CN101102816B - Compositions comprising ornithine and phenylacetate or phenylbutyrate for treating hepatic encephalopathy - Google Patents
Compositions comprising ornithine and phenylacetate or phenylbutyrate for treating hepatic encephalopathy Download PDFInfo
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- CN101102816B CN101102816B CN2005800469901A CN200580046990A CN101102816B CN 101102816 B CN101102816 B CN 101102816B CN 2005800469901 A CN2005800469901 A CN 2005800469901A CN 200580046990 A CN200580046990 A CN 200580046990A CN 101102816 B CN101102816 B CN 101102816B
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Abstract
The present invention relates to use of ornithine in the manufacture of a medicament for use in combination with at least one of phenylacetate and phenylbutyrate for preventing or treating liver decompensation or hepatic encephalopathy. The invention also relates to use of at least one of phenylacetate and phenylbutyrate in the manufacture of a medicament for use in combination with ornithine for preventing or treating liver decompensation or hepatic encephalopathy.
Description
Technical field
The present invention relates to liver is lost the prevention and the treatment of compensatory or hepatic encephalopathy.
Background technology
The feature of chronic hepatopathy is that hepatic tissue is destroyed in time gradually, thereby causes healthy slowly being substituted by scar tissue and slough with regenerated hepatic tissue.This phenomenon is considered to liver cirrhosis.The normal hepatocytes function suffers damage, and scar tissue reduces blood flow in the liver gradually.When normal regenerating hepatic tissue was lost, nutrient, hormone, medicine and toxin just obtained handling no longer validly.
This just may cause multiple symptom, comprising: the proteinic removing by intestinal absorption causes accumulating of ammonia unusually; Diacrisis causes blood mesobilirubin to be accumulated, and produces jaundice; Hole is pressed to raise and is caused abdominal fluid to accumulate (ascites); And portal hypertension (door body circulation shunting)---hepatic tissue that wherein forms cicatrix plays the effect of blood flow barrier---causes portal blood pressure to raise and esophageal varicosis.
Chronic hepatitis patients can have very stable clinical state, and shows symptom seldom or do not show symptom.Yet this class patient has the risk that disease worsens suddenly, and this deterioration can cause slow extra urgaent dispatch liver failure.This relevant to the transformation of " losing compensatory " state of liver unable to get up effect with the effect that inspires incident from can work " compensatory " state of (even if level decreases) of liver.The inspire incident relevant with chronic hepatopathy comprises gastrointestinal hemorrhage, infection (sepsis), portal thrombosis and dehydration.
For example, 50% liver cirrhosis patient suffers from esophageal varicosis, wherein esophageal varicosis can take place suddenly what make a definite diagnosis in 1/3rd patient in two years, and causes gastrointestinal hemorrhage (Grace ND (1992) Gastroenterol Clin North Am21:149-161).Known upper gastrointestinal hemorrhage can increase the sensitivity to life-threatening complication, and described complication is bacterial peritonitis, sepsis, renal failure and hepatic encephalopathy (Teran et al. (1997) Gastroenterology112:473-482 for example; Garden et al. (1985) Br J Surg72:91-95; Pauwels et al. (1996) Hepatology24:802-806; Bleichner et al. (1986) Br J Surg73:724-726), although carried out enough control, but still cause about 30% death (Grace1992, the same) thus to hemorrhage.
Hepatic encephalopathy (HE) is a kind of complicated neuropsychopathy disease that betides in for example acute or chronic hepatopathy of various clinical condition and the shunting of spontaneous door vena systemica.Change of spirit can take place slightly hepatic encephalopathy in early days, and for example thinking is not concentrated, confusion of consciousness and disorientation.Under serious situation, liver property brain also can cause numb, stupor, brain swelling (cerebral edema) and death.For the patient that HE takes place because of chronic hepatopathy, the morbidity of HE is normally by the clinical for example result that causes of gastrointestinal hemorrhage, sepsis (infection), portal thrombosis or dehydration of incident that inspires.
Gastrointestinal hemorrhage and the shunting of door body can make common toxicant by hepatic metabolism enter the body circulation through liver, and stride across blood brain barrier, the central nervous system is produced direct or indirect neurotoxic effect.Accumulating of ammonia is considered to have important effect in hepatic encephalopathy and multiple organ failure, MOF's's (respiratory failure, cardiovascular failure, renal failure) process.Except that ammonia, the septicemia (or bacterial peritonitis) that takes place immediately behind the gastrointestinal hemorrhage also may be a factor that inspires hepatic encephalopathy.
Liver is lost compensatory multiple organ failure, MOF and the hepatic encephalopathy of causing thus.In hepatic encephalopathy some small variations can take place in early days, for example thinking is not concentrated and maybe can not be made up simple objects.Under the serious situation, that hepatic encephalopathy can cause is numb, stupor, brain swelling and death.
Because there are many causes of disease in chronic hepatopathy, therefore be difficult to the prognosis of chronic hepatitis patients is made an estimate.Do not make compensatory state comprise other paathogenic factors of avoiding to make disease progression, for example thoroughly alleviating alcohol addiction and inoculate at first type and hepatitis B to the preventive measure of losing compensatory state development as far as possible.
Yet in case it is compensatory that the liver mistake takes place, the probability of existence just descends to some extent, and liver transplantation is unique Therapeutic Method that prolongs life.Because liver is lost the compensatory lost of life that causes, therefore very need prevent the compensatory generation of liver mistake.
Common therapy to the hepatic encephalopathy patient comprises the method that ammonia concentration is reduced.These methods comprise the proteinic absorption of RD, give lactulose, neomycin, L-ornithine L-aspartic acid (LOLA) or sodium benzoate, and cleansing enema.
Summary of the invention
At least a and the ornithine that the present invention relates in phenylacetic acid and the phenylbutyric acid is used for prevention or treats the purposes that the patient liver is lost compensatory or hepatic encephalopathy (HE).Also can give isoleucine for the patient who also suffers from the isoleucine shortage because of for example gastrointestinal hemorrhage.Therefore, the invention provides:
---ornithine is used for preparing with at least a of phenylacetic acid and phenylbutyric acid unites use to prevent or to treat the purposes that liver is lost the medicine of compensatory or hepatic encephalopathy;
---at least a in phenylacetic acid and the phenylbutyric acid is used to prepare with ornithine unites the medicine of compensatory or hepatic encephalopathy is lost in use with prevention or treatment liver purposes;
---at least a and ornithine in phenylacetic acid and the phenylbutyric acid is used to prepare prevention or treats the purposes that liver is lost the medicine of compensatory or hepatic encephalopathy;
---contain the product of at least a and ornithine in phenylacetic acid and the phenylbutyric acid, use simultaneously, respectively or in succession with prevention or treatment liver and lose compensatory or hepatic encephalopathy;
---a kind of pharmaceutical composition that contains at least a and ornithine in phenylacetic acid and the phenylbutyric acid;
---a kind of being used to prevents or treats the medicament that liver is lost compensatory or hepatic encephalopathy, contains at least a and ornithine in phenylacetic acid and the phenylbutyric acid; With
---a kind ofly treat liver and lose compensatory or hepatic encephalopathy patient or have the method that liver is lost the patient of compensatory or the ill risk of hepatic encephalopathy, described method comprises to described patient and gives the phenylacetic acid of effective dose and at least a and ornithine in the phenylbutyric acid.
Description of drawings
Fig. 1 represents that cirrhotic's neutrophil cell function changes, and increases the weight of and worsen with hepatopathy.
Fig. 2 represents that ammonia weakens the phagocytosis of neutrophil cell.
Fig. 3 represents that ammonia weakens the chemotaxis of neutrophil cell.
Fig. 4 represents that ammonia can obtain reversing to the phagocytotic influence of neutrophil cell by intervention.
Fig. 5 represents that mimic gastrointestinal hemorrhage can weaken the chemotaxis of neutrophil cell, and weakening of described chemotaxis can partly be reversed by giving isoleucine.
Fig. 6 represents mimic hemorrhage minimizing protein synthesis and stimulates the oxidation of isoleucine inadequately.
Fig. 7 is illustrated in and gives isoleucine in the mimic hemorrhage process and can strengthen protein synthesis, but does not reduce ammonia concentration.
Fig. 8 represents to give LOLA and can reduce ammonia concentration but can make ammonia regeneration.
Fig. 9 represents initiatively to remove glutamine can prevent that ammonia concentration from raising once more.
Figure 10 represents that thereby phenylacetic acid combines generation and can secrete chemical compound with glutamine, and phenylacetic acid prevention ammonia increases once more.
Figure 11 represents the influence of ammonia level to the cirrhotic in late period of ornithine and phenylbutyric acid.
Figure 12 represents the influence of glutamine level to the cirrhotic in late period of ornithine and phenylbutyric acid.
Figure 13 represents the variation with the patient's of placebo, O, P or O+P treatment the mental status.
Figure 14 represents the influence of ammonia level to the cirrhotic in late period of ornithine, phenylbutyric acid and isoleucine.
Figure 15 represents the influence of glutamine level to the cirrhotic in late period of ornithine, phenylbutyric acid and isoleucine.
Figure 16 represents the influence of glycine level to the cirrhotic in late period of ornithine, phenylbutyric acid and isoleucine.
Figure 17 represents the influence of isoleucine level to the cirrhotic in late period of ornithine, phenylbutyric acid and isoleucine.
Figure 18 represents the influence of ornithine level to the cirrhotic in late period of ornithine, phenylbutyric acid and isoleucine.
Figure 19 is illustrated in the bile duct ligation rat model, and ornithine and phenylbutyric acid are to the influence of ammonia in the tremulous pulse.
Figure 20 is illustrated in the bile duct ligation rat model, and ornithine and phenylbutyric acid are to the influence of ornithine in the blood plasma.
Figure 21 is illustrated in the hyperammonemia acute hepatic failure rat model, and ornithine, phenylbutyric acid and isoleucine are to the influence of tremulous pulse blood plasma ammonia level.
Figure 22 is illustrated in OP and treats in the devasation pig model of acute hepatic failure, and the increase degree of tremulous pulse ammonia level diminishes.
Figure 23 is illustrated in the animal of O and OP treatment, removes blood ammonia (taking a sample) by muscle from femoral vein-femoral artery.By contrast, use placebo and the ammonia that the animal of using P separately shows the muscle generation to increase.
Figure 24 is illustrated in all animals except that the animal of OP treatment, and digestive tract produces ammonia (taking a sample from portal vein current drainage tissue (portal drained viscera)-tremulous pulse).
Figure 25 represents to use separately O to increase the release of muscle glutamine, but uses P not make it to increase separately.OP makes the muscle glutamine discharge (catching ammonia with the form of glutamine in the muscle thus) significantly more.
Figure 26 represents that 0 strengthens the absorption of digestive tract to glutamine, reduces (reducing the ammonia that produces in the digestive tract thus) but OP absorbs it.
Figure 27 is illustrated in two treated animals (give the group of O separately and give the group of OP) of administration, and tremulous pulse ornithine level raises.
Figure 28 represents to use 0 o'clock tremulous pulse glutamine level to raise, but this level raises less when using OP.
Figure 29 represents to unite the increase that use OP can prevent ammonia source aminoacid glycine.
Figure 30 represents to use separately ornithine can cause hydrocephalus to increase, and the degree that phenylacetic acid induces hydrocephalus to reduce is very little, but these medicament associatings are just significantly reduced hydrocephalus (contrast %).
The specific embodiment
This description and the claims of enclosing word in the whole text " comprises " and " comprising " and version for example " has comprised ", " including ", " having comprised ", " containing " all do the nonexcludability explanation.Just, these words be intended to express possibility comprise clearly do not address but other key elements or integer that context allowed.
The present invention relates to develop into liver lose compensatory before and before therefrom hepatic encephalopathy taking place, for prevention or postpone liver and lose the early treatment that compensatory morbidity is carried out the hepatopath.In addition, the present invention relates to by effective minimizing ammonia concentration and keep the neutrophil cell function and come treatment that hepatic encephalopathy is carried out.
Experimenter to be treated
The present invention relates to prevention or the compensatory or hepatic encephalopathy of treatment liver mistake.Therefore experimenter's liver should be in compensatory state.The experimenter can suffer from chronic hepatopathy.The experimenter can suffer from liver cirrhosis.The experimenter can suffer from acute hepatic failure.Experimenter to be treated can suffer from hepatic encephalopathy.
Acute and morbidity chronic hepatopathy is attributable to heteroplasia thing factor.For example the experimenter may be exposed to certain chemical substance that causes hepatic injury, medicine or some other medicaments.The experimenter may respond to nonprescription drugs, prescription drugs or " property for amusement " medicine that causes hepatic injury.The experimenter may take Rezulin
TM(troglitazone; Parke-Davis), Serzone
TM(nefazodone; Bristol-MyersSquibb) or other be considered to cause the medicine of hepatic injury.The experimenter may take excessive certain drug or take and surpass medicine recommended dose, that can cause hepatic injury.For example the experimenter may take excessive acetaminophen.The experimenter may for example be exposed to the chemical substance that can cause hepatic injury in their job site.For example, the experimenter may be exposed to this class chemical substance in industry or agricultural environment.The experimenter may take in the plant that contains the chemical compound that can cause hepatic injury, especially when the experimenter be that animal for example may this thing happens during herbivore.For example, the experimenter may take in the plant tansy ragwort for example that contains pyrrolizidine alkaloid.The experimenter may be exposed to the environmental toxin that is considered to cause hepatopathy.
The relevant liver toxicity of medicine causes more than 50% of all acute hepatopathys (acute hepatic failure) case.In the U.S. and Britain, acetaminophen (being also referred to as acetaminophen and N-acethyl-p-aminophenol) toxicity is the common cause that causes acute hepatic failure.The long-term middle heavy drinker who takes therapeutic dose or excessive a little acetaminophen has the severe liver injury of suffering from and may be the risk of acute liver failure.Drink and to strengthen the toxic action of acetaminophen.The atopy drug toxicity also can cause acute hepatic failure.The atopy drug toxicity is considered to a kind of allergy, and the experimenter produces reaction to medicine in unusual pharmacology's mode in this reaction.This abnormal response can cause acute hepatic failure.
Acute hepatic failure or chronic hepatopathy can be by due to the cause pathogeny imcrobe infection.For example, hepatopathy can be by due to the viral infection.In particular, the experimenter may by or caused the viral infection of hepatitis.The experimenter may suffer from chronic viral hepatitis.Described virus can be for example B-mode, third type or hepatitis D virus.In some cases, especially suffer under the situation of viral hepatitis the experimenter, this experimenter also can be infected by HIV-I or II.The experimenter can be AIDS patient.The experimenter may be by or will be caused the microorganism of hepatopathy, especially those some stages to be present in the infected by microbes in the liver by other at its life cycle.For example, have among the experimenter or existing Liver fluke.
The experimenter can suffer from the hereditary that causes chronic hepatopathy or increase trouble chronic hepatopathy risk.For example the experimenter can suffer from one or more diseases in liver blood pigmentation disease, inferior (family name) disease of Weir or the alpha-1-amtitrypsin deficiency.The experimenter can suffer from and causes certain liver structure or parafunctional heritability disease, and described liver structure or dysfunction have increased the probability of hepatic fibrosis.The infringement liver can easily be taken place and therefore be caused the autoimmune disease of hepatic fibrosis in the experimenter in heredity.
Chronic hepatopathy can be that ethanol is inductive.Sex to be treated may be or be the alcohol user.He or she may or on average take in the above ethanol of 50 or 50 units, the above ethanol of 60 or 60 units, above ethanol of 75 or 75 units or even the above ethanol of 100 or 100 units weekly weekly weekly weekly.This sex possibility or the average weekly the most nearly ethanol of 100 units of taking in reach the ethanol of 150 units weekly most, even reach the ethanol of 200 units weekly most.The various countries that measure of a unit of ethanol differ.Herein, according to the United Kingdom's standard, a unit equals 8 gram ethanol.
The ethanol that sex is taken in above-mentioned level can have 5 years or more than 5 years, 10 years or more than 10 years, and 15 years or more than 15 years, perhaps 20 years or more than 20 years.The ethanol that the experimenter takes in above-mentioned level can reach maximum 10 years, maximum 20 years, maximum 30 years and even maximum 40 years.For the inductive liver cirrhosis of ethanol, the experimenter can for for example more than 25 years old or 25 years old, more than 35 years old or 35 years old, more than 45 years old or 45 years old or even more than 60 years old.
The experimenter can be a sex.The women may be more responsive than the male to the ill effect of ethanol.Relative male, the women can be in the shorter time period, by the ethanol generation ethanol chronic hepatopathy of less amount.As if causing the women is not unique to the higher reason of the sensitivity of alcoholic liver damage, but hormone may have important effect to the influence of alcohol metabolism.
In other embodiments of the present invention, the experimenter suffers from many one or more of the other diseases that causes hepatic injury of having notified, and described disease for example is primary biliary cirrhosis, ACAH and/or schistosomicide (parasitic infection).The experimenter may will suffer from or suffer from bile duct obstruction.May not know the potential cause that causes chronic hepatopathy in some cases.For example the experimenter may be diagnosed as agnogenic cirrhosis.In one embodiment, the experimenter can under a cloudly suffer from the listed any disease of this paper.
The method of diagnosing chronic hepatopathy, acute hepatic failure and hepatic encephalopathy is known in the art, especially knows for the clinicist of this area and veterinary.Preferably, the experimenter will be diagnosed as by for example medical science or veterinary professional and suffer from hepatopathy or hepatic encephalopathy.The experimenter can show one or more symptoms relevant with hepatopathy, one or more following symptoms for example: jaundice, ascites, skin change, fluid retention, refer to that (toe) first changes, easily contusion, epistaxis, esophageal varicosis, and male subject may have breast and increases.The experimenter can show collapse, fatigue, anorexia, feels sick, weak and/or lose weight.The experimenter also can show one or more symptoms relevant with hepatic encephalopathy, for example one or more following symptoms: confusion of consciousness, disorientation, dementia, numb, stupor, cerebral edema, multiple organ failure, MOF's (respiratory failure, cardiovascular failure or renal failure), myotonia/muscle rigidity, epilepsy or speech disorder.Experimenter to be treated may take or not take the other drug of treatment hepatopathy.Experimenter to be treated can have the risk of suffering from hepatic encephalopathy.
Hepatopathy may be by maybe will be by comprising that for example the physiology inspection of ultrasonic technique confirms.Can carry out liver biopsy with fibrosis, non-viable non-apoptotic cell, cytopathy and/or the inflammation of finding out accumulation and other characteristic features of hepatopathy.Can in the experimenter, carry out the liver function evaluation, to determine among the experimenter whether liver function injury taking place.The character of hepatopathy and the potential cause of disease can obtain characterizing.Any medical history that is exposed to the hepatopathy paathogenic factor all can be determined.
Experimenter to be treated can be the patient of hepatic encephalopathy outbreak risk, for example waits for the patient of liver transplantation, operating patient and/or portal hypertension.People with hepatic encephalopathy outbreak risk is a kind of like this people: he is without successive what hepatic encephalopathy outbreak, perhaps in longer a period of time (about 12 weeks or longer), do not experience the hepatic encephalopathy outbreak, but suffer from disease or medical conditions that certain produces hepatic encephalopathy outbreak risk.Hepatic encephalopathy outbreak is a kind of clinical disease, it is characterized by hepatopathy or there is disordered brain function in the hepatic insufficiency patient.Have many kinds of abalienations in the hepatic encephalopathy, gently then it mainly influences for reducing quality of life, and is heavy then can cause stupor and final to death.
Can use marking system to estimate to the seriousness of hepatopathy and hepatic encephalopathy with to experimenter's prognosis.Can adopt Child-Pugh, West Haven standard, Glasgow coma score (GlasgowComa Scale) or improved Child-Pugh marking system.Perhaps, can adopt (APACHE) II marking system.To the parameter that comprises abnormal level of serum total bilirubin, serum albumin level etc. with comprise that the sign that has ascites or encephalopathy etc. distributes mark.Experimenter to be treated can be divided into A, B or the C grade of Child-Pugh marking system.Usually experimenter to be treated is classified as the C grade of Child-Pugh marking system.
The sex age to be treated can be at for example 25 to 80 years old.In one embodiment, this sex is 45 to 70 years old.In another embodiment, this sex is 25 to 44 years old.In a further embodiment, this sex is an over-65s.
But the present invention also has veterinary purpose really.Experimenter to be treated can be for example cow or bull, sheep, pig, cattle, goat or a horse of cultivated animals, perhaps can be for example Canis familiaris L. or cat of performing animal.Whether the experimenter is that the hepatopathy animal model all can.Animal can be any age, but should be the adult experimenter of fully-developed usually.
Preparation
Aminoacid used in the present invention can be pure crystal amino acid.Generally speaking, aminoacid is L type but not D type, or the mixture of D and L.Usually use the aminoacid of unpack format.Can use the aminoacid of any activity form to lose compensatory or hepatic encephalopathy with prevention or treatment liver.Can use the aminoacid of pharmaceutically acceptable form.The aminoacid that uses can be free aminoacid or amino acid salts or derivant.
Ornithine can be pure crystal amino acid form.Generally speaking, ornithine is a L type but not the D type perhaps is the mixture of D and L.Usually use the ornithine of unpack format.Can use the ornithine of any activity form or the ornithine of pharmaceutically acceptable form.The ornithine that uses can be free aminoacid or amino acid salts or derivant.
Usually, ornithine uses with the single monomer amino acid form.The ornithine of salt form can be used, for example dlornithine hydrochloride can be used.Ornithine can be the physiologically acceptable salt of free form.Therefore ornithine or ornithine salt do not carry out chemical bonding or covalently bound with any other medicament usually.
Can use the derivant of ornithine.For example can give the ketone group or the hydroxy analogs of the ornithine of sodium salt or calcium salt forms.The keto acid of ornithine comprises ornithine ketoglutarate, ornithine keto-leucine and ornithine keto-valine.Can use the salt of ornithine or derivant substituting free ornithine, or use free ornithine simultaneously.
Can use at least a in phenylacetic acid and the phenylbutyric acid.Phenylacetic acid and/or phenylbutyric acid can be physiologically acceptable salt form, for example alkali metal or alkali salt.Described salt can be sodium or phenylbutyrate sodium.The salt form of phenylacetic acid and phenylbutyric acid can be free form.Therefore phenylacetic acid and phenylbutyric acid or phenylacetic acid salt and phenylbutyric acid salt do not carry out chemical bonding or covalently bound with any other medicament usually.
The optional isoleucine that uses.Isoleucine can be pure crystal amino acid form.Generally speaking, isoleucine is L type but not D type, or the mixture of D and L.Usually use the isoleucine of unpack format.The isoleucine of any activity form can be used or the isoleucine of pharmaceutically acceptable form can be used.The isoleucine that uses can be free aminoacid or amino acid salts or derivant.
Usually, isoleucine uses with the single monomer amino acid form.The isoleucine of salt form can be used, for example the isoleucine hydrochlorate can be used.Isoleucine can be the physiologically acceptable salt of free form.Therefore isoleucine or isoleucine salt do not carry out chemical bonding or covalently bound with any other medicament usually.
Pharmaceutical composition
Usually the ornithine and phenylacetic acid and/or the phenylbutyric acid that are used for administration with pharmaceutically suitable carrier or diluent preparation.Therefore, one or more standard pharmaceutically suitable carrier and/or excipient of available pharmaceutical field routine are mixed with a kind of medicine with ornithine and phenylacetic acid and/or phenylbutyric acid.The definite character of preparation will depend on the multiple factor that comprises required route of administration.Usually ornithine and phenylacetic acid and/or phenylbutyric acid are mixed with and are used in oral, intravenous, gastric, the blood vessel or the intraperitoneal administration.
Described pharmaceutical carrier or diluent for example can be for example normal saline of isosmotic solution.Removing the active ingredient beyond the region of objective existence in the Peroral solid dosage form form also can contain: diluent is lactose, glucose, sucrose, cellulose, corn starch or potato starch etc. for example; Lubricant is silicon dioxide, Talcum, stearic acid, magnesium stearate or calcium stearate and/or Polyethylene Glycol for example; Adhesive is starch, arabic gum, gelatin, methylcellulose, carboxymethyl cellulose or polyvinylpyrrolidone for example; Disintegrating agent is starch, alginic acid, alginate or sodium starch glycolate for example; Effervescent mixture; Dyestuff; Sweeting agent; Wetting agent is lecithin, Polysorbate, lauryl sulfate for example; And the material of normally used nontoxic no pharmacological activity in the pharmaceutical preparation.This class pharmaceutical preparation can prepare by known way, for example by mixing, granulation, tabletting, sweet tablet or the preparation of film coating process.
The liquid oral disperse system can be syrup, Emulsion or suspending agent.Syrup can contain for example sucrose as carrier, perhaps sucrose and glycerol and/or mannitol and/or Sorbitol.
Suspending agent and Emulsion can contain for example natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethyl cellulose or the polyvinyl alcohol as carrier.Suspending agent that intramuscular injection is used or the solution at least a and ornithine in containing phenylacetic acid and phenylbutyric acid, also can contain pharmaceutically suitable carrier, for example sterilized water, olive oil, ethyl oleate, glycol propylene glycol for example if need, also can contain an amount of lidocaine hydrochloride.
Medicine of the present invention can contain ornithine as unique amino acid composition.Medicine of the present invention can contain ornithine and isoleucine as only amino acid composition.Medicine can be made up of at least a and ornithine in phenylacetic acid and the phenylbutyric acid basically.Medicine can be basically be made up of at least a, ornithine in phenylacetic acid and the phenylbutyric acid and isoleucine.
Medicine can be made up of ornithine, phenylacetic acid and/or phenylbutyric acid and pharmaceutically suitable carrier basically.Therefore this class medicine is substantially free of other aminoacid except that ornithine.Medicine can be made up of ornithine, isoleucine, phenylacetic acid and/or phenylbutyric acid and pharmaceutically suitable carrier basically.Therefore this class medicine is substantially free of other aminoacid except that containing ornithine and isoleucine.
The amount of the phenylacetic acid that exists is calculated by weight the 5%-100% that can be ornithine weight, for example 10%-50% or 20%-40%.The amount of the phenylbutyric acid that exists is calculated by weight the 5%-100% that can be ornithine weight, for example 10%-50% or 20%-40%.
Yet medicine can contain free aspartic acid, glutamic acid or the arginine of non-peptide form, and they exist with non-significant quantity usually.Generally, the aspartic acid of calculating by weight, glutamic acid or arginic amount are no more than the amount of the ornithine of calculating by weight.Non-significant quantity means aspartic acid, glutamic acid or the arginine calculated by weight or the amount of these amino acid whose combinations is no more than 20% of ornithine weight.Therefore, medicine is substantially free of aspartic acid.In one embodiment, compositions does not contain aspartic acid, glutamic acid or arginine.Aspartic acid, glutamic acid or the arginine that can have trace in the compositions.Trace means aspartic acid, glutamic acid or the arginine calculated by weight or the amount of these amino acid whose combinations is no more than 1% of ornithine weight.Preferably, the amount calculated by weight of aspartic acid, glutamic acid or arginine is no more than 0.5% of ornithine weight.
In another embodiment, compositions also can contain the aminoacid of other non-peptide forms, is generally the free form of free amino acid or its physiologically acceptable salt.Above-mentioned other amino acid whose amounts are no more than the amount of ornithine by weight usually.For example, the amino acid whose amount of other of existence is up to 20% of ornithine weight by weight, for example is the 5%-20% of ornithine weight.Above-mentioned other aminoacid that can be present in the compositions comprise essential amino acids and non essential amino acid.Compositions can contain other branched-chain amino acid (BCAA).BCAA comprises isoleucine, valine and leucine.Therefore, compositions of the present invention can further contain isoleucine and/or valine and/or leucine.
Treatment
At least a and ornithine in phenylacetic acid and the phenylbutyric acid united give the experimenter with prevention or postpone the morbidity that liver is lost compensatory or hepatic encephalopathy.Therefore can unite at least a and ornithine that gives in phenylacetic acid and the phenylbutyric acid to improve the experimenter for example suffers from the experimenter of chronic hepatopathy after inspiring incident situation.Can unite at least a and ornithine that gives in phenylacetic acid and the phenylbutyric acid to alleviate experimenter's symptom, for example with the relevant symptom of chronic hepatopathy after the experimenter inspires incident.Can unite at least a and ornithine that gives in phenylacetic acid and the phenylbutyric acid with antagonism or postpone the morbidity that liver is lost compensatory or hepatic encephalopathy.
At least a and ornithine in phenylacetic acid and the phenylbutyric acid can be united and give the experimenter with the treatment hepatic encephalopathy.Can unite at least a and ornithine that gives in phenylacetic acid and the phenylbutyric acid to improve hepatic encephalopathy patient's situation.Can unite at least a and ornithine that gives in phenylacetic acid and the phenylbutyric acid to alleviate the symptom relevant with hepatic encephalopathy.Can unite at least a and ornithine that gives in phenylacetic acid and the phenylbutyric acid with the antagonism hepatic encephalopathy.Can unite at least a and ornithine that gives in phenylacetic acid and the phenylbutyric acid shows effect with the initial hepatic encephalopathy that prevention has the people of hepatic encephalopathy outbreak risk.Can unite at least a and ornithine that gives in phenylacetic acid and the phenylbutyric acid the order of severity with the initial hepatic encephalopathy outbreak that alleviates people with hepatic encephalopathy outbreak risk.Can unite at least a and ornithine that gives in phenylacetic acid and the phenylbutyric acid shows effect with the initial hepatic encephalopathy that delay has the people of hepatic encephalopathy outbreak risk.
It is relevant with " inspiring incident " (or " acute onset ") that liver is lost compensatory development with hepatic encephalopathy.This class inspires incident and comprises gastrointestinal hemorrhage, infection (sepsis), portal thrombosis and dehydration.This class acute onset may cause being in hospital.The patient may stand the combination of certain this class acute onset or this class acute onset.
According to the present invention, associating ornithine and phenylacetic acid and/or phenylbutyric acid are treated and are lived through or the doubtful experimenter who lives through acute onset, develop to the compensatory state of mistake with the prevention liver.Therefore the present invention can prevent liver to lose compensatory medical consequences, for example hepatic encephalopathy.Ornithine and phenylacetic acid and/or phenylbutyric acid can be used for keeping liver function.Therefore, use ornithine and phenylacetic acid and/or phenylbutyric acid can prolong hepatopath's life-span.In one embodiment, prevented the metabolic consequence of gastrointestinal hemorrhage, for example the hyperammonemia of hemorrhage after date, low isoleucine mass formed by blood stasis and protein synthesis reduce.
Usually, can take place or doubtfully begin as early as possible when inspiring incident (acute onset) experimenter's treatment.Preferably before acute onset repeatedly just to experimenter's begin treatment.More preferably, behind first time acute onset to experimenter's begin treatment.
Usually after beginning, acute onset treats immediately.Can be at medical worker's begin treatment after for example doctor, paramedic or nurse detect the symptom of acute onset or doubtful acute onset.Can be after the experimenter be in hospital begin treatment immediately.Therefore, can be after detecting acute onset or doubtful acute onset symptom in 6 hours, begin treatment in 3 hours, in 2 hours or in 1 hour.Therefore, can for example begin treatment after 1-36 hour or 1-24 hour the symptom that has detected acute onset or doubtful acute onset 1 to 48 hour to the experimenter.
Can after detecting acute onset or doubtful acute onset, carry out the most nearly 8 weeks, for example the most nearly 6 weeks, the most nearly 4 weeks or the most nearly treatment in 2 weeks.Therefore can after detecting acute onset or doubtful acute onset, carry out the most nearly 48 hours, for example the most nearly 36 hours or the most nearly 24 hours treatment.General therapeutic proceeds to from acute and inspires when obviously being restored the incident.
With ornithine and phenylacetic acid and/or phenylbutyric acid treatment experimenter.Can unite at least a and ornithine that gives in phenylacetic acid and the phenylbutyric acid by single medicament forms, perhaps the form with two or three different pharmaceutical independently gives.When the medicament forms with combination gives at least a and ornithine in phenylacetic acid and the phenylbutyric acid, can administration immediately after making compositions, perhaps can be with the form storage of composition of medicine.
When giving ornithine and phenylacetic acid and/or phenylbutyric acid independently, can while or administration in succession in a period of time.Can in a period of time, give two or three medicine independently.
When giving two kinds of medicines, can give ornithine earlier, give phenylacetic acid and phenylbutyric acid, phenylacetic acid or phenylbutyric acid then.Perhaps, can give phenylacetic acid and phenylbutyric acid, phenylacetic acid or phenylbutyric acid earlier, give ornithine then.In another embodiment, unite earlier and give ornithine and phenylacetic acid, and then give phenylbutyric acid.Perhaps, unite earlier and give ornithine and phenylbutyric acid, give phenylacetic acid then.In another embodiment, can give phenylacetic acid earlier, unite then and give ornithine and phenylbutyric acid.Perhaps, give phenylbutyric acid earlier, unite then and give ornithine and phenylacetic acid.
When giving three kinds of medicines, can give ornithine, phenylacetic acid and phenylbutyric acid respectively in the different time.Ornithine can give at first, or secondly gives, or in the end gives.When at first giving ornithine, can secondly give phenylacetic acid or phenylbutyric acid, give phenylbutyric acid or phenylacetic acid afterwards again.When next gives ornithine, can at first give phenylacetic acid or phenylbutyric acid, give phenylbutyric acid or phenylacetic acid once more again.When giving ornithine at last, can at first give phenylacetic acid or phenylbutyric acid, give phenylbutyric acid or phenylacetic acid afterwards.
Can give to give second kind of medicine after first kind of medicine reaches 5 hours most and for example reach most 2 hours or reach 1 hour most.Therefore can give first kind of medicine after 15 minutes-5 hours, for example give second kind of medicine after 30 minutes-4 hours or 1 hour-3 hours.
Can give to give the third medicine after second kind of medicine reaches 5 hours most and for example reach most 2 hours or reach 1 hour most.Therefore can give second kind of medicine after 15 minutes-5 hours, for example after 30 minutes-4 hours or 1 hour-3 hours, give the third medicine.
Can give medicine of the present invention in same area or different parts.Can give medicine of the present invention by identical approach or different approaches.Can give medicine of the present invention by any suitable way.Preferably by administration in oral, intravenous, gastric, intraperitoneal or the blood vessel.For example, during at least a and ornithine in giving phenylacetic acid and phenylbutyric acid respectively, but they all can be oral or their equal intravenous administrations, perhaps ornithine Orally-administrable, but and phenylacetic acid and/or phenylbutyric acid intravenous administration, perhaps phenylacetic acid and/or phenylbutyric acid Orally-administrable, but and ornithine intravenous administration.
Treat ornithine, phenylacetic acid and/or the phenylbutyric acid of effective dose and optional isoleucine to the experimenter.The dosage of ornithine, phenylacetic acid and/or phenylbutyric acid and isoleucine can be determined the experimenter's that described parameter is for example to be treated age, body weight and disease according to various parameters; The type of hepatopathy and the order of severity; Route of administration and required therapeutic scheme.
The routine dose of the routine dose of ornithine, phenylacetic acid or phenylbutyric acid or the routine dose of isoleucine are about 0.02-1.25g/kg body weight, and for example the 0.1-0.5g/kg body weight is specifically decided according to above-mentioned parameter.Therefore, the dosage of the dosage of ornithine, phenylacetic acid or phenylbutyric acid or the dosage of isoleucine can be 1-50g, for example 5-30g.The dosage of ornithine can be 10 to 30g.The dosage of isoleucine can be 5-15g.Ornithine and phenylacetic acid/phenylbutyric acid can carry out administration with the weight ratio of 10:1-1:10, and for example weight ratio is 5:1-1:5 or 2:1-1:2 or about 1:1.The doctor can determine the dosage of required ornithine and phenylacetic acid or phenylbutyric acid and optional isoleucine at any concrete patient.
Can give the ornithine of single dose and the phenylacetic acid and/or the phenylbutyric acid of single dose.Randomly, also can give the isoleucine of single dose.Perhaps, can give multiple dose for example ornithine and/or phenylacetic acid and/or the phenylbutyric acid and/or the optional isoleucine of 2,3,4 or 5 dosage.Above-mentioned multiple dose administration can carry out one month or two weeks or week age.In another embodiment, but give single dose or multiple dose for example ornithine and/or the phenylacetic acid and/or the phenylbutyric acid of 2,3,4 or 5 dosage every day.
As mentioned above, can give other aminoacid to the experimenter.Described or every kind of other aminoacid can carry out administration with the form of same medicine with ornithine and/or phenylacetic acid and/or phenylbutyric acid, perhaps can independent administration.If carry out independent administration, then described or every kind of other amino acid whose administration can be carried out simultaneously at ornithine and/or phenylacetic acid and/or phenylbutyric acid administration, perhaps can for example give ornithine and/or phenylacetic acid and/or phenylbutyric acid in the different time and carry out before or after reaching 5 hours most, reach 2 hours most or reaching 1 hour most.Described or every kind of other aminoacid is generally oral administration or intravenous administration.
Treat the described of effective dose or every kind of other aminoacid to the experimenter.Dosage should change according to for example above parameter of addressing at ornithine, phenylacetic acid and phenylbutyric acid of different parameters.Described or every kind of other amino acid whose routine dose is the 0.02-1.25g/kg body weight, for example the 0.1-0.5g/kg body weight.Therefore described or every kind of other amino acid whose dosage is 1g-50g, for example 5g-30g.
Can give the described of single dose or every kind of other aminoacid.Perhaps, can give for example 2,3,4 or 5 dosage of multiple dose.This class multiple dose administration can carry out one month or two week or weeks.In another embodiment, but carry out single dose or for example administration of 2,3,4 or 5 dosage of multiple dose every day.
The present invention will be described for following examples.
Embodiment 1: cirrhotic's neutrophil cell function changes and increases the weight of and dislike with hepatopathy
Change
Measure the method for neutrophil cell phagocytosis and oxidative burst
Phagocytosis test: escherichia coli and the CD16 with the FITC labelling that opsonizes cultivates with the heparinization whole blood.Use flow cytometry (FACScan Becton Dickinson) pair cell to analyze then, establish door by forward angle light scatter and lateral angle scattering, subsequently based on phycoerythrin (PE) [Immunotech, Marseille, France] fluorescent dye expresses pair cell and estimates the positive cell with identification CD16.The opposite house inner cell mass is estimated the situation that exists with the antibacterial of determining the FITC labelling then.
Engulf outburst: the whole blood of heparinization is cultivated to excite oxidative burst with the escherichia coli suspension that opsonizes.Add substrate solution to measure dihydro rhodamine (DHR) 123 conversion situations to fluorescence source chemical compound rhodamine (R) 123.Make reaction terminating and fixing, cultivate to discern positive neutrophil cell with CD16 antibody then.Analyze with flow cytometry then.
The chemotaxis of neutrophil cell: by improved Boyden cell method, utilize interleukin 8 as the chemical attractants material to excite the chemokinesis effect, measure the chemotaxis of neutrophil cell.
Patient and method
We are to 30 cirrhotic's (ethanol cirrhosis; 53.2 years old mean age (SEM4.6)) and 20 healthy volunteers study.The cirrhotic is divided into (AH+) the compensatory or compensatory patient of liver of patient's regulating liver-QI mistake of additivity alcoholic hepatitis (superimposed alcoholic hepatitis).Utilize phagocytosis test to measure cytophagous ability, whether outburst mensuration cell is engulfed in utilization can produce oxidative burst when contacting with escherichia coli.
The result
We observe the ability of engulfing antibacterial from cirrhotic's neutrophil cell and significantly descend.We also find, make aspect the increase of oxidative burst generation rate, and the cirrhotic stimulates the effect of neutrophil cell to produce the ability of replying significantly descend (Fig. 1) to escherichia coli.This ability drop is relevant with the order of severity of hepatopathy, shows that hepatopathy is in late period more, and is just weak more to the ability that the generation of infecting is replied and resisted.
Embodiment 2: ammonia reduces the phagocytic activity of neutrophil cell
Measure the phagocytosis of neutrophil cell and the method for oxidative burst
As described in embodiment 1.
Patient and method
Collect blood from healthy volunteer (n=15), the ammonia that blood increases progressively with concentration was cultivated 1 hour.The ability of engulfing antibacterial by phagocytosis test and neutrophil cell chemotaxis assay determination neutrophil cell.In analyzing, uses the neutrophil cell chemotaxis IL-8 of 10ng/ml.
The result
Along with the concentration increase of the ammonia of cultivating, phagocytosis of neutrophil cell (Fig. 2) and neutrophil cell chemotaxis (Fig. 3) significantly weaken.
Embodiment 3: can reverse ammonia to the phagocytotic influence of neutrophil cell by intervention meansMeasure the phagocytosis of neutrophil cell and the method for oxidative burst
As described in embodiment 1.
Patient and method
Collect blood from healthy volunteer (n=15), blood was cultivated 1 hour with ammonia and selected aminoacid.Measure the ability that neutrophil cell is engulfed antibacterial by phagocytosis test.
The result
We observe, and phagocytotic the weakening of the inductive neutrophil cell of ammonia can partly be reversed (Fig. 4) by ornithine and glutamine.Yet ammonia and aspartic acid are cultivated altogether and are made the neutrophil cell phagocytosis worsen, but can remain unchanged when using L-ornithine L-aspartic acid.
Embodiment 4: the simulation gastrointestinal hemorrhage make the neutrophil cell chemotaxis weaken, can be by giving
Giving isoleucine makes weakening of described chemotaxis be reversed
Method
To 10 [9 male and women; Mean age is 49.6 years old (SEM9.1); The Child-Pugh average score is 7.8 (SEM1.2)] one night of fasting, metabolic stability, the liver cirrhosis patient that confirms through biopsy study, described research is at orally give 75g simulation haemoglobin molecule (Nutricia, carry out after 2 hours before the Cuijk, ispol Netherlands) and in administration.In 7 other patients [4 male and 3 women; Mean age is 51.4 years old (SEM6.7); The Child-Pugh average score is 8.1 (SEM1.4)] in, after giving ispol, give isoleucine (isosmotic solution that contains the 40mg/l isoleucine, speed are 100ml/hr) in 2 hours angular veins.Measure the neutrophil cell chemotaxis (referring to the method for embodiment 1) and the plasma ammonia of PeV blood sample.
The result
Compare with the contrast (53.3SEM4.6) of age-matched, the chemotaxis of these cirrhotics' neutrophil cell is obviously lower, and after simulation is hemorrhage, significantly weaken, reduce to the individual cell/high power fields in 8 (± 5.4) (p＜0.0001) from 30 (± 4.2) (Fig. 5).The plasma concentration of ammonia significantly increases, and increases to 124 (± 8.5) (p＜0.001) from 75.1 (± 4.2).The change relevant (r=0.65, p＜0.05) of the change of ammonia concentration and neutrophil cell chemotaxis.In patient's group that weakening of the observed neutrophil cell chemotaxis of simulation bleeding group used the isoleucine treatment, be eliminated (25.4 (± 6.0) cell/high power field).
Embodiment 5: simulate the hemorrhage proteinic synthetic isoleucine oxygen that also stimulates inadequately that reduces
Change
Method
Recruit the liver cirrhosis patient at 5 one nights of fasting.Collect blood sample and gather the expired gas sample, begin the stable isotope of infusion then to measure the isotopic enrichment degree of background.Then, the patient accepts pre-prepd [1-
13C]-the continuous venoclysis (1mg/kg bw/h) of isoleucine is until off-test (t=480min).
The result
Fig. 6 show infusion of saline (black bar post) and aminoacid (brown post) in last hour the apparent rate of the average whole body of isoleucine (Wb Ra) and the isoleucine Oxidation (value is represented with meansigma methods ± SEM; # represents p＜0.05).Cirrhotic's upper gastrointestinal hemorrhage has caused the minimizing of isoleucine and the remarkable minimizing of whole body protein synthesis.Although isoleucine concentration significantly reduces, the isoleucine circulation part that is used for Oxidation does not change after simulation is hemorrhage, and this shows and the BCAA antagonism occurred.
Embodiment 6: give isoleucine during hemorrhage in simulation and strengthened protein synthesis but do not reduce
Ammonia concentration
Method
The liver cirrhosis patient that confirms to 16 metabolic stabilities, through biopsy is studied.During 4 hours simulation is hemorrhage, at random the patient is replenished isoleucine (40mg/L solution; 50ml/hr) or placebo.Ammonia and (by the ring of continuous infusion L-[in advance-
2H
5] phenylalanine, L-[ring-
2H
4]-tyrosine and L-[ring-
2H
2]-tyrosine is measured) protein synthesis.
The result
The result shows infusion leucine during the liver cirrhosis patient simulation is hemorrhage, makes the protein synthesis that is damaged of liver and muscle be restored, and has caused the clean anastate (table 1) of these organs.Two groups ammonia concentration significantly increases, but and gives isoleucine and give to there is no significant difference (Fig. 7) between the group of placebo.
Embodiment 7: the aspartic acid accumulation behind late period cirrhotic's infusion L-ornithine L-aspartic acid
Method
With L-ornithine L-aspartic acid, with 40g/ days cirrhotic in late period (ages: 59 to 5 wait liver transplantations; 3 male, Child C level disease, serious ascites, kreatinin 102 μ mol/L) treat.
The result
Aspartic acid concentration significantly increased progressively in 3 day time, increased to 5 times (table 2) of basic value.
Table 2
| Before the treatment | The 1st day | The 2nd day | The 3rd day | |
| Aspartic acid (μ mol/L) | 72(11.8) | 178(23.2) | 289(27.1) | 354(31.1) |
Table 1
The protein dynamics that utilizes the Phe model when t=0 hour and research finish, to measure
Data are meansigma methods ± SEM nmol/kg BCM/min.The meansigma methods of numerical value represented amino acid infusion last hour during end.The data of hepatic and/or renal protein synthesis are carried out hydroxylating proofread and correct (square method).Statistics: the group difference that Mann-Whitney U check is carried out in the reflection of p value; There was no significant difference between the discovery group.
The administration of embodiment 8:LOLA reduces ammonia concentration but can make ammonia regeneration
Patient and method
To 8 cirrhotics (age 56 (5.6), 5M, ALD-6; 2 grades of HE:4 examples; 3-4 level HE:4 example) carries out LOLA infusion (40g, 8 hours) treatment.Blood sample collection is to measure ammonia and glutamine.
The result
The result shows, gives LOLA and makes ammonia concentration significantly descend, and is attended by glutamine concentration rising (Fig. 8) simultaneously.The minimizing of this ammonia has beneficial effect to the order of severity of HE.Yet when stopping the LOLA administration, clear existing bounce-back of cyclic ammonia water raises, and causes the HE recurrence of 3 patients among improved 6 patients.
Embodiment 9: initiatively remove glutamine and prevented that ammonia concentration from raising once more
Patient and method
3 patients carrying out hemofiltration (heamofiltration (CVVH)) (ages 45 (4.1) 2M, ALD, HE all are 3 grades, HRS all is 3) are carried out LOLA infusion (40g, 8 hours) treatment.Blood sample collection is to measure ammonia and glutamine.
The result
The result shows, LOLA makes ammonia concentration reduce, and stoped glutamine concentration raise simultaneously (Fig. 9) but add dialysis.Therefore, we think that ammonia concentration is to continue to reduce.
Embodiment 10: phenylacetic acid combines with glutamine, thus generate can excretory chemical compound and
Prevented that ammonia from raising once more
Patient and method
Patient to 6 acute hepatic failures (5 routine non-A non-B hepatitis) and serious hepatic encephalopathy (3-4 level) treats with LOLA and phenylacetic acid (40g/ days, 8 hours).
The result
Therapeutic alliance does not make that glutamine concentration significantly increases, but makes ammonia level descend (Figure 10).Do not observe the increase of ammonia bounce-back property.
Embodiment 11: ornithine and phenylbutyric acid are to hepatic encephalopathy patient's effect
The patient
1. grouping: every group of 3 patients, 12 altogether.
2. be selected into standard
The adult patients in-18-80 year ,-liver cirrhosis confirmed by histology or clinical criteria
-C type HE ,-ammonia concentration〉80 μ mol/L, inform to agree/agree with
3. exclusion standard
-other concurrent nervous system diseasies,-use the another kind of specific ammonia medicine that falls,-need mechanical ventilation and abirritative respiratory failure,-the gastrointestinal hemorrhage do not controlled ,-need the hypotension of inotrope, obvious renal failure (kreatinin〉2mg/d1), hemodialysis,-external rami hepatici is held, known hypersensitivity to any research medicine ,-gestation.
Evaluation to the mental status
Hepatic encephalopathy classification (West Haven standard)
| 0 grade (minimum level HE) | Normal mental state (one or more in the psychology test are gageable unusual) |
| 1 grade | Slight consciousness lacks glad or anxiety attention range shortens that to add judicial act impaired |
| 2 grades | Drowsiness or the apathy slight personality changes misbehave of minimum disorientation subtraction behavior to time or place is impaired |
| 3 grades | Somnolence half is numb, but speech is stimulated the serious disorientation of confusion of consciousness that responds |
| 4 grades | Stupor (reactionless) to speech or destructive stimulus |
Method
In open labelling Journal of Sex Research, we have been selected into 8 patients that suffer from cirrhosis and hyperammonemia.Seriousness according to hepatopathy is mated (seeing Table 3) to them.Adopt one of following scheme in 3 day time, they to be treated, carry out the observation of 5 day time.The research group is:
(i) placebo: 5% glucose, 4 hours;
(ii) list uses ornithine: 20g in the 500ml5% glucose, and 0800 up to 1200 o'clock;
(iii) phenylbutyric acid: every day twice, each 10g, oral (0800 o'clock and 1600 o'clock); With
(iv) ornithine+phenylbutyric acid: 20g is in the 500ml5% glucose, and 0800 up to 1200 o'clock+every day twice, each 10g, oral (0800 o'clock and 1600 o'clock).
The patient from midnight 0000 up to one night of the morning 0800 fasting.Provide the gastric meals by 25KCal/Kg to them, finish, wherein contain the protein meals of 1g/Kg in the 25KCal/Kg meals since 0800 to midnight.At 0730 o'clock and afterwards 1800 o'clock blood sample collections, so that ammonia and glutamine are measured.Monitoring is to patient's side effect closely.The equal well-tolerated of medicine of each group is not observed adverse events.
Table 3 patient demographics
| Placebo | Singly use ornithine | Singly use phenylbutyric acid | OP | |
| Age | P1：47P2：57 | P3：46P4：40 | P5：56P6：48 | P7：52P8：52 |
| Sex | P1：M?P2：M | P3：FP4：F | P5：FP6：M | P7：MP8：F |
| The hepatopathy etiology | P1：HCV?P2：HBV | P3：HBV?P4：NASH | P5：NASHP6：HBV? | P7：HBVP8：HBV |
| Hepatopathy seriousness (Pugh scoring) | P1：9?P2：12 | P3：13P4：13 | P5：14P6：13 | P7：14P8：12 |
| Precipitating factor | P1: infect P2: infect | P3:SBP P4: infect | P5:SBP P6:? infect | P7:SBP P8: infect |
| HE seriousness (West-Haven standard) | P1：2?P2：3 | P3：3P4：3 | P5：3P6：3 | P7：3P8：3 |
| HE seriousness (Glasgow fan scoring) | P1：9P2：8 | P3：8P4：8 | P5：9?P6：10 | P7：9P8：9 |
| Other organ failuries | P1: no P2: hypotension | P3: property before the kidney, hypotension P4: hypotension | P5: no P6: property before the kidney | P7: no P8: do not have |
| Dead (D)/survival (A) | P1：AP2：A | P3：DP4：A | P5：AP6：A | P7：AP8：A |
| Complication | P1: infect SBP P2: infect, varicosis is hemorrhage | P3:HRS P4: recurrent infection | P5: sepsis, ICUP6: recurrent SBP | P7: no P8: hemorrhage, the 14th day |
SBP: SBP, non-alcoholic fatty liver disease inflammation, ICU: necessary Intensive Care Therapy support, HRS: hepatorenal syndrome
The result
Figure 11 shows that the average ammonia level of placebo group during treating remains unchanged basically.In L-ornithine group and the phenylbutyric acid group, the relative baseline value of ammonia concentration raises to some extent.In the group that L-ornithine and phenylbutyric acid are treated together, ammonia significantly reduces.In the animal of OP treatment, except ammonia concentration reduced, the degree of ammonia increase had after the meal also reduced.By the 3rd day, two patients' of OP group hepatic encephalopathy scoring obtained the two-stage improvement, but does not observe this phenomenon in arbitrary other six patients.
Figure 12 shows that OP organizes during treating, though the minimizing of ammonia is arranged, average glutamine level remains unchanged basically.In the phenylbutyric acid group, glutamine reduces, and this is likely deleterious.In L-ornithine group and placebo group, glutamine concentration increases, and this phenomenon is significantly strengthened in state after the meal.
Figure 13 represents the variation with the mental status of the group of placebo, O, P and OP treatment.
Embodiment 12: ornithine, phenylbutyric acid and isoleucine are to hepatic encephalopathy patient's effect
The patient
1. grouping: every group of 2 patients, 6 altogether.
2. be selected into standard
The adult patients in-18-80 year confirms liver cirrhosis by histology or clinical criteria, and Child B or C have recently because of cirsoid gastrointestinal hemorrhage (manifesting in back 6 hours), inform to agree/agree with
3. exclusion standard
-other concurrent nervous system diseasies, use the another kind of specific ammonia medicine that falls, need mechanical ventilation and abirritative respiratory failure, the gastrointestinal hemorrhage of not controlling need the hypotension of inotrope, obviously renal failure (kreatinin〉2mg/d1), hemodialysis, external rami hepatici is held, known hypersensitivity to any research medicine, gestation/suckling.
Method
In open labelling Journal of Sex Research, we have been selected into 6 cirrhotics, and these patients varicosis is hemorrhage is accepted because of treatment.Seriousness according to hepatopathy is mated (seeing Table 4) to them.Adopt one of following scheme in 3 day time, they to be treated, carry out the observation of 5 day time.The research group is:
I. placebo: 5% glucose, 4 hours (250ml)
Ii. list uses isoleucine: 10gm to be dissolved in the 250ml5% glucose, is divided into two dosage, injection in 2 hours angular veins
Iii. isoleucine+ornithine+phenylbutyric acid: isoleucine: 10gm is dissolved in the 250ml5% glucose, is divided into two dosage, injection in 2 hours angular veins; Ornithine: 20g is (t=0,24,48hr) in the 250ml5% glucose; Phenylbutyric acid: every day twice, each 10g, oral (t=0,12,24,36,48hr)
The patient from midnight 0000 up to one night of at 0800 o'clock in morning fasting.Provide the gastric meals by 25KCal/Kg to them, finish, wherein contain the protein meals of 1g/Kg in the 25KCal/Kg meals since 0800 to midnight.At 0730 o'clock and afterwards 1800 o'clock blood sample collections, so that ammonia and glutamine are measured.Monitoring patient's side effect closely.The equal well-tolerated of medicine of each group is not observed adverse events.The patient has accepted tranquilizer owing to having carried out the endoscopy at first, so mental status evaluation can not be used for explaining.Each patient of placebo group and isoleucine group because of the multiple organ failure, MOF in hospital's death.All the other patient's survivals.
Table 4
| Placebo | Singly use isoleucine | OIP | |
| Age | P1：43P2：62 | P3：57P4：42 | P5：43P6：45 |
| Sex | P1：M P2：M | P3：F P4：M | P5：M P6：M |
| The hepatopathy etiology | P1：ALD?P2：HCV | P3：HBVP4：ALD | P5：HBV?P6：NASH |
| Hepatopathy seriousness (Pugh scoring) | P1：13P2：14 | P3：13P4：11 | P5：14P6：10 |
| HE seriousness (West-Haven standard) | P1：2P2：3 | P3：2P4：1 | P5：2P6：2 |
| Lose blood (u) that estimates | P1：9?P2：10 | P3：7P4：8 | P5：7?P6：10 |
| Dead (D)/survival (A) | P1：DP2：A | P3：AP4：D | P5：AP6：A |
| Complication | P1: infect hemorrhage once more P2: serious hepatic encephalopathy | P3:HRS P4: recurrent infection | P5: thoracic cavity infection P6: do not have |
SBP: SBP, non-alcoholic fatty liver disease inflammation, ICU: necessary Intensive Care Therapy support, HRS: hepatorenal syndrome
The result
Figure 14 shows that the ammonia concentration of placebo group and isoleucine group do not have significant change.The ammonia concentration of OIP treatment group significantly reduces.
Figure 15 shows, gives isoleucine, placebo or OIP and does not significantly change the glutamine level.Ammonia concentration only has remarkable reduction in the OIP group.
Figure 16 shows that the another kind of mode of OIP effect is is glycine by reducing ammonia source aminoacid.Only observe the remarkable minimizing of glycine in the OIP group.
Figure 17 shows that the isoleucine level of each group beginning is all very low, but this level of isoleucine treatment group increases to the twice of normal value.The concentration of placebo group keeps low-level and does not change.
Figure 18 shows, in the therapeutic process variation of patient's ornithine level show that the remarkable persistence of ornithine concentration raises and after drug withdrawal described concentration significantly reduce to basic value, shown the absorption in the different tissues thus.
Embodiment 13: ornithine and phenylbutyric acid are to the effect of the rat of bile duct ligation
Method
(BDL) induces cirrhosis by the bile duct ligation
Use male SD rat (Sprague-Dawley rat) in the method (200-250g).After the anesthesia, carry out the median line laparotomy, expose bile duct,, between second ligation place and the 3rd ligation place, cut off with the triple ligation of 4.0 silk thread.With absorbable suture wound is carried out layering and sew up, make animal, put back to animal feeding room afterwards in quiet indoor recovery.Animal is placed under the room temperature (20 ℃), carry out 12 hours illumination/lucifuge circulation, and make it arbitrarily near the rodent food of water and standard.
After five weeks of BDL (or sham-operation), the rodent food that gives animal is converted to fully liquid food (Liquidiet, Bio-Serv, Frenchtown NJ, USA), added in the described fully liquid food simulation hemoglobin compositions ispol (2.8g/Kg/ days, Nutricia Cuijk, The Netherlands, ProdUct No.24143).The 6th week under narcotism, insert the right carotid artery conduit, and with its blood sample collection repeatedly.Collect baseline sample after this step, give the preparation studied by the IP injection then.Seminar is: BDL contrast+saline (n=5), BDL+IP ornithine (0.22g/Kg, n=6) saline, BDL+IP phenylbutyric acid (0.3g/Kg, n=7) saline, BDL+IP OP saline (0.22g/Kg/0.3g/Kg, n=7).
Blood sample collection to the heparinization test tube of pre-cooling, is prepended to preservation on ice in processing.Centrifugal (3,000rpm, 10min) blood plasma is collected in the back, before analysis in-80 ℃ of preservations.
Utilize COBAS Mira S, measure ammonia, glucose, lactate and urea according to manufacturers instruction.HPLC with fluoroscopic examination carries out quantitatively aminoacid.
The result
Compare with normal healthy controls (25.6 ± 2 μ mol/L, p＜0.001, data not shown), (205 ± 11 μ mol/L, in the meansigma methods ± SEM), tremulous pulse blood plasma ammonia level significantly raises at the rat model of the bile duct ligation of cirrhosis.In this model, we find that in the placebo group of brine treatment the tremulous pulse ammonia level did not change in three hours.
Figure 19 represent BDL cirrhosis rat the IP pump pickle (BDL contrast, n=5), ornithine (Orn, 0.22g/Kg, n=6), phenylbutyric acid (PB, 0.3g/Kg, n=7) and ornithine phenylbutyric acid (OP, 0.22g/Kg+0.3g/Kg, the n=7) variation of the tremulous pulse blood plasma ammonia level after.* show OP and Orn comparison p＜0.05 (two-way analysis of variance) in the time of 3 hours.
This figure shows, detecting ammonia concentration in the animal of ornithine treatment has a little reduction, but do not find that it and placebo are variant.In phenylbutyric acid treatment group, find that plasma ammonia significantly increases (comparing p＜0.01 with other all groups) after 1 hour, but find that this species diversity diminishes when 3 hours time points.This result and phenylbutyric acid (phenylacetic acid) only coincide to the effective hypothesis of patient that glutamine concentration raises.In the animal that does not give ornithine (but metabolism formation glutamine), the effect of simple P is undesired, also is potential deleterious.In the treatment group of ornithine+phenylbutyric acid (OP), observed the remarkable reduction of ammonia level.In these animals, measure ammonia continuous decrease in three hours of research, when finishing, research finds that its level significantly is lower than single level (p＜0.05) of using the group of ornithine.
The above results has proved that clearly aspect the minimizing plasma ammonia, OP Combined Ration list is renderd a service stronger with O or P.And in single animal with the P treatment, the plasma ammonia level of rising may be deleterious.
We with a series of samples to IP injection O or OP after ornithine be absorbed the situation that enters blood flow and detect.Figure 20 represents the tremulous pulse ornithine concentration of supplementation group.Can be clear that when IP injected back 1 hour, two groups blood plasma ornithine concentration significantly raise, in the time of 3 hours, reduce again subsequently, this be since this ornithine in vivo by metabolism.Point at any time, there were significant differences all not find blood plasma ornithine concentration between these groups.
This discovery is very important, because it has confirmed that selected medication can be sent effectively and has passed ornithine in these animal bodies.And the level reduction in fast Absorption and the viewed blood plasma shows that initiatively metabolism is just taking place this aminoacid.
Embodiment 14: ornithine, phenylbutyric acid and isoleucine are to the effect of the rat of bile duct ligation
Method
Use male SD rat (200-250g) in the method.The standard rodent food that will give animal before the sacrifice of animal during 48hr is converted to fully liquid food (Liquidiet, Bio-Serv, Frenchtown NJ, USA), ispol (the 2.8g/Kg that has added simulation hemoglobin compositions in the described fully liquid food, Nutricia Cuijk, TheNetherlands, Product No.24143).When putting to death preceding 24 hours, induce acute hepatic failure (ALF) (every group of n=5) by IP injection galactosamine (1g/Kg, Sigma, Poole UK) saline.Sacrifice of animal in the time of preceding 3 hours, is treated with OIP (ornithine 0.22g/Kg, isoleucine 0.25g/Kg, phenylbutyric acid 0.3g/Kg, IP in saline) preparation or saline control.When experiment stops, arterial blood is collected in the heparinization test tube of pre-cooling, be prepended on ice in processing and preserve.Collect blood plasma and preservation as mentioned above.Measure ammonia as mentioned above.
The result
Compare the tremulous pulse ammonia level of 0IP treatment acute hepatic failure rat significantly descend (Figure 21) with placebo.This research is whether can effectively reduce plasma ammonia in order to test isoleucine and ornithine and phenylbutyric acid (phenylacetic acid) associating.Before confirm in research that list did not influence ammonia level with isoleucine, but it was not tested with the effectiveness of O and P associating before to the mankind.
Figure 21 represents with the tremulous pulse blood plasma ammonia level in the hyperammonemia acute hepatic failure model of saline placebo (ALF) and OIP treatment (ALF+OIP).The significance level (T check) that has p＜0.01 between these two groups.
This result has supported the hypothesis of isoleucine and ornithine and phenylbutyric acid associating can effectively reduction ammonia level.This be isoleucine except previously described for the another beneficial effect the beneficial effect of protein synthesis.
Embodiment 15: ornithine and phenylbutyric acid are to the effect of the pig model of devasation
Method
5 pigs are divided into 4 groups at random: acute hepatic failure (ALF)+placebo+placebo (n=2), ALF+ ornithine+placebo, ALF+ phenylbutyric acid+placebo, ALF+ ornithine and phenylbutyric acid.Conduit is inserted femoral artery and femoral vein, portal vein, renal veins and the pulmonary artery of pig.Begin experiment in the time of preceding 1 hour at beginning placebo or therapeutic agent infusion.
1. placebo: infusion 5% glucose in 3 hours, oral water placebo
2. list is used ornithine: 0.3g/Kg, and 5% glucose instiled in the blood vessel in 3 hours
3. phenylbutyric acid: 0.3g/Kg, 5% glucose, gastric feed in 3 hours
Ornithine+phenylbutyric acid: 0.3g/Kg, 5% glucose instiled in the blood vessel in 3 hours, 0.3g/Kg5% glucose, gastric feed in 3 hours.
By time=portal vein during 0hr engages with inferior caval, and hepatic artery ligation subsequently (devasation) is induced ALF; Time=+ stop infusion during 2hr, time=experiment stopped during 8hr.In time=0,1,3,5,7 and collect blood sample and urine sample during 9hr so that measure local ammonia and amino acid whose variation.When experiment finishes, get volume cortex part to measure hydrocephalus.
The result
Produce behind the infusion ornithine in the cell glutamic acid and simultaneously gastric provide the result of phenylacetic acid to show, in this liver failure catastrophe model, whole ammonia level and the situation of utilizing of glutamine obviously changed.
In the animal of placebo treatment, after devasation, tremulous pulse ammonia concentration continues to raise (Figure 22) in time, and some are wherein arranged is that muscle produces (Figure 23), and a large amount of ammonia is then from digestive tract (Figure 24).This animal has shown glutamine less (Figure 25) that muscle discharges and the glutamine that absorbs by digestive tract significantly (Figure 26).
In the animal for the treatment of with ornithine separately, early stage ammonia raises and originally is suppressed, but it rises to the highest (Figure 22) when experiment finishes afterwards.In this animal, muscle is clean absorb (Figure 24) to ammonia, compares with the animal of placebo treatment, and the amount of the glutamine that discharges from muscle is (Figure 25) substantially quite, and digestive tract increases (Figure 26) to the absorption of glutamine.
Single initial inhibition that also shows the tremulous pulse ammonia level with phenylbutyric acid, but this level rises to single very soon with the suitable level (Figure 22) of ornithine when experiment finishes, and muscle is to the absorption of ammonia no change (Figure 23) basically, but the ammonia that digestive tract produces significantly (Figure 24).Ironically, compare with the animal of placebo treatment, single with in the treatment of phenylbutyric acid, for removing only, and this treatment does not have obvious influence (Figure 26) to the absorption of gastral glutamine to muscle to glutamine.
Ornithine and phenylbutyric acid coupling have the greatest impact to the tremulous pulse ammonia level, compare with every other animal, and it makes the cyclical level when experiment finishes significantly reduce (Figure 22).In this animal, muscle is initiatively removed ammonia from blood, and the ammonia that digestive tract produces significantly reduces (Figure 24).Ironically, notice with placebo treatment and compare that the glutamine that muscle discharges increases (Figure 25) with single animal with the ornithine treatment.Though the glutamine that produces in muscle increases, digestive tract significantly reduces (Figure 26) to the absorption of glutamine.
As shown in figure 27, confirmed that in the animal of ornithine treatment, the cyclical level of ornithine raises.
Devasation and treatment are intervened to the influence of tremulous pulse glutamine as shown in figure 28.In the animal of ornithine treatment, the cyclical level of glutamine raises, and this phenomenon can give phenylacetic acid and improves by uniting.An interesting discovery is, in the animal of ornithine and phenylbutyric acid therapeutic alliance, and tremulous pulse glycine level significantly improve (Figure 29).
When experiment finishes, get brain volume cortex, and hydrocephalus content is measured (Figure 30).
One independently the pathologist cyto-anotomy of the brain of these laboratory animals has been made report.Report to him is summarized as follows:
ALF: blood capillary blood vessel peripheral edema has vesicle on every side.Neuronal necrosis around the vesicle sexually revises.
ALF+O+P: blood capillary blood vessel peripheral edema has vesicle (degree of not having any treatment ALF is light) on every side.Intracellular edema.
Sham-operation: cerebral tissue ultrastructural change minimum=normal cerebral tissue.
Conclusion
The inventor finds, the simulation of some symptoms of the acute onset relevant with chronic hepatopathy is for example improved ammonia concentration or simulates gastrointestinal hemorrhage, can cause the neutrophil cell miopragia, and this weakening can partly be reversed by ornithine or isoleucine.Unite by ornithine and isoleucine remedying in prevention of neutrophil cell function had important function in the sepsis, and the described sepsis common precipitating factor that to be liver lose in the compensatory process.
In addition, the inventor finds that also behind the simulation gastrointestinal hemorrhage, isoleucine does not have influence to the rising of ammonia concentration.Therefore, the impregnable result of ammonia level is opposite with following hypothesis, and described hypothesis is for after giving isoleucine, because stimulating protein is synthetic, ammonia level will reduce.Therefore, it is particularly advantageous uniting use isoleucine and ornithine, the known ammonia level that reduces of this use.
Therefore, give ornithine and isoleucine and can prevent the consequence of gastrointestinal hemorrhage in metabolism.The rising of ammonia level is suppressed, and the shortage of isoleucine is remedied, and the neutrophil cell function is remedied.Therefore unite and use ornithine and isoleucine to provide a kind of new method that the patient who inspires after the incident is treated to lose compensatory generation with the prevention liver.
The inventor also finds, is used for reducing the L-ornithine L-aspartic acid (LOLA) of ammonia in the hepatic encephalopathy patient, does not reverse the influence of ammonia to the neutrophil cell function.Therefore, single more more favourable than using LOLA with ornithine, because ornithine can reduce the function that ammonia can be remedied neutrophil cell again.In addition, the aspartic acid component of LOLA also can be accumulated in vivo.In fact this accumulating of aspartic acid may be deleterious to the patient, because aspartic acid makes ammonia worsen the influence of neutrophil cell function, further weakens the function of neutrophil cell.Therefore, prevention or delay liver are lost compensatory outbreak and can use ornithine and isoleucine realize by uniting, and preferably do not give aspartic acid.
In addition, the inventor also finds can reduce ammonia level, thereby raise the glutamine level with L-ornithine L-aspartic acid (LOLA) treatment hepatic encephalopathy (HE) patient.Yet glutamine is temporary transient ammonia buffer agent, because it can carry out recirculation and produce ammonia again in kidney and small intestinal.Therefore single the treatment with LOLA can cause ammonia level to raise once more, further increases the weight of the condition of illness of hepatic encephalopathy.
Child to urea cycle disorder uses phenylacetic acid or phenylbutyric acid can reduce the unusual high-level of glutamine.Comparatively speaking, HE patient has normal glutamine level, but except with LOLA they being treated shown in embodiment 1, described LOLA reduces ammonia level but increases the glutamine level.Therefore use phenylacetic acid and/or phenylbutyric acid can remove glutamine, thereby prevention HE patient's ammonia level raise once more.
So, can realize the property improved treatment by uniting at least a and ornithine that gives in phenylacetic acid and the phenylbutyric acid to hepatic encephalopathy, preferably do not give aspartic acid.
We have supported a kind of like this viewpoint at the broad research in cirrhosis animal model and cirrhosis patient, and the major organs of promptly removing ammonia among the cirrhotic is a muscle, in that ammonia is changed in the reaction of glutamine, has utilized glutamic acid.In liver failure, to be responsible for the enzyme glutamine synthetase of this reaction and to be induced, the supply of glutamic acid can strengthen the aminolysis toxic action.
The precursor ornithine of glutamic acid detoxifies to ammonia by changing into glutamine.Yet our preliminary study shows that this glutamine can make ammonia recirculation and regeneration.Our invention provides a kind of new method, and this method is not only detoxified to ammonia is converted into glutamine, pays off unnecessary glutamine except producing.Therefore, OP is than single wherein a kind of ammonia concentration that obviously reduces cirrhosis and hyperammonemia patient more significantly of using.This effect obviously is synergism but not adduction.In addition, ammonia increase after the meal can be eliminated by giving OP.This can provide the meals of rich in proteins to losing compensatory cirrhotic with regard to making, and does not have the hyperammonemia risk.The minimizing of ammonia is relevant with the improvement of the mental status.It can reduce ammonia concentration by the increase that prevents glutamine and realize.This is consistent with a kind of hypothesis, described hypothesis is in muscle ornithine and impels and produce glutamine (catching the ammonia of a part thus), but this glutamine is discharged from (may with the adduct form of phenylacetic acid), raise with the glutamine that prevents general, prevented anti-elastic hyperammonemia thus.
Phenylacetic acid make the ammonia in presenting the hyperammonemia baby of urea cycle disorder reduce this conclusive evidence knowledge validation ammonia be hunted down and be transformed into glutamine, discharge with phenylacetic acid glutamine addition product form thereby glutamine is transported to kidney.These babies show hyperammonemia, and the very important point is to show high glutamine.On the contrary, the cirrhotic shows hyperammonemia and normal to lower glutamine.Above-mentioned pig model is isolated the back glutamine liver and is not raise, and ammonia level significantly increases.
The single treatment with ornithine can increase the blood glutamine, and ammonia level is unaffected.List increases glutamine on a small quantity with phenylbutyric acid, and ammonia level is also had no significant effect.Distinct is that in the catastrophe model that blood ammonia raises, coupling ornithine and phenylbutyric acid (OP) make circulation ammonia significantly reduce, and have improved the increase of viewed glutamine when list is used ornithine.Glycine---a kind of aminoacid that produces ammonia---all increases in all animals, but only in the animal of OP treatment, this amino acid whose increase is suppressed basically, demonstrates the additional benefit of the intervention of this form thus.Definite consequence that ammonia raises is owing to water content in the brain increases caused brain swelling.From the brain demonstration of list with the pig of ornithine treatment, water content significantly increases, the water content of ornithine and phenylbutyric acid associating then minimizing brain.On the histology, to compare with the animal of placebo treatment, the microstructure damage of the brain of the animal of ornithine and phenylbutyric acid therapeutic alliance is more not obvious.
Claims (34)
1. at least a in preparation and phenylacetic acid and phenylbutyric acid of ornithine united use and loses purposes in the medicine of compensatory or hepatic encephalopathy with prevention or treatment liver.
2. at least a in phenylacetic acid and the phenylbutyric acid united use at preparation and ornithine and loses purposes in the medicine of compensatory or hepatic encephalopathy with prevention or treatment liver.
3. at least a and ornithine in phenylacetic acid and the phenylbutyric acid loses purposes in the medicine of compensatory or hepatic encephalopathy preparation prevention or treatment liver.
4. it be that the liver mistake of chronic hepatitis patients is compensatory that each purposes of claim 1-3, wherein said liver are lost compensatory.
5. each purposes of claim 1-3, wherein said prevention or treatment comprise that postponing liver loses compensatory morbidity.
6. each purposes of claim 1-3 exists among the wherein said patient or doubtful existence inspires incident.
7. the purposes of claim 6, the wherein said incident that inspires is gastrointestinal hemorrhage, infection, portal thrombosis or dehydration.
8. claim 6 or 7 purposes are wherein given and described medicine in 6 hours detecting described incident or the doubtful symptom that inspires incident of inspiring.
9. each purposes of claim 1-3 is wherein to chronic hepatopathy or acute hepatic failure patient treatment hepatic encephalopathy.
10. each purposes of claim 1-3, wherein said ornithine exists with the form of free single amino acid or physiologically acceptable salt.
11. each purposes of claim 1-3, at least a existence form in wherein said phenylacetic acid or the phenylbutyric acid is sodium or phenylbutyrate sodium.
12. each purposes of claim 1-3, wherein said medicine also contains isoleucine.
13. the purposes of claim 12, wherein said isoleucine exists with the form of free single amino acid or physiologically acceptable salt.
14. each purposes of claim 1-3, wherein said medicine does not contain other aminoacid.
Be used in intravenous, intraperitoneal, gastric, the blood vessel or oral administration 15. each purposes of claim 1-3, wherein said medicine are formulated into.
16. each purposes of claim 1-3, described medicine are used to prevent or treat the liver that suffers from chronic hepatitis patients and lose compensatory or hepatic encephalopathy.
17. each purposes of claim 1-3, described medicine are used to prevent or the liver for the treatment of the suffering from liver cirrhosis patient is lost compensatory or hepatic encephalopathy.
18. each purposes of claim 1-3, described medicine are used to prevent or treat the liver that suffers from the acute hepatic failure patient and lose compensatory or hepatic encephalopathy.
19. each purposes of claim 1-3, described medicine are used for prevention or treatment hepatic encephalopathy.
20. each purposes of claim 1-3, wherein said medicine does not contain aspartic acid.
21. at least a and ornithine in phenylacetic acid and the phenylbutyric acid is used for the treatment of or prevents in advance chronic hepatopathy or acute hepatic failure patient's hepatic encephalopathy in preparation, perhaps is used for postponing suffering from the medicine purposes of chronic hepatopathy or acute hepatic failure patient's hepatic encephalopathy morbidity.
22. contain the product of at least a and ornithine in phenylacetic acid and the phenylbutyric acid, as simultaneously, use the combination preparation that loses compensatory or hepatic encephalopathy with prevention or treatment liver respectively or in succession.
23. the product of claim 22, described product also contains isoleucine.
24. the product of claim 22 or 23, described product does not contain other aminoacid.
25. a pharmaceutical composition, described pharmaceutical composition contain at least a and ornithine in phenylacetic acid and the phenylbutyric acid.
26. the pharmaceutical composition of claim 25, described pharmaceutical composition also contains isoleucine.
27. the pharmaceutical composition of claim 25, at least a weight ratio in described ornithine and described phenylacetic acid and the phenylbutyric acid is 10: 1 to 1: 10.
28. the pharmaceutical composition of claim 25, at least a weight ratio in described ornithine and described phenylacetic acid and the phenylbutyric acid is 5: 1 to 1: 5.
29. the pharmaceutical composition of claim 25, at least a weight ratio in described ornithine and described phenylacetic acid and the phenylbutyric acid is 2: 1 to 1: 2.
30. each pharmaceutical composition of claim 25-29, described pharmaceutical composition does not contain other aminoacid.
31. each pharmaceutical composition of claim 25-29, described pharmaceutical composition does not contain aspartic acid.
32. each pharmaceutical composition of claim 25 to 31 uses described pharmaceutical composition in prevention or treatment liver are lost the method for compensatory or hepatic encephalopathy.
33. one kind is used to prevent or treat the medicament that liver is lost compensatory or hepatic encephalopathy, described medicament contains at least a and ornithine in phenylacetic acid and the phenylbutyric acid.
34. the medicament of claim 33, described medicament also contains isoleucine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110304561.7A CN102512408B (en) | 2004-11-26 | 2005-11-28 | Be used for the treatment of the compositions containing ornithine and phenylacetic acid or phenylbutyric acid of hepatic encephalopathy |
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| GB0426142.6 | 2004-11-26 | ||
| GB0426141.8 | 2004-11-26 | ||
| GB0426141A GB0426141D0 (en) | 2004-11-26 | 2004-11-26 | Treatment |
| GB0426142A GB0426142D0 (en) | 2004-11-26 | 2004-11-26 | Formulation |
| PCT/GB2005/004539 WO2006056794A1 (en) | 2004-11-26 | 2005-11-28 | Compositions comprising ornithine and phenylacetate or phenylbutyrate for treating hepatic encephalopathy |
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| CN201110304561.7A Division CN102512408B (en) | 2004-11-26 | 2005-11-28 | Be used for the treatment of the compositions containing ornithine and phenylacetic acid or phenylbutyric acid of hepatic encephalopathy |
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| WO2006056794A1 (en) | 2004-11-26 | 2006-06-01 | Ucl Business Plc | Compositions comprising ornithine and phenylacetate or phenylbutyrate for treating hepatic encephalopathy |
| SG10202010988WA (en) * | 2009-04-03 | 2020-12-30 | Ocera Therapeutics Inc | L-ornithine phenyl acetate and methods of making thereof |
| EA201691430A1 (en) * | 2009-06-08 | 2017-02-28 | ЮСиЭл БИЗНЕС ПиЭлСи | TREATMENT OF PORTAL HYPERTENSION AND RESTORATION OF LIVER FUNCTION BY MEANS OF L-ORNITINPHENYL ACETATE |
| ES2769000T3 (en) | 2014-11-24 | 2020-06-24 | Ucl Business Ltd | Treatment of diseases associated with the activation of liver stellate cells using ammonia-reducing therapies |
| CA2995823A1 (en) | 2015-08-18 | 2017-02-23 | Ocera Therapeutics, Inc. | Treatment and prevention of muscle loss using l-ornithine in combination with at least one of phenylacetate and phenylbutyrate |
| RU2018113801A (en) * | 2015-11-13 | 2019-12-16 | Осера Терапьютикс, Инк. | Compositions of L-Ornithine Phenylacetate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4228099A (en) * | 1978-03-17 | 1980-10-14 | The Johns Hopkins University | Ornithine and arginine salts of branched chain keto acids and uses in treatment of hepatic and renal disorders |
| CN1383815A (en) * | 2002-05-08 | 2002-12-11 | 刘万忠 | Compound prepn of ornithine and asparagic acid for preventing and treating hepatosis and hepatic encephalopathy and its prepn process |
-
2004
- 2004-11-26 GB GB0426141A patent/GB0426141D0/en not_active Ceased
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2005
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4228099A (en) * | 1978-03-17 | 1980-10-14 | The Johns Hopkins University | Ornithine and arginine salts of branched chain keto acids and uses in treatment of hepatic and renal disorders |
| CN1383815A (en) * | 2002-05-08 | 2002-12-11 | 刘万忠 | Compound prepn of ornithine and asparagic acid for preventing and treating hepatosis and hepatic encephalopathy and its prepn process |
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| GB0426141D0 (en) | 2004-12-29 |
| ZA200704950B (en) | 2008-09-25 |
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