifically, the present invention relates to preventing and / or reducing and / or repairing damage to liver tissue and cells by administration of histamine and histamine-associated compounds. In one aspect, methods are provided for inhibiting and reducing reactive oxygen species (ROS) -mediated oxidative damage in liver cells and tissues of a subject. One aspect of this method involves administering to a patient with liver disease caused or exacerbated by ROS-mediated oxidative damage a compound effective to inhibit the production or release of ROS produced enzymatically. Although the compositions and methods are applicable to any liver disease, the methods are particularly portal hypertension, allyl syndrome, alpha-1-antitrypsin deficiency, autoimmune hepatitis, cholangioplasia, chronic hepatitis, liver cancer, cancer metastasis to liver, Liver cirrhosis, hepatic biliary tract, hepatic venous thrombosis, hepatic vein occlusion disease, hepatic lens degeneration, hepatomegaly, hepatic pulmonary syndrome, hepatic nephrotic syndrome, hepatic cyst, hepatic abscess, fatty liver, galactosemia, gilbert syndrome, portal hypertension, alcoholic Liver disease (ALD), parasitic liver disease, hepatic purpura, erythroid porphyria, hepatic porphyria, hepatic pneumonia, primary biliary cirrhosis, primary sclerosing cholangitis, Laie's syndrome, sarcoidosis, hypertyrosinemia, type I glycopathy, Wilson Particularly relevant for the treatment of diseases of the liver, neonatal hepatitis, nonalcoholic steatohepatitis, hemochromatosis and Zellweger syndrome.
    [8] Another aspect of the invention relates to a method for treating a patient suffering from a disease state produced by phagocytes and in which reactive oxygen species (ROS) -mediated oxidative damage may occur. Aspects of this method include administering compounds effective for classifying patients with liver disease in which ROS cause ROS-mediated oxidative damage and inhibiting the production or release of ROS.
    [9] In another aspect of the present invention, there is provided a composition comprising a compound and a hepatotoxic drug effective for inhibiting the production or release of reactive oxygen species. Hepatotoxic drugs include azathioprine, methyldopa, nitrofuratoin, clofibrate, troglitazone, ibuprofen, allopurinol, indomethacin, leflunomide, acetaminophen, diclofenac, isoniazide, tetracycline, erythr Romaine, nitrofuratoin, amoxicillin, rifampin, ketoconazole, flucloxacillin, trobafloxacin, sulfonamide, estradiol, iron, glutathione, halotan, isoflurane, captopril, diltiazem, phenytoin, val. Proic acid, cambamazepine, phenobarbitone, primidone, trazodone, chlorpromazine, quinidine, procainamide, amiodarone, methotrexate, cyclophosphamide, corticosteroids, assimilation steroids, glucocorticoids, pyrazineamides, para -Aminosalicylic acid, ethionamide, trimetaprim-sulfamethoxazole, pentamidine, zidobudine, dideoxyinosine, penny It may be incorrect, or cephalosporin.
    [10] In another aspect of the present invention, the herbal formulation is formulated with a compound effective to inhibit the production or release of reactive oxygen species, with the result that the hepatotoxic effect of the herbal formulation is minimized. Examples of suitable herbs are Larrea tridentata , Teucrium chamaedrys , jin bu huan, Valerian officinalis , Scutellaria galericulata , Mistletoe Viscum species. ), Jamaican shrub tea , Cassia angustfolia , Symphytum officinale and Caba root extract.
    [11] Among the compounds effective in inhibiting the production or release of reactive oxygen species are advantageous histamine, histamine receptor agonists, NADPH oxadase inhibitors, serotonin or serotonin agonists. Optionally, the composition further contains an effective amount of a ROS remover. The ROS remover can be catalase, peroxide dismutase, glutathione peroxidase or ascorbate peroxidase.
    [12] In another aspect of the present invention, a method of reducing hepatotoxicity of a drug is provided by administering to a patient taking a hepatotoxic drug an effective amount of a compound effective to inhibit the production or release of ROS. Compounds effective for inhibiting the production or release of ROS may include histamine, histamine receptor agonists, NADPH oxidase inhibitors, serotonin or serotonin agonists.
    [13] Optionally, the method comprises the additional step of administering an effective amount of the ROS remover. Advantageously, administering the ROS remover acts as a catalyst to result in the degradation of the ROS. The scavenger may include catalase, glutathione peroxidase, ascorbate peroxidase, peroxide dismutase, glutathione peroxidase, ascorbate peroxidase, vitamin A, vitamin E or vitamin C.
    [14] Hepatotoxic drugs may be azathioprine, methyldopa, nitrofuratoin, clofibrate or troglyzatuzon. In one aspect of the invention, the hepatotoxic drug is an arthritis treatment drug such as ibuprofen, allopurinol, indomethacin, leflunoamide, acetaminophen or diclofenac. In another aspect, the hepatotoxic drug is an antibiotic such as isoniazid, tetracycline, erythromycin, nitrofuratoin, amoxicillin, rifampin, ketoconazole, flucloxacillin, trobafloxacin or sulfonamide. Hepatotoxic drugs include estradiol, iron, glutathione, halotane, isoflurane, captopril, diltiazem, phenytoin, valproic acid, carbamazepine, phenobarbitone, primidone, trazodone, chlorpromazine, quinidine , Procainamide or amidodarone. Hepatotoxic drugs may similarly include chemotherapeutic agents, corticosteroids, anabolic steroids or glucocorticoids.
    [15] In another aspect of the invention, hepatotoxic drugs are drugs used for the treatment of HIV / AIDS patients, for example pyrazinamide, para-amino salicylic acid, ethionamide, trimetaprim-sulfamethoxazole, pentamidine, zidobudine, Dideoxyinosine, penicillin and cephalosporin.
    [16] Methods of lowering the hepatotoxicity of certain herbal formulations are also provided. Compounds effective for inhibiting the production or release of reactive oxygen species include, for example, Larrea tridentata , Teucrium chamaedrys , jin bu huan, Valerian officinalis , It is administered to people who consume thirsty thimble flowers ( Scutellaria galericulata ), mistletoe ( Viscum species), Jamaican shrub tea , Senna ( Cassia angustfolia ), rapeseed ( Symphytum officinale ), and kava root extract.
    [17] Another aspect of the invention is a method of reducing liver tissue damage caused by exposure to environmental or industrial toxins. This method involves administering to a subject in need thereof an effective amount of a compound effective to inhibit the production or release of ROS. Advantageously, compounds effective for inhibiting the production or release of ROS include histamine, histamine receptor agonists, NADPH oxidase inhibitors, serotonin and serotonin agonists. Optionally, the method may include the additional step of administering an effective amount of the ROS remover. Preferably, the step of administering the ROS remover acts as a catalyst to decompose the ROS as a result. The scavenger may include catalase, glutathione peroxidase, ascorbate peroxidase, peroxide dismutase, glutathione peroxidase, ascorbate peroxidase, vitamin A, vitamin E or vitamin C. Environmental toxins can include poison mushrooms of the genus Amanita , Galerina or Gyromitra . Additionally, environmental or industrial toxins may include tobacco smoke, pesticides, food additives and / or preservatives, heavy metals, organic solvents or industrial cleaners, in particular detergents containing chlorinated solvents.
    [1] The description below relates to methods for treating and / or preventing liver tissue and cell damage caused by reactive oxygen species in a mammal. More specifically, the following description relates to preventing and / or reducing and / or repairing damage to liver tissue and cells by administration of histamine and histamine-associated compounds.
    [18] The description below relates to compositions and methods for preventing and / or reducing liver cell and tissue damage caused by reactive oxygen species.
    [19] The liver plays a key role in many metabolic functions. Liver disease is typically a serious consequence for patients ranging from morbidity to mortality. Examples of liver diseases include portal hypertension, allergy syndrome, alpha-1-antitrypsin deficiency, autoimmune hepatitis, cholangiovascular dysfunction, chronic hepatitis, liver cancer, cancer metastasis to the liver, cirrhosis, hepatic biliary tract, hepatic venous thrombosis, Hepatic venous obstruction, hepatolens degeneration, hepatomegaly, hepatic pulmonary syndrome, hepatic syndrome, hepatic cyst, liver abscess, fatty liver, galactosemia, Gilbert syndrome, portal hypertension, alcoholic liver disease (ALD), parasitic liver disease, Hepatic purpura, erythrohepatic porphyria, hepatic porphyria, hepatic pneumonia, primary biliary cirrhosis, primary sclerosing cholangitis, Laie's syndrome, sarcoidosis, hypertyrosinemia, hepatitis I disease, Wilson's disease, neonatal hepatitis, nonalcoholic steatohepatitis, Hemochromatosis and Zellweger syndrome. As used herein, “alcoholic liver disease” (ALD) includes, but is not limited to, alcoholic fatty liver, alcoholic hepatitis, alcoholic cirrhosis, and liver fibrosis.
    [20] Recent studies have found that these and other liver diseases can be caused or exacerbated by ROS. ROS can induce apoptosis by directly affecting several cells in the liver parenchema. Another possible mechanism by which these molecules can damage liver cells and tissues may be related to the effect of ROS on the actuator cells of the immune system. For example, ROS generated from monocytes and other sources have been shown to effectively inhibit the activation and activity of NK cells and T-cells.
    [21] The effects of ROS generation are well known. ROS is known to cause apoptosis of NK cells. ROS are also known to cause anergy and / or apoptosis of T-cells. Nevertheless, some researchers believe that ROS causes cell death by disrupting cell membranes, by changing the pH of cell pathways critical for cell survival, and by direct damage to DNA.
    [22] Compounds that reduce the amount of ROS production and release and the following methods relate to the reduction and prevention of ROS mediated damage of liver cells and tissues. In a preferred embodiment, several histamine and histamine-associated compounds are used to achieve enzymatic ROS production and release or beneficial reduction or inhibition of their total concentration. The term "histamine" as used herein includes various histamine and histamine related compounds. For example, histamine, dihydrochloride salt form of histamine (histamine dihydrochloride), histamine diphosphate, other histamine salts, esters or prodrugs and histamine receptor agonists. In addition, the term "histamine" includes histamine binding mimetics and NADPH oxidase inhibitors.
    [23] Administration of a compound that induces release of endogenous histamine from a patient's own tissue reservoir is also within the scope of the present invention. Such compounds include IL-3, retinoids and allergens. Known scavengers of ROS include enzyme catalase, peroxide dismutase (SOD), glutathione peroxidase and ascorbate peroxidase. In addition, it is known that vitamins A, E and C exhibit scavenger activity. In addition, minerals such as selenium and manganese may be effective in healing ROS-mediated damage. The scope of the methods described herein includes the administration of compounds listed and compounds with similar ROS inhibitory activity. The compositions and methods described herein also provide an effective means for preventing and / or inhibiting the release of enzymatically produced ROS in excessive amounts or at inappropriate times or sites.
    [24] Provided are compounds and methods for treating liver disease states implicated by deleterious release of ROS in a host or subject. The liver has many essential functions in the body. Due to this activity, the liver is exposed to a wide variety of damage and is therefore one of the most frequently damaged organs in the body. Impairment of such important functions by liver disease can have very fatal consequences. Liver damage has been associated with many causes. Hepatitis or inflammation of the liver may occur due to infection by a virus, bacterium, fungus or protozoa or may be caused by exposure to toxins such as alcohol, drugs, chemical toxins or other environmental toxins. Involvement of the liver in extrahepatic diseases such as vascular and metabolic diseases, neoplastic and / or autoimmune diseases has been similarly associated with damage to liver tissue. Examples of autoimmune diseases involving liver tissue include lupus erythematosus and rheumatoid arthritis. In addition, in patients suffering from heart failure, the liver is often damaged from congestion, scars and ascites.
    [25] In the case of industrial and environmental toxins, the primary disease is caused by ingestion, injection or inhalation of toxic substances that have a deleterious effect on the liver. For example, herbicides such as paraquat are associated with increased incidence of liver damage. Similarly, ingestion of poisonous mushrooms of a particular genus can cause fatal damage to liver cells and even cause death. Such mushrooms include the genus Amanita and Galerina , which contain flax toxins, a substance that destroys the liver and kidneys. Liver necrosis, similar to that produced by overdose acetaminophen, is a primary toxic symptom. Mushrooms of the genus Gyromitra have also been associated with hepatotoxicity and hepatic kidney syndrome in severe patients. Examples of environmental and industrial toxins that cause damage to liver tissue include, but are not limited to, tobacco smoke, industrial cleaners, diethanolamine, sodium laurel sulfate, propylene glycol, pesticides such as DDT and Mylex, food additives and preservatives , Heavy metals, organic solvents (eg formaldehyde and bromobenzene) and chlorinated solvents (eg dioxin, pullulan, TCE, PCE, DCE, tetrachloroethylene, carbon tetrachloride and vinyl chloride).
    [26] As described in more detail below, hepatic toxins also have many common drugs, such as acetaminophen, anabolic steroids, chemotherapy drugs, some antibiotics, glucocorticoids, anesthetics, parasite fighting drugs and phenylbutazone Included. Certain anticonvulsants are associated with liver disease and include, for example, phenobarbital, primidone and pentoin. Damage to liver tissue is at least in part a result of the harmful release of ROS in the host or subject itself in response to such damage. Thus, compositions and methods are provided for treating damage to liver tissue caused by exposure to toxic substances. Specifically, administration of ROS production and release inhibitory compounds is useful for reducing trauma to liver cells and tissues following exposure to industrial and / or environmental toxins.
    [27] Many drugs have been linked to liver damage. About 10% of all hepatitis patients in young adults and 40% of patients over 50 are caused by drugs. As used herein, “hepatotoxic drug” includes any substance that acts on the liver and causes tissue damage. Examples of hepatotoxic drugs include, but are not limited to, anti-diabetic and immunosuppressive drugs (eg, azathioprine, methyldopa, nitrofuratoin, clofibrate, and troglyzazone), joint treatment drugs (eg, ibuprofen, allopurinol , Indomethacin, leflunomide, acetaminophen, diclofenac), antibiotics (eg isoniazid, tetracycline, erythromycin, nitrofuratoin, amoxicillin, rifampin, ketoconazole, flucloxacillin, trobafloxacin and Sulfonamides), iron, vitamin A, glutathione, certain anesthetics (e.g. halotan and isoflurane), antihypertensive drugs (e.g. captopril and diltiazem), anticonvulsants and antidepressants (e.g. phenytoin, foot Prosan, carbamazepine, phenobarbitone, pyrimidone and trazodone), antipsychotics (e.g. chlorpromazine), antiarrhythmic drugs (e.g. quinidine, procaineamide and trazodone), chemotherapy agents ( , Methotrexate and cyclophosphamide, steroids (e.g. corticosteroids, anabolic steroids and glucocorticoids), and drugs commonly used in HIV / AIDS patients (e.g. pyrazineamide, para-amino salicylic acid, ethionamide, trimeta) Primsulfamethoxazole, pentamidine, zidobudine, dideoxyinosine, penicillin and cephalosporin). In addition, the following herbal preparations are known hepatoxins: Larrea tridentata , Teucrium chamaedrys , certain Chinese herbs (e.g., jin bu huan and ma huang). )), Valerian root ( Valeriana officinalis ), thimble ( Scutellaria galericulata ), mistletoe ( Viscum species), herbal teas (e.g. Jamaica shrub tea (pyrrolidindine alkaloids), senna ( Cassia angustfolia ), larva ( Symphytum officinale ) and kava root extract.
    [28] Compositions and methods are provided to minimize the hepatotoxicity of certain drugs. For many diseases, such as HIV / AIDS, treatment for this can be as burdensome as the disease. In the case of HIV infection, drugs designed to reduce viral levels can often damage liver cells and have fatal consequences. Thus, a ROS inhibitor or elimination compound can be administered to a patient who is concurrently taking drugs that cause hepatotoxic side effects to alleviate damage to liver cells caused by hepatotoxic drugs. In one embodiment, a patient taking a hepatotoxic drug is administered separately in an effective amount of a ROS inhibitory compound or scavenger or in a single formulation with the hepatotoxic drug. ROS inhibitory compounds or eliminators and hepatotoxic drugs can be administered substantially simultaneously or at various time intervals from one another. Administration can be by local or systemic injection or infusion. Other methods of administration, such as oral route, may also be suitable.
    [29] Administration of ROS inhibitors or scavengers is also useful for alleviating damage to liver tissue caused or exacerbated by bacterial, fungal, viral or protozoan infections. Helicobacter and leptospirosis are examples of pathogenic bacterial species that invade the liver and cause tissue damage. Stem fungi, histoplasmosis and coccidiosis are examples of fungal infections that attack liver tissue. Systemic infections such as pneumonia, candidiasis, and toxoplasmosis are often prevalent in the liver and can cause damage to liver tissue. In addition, almost all blood-derived infections are inevitably associated with the liver.
    [30] Thus, as one aspect of the invention, compositions and methods are provided that minimize damage to liver tissue associated with bacterial, fungal, viral or protozoan infections. ROS production and release inhibitory compounds are administered alone or in combination with antibiotics. As used herein, the term “antibiotic” includes any antibacterial, antifungal or antigenic compound. The ROS production and release inhibitory compounds of the present invention can be administered separately or in combination with antibiotics or in a single formulation with antibiotics. When administered separately, compounds that inhibit ROS production and release should be administered in a short period of time to increase the alleviation of damage to liver tissue. In one embodiment, the ROS production and release inhibitory compound and the antibiotic are administered within one week of each other. In another embodiment, the ROS production and release inhibitory compound and the antibiotic are administered within 24 hours of each other. In another embodiment, the ROS production and release inhibitory compound and the antibiotic are administered within 1 hour of each other. Administration can be by local or systemic injection or infusion. Other methods of administration, such as oral administration, may also be suitable.
    [31] In another aspect, compositions and methods are provided for treating secondary liver disease caused by another etiology. Because of the proximity of the pancreas to the liver and bile ducts, acute pancreatitis often leads to hepatitis. Similarly, chronic enteritis permits the portal fluid absorption of toxic enteric products and bacteria that can damage liver tissue. Shock, anemia and congestive heart failure lead to severe loss of blood circulation to the liver and oxygen deficiency, which likewise can lead to damage to liver tissue. Similarly, while primary cancer of the liver is rare, it is common for cancer to spread to the liver as secondary metastatic cancer from the colon, lung, breast or other parts of the body. Thus, compounds containing ROS inhibitor compounds or scavengers are useful for treating secondary liver disease caused by other diseases. In one embodiment, a patient suffering from acute pancreatitis is administered an effective amount of a ROS inhibitory compound or scavenger to prevent damage to liver cells. In another embodiment, an effective amount of a ROS inhibitory compound or scavenger is administered to a patient with metastatic cancer of the liver with or without chemotherapeutic agents to minimize liver damage.
    [32] Administration of the compounds described may be alone or in combination with other compounds effective for treating various liver disease states. For example, histamine can be used to treat patients suffering from nonalcoholic steatohepatitis (NASH). In addition, the methods and compounds described herein can be used in conjunction with standard NASH treatment regimens that include low fat low calorie foods, along with insulin or hypoglycemic drugs, usually for obese patients. For NASH patients who are not overweight and without diabetes, low fat foods are often recommended. In addition, as discussed above, patients with metastatic cancer of the liver are administered an effective amount of a ROS inhibitory compound or eliminator with standard chemotherapy and / or radiation protoco. In the case of a viral infection of the liver, the subject may be administered antiviral therapy concurrently with the administration of the ROS inhibitory compound or scavenger to minimize liver cell damage. For example, a ROS inhibitor compound or scavenger may be used in combination with a standard hepatitis C treatment regimen, including administration of ribavirin or phasing INF-α, to treat patients with hepatitis C.
    [33] Similarly, the methods and compounds described herein are useful for the treatment of alcoholic liver disease. Alcohol abuse is the leading cause of morbidity and mortality worldwide. It is estimated that more than 10% of men and 3% of women in the United States may have ongoing problems associated with the use of alcohol. Alcohol affects many organ systems in the body, but the most obviously affected organ is the liver, since almost all absorbed alcohol must be metabolized in the liver. Alcohol abuse usually leads to three pathologically distinct liver diseases: fatty liver (fatosis), alcoholic hepatitis, and cirrhosis. Fatty liver is characterized by the accumulation of fat in hepatocytes, which is characteristic of the hepatic dominant cell type. Alcohol can also cause acute and chronic hepatitis. Alcoholic hepatitis can induce hepatic scarring and cirrhosis and is very common among alcoholics who already have cirrhosis of the liver. Finally, cirrhosis due to alcohol abuse is characteristically mixed with fibrosis, which leads to the development of widespread nodules in the liver, which can lead to late liver disease. Alcohol-associated cirrhosis is one of the ten leading causes of death in the United States. Some of the complications of cirrhosis are jaundice, ascites, edema, hemorrhagic esophageal varices, blood clotting abnormalities, lethargy and death. Thus, in one aspect, the methods and compositions described herein are administered to a patient suffering from alcoholic liver disease (ALD). Patients suffering from ALD are sorted to administer an effective amount of a ROS inhibiting or eliminating compound.
    [34] The use of ROS inhibition or elimination compounds may be any of a number of methods known to those skilled in the art. For oral administration, the ROS inhibiting or eliminating compound may be incorporated into tablets, aqueous or oily suspensions, dispersible powders or granules, microbeads, emulsions, hard or soft capsules, syrups or elixirs. The composition may be prepared by any method known in the art for the preparation of pharmaceutically acceptable compositions and such compositions may contain one or more of the following materials: sweeteners, flavors, colorants and preservatives. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets are acceptable. "Pharmaceutically acceptable" means that the substance must be allowed in the sense of being compatible with other components of the formulation (as well as in view of being harmless to humans). Such excipients include inert diluents (e.g. calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate), granulation and disintegrants (e.g. corn starch and alginic acid), binders (e.g. starch, gelatin or acacia) and lubricants (Eg magnesium stearate, stearic acid or talc). Tablets may be uncoated or coated with known techniques to retard disintegration and absorption in the gastrointestinal tract and thereby provide long-lasting action. For example, a time lag material such as glyceryl monostearate or glyceryl stearate alone or a mixture of these and waxes can be used.
    [35] In another preferred embodiment, tablets, capsules or microbeads can be coated with enteric skin to prevent dissolution in the acidic environment of the stomach. Instead, this coating dissolves in the small intestine at more neutral pH. Such enteric coating compositions are described in Bauer et al., Coated Pharmaceutical Dosage Forms: Fundamentals, Manufacturing TEchniques, Biopharmaceutical Aspects, Test Methods and Raw Materials , CRC Press, Washington, DC, 1998.
    [36] Oral formulations may also contain a hard gelatin capsule or mixture of the active ingredient with an inert solid diluent (e.g. calcium carbonate, calcium phosphate or kaolin) or an active ingredient with water or an oil medium (e.g. peanut oil, liquid paraffin or olive oil). It may be provided as a soft gelatin capsule.
    [37] Aqueous suspensions may contain the ROS inhibiting or eliminating compounds according to the invention in admixture with excipients for the preparation of aqueous suspensions. Such excipients include suspending agents, dispersing or wetting agents, one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents (eg, sucrose or saccharin).
    [38] Oily suspensions may be formulated by suspending the active ingredient in vegetable oils (eg castor oil, olive oil, sesame oil or coconut oil) or mineral oils (eg liquid paraffin). The oily suspension may contain a thickening agent (eg beeswax, hard paraffin or cetyl alcohol). Sweetening and flavoring agents such as those described above may be added to provide sweet oral formulations. These compositions can be preserved by additional antioxidants such as ascorbic acid. Dispersible powders and granules of the compounds according to the invention suitable for the preparation of aqueous suspensions by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Additional excipients may also be present, for example sweetening, flavoring and coloring agents.
    [39] Syrups and elixirs may be formulated with sweetening agents such as glycerol, sorbitol or sucrose. Such formulations may also contain analgesics, preservatives, flavors or colorants.
    [40] The use of ROS inhibiting or eliminating compounds can also be achieved by parenteral delivery via subcutaneous, intravenous, intraperitoneal or intramuscular injection. The compound may be administered as an aqueous solution with or without a surfactant such as hydroxypropyl cellulose. Also contemplated are dispersions such as those using glycerol, liquid polyethylene glycols and oils. Injectables can include sterile aqueous solutions or dispersions and powders that can be diluted or suspended in a sterile environment prior to use. In addition, carriers such as solvents or dispersion media including water, ethanol polyols, vegetable oils and the like can be added to the compound. Coatings such as lecithin and surfactants can be used to maintain the proper fluidity of the composition. Isotonic substances, such as sugars or sodium chloride, may be added, as well as products which are intended to delay the absorption of active compounds such as aluminum monostearate and gelatin. Sterile injectable solutions are prepared according to methods well known to those skilled in the art and may be filtered prior to storage and / or use. Sterile powder may be vacuum or lyophilized from solution or suspension. It is also possible to use sustained or controlled release formulations and formulations in this manner. Typically the materials used in the methods and compositions are pharmaceutically acceptable and substantially non-toxic in use.
    [41] The compounds described herein can also be administered by inhalation. In this route of administration, the histamine is dissolved in water or some other pharmaceutically acceptable carrier liquid for inhalation, or provided as anhydrous powder and then inhaled by the patient at a dose suitable to provide the patient with a measurable amount of histamine. May be introduced into a gas or powder that may be present. Examples of administration of therapeutic compositions via inhalation are described in US Pat. Nos. 6,418,926, 6,387,394, 6,298,847, 6,182,655, 6,132,394 and 6,123,936.
    [42] Aspiration devices can be used to deliver the compounds described herein. Suitable instruments include syringe pumps, automatic injection systems, implant pumps, implant devices and minipumps. Examples of instruments include Ambulatory Infusion Pump Drive Model 30 from Microject Corp. of Salt Late City, Utah and Baxa Syringe Infuser from Baxa Corporation of Eaglewood, Colorado. Any device capable of delivering a compound of the invention in accordance with the methods described herein can be used.
    [43] Suitable aspiration devices are preferably effective amounts of histamine, histamine agonist, histamine salt, histamine prodrug, NADPH-oxidase inhibitor, histamine dihydrochloride, histamine phosphate, serotonin, 5HT agonist, histamine receptor agonist, histamine receptor binding It contains a substance that induces the release of a mimetic or intrinsic therapeutically effective amount of endogenous histamine. The instrument may be preloaded with the desired material during manufacture, or may be filled with the material immediately before use. Prefilled suction pumps and syringe pumps are well known to those skilled in the art. The active substance may be part of a formulation comprising a controlled release carrier if necessary. A controller can be used in conjunction with the instrument to adjust the rate and dosage of administration of the substance. The controller may be integral with or separate from the instrument. The controller may be preset at the time of manufacture or set by the user immediately before use. Such controllers and their use with suction devices are well known to those skilled in the art.
    [44] Controlled release vehicles are well known to those skilled in the pharmaceutical arts. Techniques and preparations in this field are variously expressed as controlled release, sustained release, extended action, storage, storage, delayed action, delayed release and timed release, and the term "controlled release" as used herein It is used with the intention of containing each said technique.
    [45] Many controlled release vehicles are known, including biodegradable or biosoluble, such as polylactic acid, polyglycolic acid, and regenerated collagen. Known controlled release drug delivery formulations include creams, lotions, tablets, capsules, gels, microspares, liposomes, ophthalmic inserts, minipumps and other suction devices (eg, pumps and syringes). Implantable or injectable polymeric matrices and transdermal formulations that slowly release the active ingredient are also well known and can be used in the methods of the present invention.
    [46] In one embodiment, the compounds described herein are administered via a topical delivery system. The controlled release component described above can be used as a means of delivering a compound of the present invention. Suitable topical delivery systems include compounds of the invention, solvents, emulsifiers, pharmaceutically acceptable carrier materials, penetration enhancers, and preservatives at concentrations taught herein. Examples of topically applied compositions include US Pat. Nos. 5,716,610 and 5,804,203. The composition also includes ingredients adapted to enhance the stability or effectiveness of the applied formulation, such as preservatives, antioxidants, skin penetration enhancers and sustained release substances. Examples of such ingredients are described in Martindale-The Extra Pharmacopoeia ( Pharmaceutical Press, London 1993) and Martin (ed.), Remington's Pharmaceutical Sciences .
    [47] Controlled release formulations can be achieved by using polymers to complex or absorb with ROS inhibiting or eliminating compounds. Controlled delivery can be accomplished by selecting appropriate macromolecules such as polyesters, polyamino acids, polyvinylpyrrolidone, ethylenevinyl acetate, methylcellulose, carboxymethylcellulose and protamine sulfate, incorporating these macromolecule concentrations as well as The method is chosen to control the release of the active compound.
    [48] Hydrogels in which ROS inhibiting or eliminating compounds are dissolved in aqueous components and gradually released over time can be prepared by copolymerizing hydrophilic mono-olefinic monomers such as ethylene glycol methacrylate. Matrix mechanisms in which the ROS inhibiting or eliminating compound are dispersed in a matrix of the carrier material can be used. The carrier may be porous, nonporous, solid, semisolid, permeable or impermeable. Alternatively, an instrument comprising a central reservoir of ROS inhibiting or eliminating compound surrounded by a rate controlling membrane can be used to control the release of the ROS inhibiting or eliminating compound. Rate controlling membranes include ethylene-vinyl acetate copolymers or butylene terephthalate / polytetramethylene ether terephthalate. The use of silicone rubber reservoirs is also contemplated.
    [49] Controlled release oral formulations are also well known. In one embodiment, the active compound is incorporated into a soluble or corrosive matrix such as a ring or lozenge. Such formulations are well known in the art. Examples of lozenges used to administer pharmaceutically active compounds are described in US Pat. No. 5,662,920. As another example, the oral formulation may be a liquid used for sublingual administration. Examples of pharmaceutical compositions for liquid sublingual administration of the compounds described herein are taught in US Pat. No. 5,284,657. These liquid compositions may also be in the form of gels or pastes. Hydrophilic gums such as hydroxymethylcellulose are commonly used. Lubricants such as magnesium stearate, stearic acid or calcium stearate may be used to facilitate the tableting process.
    [50] For the purpose of parenteral administration, the ROS inhibiting or eliminating compound may be mixed with distilled water, preferably buffered to an appropriate pH and having an appropriate (eg isotonic) salt concentration. The compounds of the present invention may also be provided as liquids or as powders which are reconstituted prior to use. These may be provided as prepackaged vials or injection systems.
    [51] Compounds of the present invention, such as histamine, may also be provided in sealed vials divided into doses of about 0.5 to 100 ml for administration to a subject. In a preferred embodiment, the vial contains doses of 0.5, 1, 3, 5, 6, 8, 10, 20, 50 and 100 ml. The vial is preferably sterile. The vial may optionally contain an isotonic carrier medium and / or preservative. Any desired amount of histamine can be used to provide the desired final histamine concentration. In a preferred embodiment, the concentration of the ROS inhibiting or eliminating compound is about 0.01 mg / ml to 100 mg / ml. More preferably, the concentration of ROS inhibiting or eliminating compound is about 0.1 to 50 mg / ml. Most preferably, the concentration of ROS inhibiting or eliminating compound is about 1 mg / ml to 10 mg / ml. It is preferred to administer individual doses at the lower end of the dose range, while at the upper limit it is preferred to administer multiple doses.
    [52] In a preferred embodiment, transdermal patches, steady state reservoirs and transdermal preparations sandwiched between the impermeable back and the membrane can also be used to deliver ROS inhibiting or eliminating compounds. Transdermal administration systems are well known in the art. Closed transdermal patches for the administration of active agents to the skin or mucous membranes are described in US Pat. Nos. 4,573,996, 4,597,961 and 4,839,174. One type of transdermal patch is a polymer matrix in which the active substance is dissolved in a polymer matrix through which the active ingredient diffuses into the skin. Such transdermal patches are described in US Pat. Nos. 4,839,174, 4,908,213 and 4,943,435. In one embodiment, the steady state reservoir contains a constant dose of histamine and a dose of about 0.2-5 mg of other ROM production and release inhibiting compound per day.
    [53] Current transdermal patch systems are designed to deliver smaller doses over longer periods, ie days and weeks. Preferred delivery systems for the compounds of the invention specifically deliver an effective amount of histamine in the range of about 2 to 60 minutes, depending on the dose, with a preferred dose delivered within about 20-30 minutes. These patches allow for rapid and controlled delivery of compounds that inhibit or eliminate ROS. The rate of release can be controlled using a rate-controlled envelope microporous membrane or micropocket of a compound according to the invention dispersed throughout the silicone polymer matrix. Such speed-control means are described in US Pat. No. 5,676,969. In another preferred embodiment, the histamine or other ROM inhibiting or eliminating compound is released from the patch into the patient's skin within about 20-30 minutes. In a preferred embodiment, the compound releases from the patch at a rate of about 0.025 mg to 0.5 mg per minute for a dose of about 0.2 mg to 5 mg per patch.
    [54] These transdermal patches and formulations can be used with or without penetration enhancers such as dimethylsulfoxide (DMSO), sulfoxides or combinations of phosphoric oxides with sucrose fatty acid esters or eugenol. Use of electrolytic transdermal patches also falls within the scope of the methods described herein. Electrolytic transdermal patches are described in US Pat. Nos. 5,474,527, 5,336,168 and 5,328,454.
    [55] In another embodiment, transmucosal patches can be used to administer the compounds according to the invention. Examples of such patches are described in US Pat. No. 5,122,127. The patch according to the invention comprises a housing capable of encapsulating an appropriate amount of therapeutic agent, the housing being able to adhere to mucosal tissue, for example the oral cavity. The drug surface area of the instrument is present for contact with the mucosal tissue of the host. The device is designed to deliver the drug in proportion to the size of the drug / mucosa interface. Thus, drug delivery rates can be controlled by changing the size of the contact area.
    [56] The housing is preferably constructed of a material which is nontoxic, chemically stable and nonreactive with the compound according to the invention. Possible construction materials include polyethylene, polyolefins, polyamides, polycarbonates, vinyl polymers and other similar materials known in the art. The housing may contain means for holding the housing opposite the mucosa. The housing may contain a steady state reservoir located in contact with the mucosal tissue in the liquid phase.
    [57] Steady state reservoirs for use with the compounds described herein deliver a suitable dose of the compound over a predetermined time. Compositions that can be absorbed through mucosal tissue and methods for their preparation are described in US Pat. No. 5,288,497. One skilled in the art can readily include the compounds according to the invention and related compositions.
    [58] Steady state reservoirs for use with the compounds according to the invention consist of compounds known in the art for controlling the rate of drug release. In one embodiment, the transmucosal patch delivers a dose of a ROS inhibiting or eliminating compound over about 2 to 60 minutes. The steady state reservoir contained within the housing has a dose of histamine and other ROS production and release inhibiting or eliminating compounds at a dose of about 0.2-100 mg per patch. Also contemplated are transdermal patches that can be extinguished for several days and release the compound according to the invention over several days. The reservoir may also contain a penetration enhancer as described above to enhance the permeability of the compound according to the invention along the mucosal tissue.
    [59] Another method of controlling the release of a compound according to the invention is to incorporate a ROS inhibiting or eliminating compound into particles of a polymeric material such as polyester, polyamino acid, hydrogel, polylactic acid or ethylene vinyl acetate copolymer.
    [60] Alternatively, instead of incorporating ROS inhibition or elimination compounds into these polymer particles, the compounds according to the invention can be prepared, for example, by coacervation techniques (e.g. hydroxymethylcellulose) or by interfacial polymerization (e.g. gelatin- In microcapsules prepared by microcapsules) or in colloidal drug delivery systems (eg liposomes, albumin microspares, microemulsions, nanoparticles and nanocapsules) or in macroemulsions. Such techniques are well known to those skilled in the pharmaceutical arts.
    [61] Preferably, the compound that inhibits or eliminates ROS is injected, infused or released into the patient at a rate of about 0.025 to 1.0 mg / min. A rate of about 0.1 mg / min is preferred. The compounds according to the invention are preferably administered over a time period of from about 1, 3 or 5 minutes to about 30 minutes, with an upper limit of about 20 minutes being preferred. As a result, the total daily adult dose of the ROS inhibiting or eliminating compound is about 0.4 to about 100.0 mg, with about 0.5 to about 20.0 mg being preferred. Compounds of the invention such as histamine administered over longer periods of time, for example over about 30 minutes, have been found to result in decreased or lost efficacy, while rapid administration over less than 1-3 minutes May cause more pronounced and severe side effects, including irritability, heart failure, bronchial spasms, severe hot flashes, discomfort, increased heart rate and respiratory rate, high blood pressure and severe headaches.
    [62] In another embodiment, from about 0.2 to 2.0 mg or 3-200 μg / kg of the ROS inhibitory compound may be administered in a pharmaceutically acceptable form. ROS elimination compounds may also be administered in admixture with the ROS generation and release inhibitory compounds described above. When the ROS inhibiting or eliminating compound is administered orally, the composition may be formulated as a tablet containing 10 mg to 2 grams of active ingredient. Tablets may comprise 10, 20, 50, 100, 200, 500, 1,000 or 2,000 milligrams of ROS inhibiting or eliminating compounds. Preferably, the amount of ROS inhibiting or eliminating compound in one tablet is 100 mg. In some embodiments, the composition comprises histamine protecting agents such as diamine oxidase inhibitors, monoamine oxidase inhibitors and n-methyl transferases.
    [63] Treatment may also be performed in a period of 1 to 2 weeks with 0.2 to 2.0 mg or 3-200 μg / kg of the compound of the present invention to establish blood levels of the ROS inhibiting or eliminating compound at a concentration desirable to ensure that ROS production and release is inhibited. Periodically injecting or injecting at regular intervals (eg, daily, every other day or weekly) over a period of time to promote the patient's blood ROS inhibition or elimination compound levels. Treatment continues until the cause of the patient's underlying disease condition is controlled or eliminated.
    [64] Each dose of a ROS inhibiting or eliminating compound may be administered from once to about four times a day, preferably twice a day. Administration can be subcutaneous, intravenous, intramuscular, intraocular, oral, transdermal, intranasal or rectal and can be controlled using direct subcutaneous or other injection or infusion means or by a controlled release mechanism of the type described above. Any controlled release vehicle or infusion device may be used in which a therapeutically effective amount of a compound according to the invention may be administered over a time period of from about 1 to about 90 minutes. In a preferred embodiment, intranasal delivery is achieved by producing a lead-free introduction into the nasal cavity using a solution of the ROS inhibiting or eliminating compound in a nozzle or nebulizer. For rectal delivery, ROS inhibiting or eliminating compounds are formulated into suppositories using methods well known in the art.
    [65] The compound that eliminates ROS can be administered in an amount of about 0.1 to about 20 mg / day. Preferred amounts are from about 0.5 to about 8 mg / day. More preferred amounts are about 0.5 to about 8 mg / day. Even more preferred amounts are from about 1 to about 5 mg / day. Nevertheless, in each case, the dose depends on the activity of the compound administered. The dose is appropriate for the enzymes described above including catalase, peroxide dismutase (SOD), glutathione peroxidase and ascorbate peroxidase. Appropriate doses for any particular host can be readily determined by empirical techniques well known to those skilled in the art.
    [66] Non-enzymatic ROS eliminators can be administered in amounts empirically determined by one skilled in the art. For example, vitamins A and E may be administered at a dose of about 1 to 5000 IU per day. Vitamin C may be administered at a dose of about 1 μg to 10 mg per day. Minerals such as selenium and manganese may be administered in an amount of about 1 picogram to 1 milligram per day. These compounds can also be administered as protective or prophylactic treatment of ROS mediated disease states.
    [67] In addition to histamine, histamine dihydrochloride, histamine phosphate, other histamine salts, esters, prodrugs and H 2 receptor agonists, compounds that induce release of histamine from serotonin, 5HT agonists and patients' own tissues also are in accordance with the present invention. Included in the method. Retinic acid, other retinoids (eg, 9-cis-retinic acid and all-trans-retinic acid), IL-3, and ingestible allergens are compounds known to induce release of endogenous histamine. These compounds can be administered to the patient by oral, intravenous, intramuscular, subcutaneous and other recognized routes. The rate of administration should release endogenous histamine such that the blood level of histamine is about 20 nmol / dl.
    [68] Each dose of a compound that induces histamine release may be administered once to four times daily, preferably two times daily. Administration can be subcutaneous, intravenous, intramuscular, intraocular, oral or transdermal and may include a controlled release mechanism of the type described above. Any controlled release vehicle capable of administering a therapeutically effective amount of a compound that induces histamine release over a period of about 1 to about 30 minutes can be used. In addition, the compounds, compositions and formulations of the invention may be administered in a sufficient amount.
    [69] The following examples teach several methods for treating liver disease with the compounds inhibiting ROS production and release according to the present invention. These embodiments are merely illustrative and are not intended to limit the claims. The following treatment methods can be optimized using empirical techniques well known to those skilled in the art. In addition, those skilled in the art will be able to practice the claims using the teachings described in the Examples below. Although the examples suggest that ROS inhibitory compounds or eliminators may be administered in a single dose, it is obvious that the compounds can be dispensed over longer periods of time. In addition, the daily dose may be administered in one dose or divided into several doses.
    [70] Example 1
    [71] Analysis of the Effect of Histamine Dihydrochloride on the Protection of Early Alcohol-Induced Liver Injury in the Rat Model
    [72] Liver diseases that induce hepatitis or inflammation of the liver can be caused by a number of factors, including infectious bacteria and toxins. The two most common factors are viral infections and chronic alcohol abuse, and in both cases the disease exhibits similar symptoms. The data below strongly supports the hypothesis that free radicals generated from NADPH oxidase in hepatic Kupffer cells and infiltrated lymphocytes play a leading role in the pathogenesis of early alcohol-induced hepatitis. In this study, we studied the effects of histamine treatment on early alcohol-induced liver injury in a rat model.
    [73] Animals and treatment. Female Wistar rats weighing between 200 and 275 grams provide 35% of calories, 23% protein, 5% vitamins, 11% maltose-dextrin and 36% ethanol for corn oil. Feed (Dyets, Bethlehem, PA # 710034) was fed randomly and continuously for 4 weeks. Isocal maltose-dextrin feed (Dyets, # 710270) was used as a control. Every 24 hours, 18-gauge oral biomedical devices (Popper & Sons, Inc., New Hyde Park, NY) diluted in PBS (pH 7.2; GIBCO Laboratories Life Technologies Inc., Grand Island, NY) A single dose (5 g / kg body weight into the gastrointestinal tract) was administered to the rat. Control animals received only PBS. Histamine dihydrochloride (0.5 mg / kg or 5.0 mg / kg; Sigma Chemical Co., St. Louis, MO) or vehicle (PBS, pH 7.4; Sigma Chemical Co., St. Louis, MO) Administration was by subcutaneous injection once. Each rat was weighed daily. The rats were reared in a pathogen-free facility and the experimental animal control committee approved the surgical procedure used in this study.
    [74] Blood collection and enzymatic assays. After 2 and 4 weeks of ethanol treatment, autopsies were collected by cardiac puncture and centrifuged. Serum was stored at −20 ° C. until assayed for alanine aminotransferase (ALT) and aspartate aminotransferase (AST) by Sigma Chemical Co., St. Louis, Mo.
    [75] Pathological evaluation. After 2 and 4 weeks of ethanol treatment, the liver was treated with formalin, fixed in paraffin and stained with hematoxylin and eosin to assess liposis, inflammation and necrosis. Pathology of the liver was blinded by an external expert and scored as follows:
    [76] 1. Degree of steatosis, score 0-4 (% of hepatocytes containing lipids)
    [77] 0 none
    [78] 1 min (0-24%)
    [79] 2 slightly (25-49%)
    [80] 3 medium (50-74%)
    [81] 4 severe (> = 75%)
    [82] 2. Degree of Inflammatory Cell Infiltration, Score 0-4
    [83] 0 none, 1 min, 2 slightly, 3 medium, 4 severe
    [84] 3. Degree of degeneration and necrosis, score 0-4
    [85] 0 none
    [86] 1 Hepatocellular Degeneration Without Necrosis
    [87] 2 minimal to slight hepatocellular necrosis (with or without degeneration)
    [88] 3 intermediate hepatocyte necrosis (with or without degeneration)
    [89] 4 severe necrosis (with or without regression)
    [90] The score for each grade of organizational assessment was reflected in the overall score of each liver.
    [91] The results of this study on the effect of histamine dihydrochloride on protection against early alcohol-induced liver damage in a rat model are summarized in Table 1 below.
    [92] Table 1: Liver tissue findings. Average group severe score
    [93] Total scoreControlethanolLow histamineHigh histamine 2nd week2.672.333.332.00 4th week2.633.863.172.57
    [94] The severe scores of each survey for each group were summed and divided by the number of animals evaluated per group. Scores given to groups are as follows: none = 0; Minimum = 3; Slightly = 6; medium = 9; Severe = 12. This method demonstrates the propensity between groups. Untreated rats scored 1.00 on normal diet.
    [95] Animals fed a high fat liquid diet and ethanol developed into typical liver tissue of alcoholic liver injury, including increased numbers of adiposity, inflammation, necrosis and infiltrating leukocytes, mainly neutrophils and monocytes. The levels of alanine and aspartate transaminase (ALT / AST) in serum increased about 2 to 4 fold in ethanol treated animals.
    [96] Animals administered twice daily by subcutaneous injection of histamine (0.5 mg / kg or 5 mg / kg) slowed liver damage in a dose dependent manner and were the most effective at the highest dose. This was assessed by pathology scores and standardization of transaminase levels in serum. In addition, livers dissected from histamine treated animals were compared with livers dissected from non-ethanol treated groups. The livers of ethanol treated animals were overall faint and showed more pronounced lobules pattern.
    [97] Histamine treated animals showed normal liver appearance and were more resistant to ethanol administration. Initially, all animals receiving ethanol lost weight compared to animals fed control diets. However, both histamine treated groups recovered body weight faster than ethanol only treated groups. In addition, these groups showed similar body weights to the non-ethanol treated controls at the end of this study.
    [98] Preliminary results demonstrated a propensity for some normal ALT activity in the control and histamine treated groups, and the ethanol control showed a 2-3-fold increase in ALT activity. These results show that histamine significantly reduces liver damage caused by chronic ethanol administration under high fat diet. In addition, the results of this study suggest that histamine and histamine receptor agonists protect early alcohol-induced liver damage in rats.
    [99] Example 2
    [100] In vitro study of liver NK cell and T cell activity
    [101] This example demonstrates the effect of histamine on lymphocytes isolated from human liver. Three types of human lymphocytes, CD3 + T-cells, CD3- / 56 + NK-cells and CD3 + / 56 + NK / T-cells, were investigated for the role involved in oxidatively induced cell death in vitro. All three cell types died after incubation with autologous mononuclear cells (MO) or granulocytes (GR) or after treatment with hydrogen peroxide, the active species of oxygen. Thus, at a lymphocyte to MO ratio of 1: 1, 35 ± 5% of T-cells, 55 ± 5% of NK-cells and 76 ± 7% of NK / T-cells apoptized. At a lymphocyte to GR ratio of 1: 1, the corresponding frequencies of apoptosis were 21 ± 4% (T-cells), 30 ± 7% (NK-cells) and 66 ± 8% (NK / T-cells). All data are mean ± standard deviation (n = 15-30 donors). Apoptosis in all cell types was significantly prevented by histamine (p <0.001). Higher sensitivity to oxidatively induced apoptosis in NK / T cells and NK-cells was demonstrated in experiments in which apoptosis was induced by exogenous hydrogen peroxide: 35 ± 5 of T-cells at 25 μM hydrogen peroxide. %, 65 ± 7% of NK-cells and 78 ± 7% of NK / T-cells (n = 8) apoptosis. We conclude that liver-type lymphocytes, particularly NK / T-cells, are specifically sensitive to oxidative stress. Thus, antioxidants such as histamine may be more effective against liver neoplasms or chronic infections as a result of higher sensitivity to oxidatively induced apoptosis in liver-infiltrating lymphocytes.
    [102] Example 3
    [103] Simultaneous administration of histamine and hepatotoxic drugs as a single agent
    [104] Drug-induced liver disease is represented by significant challenges for physicians, the pharmaceutical industry and regulatory bodies. Hepatotoxicity of drugs is the only first cause of acute liver abnormalities, according to research from major medical centers in the United States (Kaplowitz, N., Hepatology 33 (1): 308-310 (2001)).
    [105] Most of the adverse drug accidents are acute and manifest as cytotoxic-hepatitis-like disease or bile disease. Other responses to hepatotoxic drugs include chronic hepatitis, reflux cholangiopathy, fatty liver, nonalcoholic steatohepatitis, fibrosis, cirrhosis, granulomatous disease, venous obstruction, hepatic purpura and benign and malignant neoplasms. Liver damage can occur due to the dose of drug consumed, pronounced hypersensitivity or metabolic specific reactions.
    [106] Without being limited to a particular theory, it is believed that trauma to liver cells in response to damage by hepatotoxic drugs can be caused or worsened by ROS. As discussed above, ROS may exhibit a direct effect on several cells in the hepatic milk tissue that induce apoptosis. Another possible mechanism by which these molecules can damage hepatocytes and tissues may be related to the effect of ROS on activated cells of the immune system. ROS generation and release inhibitory compounds reduce and / or prevent ROS mediated damage of liver cells and tissues caused by exposure to hepatotoxic drugs.
    [107] Pneumonia patients are prescribed oral tablets containing isoniazid and an effective amount of histamine for a period of 6 to 12 months. During the treatment period, the doctor monitors the patient and performs laboratory tests to check the liver condition of the patient in response to the prescription. The results show that patients who take a compound containing isoniazid and an effective amount of histamine have no liver damage compared to patients taking only isoniazid, and patients taking only isoniazid can have severe, and sometimes fatal, liver damage.
    [108] Example 4
    [109] Coadministration of Histamine Dihydrochloride and Hepatotoxic Drugs
    [110] To prevent seizures, hepatic patients who take phenytoin three times a day are supplemented with 10 mg of histamine dihydrochloride in a daily oral dose. Prior to supplementing histamine dihydrochloride, the liver disease patient experiences liver damage as a result of taking phenytoin as verified by liver necropsy. After supplementation with histamine dihydrochloride, further damage to liver tissue is prevented.
    [111] Example 5
    [112] Herbal formulations including ROS removers
    [113] Herbal therapies, vitamins and herbal supplements have been in the limelight over the past decade. Comfrey has been used successfully for centuries to promote wound healing and bone health. Comfrey has also been used as a powerful treatment for coughs, colds, intestinal and stomach ulcers.
    [114] Comfrey as a common herb can be administered as a pape or drink as an expectorant, analgesic and / or tonic. However, the consumption of comfrey has been associated with liver damage. In order to minimize the hepatotoxic effects of Comfrey, 8 mg / day of catalase is supplemented to those using Comrade Jazz as herbal remedies. No liver damage is observed.
    [115] Example 6
    [116] Prevention of secondary liver tissue damage caused by pancreatitis
    [117] The present invention contemplates the treatment of pancreatitis and other inflammatory diseases in addition to hepatitis. Inflammation caused by TNF-α and interleukin as part of an individual's immune response can also damage tissue. Histamine and histamine-associated compounds block these anti-inflammatory cytokines, thereby alleviating some of the damage to cells caused by inflammation. See US Pat. No. 6,242,473 and US Patent Application Serial No. 09 / 139,281 for a detailed discussion of the role of histamine and histamine-associated compounds in mitigating tissue damage caused by anti-inflammatory cytokines.
    [118] Determine patients with acute pancreatitis. Patients receive 100 μg / kg of histamine diphosphate per day over a period of 1 to 2 weeks. When the pancreatitis is cured, the liver is autopsied. Administration of histamine diphosphate prevents damage to liver tissue and reduces the incidence of infections associated with pancreatitis.
    [119] Example 7
    [120] Treatment of bacterial infections of the liver
    [121] Patients with bacterial infections caused by Helicobacter spp. Are identified. Patients receive an effective amount of histamine prodrug with antibiotics. The duration of infection is reduced and the trauma of hepatocytes is minimized.
    [122] The foregoing description illustrates certain aspects of the invention. However, although the present invention has been described in detail above, the present invention can be implemented in many ways. Also, as noted above, the use of certain terms in describing particular features or aspects of the invention is not intended to imply a limitation on the terminology as including any specific features or aspects of the invention related thereto. Accordingly, the scope of the invention should be construed in accordance with the appended claims and their equivalents.
    权利要求:
    Claims (43)
    [1" claim-type="Currently amended] Use of a composition containing a compound effective for reducing the amount of reactive oxygen species (ROS) in an individual for use in the manufacture of a medicament for the treatment of ROS-mediated oxidative damage to liver cells and tissues.
    [2" claim-type="Currently amended] The use according to claim 1, wherein said compound is selected from the group consisting of compounds, ROS removers and mixtures thereof which are effective for inhibiting the production or release of enzymatically produced ROS.
    [3" claim-type="Currently amended] 3. Use according to claim 2, wherein the ROS are constitutively released.
    [4" claim-type="Currently amended] The method of claim 1, wherein the injury is portal hypertension, allyl syndrome, alpha-1-antitrypsin deficiency, autoimmune hepatitis, cholangiodysplasia, chronic hepatitis, liver cancer, cancer metastasis to the liver, cirrhosis, hepatic cholestasis, Hepatic vein thrombosis, hepatic vein occlusion disease, hepatic lens degeneration, hepatomegaly, hepatic pulmonary syndrome, hepatic syndrome, hepatic cyst, hepatic abscess, fatty liver, galactosemia, gilbert syndrome, portal hypertension, alcoholic liver disease (ALD), parasite Sexual liver disease, hepatic purpura, erythrocyte porphyria, hepatic porphyria, hepatic pneumonia, primary biliary cirrhosis, primary sclerosing cholangitis, Laie's syndrome, sarcoidosis, hypertyrosinemia, hepatitis I disease, Wilson's disease, neonatal hepatitis, non-alcoholic Use associated with liver disease selected from the group consisting of sex steatitis, hemochromatosis and Zellweger syndrome.
    [5" claim-type="Currently amended] The use according to claim 2, wherein the compound effective to inhibit the production or release of enzymatically produced ROS is selected from the group consisting of histamine, histamine receptor agonists, NADPH oxidase inhibitors, serotonin and serotonin agonists.
    [6" claim-type="Currently amended] 3. The method of claim 2 wherein the remover is selected from the group consisting of catalase, glutathione peroxidase, ascorbate peroxidase, peroxide dismutase, glutathione peroxidase, ascorbate peroxidase, vitamin A, vitamin E and vitamin C. Intended use.
    [7" claim-type="Currently amended] The use of claim 1, wherein the injury is associated with a liver disease selected from the group consisting of bacterial infections, fungal infections and protozoan infections.
    [8" claim-type="Currently amended] 8. Use according to claim 7, wherein said composition further contains antibiotics.
    [9" claim-type="Currently amended] The use of claim 8, wherein the antibiotic is administered substantially simultaneously with said compound effective to inhibit the production or release of enzymatically produced ROS.
    [10" claim-type="Currently amended] The use of claim 8, wherein the antibiotic is administered within 24 hours of the compound effective to inhibit the production or release of enzymatically produced ROS.
    [11" claim-type="Currently amended] Use of a composition containing a compound effective for reducing the amount of reactive oxygen species (ROS) in an individual for use in the manufacture of a medicament for the treatment of a patient suffering from a liver disease.
    [12" claim-type="Currently amended] 12. The method of claim 11, wherein the injury is portal hypertension, allyl syndrome, alpha-1-antitrypsin deficiency, autoimmune hepatitis, cholangiodysplasia, chronic hepatitis, liver cancer, cancer metastasis to the liver, cirrhosis, hepatic cholestasis, Hepatic vein thrombosis, hepatic vein occlusion disease, hepatic lens degeneration, hepatomegaly, hepatic pulmonary syndrome, hepatic syndrome, hepatic cyst, hepatic abscess, fatty liver, galactosemia, gilbert syndrome, portal hypertension, alcoholic liver disease (ALD), parasite Sexual liver disease, hepatic purpura, erythrocyte porphyria, hepatic porphyria, hepatic pneumonia, primary biliary cirrhosis, primary sclerosing cholangitis, Laie's syndrome, sarcoidosis, hypertyrosinemia, hepatitis I disease, Wilson's disease, neonatal hepatitis, non-alcoholic Use associated with liver disease selected from the group consisting of sex steatitis, hemochromatosis and Zellweger syndrome.
    [13" claim-type="Currently amended] The compound of claim 11, wherein said compound effective for reducing the amount of reactive oxygen species (ROS) in an individual is selected from the group consisting of compounds effective for inhibiting the production or release of enzymatically produced ROS, ROS removers, and mixtures thereof. Intended use.
    [14" claim-type="Currently amended] Use according to claim 13, wherein the compound effective for inhibiting the production or release of ROS is selected from the group consisting of histamine, histamine receptor agonists, NADPH oxidase inhibitors, serotonin and serotonin agonists.
    [15" claim-type="Currently amended] The use according to claim 13, wherein said scavenger is selected from the group consisting of catalase, peroxide dismutase, glutathione peroxidase and ascorbate peroxidase.
    [16" claim-type="Currently amended] A composition containing a compound and a hepatotoxic drug effective for reducing the amount of ROS in an individual.
    [17" claim-type="Currently amended] 17. The method according to claim 16, wherein the hepatotoxic drugs are azathioprine, methyldopa, nitrofuratoin, clofibrate, troglitazone, ibuprofen, allopurinol, indomethacin, leflunomide, acetaminophen, diclofenac, isonia Zaid, tetracycline, erythromycin, nitrofuratoin, amoxicillin, rifampin, ketoconazole, flucloxacillin, trobafloxacin, sulfonamide, estradiol, iron, glutathione, halotane, isoflurane, captopril, Diltiazem, phenytoin, valproic acid, cambamazepine, phenobarbitone, primidone, trazodone, chlorpromazine, quinidine, procainamide, amiodarone, methotrexate, cyclophosphamide, corticosteroids, assimilation steroids, Glucocorticoids, pyrazineamides, para-aminosalicylic acid, ethionamides, trimetaprim-sulfamethoxazole, pentamidine, zidobudine, A composition selected from the group consisting of dideoxyinosine, penicillin and cephalosporin.
    [18" claim-type="Currently amended] 17. The method according to claim 16, wherein the hepatotoxic drugs are Larrea tridentata , Teucrium chamaedrys , jin bu huan, Valeriana officinalis , Scutellaria galericulata , Mistletoe ( Viscum spp.), Jamaica shrub tea , Senna ( Cassia angustfolia ), Narcissus ( Symphytum officinale ) and Caba root extract.
    [19" claim-type="Currently amended] The composition of claim 16, wherein said compound is selected from the group consisting of compounds, ROS scavengers, and mixtures thereof that are effective for inhibiting the production or release of reactive oxygen species.
    [20" claim-type="Currently amended] 20. The composition of claim 19, wherein said compound effective to inhibit the production or release of ROS is selected from the group consisting of histamine, histamine receptor agonists, NADPH oxidase inhibitors, serotonin and serotonin agonists.
    [21" claim-type="Currently amended] 20. The composition of claim 19, wherein said ROS remover is selected from the group consisting of catalase, peroxide dismutase, glutathione peroxidase, and ascorbate peroxidase.
    [22" claim-type="Currently amended] Use of a composition containing a compound effective for reducing the amount of reactive oxygen species (ROS) for an individual for use in the manufacture of a drug for reducing the hepatotoxicity of the drug.
    [23" claim-type="Currently amended] 23. The use according to claim 22, wherein said compound is selected from the group consisting of compounds, ROS removers and mixtures thereof which are effective for inhibiting the production or release of enzymatically produced ROS.
    [24" claim-type="Currently amended] 24. The use according to claim 23, wherein said compound effective to inhibit the production or release of enzymatically produced ROS is selected from the group consisting of histamine, histamine receptor agonists, NADPH oxidase inhibitors, serotonin and serotonin agonists.
    [25" claim-type="Currently amended] The method of claim 23, wherein the remover is selected from the group consisting of catalase, glutathione peroxidase, ascorbate peroxidase, peroxide dismutase, glutathione peroxidase, ascorbate peroxidase, vitamin A, vitamin E and vitamin C. Intended use.
    [26" claim-type="Currently amended] 23. The use of claim 22, wherein the hepatotoxic drug is selected from the group consisting of azathioprine, methyldopa, nitrofuratoin, clofibrate, and troglyzazone.
    [27" claim-type="Currently amended] 23. The use of claim 22, wherein the hepatotoxic drug is an antiarthritis drug selected from the group consisting of ibuprofen, allopurinol, indomethacin, leflunomide, acetaminophen and diclofenac.
    [28" claim-type="Currently amended] 23. The antibiotic according to claim 22, wherein the hepatotoxic drug is selected from the group consisting of isoniazid, tetracycline, erythromycin, nitrofuratoin, amoxicillin, rifampin, ketoconazole, flucloxacillin, trobafloxacin and sulfonamide Use as a substance.
    [29" claim-type="Currently amended] 23. The use of claim 22, wherein the hepatotoxic drug is selected from the group consisting of estradiol, iron and glutathione.
    [30" claim-type="Currently amended] The use according to claim 22, wherein the hepatotoxic drug is selected from the group consisting of halotane and isoflurane.
    [31" claim-type="Currently amended] 23. The method of claim 22, wherein the hepatotoxic drug is captopril, diltiazem, phenytoin, valproic acid, cambamazepine, phenobarbitone, primidone, trazodone, chlorpromazine, quinidine, procainamide and amiodarone. Use selected from the group consisting of.
    [32" claim-type="Currently amended] Use according to claim 22, wherein the hepatotoxic drug is a chemotherapeutic agent.
    [33" claim-type="Currently amended] 23. The use according to claim 22, wherein said hepatotoxic drug is selected from the group consisting of corticosteroids, anabolic steroids and glucocorticoids.
    [34" claim-type="Currently amended] The use of claim 22, wherein the hepatotoxic drug is used to treat HIV / AIDS patients.
    [35" claim-type="Currently amended] 35. The method according to claim 34, wherein the hepatotoxic drug is selected from the group consisting of pyrazineamide, para-aminosalicylic acid, ethionamide, trimetaprim-sulfamethoxazole, pentamidine, zidobudine, dideoxyinosine, penicillin and cephalosporin. Usage.
    [36" claim-type="Currently amended] 23. The method of claim 22, wherein the hepatotoxic drugs are Larrea tridentata , Teucrium chamaedrys , jin bu huan, Valeriana officinalis , Scutellaria galericulata , Mistletoe ( Viscum species), Jamaican shrub tea , Cassia angustfolia , Symphytum officinale and Caba root extract.
    [37" claim-type="Currently amended] Use of a composition containing a compound effective to reduce the amount of reactive oxygen species (ROS) in an individual for use in the manufacture of a medicament for reducing liver tissue damage associated with exposure to environmental or industrial toxicity.
    [38" claim-type="Currently amended] 38. The use according to claim 37, wherein said compound is selected from the group consisting of compounds, ROS removers and mixtures thereof which are effective for inhibiting the production or release of enzymatically produced ROS.
    [39" claim-type="Currently amended] The use according to claim 38, wherein said compound effective to inhibit the production or release of enzymatically produced ROS is selected from the group consisting of histamine, histamine receptor agonists, NADPH oxidase inhibitors, serotonin and serotonin agonists.
    [40" claim-type="Currently amended] The method of claim 38, wherein the remover is selected from the group consisting of catalase, glutathione peroxidase, ascorbate peroxidase, peroxide dismutase, glutathione peroxidase, ascorbate peroxidase, vitamin A, vitamin E and vitamin C. Intended use.
    [41" claim-type="Currently amended] 38. The use of claim 37, wherein said toxin is a genus of poisonous mushrooms selected from the group consisting of Amanita , Galerina and Gyromitra .
    [42" claim-type="Currently amended] 38. The use of claim 37, wherein the toxin is selected from the group consisting of tobacco smoke, diethanolamine, sodium laurel sulfate, propylene glycol, pesticides, food additives, food preservatives, heavy metals, formaldehyde, bromobenzene and chlorinated solvents. .
    [43" claim-type="Currently amended] 43. The use of claim 42, wherein the chlorinated solvent is selected from the group consisting of dioxin, pullulan, TCE, PCE, DCE, tetrachloroethylene, carbon tetrachloride and vinyl chloride.
    类似技术:
    公开号 | 公开日 | 专利标题
    EP1124551B1|2008-04-09|Delta 9tetrahydrocannabinol | solution metered dose inhalers and methods of use
    Bender et al.1996|Efficiency of nanoparticles as a carrier system for antiviral agents in human immunodeficiency virus-infected human monocytes/macrophages in vitro.
    US6793942B2|2004-09-21|Composition and method for treating the effects of diseases and maladies
    US6350467B1|2002-02-26|Pharmaceutical preparations of glutathione and methods of administration thereof
    US5457130A|1995-10-10|Eicosapentaenoic acid used to treat cachexia
    DE69927125T2|2006-05-18|Composition against increase or decrease of blood sugar level
    CN101287457B|2011-11-16|Use of treprostinil to treat neuropathic diabetic foot ulcers
    Nakajima et al.2001|Normalization of retinal vascular permeability in experimental diabetes with genistein
    Lai et al.1995|Selective cancer cell cytotoxicity from exposure to dihydroartemisinin and holotransferrin
    Santos et al.2004|1, 8-cineole |, a monoterpene oxide attenuates the colonic damage in rats on acute TNBS-colitis
    RU2421209C2|2011-06-20|Pharmaceutical compositions containing cyclosporine
    US6827932B2|2004-12-07|Activated charcoal based composition and method for reducing hangover symptoms associated with the consumption of alcohol containing beverages
    US20160166533A1|2016-06-16|Synergistic compositions and methods for potentiating anti-oxidative activity
    Wolfensberger1999|The role of carbonic anhydrase inhibitors in the management of macular edema
    Kazazis et al.2014|The therapeutic potential of milk thistle in diabetes
    RU2498795C2|2013-11-20|Method of treating non-alcoholic steatohepatitis | with using cysteamine products
    US7270838B2|2007-09-18|Composition for treating chronic venous insufficiencies using an extract of red vine leaves
    US20050222046A1|2005-10-06|Pharmaceutical preparations of glutathione and methods of administration thereof
    EP1643999B1|2011-09-28|Pyridoxamine for use in the treatment of diabetic neprhopathy in type ii diabetes
    US20080102137A1|2008-05-01|Composition and method for etiological treatment and prevention of diseases and/or complications associated with chronic glucose metabolism destabilization
    Bonkovsky1997|Therapy of hepatitis C: other options
    KR100877600B1|2009-01-08|Pharmaceutical composition comprising metadoxine and garlic oil for preventing and treating alcohol-induced fatty liver and steatohepatitis
    JP5869469B2|2016-02-24|Treatment of liver diseases where iron is involved in the pathogenesis
    AU765625B2|2003-09-25|Activation and protection of T-cells | using an H2 receptor agonist and other T-cell activating agents
    US6576267B2|2003-06-10|Composition and method for treating the effects of diseases and maladies
    同族专利:
    公开号 | 公开日
    JP2005510501A|2005-04-21|
    EP1435984A1|2004-07-14|
    CN1571674A|2005-01-26|
    US20030091553A1|2003-05-15|
    CA2461661A1|2003-05-01|
    WO2003035095A1|2003-05-01|
    IL160928D0|2004-08-31|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    2001-10-19|Priority to US34362801P
    2001-10-19|Priority to US60/343,628
    2001-10-30|Priority to US34001101P
    2001-10-30|Priority to US60/340,011
    2002-10-11|Application filed by 맥심 파마수티컬즈 인크.
    2002-10-11|Priority to PCT/US2002/032675
    2004-07-03|Publication of KR20040058192A
    优先权:
    申请号 | 申请日 | 专利标题
    US34362801P| true| 2001-10-19|2001-10-19|
    US60/343,628|2001-10-19|
    US34001101P| true| 2001-10-30|2001-10-30|
    US60/340,011|2001-10-30|
    PCT/US2002/032675|WO2003035095A1|2001-10-19|2002-10-11|Use of histamine to treat liver disease|
    [返回顶部]