• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    The present invention generally belongs to the field of psychiatry. In particular, the present invention can be used in a method of preventing weight gain induced by antipsychotics with a medicament capable of inhibiting the binding of cortisol to its receptor. Mifepristone, a potent specific glucocorticoid receptor antagonist, can be used in these methods. The invention also provides kits for preventing weight gain induced by AP in humans, including indications, dosages, and dosing schedules of glucocorticoid receptor antagonists and glucocorticoid receptor antagonists.
    公开号:KR20040028942A
    申请号:KR10-2004-7001039
    申请日:2002-07-22
    公开日:2004-04-03
    发明作者:조셉 케이. 베라노프；알란 에프. 샤츠버그
    申请人:코어셉트 쎄라퓨틱스, 잉크.；
    IPC主号:
    专利说明:

    Methods for preventing weight gain caused by antipsychotics {Methods for Preventing Antipsychotic-Induced Weight Gain}
    [3] The present invention relates to the discovery that agents capable of inhibiting the biological activity of glucocorticoid receptors can be used in methods for preventing weight gain caused by antipsychotics.
    [4] AP medication is one of the most important treatments for treating various psychotic disorders. In order for these antipsychotics to be of maximum benefit, adverse side effects of antipsychotics, particularly those associated with long-term administration, should be minimized. However, a number of reports based on large-scale clinical studies report that 40-80% of patients taking chronic antipsychotics are experiencing substantial weight gain, often exceeding their ideal weight by 20%. (See Umbricht et al., J. Clin. Psychiatry 55 (Suppl. B): 157-160, 1994; Baptista, Acta Psychiatr. Scand. 100: 3-16, 1999). This weight gain can substantially offset the benefits of treating psychotic disorders. First of all, a person who weighs much more than a healthy weight range dramatically increases the risk of being exposed to many serious health problems related to obesity, such as cardiovascular disease, stroke, high blood pressure, type II diabetes, and certain types of cancer. Next, this unintentional gain in weight is one of the most common reasons why patients are less likely to follow antipsychotic medications on a scheduled schedule. Eventually, they can't cure psychotic disorders.
    [5] The degree of weight gain caused by different antipsychotics is different. Newer or atypical antipsychotics, such as clozapine or olanzapine, have been found to have a greater ability to induce weight gain (Allison et al., Am. J. Psychiatry 156: 1686-1696, 1999). ). Although research suggests that insulin, leptin, and certain reproductive hormones play an important role in this process, the exact mechanisms of weight-induced weights caused by antipsychotics are related to many factors and their complex interactions. Should remain a challenge.
    [6] Insulin is the synthesis and secretion of pancreatic β-cells in response to an increase in blood glucose levels, more than any other cause. Insulin can induce body weight fluctuations by acting on cell surface receptors, stimulating cellular glocos uptake, directly affecting adipose tissue or inducing hypoglycemia and stimulating appetite (Melkersson & Hulting, Psychopharmacology 154: 205). -212, 2001). Leptin is another important hormone that controls your weight. Leptin, encoded by the ob gene, is produced primarily by adipose tissue, and its circulating concentration certainly correlates with the body fat percentage (percent) and the baseline concentration of insulin. Leptin and insulin work together to regulate long-term body fat storage homeostasis with lipid and carbohydrate metabolism (Baptista et al., Pharmacopsychiatry 33: 81-88, 2000).
    [7] Glucocorticoid hormones are synthesized in the adrenal cortex under the control of the hypothalamic-pituitary-adrenal axis. It is an important factor in responding to many physical and mental stresses and plays a pivotal role in regulating the metabolism of salt and water, blood pressure, immune function, and metabolism. Cortisol is the major glucocorticoid hormone in humans. Lack of this (Addison's disease or hypothalamus) is associated with postural hypotension, weight loss, and hypoglycemia, and its excess (Cushing's disease) is associated with hypertension, obesity, and glucose intolerance. The effect of cortisol depends at least in part on the action by which cortisol antagonizes the activity of insulin (ie, inducing insulin resistance) (Andrews & Walker, Clin. Sci. 96: 513-523, 1999). .
    [8] Researchers have reported hormonal abnormalities in patients receiving long-term antipsychotics, including changes in reproductive hormone levels and increased insulin and leptin levels in both men and women (Baptista et al., Pharmacopsychiatry 33: 81-88, 2000 and Melkersson & Hulting, Psychopharmacology 154: 205-212, 2001). However, these studies do not establish a clear and consistent relationship between weight gain induced by antipsychotics and certain hormone (eg insulin and cortisol) concentrations. Thus, prior to the present invention, there was no evidence that glucocorticoid receptor antagonists could be effective agents to prevent or reverse weight gain induced by antipsychotics (especially in patients with normal ranges of cortisol concentrations). Many cortisol activity is mediated by binding to type I (mineral corticoid) receptors that preferentially bind to type II (glucocorticoid) receptors at physiological cortisol concentrations. As the cortisol concentration increases, more glucocorticoid receptors are bound and activated. Because cortisol plays a key role in metabolism, it can be fatal to inhibit all of the activity mediated by cortisol. Therefore, in the present invention, an antagonist that selectively inhibits the action of the type II glucocorticoid receptor while not antagonizing the action of the type I mineral corticoid receptor is very useful. Examples of such receptor antagonists include RU486 and similar antagonists.
    [9] The inventors of the present application conclude that glucocorticoid receptor antagonists such as RU486 are useful agents for preventing or reversing the weight gain induced by antipsychotics in patients with normal cortisol concentrations, increased cortisol concentrations, and decreased cortisol concentrations. Built. Accordingly, the present invention satisfies the need to effectively inhibit unwanted weight gain caused by antipsychotics by administering glucocorticoid receptor antagonists to patients under a long-term antipsychotic medication plan.
    [1] <Cross Reference to Related Application>
    [2] This application claims priority based on US patent application Ser. No. 60 / 307,693, filed July 23, 2001. The application is hereby incorporated by reference in its entirety in all respects.
    [10] Summary of the Invention
    [11] The present invention provides a method of inhibiting or reversing the weight gain induced in a patient by antipsychotics. The method comprises administering to a patient an effective amount of a glucocorticoid receptor antagonist. At this time, however, the patient should not have to be treated with glucocorticoid receptor antagonist otherwise, and there should be no psychotic major depression.
    [12] One aspect of the invention is to provide a method for inhibiting or reversing weight gain caused by antipsychotics in a patient treated with atypical antipsychotics.
    [13] Another form of the present invention is a method of inhibiting or reversing the weight gain induced by antipsychotics in a patient treated with antipsychotics selected from clozapine, olanzapine, risperidone, ketiapine, and sertindol.
    [14] Another form of the invention is the administration of a glucocorticoid receptor antagonist to a patient who has gained at least 2 kg of weight after treatment with antipsychotics for 10 weeks.
    [15] Another form of the invention is the administration of a glucocorticoid receptor antagonist to a patient who is at least 20% above the healthy body weight range.
    [16] Another form of the invention is that the glucocorticoid receptor antagonist comprises a steroid structure having at least one phenyl containing moiety at the 11-beta position. The phenyl containing residue at the 11-beta position of the steroid structure may be a dimethylaminophenyl residue. In another embodiment the glucocorticoid receptor antagonist may comprise mifepristone. In other words, the glucocorticoid receptor antagonist may be selected from the group consisting of RU009 and RU044.
    [17] Another form of the invention is that the glucocorticoid receptor antagonist is administered daily in an amount of about 0.5 to about 20 mg or in an amount of about 1 to about 10 mg or in an amount of about 1 to about 4 mg per kg of body weight per day. . Administration may be only once a day. In another embodiment the method of administering a glucocorticoid receptor antagonist may be oral administration, transdermal administration, administration by nebulized suspension or administration by aerosol spray.
    [18] The invention also provides a kit for inhibiting or reversing weight gain in humans caused by antipsychotics, which instructions, dosages, schedules, etc., regarding the administration of glucocorticoid receptor antagonists and glucocorticoid receptor antagonists Include explanatory material indicating In another embodiment, the descriptive data may be used to administer the glucocorticoid receptor antagonist in an amount of about 0.5 to about 20 mg per kilogram of body weight or in an amount of about 1 to about 10 mg or in an amount of about 1 to about 4 mg per kg body weight daily. To instruct. This explanatory data demonstrates that cortisol can increase the weight of patients taking antipsychotics and indicates that glucocorticoid receptor antagonists can be used to inhibit or reverse this weight gain. In one embodiment the glucocorticoid receptor antagonist included in the kit may be mifepristone. This mifepristone may be a tablet.
    [19] With reference to the rest of the specification and claims of the present application, one may better understand the nature and usefulness of the present invention.
    [20] All publications, patents, and patent applications cited herein are incorporated herein for all purposes.
    [21] Justice
    [22] The term "inhibition" means any indication that successfully prevents or reduces the weight gain caused by antipsychotics. Prevention or reduction of weight gain caused by administration of antipsychotics can be measured by objective parameters (eg, physical examination results). For example, the method of the present invention can successfully inhibit weight gain caused by antipsychotics by limiting weight gain to 1 kg or less for 10 weeks in patients receiving antipsychotics.
    [23] The term "inversion" refers to any indication that successfully reduces the weight gain already caused by antipsychotics before administering the glucocorticoid receptor antagonist. Already increased weight loss can be measured by objective parameters (eg physical examination results). For example, the method of the present invention successfully reverses the weight of a patient induced by antipsychotics by reducing at least 50% of the increased body weight after administration of the antipsychotic but before the administration of the glucocorticoid receptor antagonist. You can.
    [24] The term "antipsychotic" refers to a medicament capable of alleviating psychotic disorders in its broadest sense and function with acceptable safety and practicality. Alleviation of symptoms can be measured by subjective and objective criteria. Antipsychotics are one agent or derivative thereof, or more than one agent or tricyclic phenothiazine, derivatives and dibenzepines from thioxanthene, as well as butytrophenone and classes, other heterocycles, and It may be a bond of experimental benzamide. Its action may depend on the interaction with D1 or D2 dopamine, 5-HT 2 serotonin, α-adrenergic receptor, or other dopamine receptor yet to be identified. For example, chlorprotisene, clozapine, haloperidol, roxazine, mesozinazine / thiolidazine, mollindon, olanzapine, perphenazine, pimozide, prochlorperazine, quetiapine, risperidone, sertindol, thio Thixen, trifluoroperazine, ziprasidone, and zucopentisol are antipsychotics.
    [25] See also "Psychiatric Depression" (Schatzberg, Am. J. Psychiatry 149: 733-745, 1992), "Psychotic (delusional) Depression" (e.g.), "Delusional Depression" (Glassman, Arch. Gen. Psychiatry 38: 424-427, 1981), and the term "psychiatric major depression," also referred to as "major depression with psychotic characteristics" (see American Psychiatric Association, Diagnostic and Statistical manual of Mental Disorders (DSM), Third Edition). Is a specific psychotic disorder that includes both depressive and psychotic features. Individuals who exhibit both depression and psychiatric disorders, ie, psychotic depression, are referred to herein as "psychiatric depressive." For example, as previously described by Schatzberg in 1992, it has long been recognized as a unique syndrome in the art. The explanation for its uniqueness is to be studied in the significant differences between patients with psychotic and nonpsychotic depression in glucocorticoid activity, dopamine-hydrolase activity, amounts of dopamine and serotonin metabolites, sleep methods and ventricular to brain ratios. Can be. Psychotic depression responds very differently to treatment compared to individuals with other forms of depression, such as “non-psychiatric major depression”. Psychotic depression does not respond significantly to tricyclic (antidepressant) drug treatment (Glassman et al., Am. J. Psychiatry 1332: 716-719, 1975). Psychotic depression can respond to electroconvulsive therapy (ECT), while their response time is relatively slow, and ECT has a high level of relative morbidity. Clinical findings and diagnostic parameters of "psychiatric major depression" are described in detail in DSM (Fourth Edition, 1995).
    [26] The term “atypical” refers to the character of a new class of antipsychotics that do not have extrapyramidal side effects associated with conventional antipsychotics. For example, clozapine and olanzapine are atypical antipsychotics.
    [27] The term "healthy weight range" was developed by the National Heart, Lung, and Blood Institute in collaboration with the National Institute of Diabetes and Digestive and Kidney Diseases. Refers to a body weight index (BMI) of just 19 to 25 as defined by primary federal standards for identification, evaluation and treatment of overweight and obesity (Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults: Evidence Report, 1998].
    [28] The term "cortisol" refers to a group of complexes, also called hydrocortisone, and any synthetic or natural analogs thereof.
    [29] The term “glucocorticoid receptor” (“GR”) refers to a group of intracellular receptors called cortisol receptors that specifically bind to cortisol and / or cortisol analogs. The term includes the heterostructure of GR, recombinant GR and mutated GR.
    [30] The term “mifepristone” refers to RU486 or RU38.486, or 17-beta-, which typically binds GR with high affinity and inhibits biological effects initiated / mediated by binding of cortisol or cortisol analogs to GR receptors. Hydroxy-11-beta- (4-dimethyl-aminophenyl) -17-alpha- (1-propynyl) -estra-4,9-dien-3-one), or 11-beta- (4-dimethylamino Phenyl) -17-beta-hydroxy-17-alpha- (1-propynyl) -estra-4,9-dien-3-one) or a group of compositions or analogs thereof. There are several chemical names for RU-486. For example, RU486 is 11B- [- (dimethylamino) phenyl] -17B-hydroxy-17- (1-propynyl) -estra-4,9-dien-3-one; 11B- (4-dimethyl-aminophenyl) -17B-hydroxy-17A- (prop-1-ynyl) -estra-4,9-dien-3-one; 17B-hydroxy-11B- (4-dimethylaminophenyl) -17A- (propynyl-1) -estra-4,9-dien-3-one; 17B-hydroxy-11B- (4-dimethylaminophenyl) -17A- (propynyl-1) -E; (11B, 17B) -11- [4-dimethylamino) -phenyl] -17-hydroxy-17- (1-propynyl) -estra-4,9-dien-3-one; And 11B- [4- (N, N-dimethylamino) phenyl] -17A- (prop-1-ynyl) -D-4,9-estradione-17B-ol-3-one.
    [31] The term “specific glucocorticoid receptor antagonist” refers to a composition or compound that partially or completely inhibits (or antagonizes) binding of a glucocorticoid receptor (GR) antagonist to GR, such as cortisol or a synthetic or natural cortisol analogue. A "specific glucocorticoid receptor antagonist" also refers to a composition or compound that inhibits any biological response associated with binding of GR and antagonist. By "specific" is meant to preferentially bind a drug to the GR at least 100 times, and often at least 1000 times, rather than the mineralocorticoid receptor (MR).
    [32] A patient who does not require glucocorticoid receptor antagonist treatment for other reasons refers to a patient who is not suffering from conditions known in the art to be effectively treated with glucocorticoid receptor antagonists. Conditions known or reported in the art to be effectively treated with glucocorticoid receptor antagonists include Cushing's disease, drug withdrawal, schizophrenia, dementia, stress disorders, and psychotic major depression.
    [33] Detailed description of the invention
    [34] The present invention relates to the surprising discovery that a medicament capable of inhibiting the biological response induced by glucocorticoids is effective in preventing weight gain induced by AP. In patients who have begun prolonged AP administration or are already receiving prolonged AP administration and as a result have gained substantial weight, the method of the present invention may preferably inhibit weight gain caused by AP. In one embodiment, the methods of the present invention employ a medicament that acts as a GR antagonist to prevent or reverse weight gain caused by AP drugs. The methods of the present invention are effective in preventing weight gain caused by AP in patients suffering from moderate, increased or decreased levels of cortisol or other natural or synthetic glucocorticoids.
    [35] Cortisol works by binding to intracellular glucocorticoid receptors (GR). In humans, glucocorticoid receptors come in two forms: ligand bound GR-alpha of 777 amino acids; And only the last 15 amino acids are in other GR-beta isoforms. Both types of GR show high affinity for specific ligands and are thought to function through the same signal transduction pathway.
    [36] The biological effects of cortisol, including lesions and dysfunctions caused by cortisol hyperemia, can be modulated and controlled at GR levels using receptor antagonists. Several different kinds of agents can act as GR antagonists, ie block the physiological effects of GR-antagonist binding (natural antagonists are cortisol). These antagonists include compounds that bind to GR and block the ability of the antagonist to bind and / or activate GR effectively. Mifepristone and related compounds, a group of known GR antagonists, are effective and potent antiglucocorticoid agents in humans (Bertagna, J. Clin. Endocrinol. Metab. 59: 25, 1984). Mifepristone binds to GR with a high affinity of dissociation constant K <10 -9 M (Cadepond, Annu. Rev. Med. 48: 129, 1997). Thus, in one embodiment of the present invention, mifepristone and related compounds are used to prevent weight gain induced by AP drugs.
    [37] Weight gain caused by AP can be easily detected by regular medical examination. Thus, various methods of monitoring weight change by the method of the present invention and estimating the success and extent of weight management success, i.e., weight gain induced by AP, may be inhibited or reversed, and some exemplary means are described herein. Indicated. These means may include simple weight measurement and complex means of determining body fat percentage as described below.
    [38] Since the methods of the present invention include the use of any means of inhibiting the biological effects of GR bound to antagonists, exemplary compounds and compositions that can be used to treat delirium are also listed. Also described are conventional procedures that can be used to identify additional compounds and compositions that can block biological responses caused by GR-antagonist interactions for use in practicing the methods of the present invention. Since the present invention suggests administering these compounds and compositions as drugs, the usual means of determining the dosing schedule and formulation of the GR antagonist drug for practicing the methods of the present invention are listed below.
    [39] 1. Determination of weight gain induced by antipsychotics
    [40] Weight gain resulting from long-term antipsychotics can, in principle, be obtained by comparing the weights of patients before and after administration. Weight gain can be reflected in increased body fat percentage (percentage). In order to gain weight by antipsychotic treatment, the body weight of the patient should be increased by 2 kg or more after administration of antipsychotic medicine for 10 weeks. In some aspects of the invention, the increase in patient weight may be greater than this. That is, the weight gain may be 3, 4, 5, 10, 15, or 20 kg or more after administration of the antipsychotic for 10 weeks. Weight gain can also be measured as a percentage increase in body weight while administering antipsychotics. That is, the weight gain after 10 weeks of antipsychotics can be measured by 5%, 10%, 15% or 20% increase. Percent body fat gain can be used to measure weight gain. That is, after 10 weeks of administration of antipsychotics, increased body fat may be measured at 2% or more, 5% or more, 10% or more or 15% or more.
    [41] Weight gain induced by antipsychotics can be measured and assessed using any of a variety of objective standard equipment known in the art. These include scales and equipment for measuring the percentage of body fat. A simple instrument, the scale, is commonly used by all doctors who specialize in health care. More complex instruments for measuring the percentage of body fat are based on skin-fold methology or body weight or electrical resistance.
    [42] 2. General laboratory test procedures
    [43] In practicing the methods of the present invention, various general laboratory tests may be used, including monitoring parameters such as blood cortisol, drug metabolism, and the like. This procedure can be helpful because every patient uniquely metabolizes and responds to the drug. Such monitoring may also be important because each GR antagonist exhibits different pharmacokinetic properties. Different patient and antipsychotics may require different dosage plans and formulations. Such procedures and means of determining dosage plans and formulations are well described in the academic and patent literature. Some descriptive examples are detailed below.
    [44] a. Measurement of Blood Cortisol Concentration
    [45] Although the present invention may be apparently performed in patients with normal blood cortisol concentrations, it has been believed that varying blood cortisol levels are associated with weight gain induced by antipsychotics. Therefore, monitoring cortisol in blood and estimating the cortisol concentration as a baseline is a useful laboratory test to help prevent weight gain induced by antipsychotics. There are a variety of laboratory tests that can be used to determine whether an individual's blood cortisol levels are normal, low, or excessive. Patients treated or treated with long-term antipsychotics usually have normal cortisol concentrations, often less than 25 μg / dl in the morning and often less than about 15 μg / dl in the afternoon, often in the afternoon at 5- It corresponds to the higher end of the normal range, which is considered to be 15 μg / dl.
    [46] Immunoassays such as radioimmunoassays are commonly used because they are accurate, easy to implement and relatively inexpensive. Because the amount of circulating cortisol exhibits adrenal cortex function, various stimulation and inhibition tests such as ACTH stimulation, ACTH stockpiling, dexamethasone inhibition testing (see Greenwald, Am. J. Psychiatry 143: 442-446, 1986, etc.) It may provide diagnostic, prognostic or other information that is used as ancillary in the method.
    [47] One such assay, available in kit form, is a radioimmunoassay available as "Dual Antibody Cortisol Kit" (Diagnostic Products Corporation, Los Angeles, CA, Acta Psychiatr. Scand. 70: 239-247, 1984). . This test is a competitive radioimmunoassay in which 125 I-labeled cortisol competes with cortisol from clinical samples for antibody sites. In this test, serum and plasma samples need not be pre-extracted or pre-diluted due to the lack of specificity and significant protein effects of the antibody. This assay is described in more detail in Example 2 below.
    [48] b. Determination of Mifepristone Concentrations in Blood / Urine
    [49] It may be necessary to measure blood and urinary GR antagonist concentrations as patient metabolism, rate of clearance, and toxicity levels depend on differences in underlying primary or secondary disease, drug history, age, and overall medical condition. Means for such monitoring are well described in the academic and patent literature. In one embodiment of the present invention, since mifepristone is administered to prevent weight gain caused by antipsychotics, an example of measuring mifepristone concentrations in blood and urine is described in the following Examples.
    [50] c. Other laboratory test procedures
    [51] Because weight gain induced by antipsychotics can be complex, a number of additional laboratory tests may be used in the methods of the present invention to assist in diagnosis, treatment efficacy, prognosis, toxicity, and the like. For example, glucocorticoid sensitivity variables such as fasting blood glucose levels, glucose levels after oral glucose administration, thyroid stimulating hormone (TSH) plasma concentrations, corticosteroid binding globulins, progesterone hormone (LH), testosterone-estradiol binding globulins, leptin, insulin And / or monitoring and measuring total testosterone, free testosterone, and the like, to enhance diagnostic and therapeutic assessment.
    [52] Laboratory tests that monitor and measure GR antagonist metabolite production, plasma concentrations and clearance rates, such as urine antagonist and metabolite concentrations, may also be useful in practicing the methods of the present invention. For example, mifepristone has two hydrophilic metabolites, N-monomethylated and N-dimethylated metabolites. Plasma and urine concentrations of these metabolites (in addition to RU486) are described in Kawai, Pharmacol. and Experimental Therapeutics, 241: 401-406, 1987, can be measured using thin layer chromatography or the like.
    [53] 3. Glucocorticoid receptor antagonists to inhibit or reverse weight gain caused by antipsychotics
    [54] The present invention provides a method of inhibiting or reversing weight gain caused by antipsychotics utilizing any composition or compound capable of blocking the biological response associated with binding of cortisol or cortisol analogs to GR. Antagonists of GR activity used in the methods of the invention are well described in the patent and academic literature. Some descriptive examples are detailed below.
    [55] a. Steroidal antiglucocorticoids as GR antagonists
    [56] Steroidal glucocorticoid antagonists are administered in various embodiments of the present invention to inhibit or reverse weight gain caused by antipsychotics. Steroidal antiglucocorticoids can be obtained through modification of the basic structure of the glucocorticoid antagonist, ie, various forms of the steroid backbone. The structure of cortisol can be modified in a variety of ways. The two most commonly known structural modifications of the cortisol steroid backbone for making glucocorticoid antagonists include modifications of 11-beta hydroxyl groups and modifications of 17-beta side chains (eg Lefebvre, J. Steroid Biochem. 33: 557-). 563, 1989).
    [57] Examples of steroidal GR antagonists include androgen type steroid compounds described in US Pat. No. 5,929,058, and US Pat. No. 4,296,206; 4,386,085; 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; Compounds disclosed in 5,616,458, and 5,696,127. Such steroidal GR antagonists include cortexsolone, dexamethasone oxetanone, 19-nordeoxycorticosterone, 19-norprogesterone, cortisol-21-mesylate, dexamethasone-21-mesylate, 11β- (4-dimethylamino Ethoxyphenyl) -17α-propynyl-17β-hydroxy-4,9-estradion-3-one (RU009), and 17β-hydroxy-17α-19- (4-methylphenyl) androstar-4,9 (11) -dien-3-one (RU044).
    [58] i) removal or substitution of 11-beta hydroxy groups
    [59] In one embodiment of the present invention, a glucocorticoid antagonist with modified steroid backbone is administered, including the removal or substitution of the 11-beta hydroxyl group. This class includes natural antiglucocorticoids and synthetic compositions, including cortexsolone, progesterone and testosterone derivatives, such as mifepristone (Lefebvre, et. Al., Supra). Preferred embodiments of the present invention include all 11-beta-aryl steroid backbone derivatives because these compounds lack progesterone receptor (PR) binding activity (Agarwal, FEBS 217: 221-226, 1987). Another preferred embodiment includes 11-beta-phenyl-aminodimethyl steroid backbone derivative, mifepristone, which is an effective antiglucocorticoid and antiprogesterone. These compositions act as reversible binding steroid receptor antagonists. For example, when bound to an 11-beta-phenyl-aminodimethyl steroid, the steroid receptor remains in a shape that cannot bind to its native ligand, such as cortisol, for GR (Cadepond, 1997, supra).
    [60] Synthetic 11-beta phenyl-aminodimethyl steroids include RU486, or 17-beta-hydroxy-11-beta- (4-dimethyl-aminophenyl) 17-alpha- (1-propynyl) estra-4,9-diene- Mifepristone, also known as 3-on. Mifepristone has been shown to be a potent antagonist to both progesterone and glucocorticoid (GR) receptors. Other 11-beta phenyl-aminodimethyl steroids found to have GR antagonist effects include RU009 (RU39.009), 11-beta- (4-dimethyl-aminoethoxyphenyl) -17-alpha- (propynyl-17- Beta-hydroxy-4,9-estradion-3-one) and the like (see Bocquel, J. Steroid Biochem. Molec. Biol. 45: 205-215, 1993). Another GR antagonist associated with RU486 is RU044 (RU43.044) 17-beta-hydroxy-17-alpha-19- (4-methyl-phenyl) -androstar-4,9 (11) -dien-3-one (Bocquel, 1993, formerly). Teutsch, Steroids 38: 651-665, 1981; See also US Pat. Nos. 4,386,085 and 4,912,097.
    [61] One embodiment includes a composition having a basic glucocorticoid steroid structure, which is an irreversible antiglucocorticoid agent. Such compounds include cortisol-21-mesylate (4-pregnene-11-beta, 17-alpha, 21-triol-3,20-dione-21-methanesulfonate and dexamethasone-21-mesylate (16-methyl Alpha-keto- of cortisol, including (9-alpha-fluoro-1,4-pregnadiene-11-beta, 17-alpha, 21-triol-3,20-dione-21-methanesulfonate) Methanesulfonate derivatives, etc. See Simons, J. Steroid Biochem. 24; 25-32 1986; Mercier, J. Steroid Biochem. 25; 11-20, 1986, and US Pat. No. 4,296,206.
    [62] ii) modification of the 17-beta side chain group
    [63] Steroidal antiglucocorticoids, which can be obtained with various structural modifications of the 17-beta side chain, are also used in the methods of the present invention. This class includes synthetic antiglucocorticoids such as dexamethasone-oxetanone, various 17,21-acetonide derivatives of dexamethasone, and 17-beta-carboxamide derivatives (Lefebvre, 1989, formerly; Rousseau, Nature 279: 158). -160, 1979).
    [64] iii) other steroid skeletal modifications
    [65] GR antagonists used in various embodiments of the present invention include any steroid backbone modification that results in a biological response resulting from GR-antagonist interaction. Steroid skeletal antagonists can be all natural or synthetic variants of cortisol, such as 19-nordeoxycorticosterone and 19-norprogesterone, C-19 methyl-free adrenal steroids (Wynne, Endocrinology 107: 1278-1280, 1980) .
    [66] In general, the size of the 11-beta side chain substituents and especially those substituents may play a key role in determining the extent of the antiglucocorticoid activity of the steroid. Substitutions in the A ring of the steroid backbone may also be important. 17-hydroxypropenyl side chains generally reduce antiglucocorticoid activity as compared to 17-propynyl side chain containing compounds.
    [67] Additional glucocorticoid receptor antagonists known in the art and suitable for the practice of the present invention include 21-hydroxy-6,19-oxidoprogesterone (see Vicent, Mol. Pharm. 52: 749-753 (1997)), (6β, 11β17β) -11- (4-dimethyl-aminophenyl) -6-methyl-4 ', 5'-dihydro [estra-4,9-diene-17,2' (3H ')-furan] -3-one (See "Org31710", Mizutani, J Steroid Biochem Mol Biol 42 (7): 695-704 (1992)), Org31806, Org34517, RU43044, (17-beta-hydroxy-11-beta- / 4- / [Methyl]-[1-methylethyl] aminophenyl / -17alpha- [rop-1-ynyl] estra-4-9-dien-3-one ("RU40555", Kim, J Steroid Biochem Mol Biol 67 (3): 213-22 (1998)), RU28362, ZK98299 and the like.
    [68] b. Non-steroidal antiglucocorticoids as antagonists
    [69] Non-steroidal glucocorticoid antagonists are also used in the methods of the present invention to inhibit or reverse weight gain caused by antipsychotics. This includes synthetic analogs and analogs of proteins, including partially peptided, pseudopeptide and nonpeptide molecules. For example, oligomeric peptide analogs useful in the present invention include (alpha-beta-unsaturated) peptidosulfonamides, N-substituted glycine derivatives, oligo carbamates, oligourea peptide analogs, hydrazino peptides, Oligosulfones and the like (see, eg, Amour, Int. J. Pept. Protein Res. 43: 297-304, 1994; de Bont, Bioorganic & Medicinal Chem. 4: 667-672, 1996). Screening and simultaneous screening of large-scale libraries of synthetic molecules can be performed using techniques known in the art of combinatorial chemistry. Examples are described in van Breemen, Anal Chem 69: 2159-2164, 1997; And Lam, Anticancer Drug Des 12: 145-167, 1997. Design of peptide analogs specific for GR can be accomplished using computer programs in combination with combinatorial chemistry (combinatorial library) screening methods (Murray, J. of Computer-Aided Molec. Design 9: 381-395, 1995; Bohm, J.). of Computer-Aided Molec.Design 10: 265-272, 1996). Such “reasonable drug design” can help to develop peptide and morph isomers, including cyclic isomers, retro-inverso isomers, retro isomers, etc. (Chorev, TibTech 13: 438-445, 1995 As discussed in the following).
    [70] Examples of nonsteroidal GR antagonists include ketoconazole, clotrimazole; N- (triphenylmethyl) imidazole; N-([2-fluoro-9-phenyl] fluorenyl) imidazole; N-([2-pyridyl] diphenylmethyl) imidazole; N- (2- [4,4 ', 4 "-trichlorotrityl] oxyethyl) morpholine; 1- (2 [4,4', 4" -trichlorotrityl] oxyethyl) -4- (2- Hydroxyethyl) piperazine dimaleate; N-([4,4 ', 4 "] trichlorotrityl) imidazole; 9- (3-mercapto-1,2,4-triazolyl) -9-phenyl-2,7-difluorofluorenone 1- (2-chlorotrityl) -3,5-dimethylpyrazole; 4- (morpholinomethyl) -A- (2-pyridyl) benzhydrol; 5- (5-methoxy-2- (N-methylcarbamoyl) -phenyl) dibenzosuberol, N- (2-chlorotrityl) -L-prolinol acetate, 1- (2-chlorotrityl) -2-methylimidazole; 1- (2-chlorotrityl) -1,2,4-triazole; 1, S-bis (4,4 ', 4 "-trichlorotrityl) -1,2,4-triazole-3-thiol ; N-((2,6-dichloro-3-methylphenyl) diphenyl) methylimidazole (see US Pat. No. 6,051,573); GR antagonist compounds disclosed in US Pat. No. 5,696,127; 4a (S) -benzyl-2 (R) -chloroethynyl-1,2,3,4,4a, 9,10,10Oa (R) -octahydro-phenanthrine-2,7-diol (CP 394531) And 4a (S) -benzyl-2 (R) -prop-1-ynyl-1,2,3,4,4a, 9,10,10a (R) -octahydro-phenanthrine-2,7-diol (CP 409069), Bradley et al., J. Med. Chem. 45,2417-2424 (2002); glucocorticoid receptor antagonists; See Hoyberg et al., Int'l J. of Neuro-psychopharmacology, 5: Supp. 1, S148 (2002), ORG 34517; PCT International Application WO 96/19458, which describes nonsteroidal compounds which are high affinity and high selectivity antagonists for steroid receptors, such as 6-substituted-1,2-dihydro-N-protected-quinoline. Compound; κ opioid compound dinorphine-1,13-diamide, U50,488 (trans- (1R, 2R) -3,4-dichloro-N-methyl-N- [2- (1-pyrrolidinyl) cyclohexyl] Some κ opioid ligands such as benzeneacetamide), bremmazosin and ethyl ketocyclazoster; Nonspecific opioid receptor ligands, naloxones, disclosed in Evans et al., Endocrin., 141: 2294-2300 (2000).
    [71] c. Identification of Specific Glucocorticoid Receptor Antagonists
    [72] In addition to the compounds and compositions described above, any specific GR antagonist can be used to inhibit or reverse weight gain caused by antipsychotics in the methods of the present invention, so those skilled in the art can identify additional useful GR antagonists. Various such conventional and known methods can be used, which are described in the academic and patent literature. This includes in vitro and in vivo assays for the identification of additional GR antagonists. Some descriptive examples are described below.
    [73] One assay that can be used to identify GR antagonists of the invention is described in Granner, Meth. Enzymol. 15: 633, 1970] to determine the effect of a potential GR antagonist on tyrosine amino-transferase activity. This assay is based on measuring the activity of the liver enzyme tyrosine amino-transferase (TAT) in culture of rat hepatocellular carcinoma cells (RHC). TAT catalyzes the first step in tyrosine metabolism and is induced by glucocorticoids (cortisol) in both liver and hepatocellular carcinoma cells. This activity is easily measured in cell extracts. TAT converts the amino group of tyrosine into 2-oxoglutaric acid. P-hydroxyphenylpyruvate is also formed. It can be converted to more stable p-hydroxybenzaldehyde in alkaline solution and quantified by absorbance at 331 nm. The potential GR antagonist is co-administered with cortisol to whole liver or liver carcinoma cells or cell extracts in vivo or ex vivo. If administration of a compound decreases the amount of TAT activity induced compared to the control (ie, the addition of only cortisol or GR antagonist), the compound is identified as a GR antagonist (Shirwany, Biochem. Biophys. Acta 886: 162-168, See 1986).
    [74] In addition to the TAT assay, further examples of many assays that can be used to identify compositions utilized in the methods of the present invention are assays based on in vivo glucocorticoid activity. For example, an assay may be used to assess the ability of a potential GR antagonist to inhibit the uptake of 3 H-thymidine in cells stimulated by glucocorticoids. Alternatively, the potential GR antagonist may be allowed to compete with 3 H-dexamethasone to bind to liver carcinoma tissue culture GR. (E.g., Choi, et al., Steroids 57: 313-318, 1992). As another example, the ability of a potential GR antagonist to block radioactive binding of the 3 H-dexamethasone-GR complex can be used (Alexandrova et al., J. Steroid Biochem. Mol. Biol. 41: 723-725, 1992). To further identify potential GR antagonists, kinetic assays can also be used to distinguish glucocorticoid antagonists from antagonists via receptor binding kinetics (Jones, Biochem J. 204: 721-729, 1982). As).
    [75] In another illustrative example, see Daune, Molec. Pharm. 13: 948-955, 1977; And assays described in US Pat. No. 4,386,085 can be used to identify antiglucocorticoid activity. In summary, thymic cells of adrenally excised rats are incubated with test compounds of varying concentrations in a nutrient medium containing dexamethasone (potential GR antagonist). 3 H-uridine is added to the cell culture, which is further cultured and the extent of radiolabel uptake into the polynucleotide is measured. Glucocorticoid antagonists reduce the amount of 3 H-uridine absorbed. Therefore, GR antagonists will block this effect.
    [76] For further compounds that can be utilized in the methods of the invention and methods for identifying and preparing such compounds, high affinity, high selectivity for steroid receptors, such as 6-substituted-1,2-dihydro N-1 protected quinoline US patents describing non-steroidal compounds that are modulators (antagonists): 4,296,206 (above); 4,386,085 (above); 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 5,616,458; And International Patent Publication No. 96/19458.
    [77] The specificity of the antagonist for GR relative to MR can be measured using various assays known in the art. For example, specific antagonists can be identified by measuring the ability of the antagonist to bind GR compared to MR (see, eg, US Pat. Nos. 5,606,021; 5,696,127; 5,215,916; 5,071,773). Such assays can be performed using direct binding assays or by evaluating competitive binding to purified GR or MR in the presence of known antagonists. In an exemplary assay, cells that stably express high levels of glucocorticoid receptors or mineralocorticoid receptors (see, eg, US Pat. No. 5,606,021) are used as a source of purified receptors. The affinity of the antagonist for the receptor is then measured directly. Antagonists that display at least 100-fold and often 1000-fold higher affinity for GR as compared to MR are selected for use in the methods of the invention.
    [78] GR-specific antagonists can also be defined as compounds that have the ability to inhibit GR-mediated activity but not MR-mediated activity. One way to identify such GR-specific antagonists is to use transfection assays to assess the ability of the antagonist to prevent activation of the reporter construct (eg, Bocquel et al, J. Steroid Biochem Molec. Biol. 45 : 205-215, 1993, US Pat. Nos. 5,606,021, 5,929,058). In one exemplary transfection assay, the reporter plasmid containing the expression plasmid encoding the receptor and the reporter gene linked to receptor specific regulatory elements is cotransfected into the appropriate receptor-negative host cell. The transfected host cell is then cultured in the presence or absence of a hormone capable of activating the hormone reactive promoter / enhancer element of the reporter plasmid, such as cortisol or an analog thereof. Next, the transfected and cultured host cells are monitored for induction (ie, presence) of the product of the reporter gene sequence. Finally, expression of hormone receptor proteins (produced in host cells encoded and transfected and cultured by receptor DNA sequences on expression plasmids) by measuring the activity of reporter genes in the presence and absence of antagonists and / or steroids Measure binding capacity. Antagonist activity of the compounds can be confirmed in comparison to known GR and MR receptor antagonists (see, eg, US Pat. No. 5,696,127). Efficacy is then expressed as a percentage of the maximum response observed for each compound relative to the reference antagonist compound. GR-specific antagonists are believed to exhibit at least 100-fold and often 1000-fold greater activity against GR than MR.
    [79] 4 . Inhibition or reversal of weight gain induced by AP with glucocorticoid receptor antagonists
    [80] For use in the methods of the invention that prevent or reverse weight gain caused by AP, antiglucocorticoids such as mifepristone are formulated into a drug. Any composition or compound capable of blocking the biological response associated with the binding of cortisol or cortisol analogs to GR can be used as a medicament in the present invention. Conventional means for determining GR antagonist drug dosing schedules and formulations for practicing the methods of the invention are well described in the patent and academic literature, and some descriptive examples are described below.
    [81] a. Glucocorticoid receptor antagonists in the form of pharmaceutical compositions
    [82] GR antagonists used in the methods of the invention can be administered by any method known in the art, for example, parenterally, topically, orally, or by topical administration, such as by aerosol or transdermal. The methods of the present invention define prophylactic and / or therapeutic treatments. GR antagonists in the form of pharmaceutical formulations can be administered in a variety of unit dosage forms, depending on the condition or extent of the disease and psychosis, the overall medical condition of each patient, and the preferred method of administration. Details of the techniques for formulation and administration are well described in the academic and patent literature. See, eg, the latest edition of Remington's Pharmaceutical Sciences, Maack Publishing Co, Easton PA (hereinafter "Remington's"). Therapeutically, the effective amount of a glucocorticoid blocker suitable for the practice of the method of the present invention is about 0.5 to about 25 milligrams per kilogram (mg / kg). One skilled in the art will be able to determine the therapeutically effective amount of a specific glucocorticoid blocker compound used in the practice of the present invention without reference to this technique and this disclosure.
    [83] In general, the glucocorticoid blocker compound may be administered in a pharmaceutical composition by any method of drug preparation known in the art. The compositions may take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other suitable composition, wherein one or more compounds of the invention are one or more pharmaceutically acceptable excipients It can be included with. Suitable excipients are well known to those skilled in the art, and methods for formulating these and compositions can be found in standard references such as Alfonso AR: Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton PA, 1985. Suitable liquid carriers, especially injectable solution carriers, include water, aqueous saline solutions, aqueous dextrose solutions and glycols.
    [84] In the aqueous suspension of the present invention, the GR antagonist is mixed with excipients suitable for the preparation of the aqueous suspension. Such excipients include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and acacia gum, and natural phosphatides (eg lecithin), alkyl Condensation products of ethylene oxide and fatty acids (e.g. polyoxyethylene stearate), condensation products of ethylene oxide and long chain aliphatic alcohols (e.g. heptadecaethylene oxycetanol), partial esters derived from ethylene oxide and fatty acids and hexitol Dispersing or wetting agents such as condensation products (e.g. polyoxyethylene sorbitol mono-oleate) or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydride (e.g. polyoxyethylene sorbitan mono-oleate) Included. The aqueous suspension may also comprise one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate, one or more colorants, one or more flavoring agents and one or more sweetening agents such as sucrose, aspartame or saccharin. The formulation can be adjusted for osmolality.
    [85] Oily suspensions can be prepared by suspending GR antagonists in vegetable oils such as arachis oil, olive oil, sesame oil or coconut oil, or mineral oils such as liquid paraffin, or mixtures thereof. Oily suspensions may contain thickening agents such as beeswax, light paraffin or cetyl alcohol. Sweeteners such as glycerol, sorbitol or sucrose can be added to make edible oral preparations. Such formulations can be preserved by adding antioxidants such as ascorbic acid. Examples of oily vehicles for injection are described in Minto, J. Pharmacol. Exp. Ther. 281: 93-102, 1997. Pharmaceutical formulations of the invention may also be in the form of oil-in-water emulsions. The oily phase may be the vegetable oil or mineral oil described above, or a mixture thereof. Suitable emulsifiers include natural gums such as acacia gum or tragacanth gum, natural phosphatides such as soy lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan mono-oleate, and these partial esters Condensation products of ethylene oxide such as polyoxyethylene sorbitan mono-oleate and the like. The emulsion may also contain sweetening and flavoring agents as well as when formulating syrups and elixirs. Such formulations may contain antiemulsifiers, preservatives or coloring agents.
    [86] Glucocorticoid blocker pharmaceutical formulations may be prepared by any method known in the art for pharmaceutical manufacture. The drug may include sweetening agents, flavoring agents, coloring agents and preservatives. Any glococorticoid blocker formulation may be mixed with a nontoxic and pharmaceutically acceptable excipient suitable for manufacture.
    [87] Typically, the glycocorticoid blocker compounds suitable for use in the practice of the present invention may be administered orally. The amount of compound in the compositions of the present invention can vary widely depending on the form of the composition, the size of the unit dosage, the type of excipient, and other factors well known to those skilled in the art. In general, the final composition may comprise from 0.000001 weight percent (% w) to 10% w, preferably 0.00001% w to 1% w of the glycocorticoid blocker compound and the remainder may comprise excipients. For example, the GR antagonist mifepristone can be taken orally in tablet form at a dosage of about 0.5 to 25 mg / kg, more preferably about 0.75 mg / kg to 15 mg / kg and most preferably about 10 mg / kg. Is given.
    [88] Pharmaceutical formulations for oral administration can be formulated using suitable and appropriate doses of pharmaceutically acceptable carriers known in the art. Such carriers can be used to formulate pharmaceutical formulations in unit dosage forms such as tablets, pills, powders, dragees, capsules, solutions, lozenges, gels, syrups, slurries, suspensions, etc., suitable for use by the patient. . Oral pharmaceutical formulations combine glucocorticoid blocker compounds with solid excipients, optionally pulverize the resulting mixture, optionally add additional compounds as appropriate, and then process the granule mixture to obtain a tablet or dragee core. You can get it through Suitable solid excipients include lactose, sucrose, mannitol or sorbitol; Starch of corn, wheat, rice, potatoes or other plants; Celluloses such as methyl cellulose, hydroxypropylmethyl-cellulose or sodium carboxymethylcellulose; Gums, including gum arabic and tragacanth; And carbohydrates or protein fillers, including but not limited to proteins such as gelatin and collagen. If desired, disintegrants or solubilizers can be added, such as crosslinked polyvinylpyrrolidone, agar, alginic acid, or salts thereof such as sodium alginate.
    [89] GR antagonists of the invention can also be administered in the form of suppositories for rectal administration of the drug. Such formulations may be prepared by mixing the drug with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
    [90] GR antagonists of the invention can also be administered by intranasal, intraocular, vaginal, and rectal routes, including suppositories, inhalations, powders, and aerosol formulations (examples of steroid inhalants are described in Rohatagi, J. Clin. Pharmacol. 35: 1187-1193, 1995; Tjwa, Ann.Allergy Asthma Immunol. 75: 107-111, 1995).
    [91] The GR antagonists of the present invention can be formulated into application sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastas, jelly, paints, powders and aerosols for delivery by transdermal and topical routes.
    [92] GR antagonists of the invention can also be delivered to the microspheres for slow release in the body. For example, microspheres may be administered via intradermal injection of drugs (eg mifepristone) -containing microspheres that slowly release subcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7: 623-645, 1995); As biodegradable and injectable gel formulations (see, eg, Gao Pharm. Res. 12: 857-863, 1995); Or as microspheres for oral administration (see, eg, Eyles, J. Pharm. Pharmacol. 49: 669-674, 1997). Both transdermal and intradermal routes allow for constant delivery over weeks or months.
    [93] The GR antagonist pharmaceutical formulations of the present invention may be provided in salt form and may be formed with a variety of acids, including but not limited to hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid and the like. Salts are more soluble in aqueous or other protic solvents than the corresponding free base forms. In other cases, the preferred formulation may be a lyophilized powder mixed with a buffer having 1 mM-50 mM histidine, 0.1% -2% sucrose, 2% -7% mannitol and a pH ranging from 4.5 to 5.5 before use.
    [94] In another embodiment, the GR antagonist formulations of the invention are useful for parenteral administration, such as intravenous (IV) administration or administration into a body cavity or tracheal lumen. Formulations for administration will usually comprise a solution of a GR antagonist (eg mifepristone) dissolved in a pharmaceutically acceptable carrier. Acceptable vehicles and solvents that may be used include water and Ringer's solution, isotonic sodium chloride solution and the like. In addition, sterile, nonvolatile oils can usually be employed as a solvent or suspending medium. Any hypoallergenic nonvolatile oil can be used for this purpose, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can likewise be used for the preparation of injectables. These solutions are sterile and are generally free of undesirable substances. Such formulations may be sterilized by conventional and known sterilization techniques. The formulations may contain pharmaceutically acceptable auxiliary substances required to approximate physiological conditions such as pH adjusting and buffers, toxicity modifiers such as sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like. The concentration of GR antagonist in such formulations can vary widely and will be chosen based primarily on fluid volume, viscosity, weight, etc., depending on the particular mode of administration chosen and the needs of the patient. For intravenous administration, the preparation may be a sterile injectable preparation, such as a sterile injectable aqueous or oily suspension. This suspension can be formulated using suitable dispersing or wetting agents and suspending agents known according to the known art. Sterile injectable preparations can be sterile injectable solutions or suspensions using nontoxic parenteral diluents or solvents, such as 1,3-butanediol solution.
    [95] In another embodiment, the GR antagonist formulations of the invention are introduced into cells using liposomes that are fused to or introduced into the cell membrane, ie, attached to liposomes or directly attached to oligonucleotides and bound to the cell's surface membrane protein receptors. Can be delivered using a ligand. By using liposomes, the delivery of GR antagonists can be concentrated in vivo into target cells, particularly if the liposome surface carries ligands specific to the target cell or otherwise preferentially directs certain organs (eg 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).
    [96] b. Determination of Dosage Plan for Glucocorticoid Receptor Antagonists
    [97] The method of the present invention treats a stress disorder. That is, the occurrence and severity of dissociative symptoms and reexperience symptoms are reduced. The amount of GR antagonist suitable to achieve this is defined as "therapeutically effective dose". Effective dosing schedules and amounts, or “dose plan,” for this use will vary depending on various factors, including the stage of the disease or condition, the severity of the disease or condition, the patient's general health, the patient's physical condition, age, and the like. In determining the dosing schedule for the patient, the mode of administration is also taken into account.
    [98] Dosage plans also take into account the pharmacokinetic parameters well known in the art, namely the rate of absorption, bioavailability, metabolism, clearance of GR antagonists (eg, Hidalgo-Aragones (1996) J. Steroid Biochem.Mol. Biol. 58: 611-617; Groning (1996) Pharmazie 51: 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; Remington latest edition, see previous text). For example, in one study, less than 0.5% of the daily dose of mifepristone was excreted in the urine and the drug was extensively bound to circulating albumin (see Kawai (1989)). The state of the art allows the clinician to determine a dosing plan for each individual patient, GR antagonist and the disease or condition being treated. As one illustrative example, the instructions provided below for mifepristone can be taken as an example to determine the dosing schedule, ie, timing and dose level of any GR antagonist administered when practicing the methods of the present invention.
    [99] GR antagonist formulations may be administered in single or multiple doses, depending on the dose and frequency required by the patient and where the patient is tolerated. The formulation should provide sufficient amounts of the active substance, mifepristone, to effectively treat dementia. Thus, one typical pharmaceutical formulation for oral administration of mifepristone is a daily dosage of about 0.5 to about 20 mg per kg of body weight per day. In another embodiment, a dose of about 1 mg to about 4 mg per kg body weight of the patient per day is used. In contrast to when administered orally, into the bloodstream, into the body cavity, or into the tracheal lumen, lower doses may be used, particularly when the drug is administered to an anatomically isolated site, such as the cerebrospinal fluid (CSF) space. For topical administration, considerably higher doses may be used. Actual methods of preparing GR antagonist formulations for parenteral administration are known or will be apparent to those skilled in the art and are described in more detail in literature such as Remington's, supra. See also Nieman, “Receptor Mediated Antisteroid Action,” in Agarwal, et al., Eds., De Gruyter, New York (1987).
    [100] After the formulation containing the GR antagonist of the present invention is formulated in an acceptable carrier, it may be placed in a suitable container and labeled for the treatment of the indication. For the administration of GR antagonists, such labels will include a description of the dosage, frequency of administration, and method of administration. In one embodiment, the present invention contemplates a kit for inhibiting or reversing the weight gain induced by a human AP, including a description of the GR antagonist and the indications, dose, and schedule of administration of the GR antagonist.
    [101] The following examples are provided to illustrate the claimed invention and are not intended to be limiting.
    [102] Example 1 Inhibition or Reversal of Weight Gain Induced by AP with Mifepristone
    [103] The following examples illustrate how to practice the method of the present invention.
    [104] Patient screening
    [105] Individuals who have started long-term AP administration or who have received long-term AP administration have substantially gained weight. Patients typically had normal amounts of cortisol relative to age.
    [106] Dosage Scheme and Administration of Mifepristone
    [107] Mifepristone, a glucocorticoid receptor (GR) antagonist, was used in this study. This material was administered at a dosage of 200 mg per day. Subjects will receive 200 mg of mifepristone per day for 6 months and will be evaluated as described below. Dosage will be adjusted if necessary and additional assessments will be made periodically throughout the treatment period.
    [108] Mifepristone tablets are manufactured by Shanghai HuaLian Pharmaceuticals Co., Ltd. It can be obtained from (China, Shanghai).
    [109] Assessment of weight gain prevention
    [110] In order to explain and evaluate the effectiveness of mifepristone in inhibiting or reversing the weight gain induced by AP, the patient's body weight was determined and recorded every two weeks.
    [111] Example 2: Cortisol Level Measurement
    [112] To measure cortisol levels in the patients of Example 1, afternoon cortisol test measurements are made and used as the cortisol standard at baseline. Cortisol levels are measured at every visit until day 0, two weeks after medication (day 14), and six months, and periodically thereafter.
    [113] Blood cortisol levels are measured using the "Double Antibody Cortisol Kit" (Diagnostic Products Corporation, Los Angeles, CA). This test is a competitive radioimmunoassay in which 125 I-labeled cortisol over an antibody site competes with cortisol from clinical samples and is performed substantially in accordance with the manufacturer's instructions using reagents provided by the manufacturer. In summary, blood is collected by venipuncture to separate serum from cells. Samples are stored at 2-8 ° C. for up to 7 days, or frozen at −20 ° C. for up to 2 months. Prior to analysis, the sample is brought to room temperature (15-28 ° C.) by slight turning or flipping. Prepare two sets of 16 tubes with 25 μl of plasma per tube. Calculate the cortisol concentration from the prepared calibration tube. The net coefficient is equal to the average CPM minus the average nonspecific CPM. Cortisol concentrations of unknown samples are estimated by interpolation in the calibration curve (Dudley, et al. (1985) Clin. Chem. 31: 1264-1271).
    [114] It is to be understood that the embodiments and embodiments described herein are for illustrative purposes only, and, in light of this, various modifications and alterations will be suggested to those skilled in the art and should be included within the spirit and scope of the present application and the appended claims.
    权利要求:
    Claims (22)
    [1" claim-type="Currently amended] If a patient does not require glucocorticoid receptor antagonist treatment for another reason and does not suffer from psychotic major depression, the glucocorticoid receptor antagonist is administered to the patient treated with antipsychotics to inhibit or reverse weight gain. A method of inhibiting or reversing weight gain in a patient being treated with an antipsychotic, comprising the step of:
    [2" claim-type="Currently amended] The method of claim 1, wherein the patient is treated with atypical antipsychotics.
    [3" claim-type="Currently amended] The method of claim 1, wherein the patient is treated with an antipsychotic selected from the group consisting of clozapine, olanzapine, risperidone, quetiapine, and sertindol.
    [4" claim-type="Currently amended] The method of claim 1, wherein the patient has gained at least 2 kg in weight during the 10 week period treated with antipsychotics.
    [5" claim-type="Currently amended] The method of claim 1, wherein the patient is at least 20% greater than the healthy weight range.
    [6" claim-type="Currently amended] The method of claim 1, wherein the glucocorticoid receptor antagonist comprises a steroidal skeleton having one or more phenyl containing residues at the 11-beta position of the steroidal skeleton.
    [7" claim-type="Currently amended] 7. The method of claim 6, wherein the phenyl containing moiety at the 11-beta position of the steroid backbone is a dimethylaminophenyl moiety.
    [8" claim-type="Currently amended] 8. The method of claim 7, wherein said glucocorticoid receptor antagonist comprises mifepristone.
    [9" claim-type="Currently amended] 8. The method of claim 7, wherein the glucocorticoid receptor antagonist is selected from the group consisting of RU009 and RU044.
    [10" claim-type="Currently amended] The method of claim 1, wherein the glucocorticoid receptor antagonist is administered at a daily dosage of about 0.5 to about 20 mg per kg of body weight per day.
    [11" claim-type="Currently amended] The method of claim 10, wherein the glucocorticoid receptor antagonist is administered at a daily dosage of about 1 to about 10 mg per kg of body weight per day.
    [12" claim-type="Currently amended] The method of claim 11, wherein the glucocorticoid receptor antagonist is administered at a daily dosage of about 1 to about 4 mg per kg of body weight per day.
    [13" claim-type="Currently amended] The method of claim 1, wherein said administration is once daily.
    [14" claim-type="Currently amended] The method of claim 1, wherein the mode of administration is oral.
    [15" claim-type="Currently amended] The method of claim 1, wherein the mode of administration is by transdermal application, by nebulized suspension, or by aerosol spray.
    [16" claim-type="Currently amended] Specific glucocorticoid receptor antagonists; And
    Instructions for administering the glucocorticoid receptor antagonist to the patient being treated with antipsychotics, including an indication of the dosage and schedule of administration,
    Kit for inhibiting or reversing weight gain in patients treated with antipsychotics.
    [17" claim-type="Currently amended] The kit of claim 16 further comprising an antipsychotic.
    [18" claim-type="Currently amended] The kit of claim 16, wherein said descriptive material indicates that the glucocorticoid receptor antagonist can be administered at a daily dosage of about 0.5 to about 20 mg per kg of body weight per day.
    [19" claim-type="Currently amended] The kit of claim 16, wherein said descriptive material indicates that the glucocorticoid receptor antagonist can be administered at a daily dosage of about 1 to about 10 mg per kg of body weight per day.
    [20" claim-type="Currently amended] The kit of claim 16, wherein said descriptive material indicates that the glucocorticoid receptor antagonist can be administered in a daily dosage of about 1 to about 4 mg per kg of body weight per day.
    [21" claim-type="Currently amended] The kit of claim 16 wherein said glucocorticoid receptor antagonist is mifepristone.
    [22" claim-type="Currently amended] The kit of claim 16 wherein the mifepristone is in tablet form.
    类似技术:
    公开号 | 公开日 | 专利标题
    Davis et al.2015|Testosterone in women—the clinical significance
    JP5762390B2|2015-08-12|Reduction of side effects with aromatase inhibitors used to treat breast cancer
    Rutkowski et al.2014|Dehydroepiandrosterone |: hypes and hopes
    LoRusso et al.2010|Phase I pharmacokinetic and pharmacodynamic study of the oral MAPK/ERK kinase inhibitor PD-0325901 in patients with advanced cancers
    Lobo2008|Metabolic syndrome after menopause and the role of hormones
    Schindler2011|Dienogest in long-term treatment of endometriosis
    EP2533799B1|2019-11-20|Methods for the use of progestogen as a glucocorticoid sensitizer
    Clark et al.2008|The effect of weight on the efficacy of biologic therapy in patients with psoriasis
    Beaulieu et al.2011|Role of GILZ in immune regulation, glucocorticoid actions and rheumatoid arthritis
    Guido et al.2004|Drospirenone for the treatment of hirsute women with polycystic ovary syndrome: a clinical, endocrinological, metabolic pilot study
    Axelrod2003|Perioperative management of patients treated with glucocorticoids
    AU2005263369B9|2009-06-04|Use of non-glucocorticoid steroids for the treatment of muscular dystrophy
    Haynes et al.2002|Anorectic, thermogenic and anti-obesity activity of a selective orexin-1 receptor antagonist in ob/ob mice
    Howell et al.1996|New endocrine therapies for breast cancer
    US20160082017A1|2016-03-24|Estriol therapy for multiple sclerosis and other autoimmune diseases
    Sood et al.2014|Prescribing menopausal hormone therapy: an evidence-based approach
    GAILLARD et al.1985|RU 486 inhibits peripheral effects of glucocorticoids in humans
    US8735381B2|2014-05-27|Progesterone antagonists such as CDB-4124 in the treatment of endometriosis, uterine fibroids, dysmenorrhea, breast cancer, etc
    Hu et al.2000|Anti-stress effects of dehydroepiandrosterone: protection of rats against repeated immobilization stress-induced weight loss, glucocorticoid receptor production, and lipid peroxidation
    Beeram et al.2007|Akt-induced endocrine therapy resistance is reversed by inhibition of mTOR signaling
    JP4152431B2|2008-09-17|Estrogen / progestin / antiprogestin method and kit for oral contraception and menstrual adjustment
    JP5128743B2|2013-01-23|Drospirenone for hormone replacement therapy
    Hale et al.2002|Endometrial cancer: hormonal factors, the perimenopausal “window of risk,” and isoflavones
    Brown et al.2004|Association of depression with medical illness: does cortisol play a role?
    US9452175B2|2016-09-27|Pregnancy hormone combination for treatment of autoimmune diseases
    同族专利:
    公开号 | 公开日
    NZ530724A|2005-09-30|
    EP1408981A4|2005-06-08|
    IL159913D0|2004-06-20|
    AU2002319665B2|2006-09-21|
    CA2454339C|2012-01-10|
    AT406166T|2008-09-15|
    JP2009102413A|2009-05-14|
    ES2312598T3|2009-03-01|
    ZA200400444B|2005-03-30|
    BR0211365A|2004-09-21|
    HK1061526A1|2008-11-07|
    DE60228579D1|2008-10-09|
    JP2004537563A|2004-12-16|
    EP1408981A1|2004-04-21|
    EP1408981B1|2008-08-27|
    PT1408981E|2008-12-04|
    CA2454339A1|2003-02-06|
    US6680310B2|2004-01-20|
    CN1547473A|2004-11-17|
    CN1853722A|2006-11-01|
    DK1408981T3|2009-01-12|
    WO2003009853A1|2003-02-06|
    CY1108562T1|2014-04-09|
    MXPA04000692A|2004-04-21|
    US20030027802A1|2003-02-06|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    2001-07-23|Priority to US30769301P
    2001-07-23|Priority to US60/307,693
    2002-07-22|Application filed by 코어셉트 쎄라퓨틱스, 잉크.
    2002-07-22|Priority to PCT/US2002/023441
    2004-04-03|Publication of KR20040028942A
    优先权:
    申请号 | 申请日 | 专利标题
    US30769301P| true| 2001-07-23|2001-07-23|
    US60/307,693|2001-07-23|
    PCT/US2002/023441|WO2003009853A1|2001-07-23|2002-07-22|Methods for preventing antipsychotic-induced weight gain|
    [返回顶部]