CN1853638A - Methods for treating delirium using glucocorticoid receptor-specific antagonists - Google Patents

Abstract

This invention generally pertains to the field of psychiatry. In particular, this invention pertains to the discovery that agents which inhibit the binding of cortisol to its receptors can be used in methods for treating delirium. Mifepristone, a potent specific glucocorticoid receptor antagonist, can be used in these methods. The invention also provides a kit for treating delirium in a human including a glucocorticoid receptor antagonist and instructional material teaching the indications, dosage and schedule of administration of the glucocorticoid receptor antagonist.

Description

Use the method for glucocorticoid receptor-specific antagonists treatment latah

The mutual reference of related application

The application requires the priority of No. the 60/288th, 619, the provisional application of May 4 calendar year 2001 application.

Invention field

The present invention relates generally to the psychiatry field.Especially, the present invention relates to the discovery to medicament, this medicament can suppress combining of hydrocortisone and glucocorticoid receptor (GR) and can be used for treating in the method for latah.

Introduction

The disturbance of consciousness that latah is normally caused by potential body illness.The patient who suffers from latah shows cognitive change (as hypomnesis, isotropic and language or perceptual disturbance), and latah is trend fluctuation that take place in a short time and interior during this period.

The nervous physiology reason that latah is detailed is still unknown.The neuro chemistry hypothesis that accounts for main flow for latah origin concentrates on the insufficiency (referring to Trzepacz, Dement Geriatr Cogn Disord 10:330-334 (1999)) of cholinergic neurotransmission in the brain specific region.Yet, in other neurotransmitters such as 5-hydroxy tryptamine, dopamine, γ-An Jidingsuan and glutamic acid, can cause under given conditions that unusually also latah is (referring to Flacker ﹠amp; Lipsitz, J Gerontol A Biol Sci Med Sci54:B239-46 (1999)).

Hydrocortisone is to respond ACTH (thyroliberin) and excretory glucocorticoid, and shows that physiological rhythm changes, but also is the important component of many healths of response and mental pressure.Propose, hydrocortisone regulation system extremely activation in some is individual with advancing age, and cause super hydrocortisone phenomenon.And infer that high-caliber hydrocortisone can poison nerve, especially hippocampal neuron, be considered in the brain structure of complex information and memory processing center and interim storage center (for example referring to, Sapolsky etc., Ann. NY Acad.Sci. 746:294-304,1994; Silva, Annu.Rev.Genet.31:527-546,1997; De Leon etc., J.Clin.Endocrinol ﹠amp; Metab.82:3251,1997).

Yet the brain of hydrocortisone and other glucocorticoid and CNS activity are not limited to poison neural.Except influencing big cerebral blood flow, oxygen consumption and brain excitement, glucocorticoid has widely effect (referring to DeKloet etc., Handbook Neurochem 8:47-91 (1985)) to the neurotransmitters function.These effects comprise the inhibition to maincenter poisonous fungus disposition cholinoceptor, to 5-hydroxy tryptamine conversion, the equilibrated adjusting of hypothalamus dopamine, reach the inhibition to beta-endorphin level in the brain.Glucocorticoid shows that to the effect that belongs to the uneasy neurotransmitters in the latah pathogeny disturbance that glucocorticoid is regulated plays a role in latah.Yet, although the cause of the higher glucocorticoid level of the morbid state picked-up of adrenal gland's disorder or synthetic hormone (result from) and latah is relevant (referring to Stroudemire etc., but the relation of physiology glucocorticoid level and latah is still unclear (sees also Flacker ﹠amp for understanding Gen Hosp Psychiatry 18:196-202 (1996)); Lipsitz, JGerontol A Biol Sci Med Sci 54:B239-46 (1999)).By dexamethasone suppress test to the assessment of latah patient's hypothalmus-pituitary-adrenal axis function be inconsistent (referring to Koponen etc., Nord Psykiatr Tidsskr 43:203-207 (1987); Mckeith, Br JPsychiatry 145:389-393 (1984); O ' Keefe ﹠amp; Devline, Neuropsychobiology30:153-156 (1994)).In addition, although some that directly measure the glucocorticoid level are discovered relevant (Gustafson etc. between latah and persistency hypercortisolism, CerebrovascDis 3:33-38 (1993)), but other research does not link up (van der Mast etc. with the generation and the higher cortisol levels of latah, in Filippini ed., Recent Advances inTryptophan Research, New York:Plenum Press, 93-96 (1996); McIntosh etc., Psychoneuroendocrinology 10:303-313 (1985)).

Yet, before the present invention, do not have evidence to show that glucocorticoid receptor antagonists can effectively treat latah, especially for cortisol levels for the patient in normal range.Many effects of hydrocortisone are by on the physiology cortisol levels, mediate in conjunction with I type (mineralocorticoid) receptor, and I type (mineralocorticoid) receptor is preferentially occupied for II type (glucocorticoid) receptor.Along with the raising of cortisol levels, more glucocorticoid receptor (GR) is occupied and is activated.Yet,, be vital so whole hydrocortisone mediates active inhibition because hydrocortisone plays a crucial role in metabolism.Therefore, can stop II type glucocorticoid receptor function especially but the antagonist of non-confrontational I type mineralcorticoid receptor function is particularly useful in the present invention.Mifepristone (RU486) is the example of this receptoroid antagonist with similar antagonist.

The inventor has recorded glucocorticoid receptor antagonists, as RU486, is efficacious agents for the specific treatment of the latah patient with normal or decline cortisol levels.Therefore, the present invention has satisfied the needs of effectively treating for the latah symptom by the method that the glucocorticoid receptor antagonists administration is suffered from the latah patient after diagnosing with treatment.

Summary of the invention

The invention provides a kind of method of the patient's of improvement latah symptom, this patient has cortisol levels normal or that descend.This method comprises that the glucocorticoid receptor antagonists with the treatment effective dose is administered to the patient.

In one embodiment of the invention, the method for treatment latah is used glucocorticoid receptor antagonists, and it contains the steroid skeleton, contains a phenyl moiety at least in 11 β positions of steroid skeleton.The phenyl moiety that contains in 11 β positions of steroid skeleton can be the dimethylaminophenyl part.In selectable embodiment, glucocorticoid receptor antagonists comprises mifepristone, and perhaps glucocorticoid receptor antagonists is selected from RU009 and RU044.

In other embodiment, glucocorticoid receptor antagonists is by the daily dose administration of the about 0.5～20mg of per kg body weight per day, the about 1～10mg of per kg body weight per day or the about 1～4mg of per kg body weight per day.Administration once a day.In selectable embodiment, the administering mode of glucocorticoid receptor antagonists is an oral administration, or transdermal application, spray suspension administration or aerosol administration.

The present invention also provides a kind of medicine box for the treatment of human latah, and this medicine box comprises glucocorticoid receptor antagonists, and a kind of guiding material that is used to illustrate indication, dosage and the administration time of glucocorticoid receptor antagonists.In selectable embodiment, this directiveness material shows that glucocorticoid receptor antagonists can be by the daily dose administration of the about 0.5～20mg of per kg body weight per day, the about 1～10mg of per kg body weight per day or the about 1～4mg of per kg body weight per day.This directiveness material shows that hydrocortisone helps latah patient's latah symptom, and glucocorticoid receptor antagonists can be used for treating latah.In one embodiment, the glucocorticoid receptor antagonists in medicine box is a mifepristone.Mifepristone can be a tablet form.

Can further understand characteristic of the present invention and advantage by reference description remaining part and claims.

All publications cited herein, patent and patent application are drawn and are reference for whole purposes clearly at this.

Definition

Term " treatment " refers to any successful phenomenon for damage, abnormality or treatment of diseases or improvement; comprise any objective or subjective parameters variation; as the elimination of symptom, alleviate, reduce; or make the patient more can stand damage, abnormality or disease; slow down the speed that worsens or fail; make and worsen not too weakness of terminal point, improve patient's body or Mental Health.The treatment of symptom or improvement can be foundation with objective or subjective parameters, comprise physical examination, neural spirit test and/or spiritual assessment result.For example, the bright method of we passes through to reduce the generation of consciousness or cognitive disorder, the latah of successfully having treated the patient.

Term " latah " refers to psychotic disorder in a broad sense, and it is defined within the mental sickness diagnostic ﹠ statistical manual that the Americanism AMA is published, the 4th edition, and text modification, Washington is among 2000 (" DSM-IV-TR ").DSM-IV-TR definition " latah " is the perceptual disturbance that takes place in a short time, and be attended by can not with preexist or development and the cognition of the better explanation of dementia that comes changes.DSM-IV-TR proposes the common acceptable standard of diagnosis and classification latah.

Term " hydrocortisone " refers to be also referred to as gang's composition of hydrocortisone and any synthetic or natural analog thereof.

Term " glucocorticoid receptor (GR) " (" GR ") refers to be also referred to as gang's intracellular receptor of cortisol receptor, and it can combine with hydrocortisone and/or hydrocortisone analog especially.This term comprises the variant of GR, reorganization GR and variation GR.

Term " mifepristone " refers to gang's composition, it is also referred to as RU486 or RU38.486 or 17 beta-hydroxies-11 β-(4-dimethyl-aminophenyl)-17 α-(1-propinyl)-female steroid-4,9-diene-3-ketone or 11 β-(4-dimethyl-aminophenyl)-17 beta-hydroxyl-17 alphas-(1-propinyl)-female steroid-4,9-diene-3-ketone or its analog, its usually can with GR with combine than high affinity and can suppress by any hydrocortisone or hydrocortisone analog and combining of GR receptor cause/biological agent that mediates.The chemical name of RU486 can change, for example RU486 also can be: 11 β-[p-(dimethylamino) phenyl]-17 beta-hydroxyl-17s-(1-propinyl)-female steroid-4,9-diene-3-ketone, 11 β-(4-dimethyl-aminophenyl)-17 beta-hydroxyl-17 alphas-(propyl group-1-alkynyl)-female steroid-4,9-diene-3-ketone, 17 beta-hydroxies-11 β-(4-dimethylaminophenyl-1)-17 α-(propynyl-11-)-female steroid-4,9-diene-3-ketone, 17 beta-hydroxies-11 β-(4-dimethylaminophenyl-1)-17 α-(propynyl-11-)-E, (11 β, 17 β)-11-[4-(dimethylamino) phenyl]-17-hydroxyl-17-(1-propinyl)-female steroid-4,9-diene-3-ketone, and 11 β-[4-(N, the N-dimethylamino) phenyl]-17 α-(propyl group-1-alkynyl)-D-4,9-estradiene-17 β-alcohol-3-ketone.

Term " specially good effect glucocorticoid receptor antagonists " refers to anyly can partially or completely suppress (antagonism) glucocorticoid receptor (GR) (GR) agonist (as synthetic or natural hydrocortisone or hydrocortisone analog) and bonded compositions of GR or chemical compound." specially good effect glucocorticoid receptor antagonists " also refers to the compositions or the chemical compound of any can inhibition relevant with the combination of GR and agonist any biological respinse.As for " specially good effect ", we refer to medicine preferably with at least 100 times normally 1000 times affinity combine with GR rather than combine with mineralcorticoid receptor (MR).

" do not suffer from other disease that to treat with glucocorticoid receptor antagonists as yet " and be meant and do not suffer from effectively other disease except that latah of the present invention of treatment of available glucocorticoid receptor antagonists well known in the art.The available glucocorticoid receptor antagonists well known in the art effectively disease of treatment comprises cushing's disease (Cushing ' s disease), drug withdrawal disease, psychosis, dementia, stress disorders and the heavy strongly fragrant disease of spirit.

Detailed description of the invention

The present invention finds surprisingly, and the medicament that can suppress by the biological respinse of glucocorticoid receptor (GR) mediation is effective for the treatment latah.In the treatment of latah, preferred method of the present invention can alleviate the latah symptom or cause potential disease is eliminated fully itself.In one embodiment, method of the present invention is used the interaction that suppresses hydrocortisone and GR as the medicament of GR antagonist, with treatment or improve latah or the symptom relevant with latah.Method of the present invention is effectively for the symptom of improving the latah patient, and this patient is meant the latah patient who tormented by normal, natural or synthetic hydrocortisone that improve or that reduce or other glucocorticoid.

Hydrocortisone works by combining with intracellular sugared cortical hormone receptor (GR).In human body, glucocorticoid receptor (GR) exists with two kinds of forms: the bonded GR-α of the part of 777 amino acid lengths, and the different GR-β variant of only last 15 aminoacid.This GR of two types has higher affinity for specific part, and is considered to work by identical transduction pathway.

The biological agent of hydrocortisone comprises the not normal and obstacle that is caused by hypercortisolism, can use receptor antagonist in horizontal adjusted of GR and control.Several inhomogeneous medicaments can be used as the GR antagonist, promptly hinder the bonded physiological action of GR-agonist (natural agonist is a hydrocortisone).These antagonisies comprise a kind of composition, can suppress the ability of agonist and bonded ability of GR and/or agonist activation GR effectively by this composition and combining of GR.The known GR of gang antagonist, mifepristone and relevant chemical compound are effective and powerful Antiglucocorticoid medicaments (Bertagna, J.Clin.Endocrinol.Metab.59:25,1984) to the mankind.Mifepristone and GR be with than the high affinity combination, its dissociation constant K＜10 ^-9M (Cadepond, Annu.Rev.Med.48:129,1997).So in one embodiment of the invention, can use mifepristone and relevant compounds for treating latah.

Latah shows by various symptoms usually, comprises memory impairment, isotropic, perceptual disturbance and the cycle disorder of sleeping-wake up.Can use various diagnosis latah and assessment treatment successful method like this,, propose the method for several exemplary here promptly by method success of the present invention and the expansion that reduces the latah symptom.These methods can comprise classical subjective psychology assessment and neural interview as described below.

Method of the present invention comprises makes the biological agent that suppresses in any way with the bonded GR of agonist, also proposes to can be used for treating the exemplary compounds and the compositions of latah.Also illustrated in method of the present invention is implemented, can be used for further identification and can hinder the chemical compound of the biological respinse that the interaction by the GR-agonist causes and the conventional program of compositions.The present invention as drug administration, is given in the usual manner that method of the present invention detects GR antagonist pharmaceuticals scheme and preparation in implementing with these chemical compounds and compositions simultaneously below.

1. the diagnosis of latah

The feature of latah is the disturbance of consciousness and cognitive variation of taking place in the relative short period.Disturbance of consciousness often shows the low identity to the environment cognition.The patient concentrate, keep in attention or transfer aspect show lower ability (DSM-IV-TR diagnostic criteria A).When following disturbance of consciousness, the latah patient shows cognitive disorder (for example, memory impairment, isotropic, language problem) or perceptual disturbance (for example, lose, illusion or hallucination) (standard B).For latah, these consciousness, cognition or perceptual disturbance should be the fluctuations (standard C) that tends to that take place at short notice and interior during this period.

Glucocorticoid receptor antagonists of the present invention is effective for treatment by the latah that any cause of disease in several possibility causes of disease causes.Latah can be caused by many general medical science diseases, comprise that central nervous system disorder (for example, wound, apoplexy, encephalopathy), metabolic disturbance (for example, kidney or hepatic inadequacy, fluid or electrolyte disturbance), the cardiopulmonary disorder (for example, congestive heart failure exhausts, myocardial infarction, shock) and systemic disease or influence (for example, infectious disease, sense organ are deprived, postoperative status).The latah that sugar cortex receptor antagonist brings out for therapeutant (for example, poison because of material or give up, latah that drug side effect and poisoning cause) also is effective.Latah also can be treated by glucocorticoid receptor antagonists of the present invention such as the latah in latah and unknown or unfiled source by multiple intercurrent disease because of causing (for example, the combination that general medical science disease and material are poisoned).

The diagnosis of latah obviously is different from dementia or psychotic diagnosis.Although memory impairment is common in latah and dementia, the patient who only suffers from dementia is watchful and the disturbance of consciousness feature that do not show latah usually and had.The symptom characteristic of crescendo and diminuendo in the dementia patient lack latah usually and had 24 hours.Similarly, although illusion, hallucination and anxiety are latah and psychotic feature, the psychotic suffers from basic obstacle on thought content.On the contrary, the latah patient mainly suffers from consciousness and directed obstacle, rather than intrinsic thought content obstacle.If having psychotic symptoms is exactly to tend to splitted rather than systematic psychosis so.By the unusual existence of facilitating factor that reaches such as general medical science disease and material poisoning of signal EEG of the characteristic symptoms of crescendo and diminuendo, explanation herein, latah can be distinguished mutually with dementia, psychosis, stress disorders and emotionally disturbed.

Although skilled clinicist can diagnose out latah at an easy rate by the clinical interaction of unstructured, can be with any diagnosis of several objective criterion detection meanss well known in the art and assessment latah.Based on DSM diagnostic criteria design, it is normally effective for the contrast by statistical study and various patient groups by experienced clinical research personnel for standardized means of testing.Generally speaking, standardization means both can have been assessed tangible psychology or physiological signs also can assess intrinsic thought process.Can measure the existence and the severity of latah by analyzing watchful obstacle, level of consciousness, cognitive function (for example, memory, attention, directed, ideological stumbling-block) and psychomotor vigor.Be used to diagnose the standardized test means of latah to be undertaken by professional health doctor usually, and can comprise the inspection of cooperation and the observation of patient's behavior.

The standardized test means that are used to assess latah comprise that the latah equal interval scale (sees also Trzepacz for understanding, Psychosomatics 40:193-204 (1999)), Memorability latah assessment scale, (Breitbart etc., J Pain Symptom Manage 13:128-137 (1997)), latah order of severity scale (Bettin etc., Am J Geriatr Psychiatry 6:296-307 (1998)) and latah symptom interview (Albert etc., J Geriatr Psychiatry Neurol 5:14-21 (1992)).Calculate the threshold value that the patient is divided into latah and non-latah group's tool statistics effect based on the positive predictive value of the best and negative predictive value, and at (for example testing foundation and report threshold value each time, for Memorability latah assessment scale is 13 or more mark, for the latah equal interval scale be 10 or more mark), threshold value can be used to need to select the patient of treatment.

Also can (see also Jacobson ﹠amp by using electroencephalography (EEG) diagnosis and assessment latah for understanding; Jerrier, Semin Clin Neuropsychiatry, 5:86-92 (2000)).The relatively poor tissue of peculiar θ that slows down or lack, unitize by the main ripple in back or δ slow-wave activity, background wave and the EEG reactivity loss when opening eyes and closing one's eyes can mark latah patient's electroencephalogram.Also can diagnose out the latah patient by quantitative EEG (QEEG), wherein they show absolute and relative slow wave (θ or the δ) energy of increase, the speed wave band energy ratio that reduces, the average frequency that reduces and the occipitalia peak frequency that reduces.Thus, EEG or QEEG can be used to select need be with the patient of glucocorticoid receptor antagonists treatment, or is used for detecting the effectiveness of glucocorticoid receptor antagonists treatment.

2. general laboratory procedure

When implementing method of the present invention, many ordinary laboratory detect and can be used for auxiliary diagnosis, development and prognosis to suffering from the latah patient, comprise the monitoring of parameter, as metabolism, brain structure and the function etc. of blood hydrocortisone, medicine.Because all patients produce metabolic alterations and unique drug reaction, so these programs are helpful.In addition, because each GR antagonist has different pharmacokinetics, so this type of monitoring is important.Different patients needs different dosage and preparation with different diseases.This kind measure the process of dosage and preparation and method in science and patent documentation by fully open.Enumerate several exemplary embodiments below.

A. measure the blood cortisol levels

Though the present invention implements the patient who has obvious normal blood cortisol levels, the variation of blood cortisol levels is also relevant with latah.Thus, monitoring of blood hydrocortisone and establishment of base line cortisol levels are the practical laboratory tests of the diagnosis, treatment and the prognosis that help the latah patient.It is that hydrocortisone is normal, hydrocortisone is not enough or hydrocortisone increases that the test of kinds of experiments chamber can be used to measure individuality.The latah patient often has in the morning less than 25 μ g/dl usually, usually is about 15 μ g/dl or normal cortisol levels still less in the afternoon, although this value often is in the high-end place of normal range, promptly is 5～15 μ g/dl usually in the afternoon.

So the immunity chemical examination is operated with relative accurately, easily because of it as the radioimmunoassay chemical examination and cheaply generally is used.Because the circulation cortisol levels is adrenocortical function indicator, so multiple stimulation and inhibition test, suppress test (for example referring to Greenwald as ACTH stimulation, ACTH deposit or dexamethasone, Am.J.Psychiatry 143:442-446,1986), also can be used to provide diagnosis, prognosis or out of Memory in the methods of the invention complementaryly.

A kind of this type of chemical examination with the kit form utilization is to utilize " double antibody hydrocortisone medicine box " (Diagnostic Products Corporation, Los Angeles, CA), (Acta Psychiatr.Scand.70:239-247,1984) do the radioimmunoassay chemical examination.This chemical examination is emulative radioimmunoassay chemical examination, wherein ¹²⁵The hydrocortisone of I spike and the hydrocortisone competition from the next clinical sample of antibody location.In this chemical examination, because the specificity of antibody and lack any tangible albumen effect, so serum and plasma sample neither need preextraction also not need pre-dilution.Among the embodiment 2 below this chemical examination has been described in more detail.

B. the mensuration of mifepristone level in blood/urine

Because patient's metabolism, clearance rate, toxic level etc. change with the difference of main or supervention disease, pharmacohistory, age, general medical science disease etc., be necessary so measure the level of the GR antagonist in blood and the urine.This kind monitoring mode in science and patent documentation by fully open.In one embodiment of the invention, use mifepristone treatment latah, enumerate the illustrative example of measuring mifepristone level in blood and the urine in the following embodiments.

C. other laboratory procedure

Because the performance of latah is complicated,, use many additional experimental determinations to help diagnosis, therapeutic efficiency, prognosis, toxicity etc. so can assisting in the method for the invention.For example, because hypercortisolism is also relevant with latah, so diagnosis and treatment assessment can and be measured the responsive variable of glucocorticoid and change by monitoring, comprise but be limited to blood glucose behind blood glucose, the oral glucose on an empty stomach, plasma concentration thyrotropin (TSH), with the bonded globulin of corticosteroid, stimulate corpus luteum to separate hormone (LH), and/or all or the anorchia hormone with the bonded globulin of testosterone estradiol.

The laboratory tests of generation, plasma concentration and the cleaning speed (urine concentration that comprises antagonist and metabolite) of monitoring and measurement GR antagonist metabolites also are useful in the enforcement of the inventive method.For example, mifepristone two hydrophilic N-monomethylations are arranged with the dimethylated metabolite of N-.Blood plasma of these metabolite (except that RU486) and urine concentration for example can use by Kawai at Pharmacol. and Experimental Therapeutics 241:401-406, and disclosed thin layer chromatography is measured in 1987.

3. treat the glucocorticoid receptor antagonists of latah

The invention provides and use any compositions of biological respinse or method of compounds for treating latah of suppressing, this biological respinse is relevant with the combination of hydrocortisone or hydrocortisone analog and GR.With the activity of in the methods of the invention GR antagonist in science and patent documentation by fully open.Enumerate several exemplary embodiment below.

A. as the steroid Antiglucocorticoid of GR antagonist

In different embodiments of the present invention, be the steroid glucocorticoid antagonist administration of treatment latah.The steroid Antiglucocorticoid can obtain by the basic structure of glucocorticoid agonists is modified, and promptly changes the skeleton form of steroid.The structure of hydrocortisone can change with multiple mode.The structural modification of hydrocortisone steroid skeleton can produce the glucocorticoid antagonist, wherein two kinds of known classification method the most general comprise to the modification of 11 β hydroxyls and to the modification of 17 β side chains (for example referring to Lefebvre, J.Steroid Biochem.33:557-563,1989).

I) 11 β hydroxyls removes or replaces

Use the glucocorticoid agonists have modified steroid skeleton in one embodiment of the invention, comprise removing or replacing of 11 β hydroxyls.This kind comprises natural Antiglucocorticoid, comprises corticosterone, progesterone and testosterone derivant, reaches synthetic compositions, as mifepristone (Lefebvre that quotes as described above etc.).The preferred embodiments of the invention comprise 11 all β aryl sleroid skeleton derivatives, are because these chemical compounds do not have the reason (Agarwal, FEBS 217:221-226,1987) of progesterone receptor (PR) binding ability.Another preferred embodiment comprises the derivant of 11 beta-phenyls-amino dimethyl steroid skeleton, i.e. mifepristone, and it is effective Antiglucocorticoid and progesterone antagonist medicament.These compositionss conducts and the reversible bonded antagonist of steroid receptor.For example, when with 11 beta-phenyls-when amino dimethyl steroid combines, the steroid receptor remain on can not with the bonded conformation of its native ligand, as the hydrocortisone under the GR situation (Cadepond that quotes as described above, 1997).

Synthetic 11 beta-phenyls-amino dimethyl steroid comprises mifepristone, is also referred to as RU486, or 17 beta-hydroxies-11 β-(4-dimethyl-aminophenyl)-17 α-(1-propinyl)-female steroid-4,9-diene-3-ketone.Shown that mifepristone is a kind of antagonist of brute force for progesterone and glucocorticoid (GR) receptor.11 beta-phenyls-amino dimethyl steroid that another kind shows the GR antagonist action comprises RU009 (RU39.009), 11 β-(4-dimethylamino ethoxyphenyl)-17 α-(propinyl-17 beta-hydroxy-4,9-estradiene-3-ketone) (referring to Bocquel, J.Steroid Biochem.Molec.Biol.45:205-215,1993).The another kind of GR antagonist relevant with RU486 is RU044 (RU43.044), i.e. 17 beta-hydroxyl-17 alphas-19-(4-aminomethyl phenyl)-androstane-4,9 (11)-diene-3-ketone (Bocquel that quotes as described above, 1993).Also referring to Teutsch, Steroids 38:651-665,1981; United States Patent (USP) the 4th, 386,085 and 4,912, No. 097.

Comprise the compositions that contains glucocorticoid steroid basic structure in the embodiment, it is irreversible Antiglucocorticoid.This chemical compound comprises the alpha-oxo-methanesulfonate derivative of hydrocortisone, comprise hydrocortisone-21-mesylate (4-pregnene-11 β, 17 α, 21-triol-3,20-diketone-21-mesylate), reach dexamethasone-21-mesylate (16-methyl-9 alpha-fluoro-1,4-pregnant diene-11 β, 17 α, 21-triol-3,20-diketone-21-mesylate).Referring to Simons, J.SteroidBiochem.24:25-321986; Mercier, J Steroid Biochem.25:11-20,1986; United States Patent (USP) the 4th, 296, No. 206.

The ii) modification of 17 β side-chain radicals

The steroid Antiglucocorticoid can be obtained by the various structural modifications that 17 β side chains are carried out, and also in the method for the invention available.This class comprises synthetic Antiglucocorticoid such as dexamethasone-Oxetanone (oxetanone), various 17,17 β of 21-acetone derivatives and dexamethasone-carboxamide derivative (Lefebvre that quotes as described above, 1989; Rousseau, Nature 279:158-160,1979).

The iii) trim of other steroid skeleton

Being used in GR antagonist in the various embodiments of the present invention comprises influencing and results from the trim of any steroid skeleton of the interactional biological respinse of GR-agonist.Steroid skeleton antagonist can be any natural or synthetic hydrocortisone variant, as lack the adrenal steroid of C-19 methyl, as 19-demethyl deoxidation Adrenalone and 19-demethyl progesterone (Wynne, Endocrinology 107:1278-1280,1980).

Generally speaking, 11 β side chain substituents, especially substituent size plays a crucial role in the level of activity of the Antiglucocorticoid of measuring steroid.Replacement in the ring A of steroid skeleton also is important.17-hydroxyl-acrylic side chain is compared the activity that can reduce Antiglucocorticoid usually with the chemical compound that contains 17-propinyl side chain.

Other is well known in the art and be suitable for glucocorticoid receptor antagonists of the invention process and comprise 21-hydroxyl-6,19-oxidation progesterone is (referring to Vicent, Mol.Pharm.52:749-753 (1997)), Org31710 is (referring to Mizutani, 695-704 (1992)), Org34517, RU43044, RU40555 (referring to Kim, J steroid Biochem MolBiol.67 (3): 213-22 (1998)), RU28362 and ZKk98299 J steroid Biochem Mol Biol 42 (7):.

B. as the non-steroids Antiglucocorticoid of antagonist

The glucocorticoid antagonist of non-steroids also can be with treating latah in the method for the invention.These comprise synthetic albumen mimetic and analog, comprise the molecular entity of partial peptide class, plan peptide class and non-peptide class.For example, oligopeptide class mimetic used in this invention comprise the aminobenzoic acid derivative that the peptide class sulfanilamide, N-of (alpha-beta-unsaturated) replaces, low polyurethanes, low polyureas peptide class mimetic, hydrazine peptide, low polysulfones etc. (for example referring to, Amour, Int.J.Pept.Protein Res.43:297-304,1994; De Bont, Bioorganic ﹠amp; Medicinal Chem.4:667-672,1996).The foundation in the big storehouse of synthetic molecules and screening simultaneously can be undertaken by technique known in combinatorial chemistry, for example referring to van Breemen, and Anal Chem 69:2159-2164,1997; Lam, Anticancer Drug Des 12:145-167,1997.Especially can be in conjunction with combinatorial chemistry (combinatorial libraries) triage techniques use a computer programming (Murray, J.ofComputer-Aided Molec. Design 9:381-395,1995 at the peptide class mimetic of GR; Bohm, J.ofComputer-Aided Molec. Design 10:265-272,1996).This " reasonably drug design " helps to form the isomer and the conformation of peptide class, comprise ring isomerism body, contrary-trans isomer, contrary isomer etc. (as by Chorev at TibTech 13:438-445, discussed in 1995).

C. the identification of specially good effect glucocorticoid receptor antagonists

Because except above-mentioned chemical compound and compositions, any specially good effect GR antagonist can both be used for the treatment of latah in the method for the invention, other useful GR antagonist can be measured by those skilled in the art.Science and patent documentation disclose spendable various this type of scheme and known method, comprise the external and intravital chemical examination that is used to discern other GR antagonist.Enumerate the example of several exemplary below.

A kind of chemical examination that is used for discerning GR antagonist of the present invention be according to Granner at Meth.Enzymol.15:633, the method in 1970 is measured the GR antagonist inferred to the active influence of tyrosine aminotransferase.This analysis is based on the activity of the liver enzyme tyrosine aminotransferase (TAT) in Hepar Mus cancerous cell (RHC) culture medium and measures.TAT is the catalysis first step in the metabolism of cheese ammonia enzyme, and is caused by the glucocorticoid in liver and hepatoma carcinoma cell (hydrocortisone).This activity is measured easily in cell extract.TAT transfers the amino of tyrosine to 2-oxopentanedioic acid, also forms p-medical midbodies of para (ortho)-hydroxybenzoic acetone acid esters, and it can be converted into more stable p-hydroxy benzaldehyde in alkaline solution, and quantitatively absorbs at the 331nm place.GR antagonist of inferring and hydrocortisone in vivo or external co-administered to whole liver, hepatoma carcinoma cell or cell extract.When the TAT live vol that has reduced initiation is compared in the administration of chemical compound with matched group (promptly only adding hydrocortisone or GR agonist), this chemical compound is identified as the chemical compound of GR antagonist (also referring to Shirwany, Biochem.Biophys.Acta886:162-168,1986).

Except TAT chemical examination, the available many further exemplary assay that is used to discern composition in the method for the invention also is based on intravital glucocorticoid activity chemical examination.For example, the GR antagonist that also can use assessment to infer is stimulated by glucocorticoid and suppresses to absorb the chemical examination that the 3H-thymidine enters the ability of the DNA in the cell.Selectively, the GR antagonist of supposition comprises with liver cancer tissue and cultivates the bonded 3H-dexamethasone of GR (for example referring to, Choi etc., Steroids 57:313-318,1992).As another embodiment, can use the GR antagonist of supposition suppress with ³The bonded ability of nuclear of H-dexamethasone-GR coordination compound (Alexandrova etc., J. Seroid Biochem.Mol.Biol.41:723-725,1992).Be the GR antagonist that further identification is inferred, can use the kinetics chemical examination (as at Biochem J.204:721-729,1982 in disclosed) of distinguishing glucocorticoid agonists and antagonist by receptors bind kinetics by Jones.

In another illustrative embodiment, can use by Daune at Molec.Pharm.13:948-955, the Antiglucocorticoid activity is discerned in disclosed chemical examination in No. the 4th, 386,085, the 1977 disclosed and United States Patent (USP)s.In brief, adrenoprival rat chest cell is cultivated in the Nutrient medium of the variable concentrations that contains dexamethasone and test compounds (the GR antagonist of supposition).In cell culture medium, add ³The H-uridnine is further cultivated, and measures the degree that radiosiotope enters polynucleotide.Glucocorticoid agonists can reduce ³The addition of H-uridnine.Like this, the GR antagonist is opposite with this effect.

As for the method for other chemical compound that can use in the method for the invention and identification and this compounds of manufacturing, referring to United States Patent (USP) the 4th, 296,206 (referring to top); 4,386; 085 (referring to top); 4,447,424; 4,477,445; 4; 519,946; 4,540,686; 4,547; 493; 4,634,695; 4,634,696; 4; 753,932; 4,774,236; 4; 808,710; 4,814,327; 4; 829,060; 4,861,763; 4; 912,097; 4,921,638; 4; 943,566; 4,954,490; 4; 978,657; 5,006,518; 5; 043,332; 5,064,822; 5; 073,548; 5,089,488; 5; 089,635; 5,093,507; 5; 095,010; 5,095,129; 5; 132,299; 5,166,146; 5; 166,199; 5,173,405; 5; 276,023; 5,380,839; 5; 348,729; 5,426,102; 5; 439,913 and 5,616, No. 458; and WO 96/19458, it discloses for the steroid receptor has high affinity; the high non-steroids of selecting regulator (antagonist) is as-1 of 6-replacement, the shielded quinoline of 2-dihydroxy-N-1.

Can use the known various chemical examinations of those skilled in the art to measure antagonist selectivity to GR for MR.For example, can compare the bonded ability of antagonist and GR with MR and identify specific antagonists (for example referring to, United States Patent (USP) the 5th, 606,021,5,696,127,5,215,916,5,071, No. 773) by measuring.This analysis can be carried out or combine with the competition of pure GR or MR by assessment in the presence of known antagonist carrying out in conjunction with chemical examination by direct.In exemplary chemical examination, but the cell of stably express higher level glucocorticoid receptor (GR) or mineralcorticoid receptor (for example referring to, United States Patent (USP) the 5th, 606, No. 021) is as the body source that is subjected to of purification.Directly measure the affinity of receptor antagonist then.Select those with respect to MR GR to be shown high at least 100 times affinity in the method for the invention then, normally 1000 times antagonist.

The GR specific antagonists also can be defined as having inhibition GR and mediate active ability and do not suppress the chemical compound that MR mediates active ability.The activation capacity that a kind of method of discerning this type of GR specific antagonists is to use transfection chemical examination assessment antagonist to stop report to form (for example referring to, J.Steroid Biochem Molec.Biol.45:205-215 such as Bocquel, 1993; United States Patent (USP) the 5th, 606,021,5,929, No. 058).In exemplary transfection chemical examination, coding receptor expression plasmid is entered suitable receptor negativity host cell with the report plasmid that contains the reporter gene that links to each other with the receptor-specific regulating element by transfection.Then the host cell of transfection have hormone in the presence of and do not have hormone (as hydrocortisone or its analog) in the presence of cultivate, it can activate the hormone response promoter/reinforcing agent element of report plasmid.Next, monitor the host cell of transfection and cultivation for introducing (promptly existing) product of reporter gene sequence.At last, by measure acceptor gene have or not antagonist in the presence of activity, measure estrogen receptor protein matter (by the receptor dna sequence at coding on the expression plasmid and in the host cell of transfection and cultivation, produce) expression and/or with the binding capacity of steroid.The antagonist activities of chemical compound can be by measuring (for example referring to United States Patent (USP) the 5th, 696, No. 127) with the contrast of known GR and MR receptor antagonist.Report effectiveness with respect to the agonist compounds of reference with observed peak response degree to each chemical compound then.With respect to MR, GR is shown high at least 100 times activity, often is that 1000 times or bigger active antagonist are considered to the GR specific antagonists.

4. use glucocorticoid receptor antagonists treatment latah

Use Antiglucocorticoid such as mifepristone to treat latah in the method for the invention as medicine.The compositions or the chemical compound of any can inhibition relevant with the combination of GR with hydrocortisone or hydrocortisone analog biological respinse can both be used as medicine of the present invention.Conventional method that measure to implement the dosage of GR antagonist of the inventive method and preparation in patent documentation and scientific literature by fully open.Enumerate some exemplary embodiments below.

A. glucocorticoid receptor antagonists is as pharmaceutical composition

The GR antagonist of Shi Yonging can be by any way administration well known in the art in the method for the invention, and for example, parenteral, epidermis administration, oral administration, or the administration of locality are as aerosol or percutaneous dosing.Method of the present invention provides preventative and/or therapeutic treatment.Depend on health status or disease, reach latah degree, each patient's general medical science disease, the method for optimizing of administration etc., can be as the GR antagonist of pharmaceutical preparation by the form administration of various unit dose.Details about preparation and administration is fully open in science and patent documentation, for example referring to Remington ' the s Pharmaceutical Sciences of latest edition, and Mack Publishing Co, Easton PA (" Remington ' s ").

Can make the known any method in field according to medicine and prepare GR antagonist pharmaceuticals preparation.These medicines can contain sweeting agent, flavoring agent, coloring agent and preservative agent.The mixed with excipients that any GR antagonist formulation can be acceptable with no cytotoxic drug, be suitable for making.

The pharmaceutical preparation that is used for oral administration can use on the materia medica well known in the art acceptable carrier with suitably and proper dosage formation.These carriers can make pharmaceutical preparation form with the form of unit dose, are suitable for the mode of patient's picked-up as tablet, pill, powder, dragee, capsule, liquid, cough drop, colloidal sol, syrup, slurry, suspended substance etc.Add other suitable chemical compound when needed with after obtaining tablet or sugar-coat core, can by mix GR agonist compounds and solid excipient, optionally grind the mixture that obtains, and the processing granular mixture obtain pharmaceutical preparation for oral use.The solid excipient that is fit to is carbohydrate or protein filler, includes but not limited to sugar, as lactose, sucrose, mannitol or Sorbitol; The starch that comes from corn, Semen Tritici aestivi, rice, Rhizoma Solani tuber osi or other plant; Cellulose is as methylcellulose, HYDROXY PROPYL METHYLCELLULOSE or sodium carboxymethyl cellulose; And rubber, comprise acacia gum and tragacanth; And albumen, as gel and collagen.If desired, can add and decompose or solubilising reagent, as crosslinked polyvinylpyrrolidone, agar, alginic acid or its salt, as sodium alginate.

The dragee core can have suitable coat, as spissated sugar juice, also can contain acacia gum, Talcum, polyvinylpyrrolidone, the poly-rare gel of carboxylic second, Polyethylene Glycol and/or titanium dioxide, lacquer solution, reach suitable organic solvent or solvent mixture.Can in tablet or dragee coat, add dyestuff or pigment to produce the amount (being dosage) of identification or sign reactive compound.Pharmaceutical preparation of the present invention also can orally use, for example, and the socket joint mode capsule that makes by gel, and the capsule of the soft seal that makes by gel, and coat such as glycerol or Sorbitol.Socket joint mode capsule can contain the GR antagonist that is mixed with filler or binding agent such as lactose or starch, lubricant such as Talcum or magnesium stearate, reaches selectable stabilizing agent.In soft capsule, GR agonist compounds solubilized or be suspended in the suitable liquid is as fatty oil, liquid paraffin, maybe can contain stabilizing agent or do not contain the liquid macrogol of stabilizing agent.

Waterborne suspension of the present invention contains and the mutually blended GR antagonist of excipient that is suitable for preparing waterborne suspension.This type of excipient comprises suspension reagent and dispersion or wetting agent, suspension reagent such as sodium carboxymethyl cellulose, methylcellulose, HYDROXY PROPYL METHYLCELLULOSE, sodium alginate, polyvinylpyrrolidone, tragacanth and Radix Acaciae senegalis, and albumen are as gel and collagen; Disperse or wetting agent such as natural phospholipid (for example lecithin), the enriched product (for example Myrj 45) that contains the epoxyalkane of fatty acid, the enriched product (for example heptadecaethylene oxycetanol) that contains the oxirane of long-chain fatty alcohol, contain from fatty acid and hexitol and derive and the enriched product (for example polyoxyethylene sorbitol monoleate) of the oxirane of the partial ester that comes, or contain from fatty acid and hexitan and derive and the enriched product (for example polyoxyethylene sorbitan monoleate) of the oxirane of the partial ester that comes.This waterborne suspension also can contain one or more antiseptic, as ethyl or n-pro-pyl-p-hydroxybenzoate, one or more coloring agent, one or more flavoring agents, and one or more sweeting agents, as sucrose, aspartame or glucide.The mole osmotic concentration is regulated preparation by weight.

Can form oil suspension, vegetable oil such as Oleum Arachidis hypogaeae semen, olive oil, Oleum sesami or Oleum Cocois, mineral oil such as liquid paraffin by suspension GR antagonist in vegetable oil, mineral oil or these oily mixture.Oil suspension can contain intensifier, as Cera Flava, hard paraffin or hexadecanol.Add sweeting agent such as glycerol, Sorbitol or sucrose delicious oral formulations can be provided.These preparations can be preserved by adding antioxidant such as ascorbic acid.The example of the oily excipient of injection can be referring to Minto, J.Pharmacol.Exp Ter.281:93-102,1997.Pharmaceutical preparation of the present invention is the form of oil-in-water emulsion also.Oil phase is aforesaid vegetable oil or mineral oil or its mixture.The emulsifying agent that is fit to comprises natural rubber, as acacia gum and tragacanth, natural phospholipid, derive and the partial ester that comes as soybean lecithin, ester or from fatty acid and hexitan, as the sorbitan monoleate and contain the partial ester enriched product of oxirane, as polyoxyethylene sorbitan monoleate.Emulsion also can contain sweeting agent and flavoring agent, as syrup and elixir.These preparations also can contain demulcent, antiseptic or coloring agent.

The present invention is suitable for preparing waterborne suspension by adding entry, dispersed powders and granule can from be mixed with dispersant, suspending agent and/or wetting agent, and the GR antagonist of one or more antiseptic make.Dispersant, wetting agent and the suspending agent that is fit to by as disclosed above those as an example.The excipient that also can have other, for example sweeting agent, flavoring agent and coloring agent.

For from rectally, GR antagonist of the present invention also can be with the form administration of suppository.These preparations can prepare by hybrid medicine and the non-irritating excipient that is fit to, and this excipient is a solid under ordinary temp, but is liquid under rectal temperature, can melt in rectum thus and discharge medicine.These materials are cupu oil and Polyethylene Glycol.

GR antagonist of the present invention also can be with intranasal, ophthalmic, intravaginal and intrarectal scheme administration, preparation (the steroid inhalant for example that comprises suppository, insufflation, powder and aerosol, referring to Rohatagi, J.Clin.Pharmacol.35:1187-1193,1995; Tiwa, Ann.AllergyAsthma Immunol. 75:107-111,1995).

GR antagonist of the present invention can pass through transdermal, local line dispensing, and makes forms such as medicated sound, solution, suspension, emulsion, colloidal sol, paste, ointment, pastel, gel, paint, powder and aerosol.

For slowly discharging in vivo, GR antagonist of the present invention also can be with the form dispensing of microsphere.For example, microsphere can contain by cortex injection can be in microsphere drug (for example mifepristone) administration of subcutaneous slow release (referring to Rao, J.Biomater Sci.Polym.Ed.7:623-645,1995), as biodegradable or injectable sol preparation administration (for example referring to Gao Pharm.Res.12:857-863,1995) or as the microsphere oral administration (for example referring to Eyles, J.Pharm.Pharmacol.49:669-674,1997).Route in transdermal and the cortex all can provide the ration distribution by the week and the moon.

GR antagonist pharmaceuticals preparation of the present invention can provide with salt, and available a lot of kind acid forms, and includes but not limited to hydrochloric acid, sulphuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid etc.Salt is easier to be dissolved in the proton solvent of aqueous or other corresponding free alkali form.In other cases, preferred preparation before use with the blended freeze-dried powder of buffer, the pH of this buffer is 4.5 to 5.5 and contains the histidine of 1mM-50mM, the sucrose of 0.1%-2%, the mannitol of 2%-7%.

In another embodiment, GR antagonist formulation of the present invention is suitable for parenteral, as intravenous (IV) administration or be administered to the body cavity or the inner chamber of organ.This drug-delivery preparation generally includes the solution of the GR antagonist (for example mifepristone) that is dissolved in the medicine acceptable carrier.These can be accepted and spendable excipient and solvent are water and perfusion solution (Ringer ' s solution), isotonic sodium chlorrde solution.In addition, aseptic fixedly oil also can be used as solvent or suspension media usually.For reaching this purpose, can use any bland fixedly oil, comprise synthetic monoglyceride or diglyceride.In addition, fatty acid such as oleic acid similarly can use in ejection preparation.These solution are aseptic, and also do not have unwanted material usually.These preparations can be by the known sterilization technology sterilization of routine.This preparation can contain under nearly physiological condition needed medicine can accept auxiliary substance, as pH regulator agent, buffer agent, toxicity regulator, for example sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate etc.According to the ad hoc fashion of administration and patient's needs, the concentration of the GR antagonist in these preparations can change on a large scale, mainly is based on fluid volume, viscosity, body weight and waits and select.For the IV administration, but this preparation aseptic injection preparation, as aseptic injection aqueous or oily suspensions.Can be according to using the suitable dispersant or the known technology of wetting agent and suspending agent to form this suspension.Aseptic injection preparation also can be aseptic injectable solution or the suspension that is present in nontoxic, acceptable diluent of parenteral or the solvent, as 1,3 butylene glycol solution.

In another embodiment, GR antagonist formulation of the present invention can transmit with liposome or the endocytosis that cell membrane merges by using, promptly utilize with the liposome adhesion or directly adhere to the part of oligonucleotide, oligonucleotide causes endocytosis by the surface membrane protein receptors bind with cell.By using liposome, particularly utilize surface of liposome delivery for the specific part of target cell, or the specific organ of opposite preferred directly sensing, people can be in vivo focus on target cell with the dispensing of GR antagonist like this.(for example referring to AL-Muhammed, J.Microencapsul.13:293-306,1996; Chonn, Curr.Opin.Biotechnol.6:698-708,1995; Ostro, Am.J Hosp.Pharm.46:1576-1587,1989).

B. the mensuration of the dosage regimen of glucocorticoid receptor antagonists

Method of the present invention can be treated latah, promptly reduces the generation and the severity of cognition, consciousness or disturbance of consciousness.The amount that can fully realize this purpose GR antagonist is defined as " treatment effective dose ".Use effective dosage and amount for this, promptly " dosage regimen " depends on various factors, comprises the common state, patient's body state, age of disease or health status, disease or healthy severity, patient health etc.When calculating patient's dosage, also should consider administering mode.

Dosage also should be considered pharmacokinetic parameter well known in the art, and promptly the absorption rate of GR antagonist, bioavailability, metabolism, removing etc. are (for example referring to Hidalgo-Aragones (1996) J.Steroid Biochem.Mol.Biol.58:611-617; Groning (1996) Pharmazie51:337-341; Fotherby (1996) Contraception 54:59-69; Johnson (1995) J.Pharm.Sci.84:1144-1146; Rohatagi (1995) Pharmazie 50:610-613; Brophy (1983) Eur.J.Clin Pharmacol.24:103-108; The latest edition Remington that quotes as described above).For example, in a certain research, the mifepristone daily dose less than 0.5% drains in urine, and this medicine can be very widely and circulation albumin bound (referring to the Kawai that quotes as described above (1989)).This state of the art can allow the clinician to measure the disease or the disease of dosage, GR antagonist and the desire treatment of each single patient.In illustrative embodiment, provide below to be used as and instruct the mifepristone guide for use of measuring dosage, be i.e. the dosage regimen and the dosage level of any GR antagonist that when implementing method of the present invention, uses.

Depend on needed and endurable dosage of patient and frequency, available one or more GR antagonist formulation administrations.This preparation should be able to provide the active agents of capacity, as mifepristone, with effective treatment latah.Thus, a kind of common drug preparation that is used for the mifepristone oral administration is the daily dose administration by the about 0.5～20mg of per kg body weight per day.At one selectively in the embodiment, use the amount administration of the about 1～4mg of the every kg body weight of each patient every day.Particularly when the administration of anatomy concealed location, as cerebrospinal fluid (CSF) position, compare with oral administration, available lower dosage enters the inner chamber of blood flow, body cavity or organ.When topical, can use higher dosage basically.The practical methods that is used to prepare the GR antagonist formulation of parenteral is known or obvious for those skilled in the art, and has more detailed open in the publication of all Remington that quotes as described above.Also referring to Nieman, " Receptor Mediated Antisteroid Action, " Agarwal etc., eds., De Gruyter, New York (1987).

The persistent period of administration is 5～14 days.After formation contains the medicine of GR antagonist of the present invention in acceptable carrier, can be placed in the suitable containers and the label of labeled for treatment indication.For the administration of GR antagonist, this indicates and can comprise, for example, and about the directions for use of administration consumption, frequency and method.In one embodiment, the invention provides a kind of medicine box that is used for the treatment of human latah, the guiding material that it comprises the GR antagonist and is used to instruct indication, dosage and the administration time of the administration of GR antagonist.

Embodiment

The following examples explanations is provided but does not limit claimed invention.

Embodiment 1: treat latah with mifepristone

How the following examples explanation implements method of the present invention.

The patient selects

Use subjectivity and objective criterion, comprise the aforesaid standard that is proposed by DSM-IV-TR, diagnosis suffers from the individuality of latah.The latah patient has normal cortisol levels usually for his or for his age.

The dosage of mifepristone and administration

In this research, use glucocorticoid receptor (GR) (GR) antagonist, i.e. mifepristone.With the dosed administration of 600～1200mg weekly.Assess patient as described below.Scalable dosage, and further assessment termly in whole therapeutic processes if desired.

The mifepristone tablet is that Hua Lian, the Shanghai Pharm Pur GmbH from Chinese Shanghai obtains.

The treatment assessment of latah

For describing and assess the effectiveness that mifepristone improves the latah symptom, all patients are carried out formal spirit assessment, reach a series of neuropsychological test and assessment.Use the standardized test means that are suitable for the latah form to measure patient's behavior under study for action.These are tested and diagnostic assessment occurs in baseline place (entering the patient of treatment) and generation regularly in whole therapeutic processes.

Embodiment 2: measure cortisol levels

For measuring the cortisol levels of patient among the embodiment 1, employing and the afternoon hydrocortisone thermometrically method of measuring as the baseline hydrocortisone.Measurement the 0th day, two weeks (the 14th day) after accepting Drug therapy, and the each observation in six months and the cortisol levels of routine observation thereafter.

(Diagnostic Products Corporation, LosAngeles CA) measure the blood cortisol levels to use " double antibody hydrocortisone medicine box ".This test is a kind of emulative radioimmunoassay chemical examination, wherein uses ¹²⁵The hydrocortisone competition of the hydrocortisone of I spike and the clinical sample that comes from antibody location, and use the reagent that manufacturer provides basically and carry out according to the indication of manufacturer.In brief, collect blood by venipuncture with from the serum that cell separation goes out.Sample is 2～8 ℃ of following preservations up to 7 days or at-20 ℃ times freezing 2 months.Before chemical examination, rotation or inversion (gentle swirling or inversion) by gentleness can make sample be raised to room temperature (15-28 ℃).Prepare 16 on all four test tubes, the serum of 25 microlitres is housed in every test tube.Calculate concentration of cortisol from the calibration test tube of preparing.Net content equals average CPM and deducts average unspecific CPM.By carrying out interpolation to estimate unknown concentration of cortisol (Dudley etc., (1985) Clin.Chem.31:1264-1271) to checking and approving curve.

Should be appreciated that, embodiment described herein and embodiment are illustrative, technical staff under this area can advise the various modifications and the variation that produce therefrom easily, and they belong to the application's spirit and scope, and also within the scope of claims.

Claims (22)

1. glucocorticoid receptor antagonists is used for improving the purposes of the medicine of patient's latah symptom in preparation, and condition is that described patient does not suffer from other disease that need treat with glucocorticoid receptor antagonists as yet.

2. purposes as claimed in claim 1, wherein said glucocorticoid receptor antagonists contains the steroid skeleton, contains a phenyl moiety at least in 11 β positions of steroid skeleton.

3. purposes as claimed in claim 2, the wherein said phenyl moiety that contains in 11 β positions of steroid skeleton is the dimethylaminophenyl part.

4. purposes as claimed in claim 3, wherein said glucocorticoid receptor antagonists comprises mifepristone.

5. purposes as claimed in claim 3, wherein said glucocorticoid receptor antagonists is selected from RU009 and RU044.

6. purposes as claimed in claim 1, wherein said medicine comprise the glucocorticoid receptor antagonists and the medicine acceptable carrier of effective dose.

7. purposes as claimed in claim 6, wherein said glucocorticoid receptor antagonists contains the steroid skeleton, contains a phenyl moiety at least in 11 β positions of steroid skeleton.

8. purposes as claimed in claim 7, the wherein said phenyl moiety that contains in 11 β positions of steroid skeleton is the dimethylaminophenyl part.

9. purposes as claimed in claim 8, wherein said glucocorticoid receptor antagonists comprises mifepristone.

10. purposes as claimed in claim 8, wherein said glucocorticoid receptor antagonists is selected from RU009 and RU044.

11. purposes as claimed in claim 6 comprises that glucocorticoid receptor antagonists and the medicine acceptable carrier with effective dose mixes.

12. purposes as claimed in claim 11, wherein said glucocorticoid receptor antagonists contains the steroid skeleton, contains a phenyl moiety at least in 11 β positions of steroid skeleton.

13. purposes as claimed in claim 12, the wherein said phenyl moiety that contains in 11 β positions of steroid skeleton is the dimethylaminophenyl part.

14. purposes as claimed in claim 13, wherein said glucocorticoid receptor antagonists comprises mifepristone.

15. purposes as claimed in claim 13, wherein said glucocorticoid receptor antagonists is selected from RU009 and RU044.

16. a medicine box for the treatment of human latah, described medicine box comprises:

The specially good effect glucocorticoid receptor antagonists; And

The directiveness material is used for illustrating to the latah patient indication, dosage and the administration time of described glucocorticoid receptor antagonists.

17. medicine box as claimed in claim 16, wherein said guiding material show that described glucocorticoid receptor antagonists can be by the daily dose administration of the about 0.5～20mg of per kg body weight per day.

18. medicine box as claimed in claim 17, wherein said guiding material show that described glucocorticoid receptor antagonists can be by the daily dose administration of the about 1～10mg of per kg body weight per day.

19. medicine box as claimed in claim 18, wherein said guiding material show that described glucocorticoid receptor antagonists can be by the daily dose administration of the about 1～4mg of per kg body weight per day.

20. as each described medicine box in the claim 16～19, wherein said glucocorticoid receptor antagonists comprises mifepristone.

21. as each described medicine box in the claim 16～19, wherein said mifepristone is a tablet form.

22. as each described medicine box in the claim 16～19, wherein said glucocorticoid receptor antagonists is selected from RU009 and RU044.