Patent Application: US-92167904-A

Abstract:
life - threatening hepatotoxicity in the setting of acetaminophen overdose is due to depletion of glutathione , a vital cysteine - containing tripeptide that protects cells and organs against oxidant injury . rapid administration of n - acetylcysteine , which provides the cysteine necessary to replenish the depleted gsh , is the standard of care for preventing injury in acetaminophen overdose . beneficial effects of nac treatment have also been demonstrated in respiratory , cardiovascular , endocrine and infectious and other diseases . in fact , over fifty randomized placebo - controlled trials conducted in diverse clinical settings document positive responses to nac treatment . the present invention relates to cysteine / glutathione deficiency as a previously unrecognized clinical entity that can complicate the course of commonly encountered diseases and methods of treatment of this generalized deficiency involving administering n - acetylcysteine or a pharmaceutically acceptable salt or derivative to a subject in need thereof and monitoring the subjects appropriate glutathione blood levels as needed .

Description:
the invention described herein provides a method of treatment to prevent development of gluathione deficiency as a consequence of disease , a treatment , or a condition comprising administering to a subject at risk of glutathione deficieny as a consequence of disease , a treatment or a condition a therapeutic amount of nac or a pharmaceutically acceptable salt or derivative sufficient to increase intracellular glutathione levels or decrease oxidative stress and measuring and monitoring the level of glutathione in blood in patients as needed . it further provides a method of treatment to restore glutathione levels comprising administering to subjects in need of glutathone level restoration , as determined by measurement or by a physician , a therapeutic amount of nac or a pharmaceutically acceptable salt or derivative thereof sufficient to increase intracellular glutathione levels or decrease oxidative stress and monitoring restoration by measuring the level of glutathione in blood as needed . it futher provides a method of treatment to decrease oxidized glutathione levels elevated as a consequence of disease , a treatment or a condition comprising administering to a subject suffering from oxidative stress a therapeutic amount of nac or a pharmaceutically acceptable salt or derivative sufficient to decrease oxidized glutathione levels elevated as a consequence of disease and monitoring the level of oxidized glutathione in blood as needed . the term “ pharmaceutical composition ” is used herein to denote a composition that may be administered to a mammalian host , e . g ., orally , topically , parenterally , by inhalation spray , or rectally , in unit dosage formulations containing conventional non - toxic carriers , diluents , adjuvants , vehicles and the like . the term “ parenteral ” as used herein , includes subcutaneous injections , intravenous , intramuscular , intracisternal injection , or by infusion techniques . the term “ therapeutically effective amount ” is used herein to denote that amount of a drug or pharmaceutical agent that will elicit the therapeutic response of an animal or human that is being sought . the pharmaceutical compositions containing nac may be in a form suitable for oral use , for example , as tablets , troches , lozenges , aqueous , or oily suspensions , dispersible powders or granules , emulsions , hard or soft capsules , or syrups or elixirs . compositions intended for oral use may be prepared according to any known method , and such compositions may contain one or more agents selected from the group consisting of sweetening agents , flavoring agents , coloring agents , and preserving agents in order to provide pharmaceutically elegant and palatable preparations . tablets may contain nac in admixture with non - toxic pharmaceutically - acceptable excipients which are suitable for the manufacture of tablets . these excipients may be for example , inert diluents , such as calcium carbonate , sodium carbonate , lactose , calcium phosphate or sodium phosphate ; granulating and disintegrating agents , for example corn starch or alginic acid ; binding agents , for example , starch , gelatin or acacia ; and lubricating agents , for example magnesium stearate , stearic acid or talc . the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period . for example , a time delay material such as glyceryl monostearate or glyceryl distearate may be employed . they may also be coated by the techniques described in u . s . pat . nos . 4 , 356 , 108 ; 4 , 166 , 452 ; and 4 , 265 , 874 , to form osmotic therapeutic tablets for controlled release . formulations for oral use may also be presented as hard gelatin capsules where nac is mixed with an inert solid diluent , for example , calcium carbonate , calcium phosphate or kaolin , or a soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium , for example peanut oil , liquid paraffin , or olive oil . aqueous suspensions may contain the active compounds in admixture with excipients suitable for the manufacture of aqueous suspensions . such excipients are suspending agents , for example sodium carboxymethylcellulose , methylcellulose , hydroxypropylmethylcellulose , sodium alginate , polyvinylpyrrolidone , gum tragacanth and gum acacia ; dispersing or wetting agents may be a naturally - occurring phosphatide such as lecithin , or condensation products of an alkylene oxide with fatty acids , for example polyoxyethylene stearate , or condensation products of ethylene oxide with long chain aliphatic alcohols , for example , heptadecaethyl - eneoxycetanol , or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate , or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides , for example polyethylene sorbitan monooleate . the aqueous suspensions may also contain one or more coloring agents , one or more flavoring agents , and one or more sweetening agents , such as sucrose or saccharin . oily suspensions may be formulated by suspending nac in a vegetable oil , for example arachis oil , olive oil , sesame oil or coconut oil , or in a mineral oil such as a liquid paraffin . the oily suspensions may contain a thickening agent , for example beeswax , hard paraffin or cetyl alchol . sweetening agents such as those set forth above , and flavoring agents may be added to provide a palatable oral preparation . these compositions may be preserved by the addition of an anti - oxidant such as ascorbic acid . dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide nac in admixture with a dispersing or wetting agent , suspending agent and one or more preservatives . suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above . additional excipients , for example , sweetening , flavoring , and coloring agents may also be present . the pharmaceutical compositions of the invention may also be in the form of oil - in - water emulsions . the oily phase may be a vegetable oil , for example , olive oil or arachis oil , or a mineral oil , for example a liquid paraffin , or a mixture thereof . suitable emulsifying agents may be naturally - occurring gums , for example gum acacia or gum tragacanth , naturally - occurring phosphatides , for example soy bean , lecithin , and esters or partial esters derived from fatty acids and hexitol anhydrides , for example sorbitan monooleate , and condensation products of said partial esters with ethylene oxide , for example polyoxyethylene sorbitan monooleate . the emulsions may also contain sweetening and flavoring agents . syrups and elixirs may be formulated with sweetening agents , for example glycerol , propylene glycol , sorbitol or sucrose . such formulations may also contain a demulcent , a preservative and flavoring and coloring agents . the pharmaceutical compositions may be in the form of a sterile injectible aqueous or oleaginous suspension . this suspension may be formulated according to the known methods using suitable dispersing or wetting agents and suspending agents described above . the sterile injectable preparation may also be a sterile injectable solution or suspension in a non - toxic parenterally - acceptable diluent or solvent , for example as a solution in 1 , 3 - butanediol . among the acceptable vehicles and solvents that may be employed are water , ringer &# 39 ; s solution , and isotonic sodium chloride solution . in addition , sterile , fixed oils are conveniently employed as solvent or suspending medium . for this purpose , any bland fixed oil may be employed using synthetic mono - or diglycerides . in addition , fatty acids such as oleic acid find use in the preparation of injectables . the compositions may also be in the form of suppositories for rectal administration of the compounds of the invention . these compositions can be prepared by mixing nac alone or in combination with a therapeutically effective amount of a therapeutic agent with a suitable non - irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will thus melt in the rectum to release the drug . such materials include cocoa butter and polyethylene glycols , for example . for topical use , creams , ointments , jellies , solutions of suspensions , etc ., containing the compounds of the invention are contemplated . for the purpose of this application , topical applications shall include mouth washes and gargles . the nac alone or in combination with a therapeutically effective amount of a therapeutic agent may also be administered in the form of liposome delivery systems , such as small unilamellar vesicles , large unilamellar vesicles , and multilamellar vesicles . liposomes may be formed from a variety of phospholipids , such as cholesterol , stearylamine , or phosphatidylcholines . pharmaceutically - acceptable salts of nac alone or in combination with a therapeutically effective amount of a therapeutic agent , where a basic or acidic group is present in the structure , are also included within the scope of the invention . the term “ pharmaceutically acceptable salts ” refers to non - toxic salts of nac alone or in combination with a therapeutically effective amount of a therapeutic agent , which are generally prepared by reacting the free base with a suitable organic or inorganic acid or by reacting the acid with a suitable organic or inorganic base . representative salts include the following salts : acetate , benzenesulfonate , benzoate , bicarbonate , bisulfate , bitartrate , borate , bromide , calcium edetate , camsylate , carbonate , chloride , clavulanate , citrate , dihydrochloride , edetate , edisylate , estolate , esylate , fumarate , gluceptate , gluconate , glutamate , glycollylarsanilate , hexylresorcinate , hydrabamine , hydrobromide , hydrocloride , hydroxynaphthoate , iodide , isethionate , lactate , lactobionate , laurate , malate , maleate , mandelate , methanesulfonate , methylbromide , methylnitrate , methylsulfate , monopotassium maleate , mucate , napsylate , nitrate , n - methylglucamine , oxalate , pamoate ( embonate ), palmitate , pantothenate , phosphate / diphosphate , polygalacturonate , potassium , salicylate , sodium , stearate , subacetate , succinate , tannate , tartrate , teoclate , tosylate , triethiodide , trimethylammonium and valerate . when an acidic substituent is present , such as - cooh , there can be formed the ammonium , morpholinium , sodium , potassium , barium , calcium salt , and the like , for use as the dosage form . when a basic group is present , such as amino or a basic heteroaryl radical , such as pyridyl , an acidic salt , such as hydrochloride , hydrobromide , phosphate , sulfate , trifluoroacetate , trichloroacetate , acetate , oxlate , maleate , pyruvate , malonate , succinate , citrate , tartarate , fumarate , mandelate , benzoate , cinnamate , methanesulfonate , ethanesulfonate , picrate and the like , and include acids related to the pharmaceutically - acceptable salts listed in the journal of pharmaceutical science , 66 , 2 ( i 977 ) p . 1 - 19 . other salts which are not pharmaceutically acceptable may be useful in the preparation of nac alone or in combination with a therapeutically effective amount of a therapeutic agent and these form a further aspect of the invention . thus , in another aspect of the present invention , there is provided a pharmaceutical composition comprising nac alone or in combination with a therapeutically effective amount of a therapeutic agent , or a pharmaceutically acceptable salt , solvate , or prodrug therof , and one or more pharmaceutically acceptable carriers , excipients , or diluents . in another aspect of the present invention , there is provided a pharmaceutical composition comprising a therapeutically effective amount of nac alone or in combination with a therapeutically effective amount of a therapeutic agent , or a pharmaceutically acceptable salt , solvate , or prodrug therof , and one or more pharmaceutically acceptable carriers , excipients , or diluents , wherein said therapeutically effective amount comprises a sufficient amount nac for at least partial amelioration of cysteine / glutathione deficiency in a disease or condition . in an embodiment of the pharmaceutical composition , the disease comprises chronic obstructive pulmonary disease ( copd ). in another embodiment of the pharmaceutical composition , the disease comprises acute renal failure . in another embodiment of the pharmaceutical composition , the disease comprises sickle cell anemia . in another embodiment of the pharmaceutical composition , the disease comprises comprises diabetes mellitus . in another embodiment of the pharmaceutical composition , the disease comprises inflammatory diseases . in another embodiment of the pharmaceutical composition , the disease comprises human immunodeficiency virus mediated disease . in another embodiment of the pharmaceutical composition , the disease comprises malaria . in another embodiment of the pharmaceutical composition , the disease comprises protein - energy malnutrition . in another embodiment of the pharmaceutical composition , the disease comprises otic disease . in another embodiment of the pharmaceutical composition , the disease comprises neurodegenerative disease . in another embodiment of the pharmaceutical composition , the disease comprises cardiovascular disease . in another aspect , the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of nac alone or in combination with a therapeutically effective amount of a therapeutic agent , and one or more pharmaceutically acceptable carriers , excipients , or diluents , wherein the pharmaceutical composition is used to replace or supplement compounds that restore cysteine / glutathione levels . in another aspect , the present invention provides a method for improvement of cysteine / glutathione deficiency in a disease or condition comprising administering to a subject in need thereof a nac alone or in combination with a therapeutically effective amount of a therapeutic agent , wherein nac alone or in combination with a therapeutically effective amount of a therapeutic agent is administered to the subject as a pharmaceutical composition comprising a therapeutically effective amount of nac and one or more pharmaceutically acceptable carriers , excipients , or diluents , wherein said therapeutically effective amount of nac comprises a sufficient amount of nac for treatment or prevention of cysteine - glutathione deficiency in the disease or condition . the term “ treatment ” as used herein , refers to the full spectrum of treatments for a given disorder from which the patient is suffering , including alleviation of one , most of all symptoms resulting from that disorder , to an outright cure for the particular disorder or prevention of the onset of the disorder . generally speaking , the amount of nac per dosage unit is preferably from 1 mg to 25000 mg , preferably at least 3 mg to 2000 mg per dosage unit for oral administration , and 20 - 20000 mg for parenteral administration . the unit dose of nac alone or in combination with a therapeutically effective amount of a therapeutic agent , will usually comprise at least about 1 . 5 mg / kg to a maximum amount of 70 mg / kg ( for pediatric doses ), usually at least about 500 mg ( for adult doses ), and usually not more than about 2000 mg at the physician &# 39 ; s discretion . patients on therapy known to deplete cysteine / glutathione or produce oxidative stress may benefit from higher amounts of nac . the amount of active ingredient that may be combined with the carrier materials to produce a single dosage will vary depending upon the host treated and the particular mode of administration . this dosage has to be individualized by the clinician based on the specific clinical condition of the subject being treated . thus , it will be understood that the specific dosage level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed , the age , body weight , general health , sex , diet , time of administration , route of administration , rate of excretion , drug combination and the severity of the particular disease undergoing therapy . while the invention has been described and illustrated with reference to certain preferred embodiments therof , those skilled in the art will appreciate that various changes , modifications and substitutions can be made therein without departing from the spirit and scope of the invention . for example , effective dosages other than the preferred dosages as set forth herein may be applicable as a consequence of variations in the responsiveness of the mammal being treated for cysteine / glutathione deficiency in a disease or condition . likewise , the specific pharmacological responses observed may vary according to and depending on the particular active compound selected or whether there are present pharmaceutical carriers , as well as the type of formulation and mode of administration employed , and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention . 1 . meister a , anderson m e : glutathione . annu rev biochem 1983 , 52 : 711 - 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controlled studies in which nac , or in some cases another gsh - replenishing drug , were administered . dosage shown is for nac unless otherwise indicated . the treatment effect is scored as “ beneficial ” when reported outcome ( s ) differs significantly from the placebo group ( p & lt ; 0 . 05 ) for a clinical parameter of importance to patient well - being in the disease under study . if a significant difference between the nac and placebo group was observed by the clinical relevance of the finding is unclear , the treatment effect is scored as “ significant (? clin rel )”. failure to find a significant difference is scored as “ not significant ” while significant negative effects of nac treatment are scored as “ adverse ”. table 1a hepatic and gi pathophysiology nac use in hepatic and gi study treatment pathophysiology n length dosage effect acetaminophen toxicity *. iv nac 50 21 days 150 mg / kg beneficial administration to subjects with for 15 min ; acetaminophen - induced fulminant 50 mg / kg hepatic failure who had not previously for 4 h ; received nac ( late presentation ) 100 mg / kg increased survival and decreased both over 16 h . the incidence of cerebral edema and the frequency of hypotension requiring inotropic support . rates of deterioration and recovery of liver function were not affected . keays , 1991 [ 2 ] hepatic transplant patients . nac 50 5 hours 150 mg / kg beneficial induces mild vasodilation , improves for 15 min ; oxygen delivery and consumption , and 12 . 5 mg / kg reduces base deficit . bromley for 4 h . 1995 [ 19 ] hepatitis c . treatment with nac in 147 1 year 1800 mg nac not addition to conventional therapy with daily with significant interferon --□ did not result in interferon -□ significant improvement of the treatment group . grant 2000 [ 265 ] colon cancer . nac lowered the 64 12 weeks 800 mg nac beneficial proliferative index in the colonic crypt daily , po epithelium of human volunteers who previously had adenomatous polyps . estensen , 1999 [ 55 ] nac safety . gastroduodenoscopic 20 7 days 200 mg 3 × safe ( no examination following oral nac daily effect ) administration disclosed no lesions . histological examination of biopsy specimens from the antrum and corpus of the stomach disclosed no pathological changes . marini , 1980 [ 62 ] hyperoxic ventilation . nac 38 72 hours 150 ml / kg iv beneficial preserved whole body oxygen uptake , over a period oxygen extraction ratio , and gastric of 15 min intramucosal ph during brief hyperoxic ventilation . reinhart , 1995 [ 266 ] gastric mucosa . the systemic effect 100 3 days 600 mg daily not of nac on gastric mucus was not prior to significant powerful enough to improve the treatment barium coating of the gastric mucosa . kinnunen , 1989 [ 267 ] helicobacter pylori . nac decreased 107 5 ml of 107 interferes the sensitivity and specificity of the 4 % nac with helicobacter pylori stool antigen test . tid for traditional demiturk , 2003 [ 268 ] 3 days clinical assay protein - energy malnutrition . 32 50 days 0 . 5 mmol per beneficial malnourished children admitted for kg per day treatment of infection were treated with nac or placebo ( alanine ). nac restored gsh synthesis rate and concentration when administered during the early phase of treatment badaloo , 2002 [ 54 ] * note : although nac is the accepted treatment for acetaminophen overdose , there do not appear to be any placebo - controlled trials that supported its initial acceptance . a series of studies that are not placebo - controlled , e . g ., smilkstein et al 127 , have served this purpose ( see the citations for acetaminophen under toxic agents in table 2 ).