111111
`
`1111111111111111111111111111111111111111111111111111111111111111111111111111
`US 20040029848Al
`
`(19) United States
`(12) Patent Application Publication
`Belanoff
`
`(10) Pub. No.: US 2004/0029848 Al
`Feb. 12, 2004
`(43) Pub. Date:
`
`(54) METHODS FOR TREATING DELIRIUM
`GLUCOCORTICOID RECEPTOR- SPECIFIC
`ANTAGONISTS
`
`(76)
`
`Inventor:
`
`Joseph K. Belanoff, Woodside, CA
`(US)
`
`Correspondence Address:
`TOWNSEND AND TOWNSEND AND CREW,
`LLP
`TWO EMBARCADERO CENTER
`EIGHTH FLOOR
`SAN FRANCISCO, CA 94111-3834 (US)
`
`(21) Appl. No.:
`
`10/257,656
`
`(22) PCT Filed:
`
`May 6, 2002
`
`(86) PCT No.:
`
`PCT/US02/14318
`
`Related U.S. Application Data
`
`(60) Provisional application No. 60/288,619, filed on May
`4,2001.
`
`Publication Classification
`
`(51)
`Int. Cl? .................................................. A61K 31/573
`(52) U.S. Cl. .............................................................. 514/179
`
`(57)
`
`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.
`
`

`

`US 2004/0029848 A1
`
`Feb. 12,2004
`
`1
`
`METHODS FOR TREATING DELIRIUM
`GLUCOCORTICOID RECEPTOR- SPECIFIC
`ANTAGONISTS
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`
`[0001] This application claims the benefit of provisional
`application No. 60/288,619, filed May 4, 2001.
`
`FIELD OF THE INVENTION
`
`[0002] This invention generally pertains to the field of
`psychiatry. In particular, this invention pertains to the dis(cid:173)
`covery that agents that inhibit the binding of cortisol to the
`glucocorticoid receptor can be used in methods of treating
`delirium.
`
`INTRODUCTION
`
`[0003] Delirium is a disturbance in consciousness that
`typically results from an underlying physical condition.
`Patients suffering from delirium display changes in cogni(cid:173)
`tion (such as memory deficits, disorientation, and language
`or perceptual disturbances) that develop over a short period
`of time and tend to fluctuate during the course of the day.
`
`[0004] The neurophysiological causes of delirium are not
`known in detail. The predominant neurochemical hypothesis
`for the origin of delirium focuses on underactivity of cho(cid:173)
`linergic neurotransmission in particular domains of the brain
`(see Trzepacz, Dement Geriatr Cogn Disord 10:330-334
`(1999)). However, abnormalities in other neurotransmit(cid:173)
`ters-such as serotonin, dopamine, gamma-aminobutryic
`acid, and glutamate-may also be involved in the develop(cid:173)
`ment of delirium under particular conditions (see Flacker &
`Lipsitz, J Gerontal A Bioi Sci Med Sci 54:B239-46 (1999)).
`
`[0005] Cortisol, a glucocorticoid hormone secreted in
`response to ACTH (corticotropin), shows circadian rhythm
`variation, and further, is an important element in respon(cid:173)
`siveness to many physical and psychological stresses. It has
`been proposed that, with age, the cortisol regulatory system
`becomes hyperactivated in some individuals, resulting in
`hypercortisolemia. It has additionally been postulated that
`high levels of cortisol are neurotoxic, particularly in the
`hippocampus, a brain structure that is thought to be central
`to the processing and temporary storage of complex infor(cid:173)
`mation and memory (see, e.g., Sapolsky et al., Ann. NY
`Acad. Sci. 746:294-304, 1994; Silva, Annu. Rev. Genet.
`31:527-546, 1997; de Leon et al., J. Clin. Endocrinol &
`Metab. 82:3251, 1997).
`
`[0006] The brain and CNS actions of cortisol and other
`glucocorticoids are not limited to neurotoxicity, however. In
`addition to influencing cerebral blood flow, oxygen con(cid:173)
`sumption, and cerebral excitability, glucocorticoids have
`extensive effects on neurotransmitter function (see DeKloet
`et al., Handbook Neurochem 8:47-91 (1985)). These effects
`include inhibition of binding to central muscarinic cholin(cid:173)
`ergic receptors, as well as modulation of serotonin turnover,
`hypothalamic dopamine balance, and suppression of beta(cid:173)
`endorphin levels in the brain. The ability of glucocorticoids
`to perturb neurotransmitters involved in the pathogenesis of
`delirium suggests that disturbance of glucocorticoid regula(cid:173)
`tion might play a role in delirium. However, while patho(cid:173)
`logically elevated glucocorticoid levels (due to adrenal
`
`dysfunction or ingestion of synthetic hormones) have been
`connected with the induction of delirium (see Stroudemire et
`al., Gen Hasp Psychiatry 18:196-202 (1996)), the relation(cid:173)
`ship between physiological glucocorticoid
`levels and
`delirium remains unclear (for review see Flacker & Lipsitz,
`J Gerontal A Bioi Sci Med Sci 54:B23946 (1999)). Assess(cid:173)
`ments of hypothalamic-pituitary-adrenal axis function in
`delirious patients by dexamethasone-suppression testing
`have been conflicting (see Koponen et al., Nord Psykiatr
`Tidsskr 43:203-207 (1987); McKeith, Br J Psychiatry
`145:389-393 (1984); O'Keefe & Devline, Neuropsychobi(cid:173)
`ology 30:153-156 (1994)). Furthermore, while some studies
`measuring glucocorticoid levels directly have found an
`association between delirium and persistent hypercortiso(cid:173)
`lism (Gustafson et al., Cerebrovasc Dis 3:33-38 (1993)),
`other studies have failed to link the incidence of delirium
`with elevated cortisol levels (van der Mast et al., in Filippini
`ed., Recent Advances in Tryptophan Research, New York:
`Plenum Press, 93-96 (1996); Mcintosh et al., Psycho(cid:173)
`neuroendocrinology 10:303-313 (1985)).
`
`[0007] There has been no evidence prior to this invention,
`however, that a glucocorticoid receptor antagonist can be an
`effective treatment for delirium, especially in patients hav(cid:173)
`ing cortisol levels that fall within a normal range. Many of
`the actions of cortisol are mediated by binding to the type I
`(mineralocorticoid) receptor, which is preferentially occu(cid:173)
`pied, relative to the type II (glucocorticoid) receptor, at
`physiological cortisol levels. As cortisol levels increase,
`more glucocorticoid receptors are occupied and activated.
`Because cortisol plays an essential role in metabolism,
`inhibition of all cortisolmediated activities, however, would
`be fatal. Therefore, antagonists that specifically prevent type
`II glucocorticoid receptor functions, but do not antagonize
`type I mineralocorticoid receptor functions are of particular
`use in this invention. Mifepristone (RU486) and similar
`antagonists are examples of this category of receptor antago(cid:173)
`nists.
`
`[0008] The present inventors have determined that gluco(cid:173)
`corticoid receptor antagonists such as RU486 are effective
`agents for the specific treatment of delirium in patients with
`normal or decreased cortisol levels. The present invention
`therefore fulfills the need for an effective treatment for the
`symptoms of delirium by providing methods of administer(cid:173)
`ing glucocorticoid receptor antagonists to treat patients
`diagnosed with delirium.
`
`SUMMARY OF THE INVENTION
`
`[0009] The invention provides a method of ameliorating
`the symptoms of delirium in a patient who has normal or
`decreased cortisol levels. The method comprises adminis(cid:173)
`tration of a therapeutically effective amount of a glucocor(cid:173)
`ticoid receptor antagonist to the patient.
`
`In one embodiment of the invention, the method of
`[0010]
`treating delirium uses a glucocorticoid receptor antagonist
`comprising a steroidal skeleton with at least one phenyl(cid:173)
`containing moiety in the 11-beta position of the steroidal
`skeleton. The phenyl-containing moiety in the 11-beta posi(cid:173)
`tion of the steroidal skeleton can be a dimethylaminophenyl
`moiety. In alternative embodiments, the glucocorticoid
`receptor antagonist comprises mifepristone, or, the gluco(cid:173)
`corticoid receptor antagonist is selected from the group
`consisting of RU009 and RU044.
`
`

`

`US 2004/0029848 Al
`
`Feb. 12,2004
`
`2
`
`[0011]
`In other embodiments, the glucocorticoid receptor
`antagonist is administered in a daily amount of between
`about 0.5 to about 20 mg per kilogram of body weight per
`day; between about 1 to about 10 mg per kilogram of body
`weight per day; or between about 1 to about 4 mg per
`kilogram of body weight per day. The administration can be
`once per day. In alternative embodiments, the mode of
`glucocorticoid receptor antagonist administration is oral, or
`by a transdermal application, by a nebulized suspension, or
`by an aerosol spray.
`
`[0012] The invention also provides a kit for the treatment
`of delirium in a human, the kit comprising a glucocorticoid
`receptor antagonist; and, an instructional material teaching
`the indications, dosage and schedule of administration of the
`glucocorticoid receptor antagonist. In alternative embodi(cid:173)
`ments, the instructional material indicates that the glucocor(cid:173)
`ticoid receptor antagonist can be administered in a daily
`amount of about 0.5 to about 20 mg per kilogram of body
`weight per day, of about 1 to about 10 mg per kilogram of
`body weight per day, or about 1 to about 4 mg per kilogram
`of body weight per day. The instructional material can
`indicate that cortisol contributes to delirium symptoms in
`patients with delirium, and that the glucocorticoid receptor
`antagonist can be used to treat delirium. In one embodiment,
`the glucocorticoid receptor antagonist in the kit is mifepris(cid:173)
`tone. The mifepristone can in tablet form.
`
`[0013] A further understanding of the nature and advan(cid:173)
`tages of the present invention is realized by reference to the
`remaining portions of the specification and claims.
`
`[0014] All publications, patents and patent applications
`cited herein are hereby expressly incorporated by reference
`for all purposes.
`
`DEFINITIONS
`
`[0015] The term "treating" refers to any indicia of success
`in the treatment or amelioration of an injury, pathology or
`condition, including any objective or subjective parameter
`such as abatement; remission; diminishing of symptoms or
`making the injury, pathology or condition more tolerable to
`the patient; slowing in the rate of degeneration or decline;
`making the final point of degeneration less debilitating;
`improving a patient's physical or mental well-being. The
`treatment or amelioration of symptoms can be based on
`objective or subjective parameters; including the results of a
`physical examination, neuropsychiatric exams, and/or a psy(cid:173)
`chiatric evaluation. For example, the methods of the inven(cid:173)
`tion successfully treat a patient's delirium by decreasing the
`incidence of disturbances in consciousness or cognition.
`
`[0016] The term "delirium" refers to a psychiatric condi(cid:173)
`tion in its broadest sense, as defined in American Psychiatric
`Association: Diagnostic and Statistical Manual of Mental
`Disorders, Fourth Edition, Text Revision, Washington, D.C.,
`2000 ("DSM-IV-TR"). The DSM-IV-TR defines "delirium"
`as a disturbance of consciousness, developing over a short
`period of time, accompanied by a change in cognition that
`cannot be better accounted for by a preexisting or evolving
`dementia. The DSM-IV-TR sets forth a generally accepted
`standard for diagnosing and categorizing delirium.
`
`[0018] The term "glucocorticoid receptor" ("GR") refers
`to a family of intracellular receptors also referred to as the
`cortisol receptor, which specifically bind to cortisol and/or
`cortisol analogs. The term includes isoforms of GR, recom(cid:173)
`binant GR and mutated GR.
`
`[0019] The term "mifepristone" refers to a family of
`compositions also referred to as RU486, or RU38.486, or
`17 -beta-hydroxy-11-beta -( 4-dimethyl-aminophenyl)-17 -al(cid:173)
`pha-(1-propynyl)-estra-4,9-dien-3-one ), or 11-beta-( 4dim(cid:173)
`ethylaminophenyl)-17-beta-hydroxy-17-alpha-(1-propy(cid:173)
`nyl)-estra-4,9-dien-3-one ), or analogs thereof, which bind to
`the GR, typically with high affinity, and inhibit the biological
`effects initiated/mediated by the binding of any cortisol or
`cortisol analogue to a GR receptor. Chemical names for
`RU-486 vary; for example, RU486 has also been termed:
`11B-[p-(Dimethylamino )phenyl ]-17B-hydroxy-17 -(1-pro(cid:173)
`pyny 1)-estra -4,9-dien-3-one;/11B-( 4-dimethy l-aminophe(cid:173)
`nyl)-17B-hydroxy-17 A-(prop-1-ynyl)-estra4,9-dien-3-one;
`17B-hydroxy-11B-( 4-dimethylaminophenyl-1)-17 A-(pro(cid:173)
`pynyl-1)-estra4,9-diene-17B-hydroxy-11B-( 4-dimethylami(cid:173)
`nophenyl-1)-17A-(propynyl-1)-E;
`(11B,17B)-11-[ 4-dim(cid:173)
`ethylamino )-phenyl]-17-hydroxy-17-(1-propynyl)estra-4,9-
`dien-3-one; and 11B-[ 4-(N,N-dimethylamino )phenyl]-17 A(cid:173)
`(prop-1-ynyl)-D-4,9-estradiene-17B-ol-3-one.
`
`[0020] The term "specific glucocorticoid receptor antago(cid:173)
`nist" refers to any composition or compound which partially
`or completely inhibits (antagonizes) the binding of a gluco(cid:173)
`corticoid receptor (GR) agonist, such as cortisol, or cortisol
`analogs, synthetic or natural, to a GR. A "specific glucocor(cid:173)
`ticoid receptor antagonist" also refers to any composition or
`compound which inhibits any biological response associated
`with the binding of a GR to an agonist. By "specific", we
`intend the drug to preferentially bind to the GR rather than
`the mineralocorticoid receptor (MR) with an affinity at least
`100-fold, and frequently 1000-fold.
`
`[0021] A patient "not otherwise in need of treatment with
`a glucocorticoid receptor antagonist" is a patient who is not
`suffering from a condition which is known in the art to be
`effectively treatable with glucocorticoid receptor antago(cid:173)
`nists. Conditions known in the art to be effectively treatable
`with glucocorticoid receptor antagonists include Cushing's
`disease, drug withdrawal, psychosis, dementia, stress disor(cid:173)
`ders, and psychotic major depression.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`[0022] This invention pertains to the surprising discovery
`that agents that can inhibit glucocorticoid-induced biologi(cid:173)
`cal responses are effective for treating delirium. In treating
`delirium, the methods of the invention can preferably relieve
`the symptoms of delirium or lead to complete resolution of
`the underlying disorder itself. In one embodiment, the
`methods of the invention use agents that act as GR antago(cid:173)
`nists, blocking the interaction of cortisol with GR, to treat or
`ameliorate delirium or symptoms associated with delirium.
`The methods of the invention are effective in ameliorating
`the symptoms of a delirium patient afflicted with either
`normal, increased or decreased levels of cortisol or other
`glucocorticoids, natural or synthetic.
`
`[0017] The term "cortisol" refers to a family of composi(cid:173)
`tions also referred to as hydrocortisone, and any synthetic or
`natural analogues thereof.
`
`[0023] Cortisol acts by binding to an intracellular, gluco(cid:173)
`corticoid receptor (GR). In humans, glucocorticoid receptors
`are present in two forms: a ligand-binding GR-alpha of 777
`
`

`

`US 2004/0029848 Al
`
`Feb. 12,2004
`
`3
`
`amino acids; and, a GR-beta isoform that differs in only the
`last fifteen amino acids. The two types of GR have high
`affinity for their specific ligands, and are considered to
`function through the same transduction pathways.
`
`[0024] The biologic effects of cortisol, including patholo(cid:173)
`gies or dysfunctions caused by hypercortisolemia, can be
`modulated and controlled at the GR level using receptor
`antagonists. Several different classes of agents are able to act
`as GR antagonists, i.e., to block the physiologic effects of
`GR-agonist binding (the natural agonist is cortisol). These
`antagonists include compositions, which, by binding to GR,
`block the ability of an agonist to effectively bind to and/or
`activate the GR. One family of known GR antagonists,
`mifepristone and related compounds, are effective and
`potent anti-glucocorticoid agents in humans (Bertagna, J.
`Clin. Endocrinol. Metab. 59:25, 1984). Mifepristone binds
`to the GR with high affinity, with a K of dissociation <10- 9
`M (Cadepond,Annu. Rev. Med. 48:129, 1997). Thus, in one
`embodiment of the invention, mifepristone and related com(cid:173)
`pounds are used to treat delirium.
`
`[0025] Delirium typically manifests itself with a variety of
`symptoms, including memory impairment, disorientation,
`perceptual disturbances, disturbances in the sleep-wake
`cycle, and disturbed psychomotor behavior. Thus, a variety
`of means of diagnosing delirium and assessing the success
`of treatment, i.e., the success and extent the symptoms of
`delirium are lessened by the methods of the invention, can
`be used, and a few exemplary means are set forth herein.
`These means can include classical, subjective psychological
`evaluations and neuropsychiatric examinations as described
`below.
`
`[0026] As the methods of the invention include use of any
`means to inhibit the biological effects of an agonist-bound
`GR, illustrative compounds and compositions which can be
`used to treat delirium are also set forth. Routine procedures
`that can be used to identify further compounds and compo(cid:173)
`sitions able to block the biological response caused by a
`GR-agonist interaction for use in practicing the methods of
`the invention are also described. As the invention provides
`for administering these compounds and compositions as
`pharmaceuticals, routine means to determine GR antagonist
`drug regimens and formulations to practice the methods of
`the invention are set forth below.
`
`[0027] 1. Diagnosis of Delirium
`
`[0028] Delirium is characterized by disturbances of con(cid:173)
`sciousness and changes in cognition that develop over a
`relatively short period of time. The disturbance in conscious(cid:173)
`ness is often manifested by a reduced clarity of awareness of
`the environment. The patient displays reduced ability to
`focus, sustain or shift attention (DSM-IV-TR diagnostic
`Criterion A). Accompanying the disturbance in conscious(cid:173)
`ness, delirium patients display a disturbance in cognition
`(e.g., memory impairment, disorientation, language difficul(cid:173)
`ties) or perceptual disturbances (e.g., misinterpretations,
`illusions, or hallucinations) (Criterion B). To be considered
`delirium, these disturbances in consciousness, cognition, or
`perception should develop over a short period of time and
`tend to fluctuate during the course of the day (Criterion C).
`
`[0029] The glucocorticoid receptor antagonists of the
`present invention are effective in treating delirium arising
`from any of several possible etiologies. Delirium may arise
`
`from a number of general medical conditions, including
`central nervous system disorders (e.g., trauma, stroke,
`encephalopathies), metabolic disorders (e.g., renal or
`hepatic insufficiency, fluid or electrolyte imbalances), car(cid:173)
`diopulmonary disorders (e.g., congestive heart failure, myo(cid:173)
`cardial infarction, shock), and systemic illnesses or effects
`(e.g., infections, sensory deprivation, and postoperative
`states). Glucocorticoid receptor antagonists are also effec(cid:173)
`tive to treat Substance-Induced Delirium (e.g., delirium
`induced by substance intoxication or withdrawal, medica(cid:173)
`tion side effects, and toxin exposure). Delirium may arise
`from multiple simultaneous etiologies (e.g., a combination
`of a general medical condition and substance intoxication)
`and such delirium, as well as delirium of unknown or
`unclassified origin, may be treated with the glucocorticoid
`receptor antagonists of the present invention.
`
`[0030] A diagnosis of delirium is distinct from a diagnosis
`of dementia or psychosis. Although memory impairment is
`common in both delirium and dementia, a patient with
`dementia alone is alert and usually does not display the
`is characteristic of
`disturbance
`in consciousness that
`delirium. Dementia patients typically lack the waxing and
`waning of symptoms over a 24-hour period that character(cid:173)
`izes delirium. Likewise, while delusions, hallucinations and
`agitation may be a feature of both delirium and psychosis,
`psychotic patients suffer from a basic disturbance in thought
`content. In contrast, delirious patients primarily suffer from
`disturbances in perception and orientation, rather than inter(cid:173)
`nal thought content. Psychotic symptoms, if present, tend to
`be fragmented rather than systematic. Delirium is also
`distinguished from dementia, psychosis, stress disorders,
`and mood disorders by the characteristic waxing and waning
`of symptoms, by signature EEG abnormalities described
`herein, and by the presence of a precipitating factor such as
`a general medical condition or substance intoxication.
`
`[0031] Delirium may be diagnosed and evaluated with any
`one of several objective, standardized test instruments
`known in the art, although skilled clinicians may readily
`diagnose delirium through unstructured clinical interactions.
`Standardized test instruments are constructed by experi(cid:173)
`enced clinical researchers based on DSM diagnostic criteria,
`and are typically validated through statistical studies and
`comparisons of various patient populations. Generally, stan(cid:173)
`dardized instruments assess both manifest psychological or
`physiological symptoms as well as internal thought pro(cid:173)
`cesses. The presence and severity of delirium may be
`determined by assessing disturbances in arousal, level of
`consciousness, cognitive function (e.g., memory, attention,
`orientation, disturbances in thinking) and psychomotor
`activity. Standardized test instruments for the diagnosis of
`delirium are usually administered by a professional health
`care practitioner, and may comprise interactive examination
`as well as observation of patient behavior.
`
`[0032] Standardized
`assessing
`for
`instruments
`test
`delirium include the Delirium Rating Scale (for review see
`Trzepacz, Psychosomatics 40:193-204 (1999)), the Memo(cid:173)
`rial Delirium Assessment Scale (Breitbart et al., J Pain
`Symptom Manage 13:128-137 (1997)), the Delirium Sever(cid:173)
`ity Scale (Bettin et al., Am J Geriatr Psychiatry 6:296-307
`(1998)), and the Delirium Symptom Interview (Albert et al.,
`J Geriatr Psychiatry Neural 5:14-21 (1992)). Cutoff scores
`yielding the most statistically valid division of patients into
`delirium and non-delirium populations are calculated based
`
`

`

`US 2004/0029848 Al
`
`Feb. 12,2004
`
`4
`
`on optimal positive and negative predictive power, and have
`been established and reported for each test (e.g., a score of
`13 or greater on the Memorial Delirium Assessment Scale or
`a score of 10 or greater on the Delirium Rating Scale) and
`may be used to select patients for therapy.
`[0033] Delirium may also be diagnosed and rated by the
`use of electroencephalography (EEG) (for review see Jacob(cid:173)
`son & Jerrier, Semin Clin Neuropsychiatry, 5:86-92 (2000)).
`Electroencephalograms of delirium patients are marked by a
`characteristic slowing or dropout of the posterior dominant
`rhythm, generalized theta or delta slow-wave activity, poor
`organization of the background rhythm, and loss of reactiv(cid:173)
`ity of the EEG to eye opening and closing. Delirium patients
`may also be diagnosed by quantitative EEG (QEEG), in
`which they display increased absolute and relative slow(cid:173)
`wave (theta and delta) power, reduced ratio of fast-to-slow
`band power, reduced mean frequency, and reduced occipital
`peak frequency. Accordingly, EEG or QEEG may be used to
`select patients for treatment with glucocorticoid receptor
`antagonists, or to monitor the effectiveness of glucocorticoid
`receptor antagonist therapy.
`[0034] 2. General Laboratory Procedures
`[0035] When practicing the methods of the invention, a
`number of general laboratory tests can be used to assist in
`the diagnosis, progress and prognosis of the patient with
`delirium, including monitoring of parameters such as blood
`cortisol, drug metabolism, brain structure and function and
`the like. These procedures can be helpful because all patients
`metabolize and react to drugs uniquely. In addition, such
`monitoring may be important because each GR antagonist
`has different pharmacokinetics. Different patients and dis(cid:173)
`ease conditions may require different dosage regimens and
`formulations. Such procedures and means to determine
`dosage regimens and formulations are well described in the
`scientific and patent literature. A few illustrative examples
`are set forth below.
`[0036]
`a. Determining Blood Cortisol Levels
`[0037] Varying levels of blood cortisol have been associ(cid:173)
`ated with delirium, although the invention may also be
`practiced upon patients with apparently normal levels of
`blood cortisol. Thus, monitoring blood cortisol and deter(cid:173)
`mining baseline cortisol levels are useful laboratory tests to
`aid in the diagnosis, treatment and prognosis of a delirium
`patient. A wide variety of laboratory tests exist that can be
`used to determine whether an individual is normal, hypo- or
`hypercortisolemic. Delirium patients typically have normal
`levels of cortisol that are often less than 25 ,ug!dl in the
`morning, and frequently about 15 ,ug/dl or less in the
`afternoon, although the values often fall at the high end of
`the normal range, which is generally considered to be 5-15
`,ug/dl in the afternoon.
`[0038]
`Immunoassays such as radioimmunoassays are
`commonly used because they are accurate, easy to do and
`relatively cheap. Because levels of circulating cortisol are an
`indicator of adrenocortical function, a variety of stimulation
`and suppression tests, such as ACTH Stimulation, ACTH
`Reserve, or dexamethasone suppression (see, e.g., Green(cid:173)
`wald, Am. J. Psychiatry 143:442446, 1986), can also pro(cid:173)
`vide diagnostic, prognostic or other information to be used
`adjunctively in the methods of the invention.
`[0039] One such assay available in kit form is the radio(cid:173)
`immunoassay available as "Double Antibody Cortisol Kit"
`
`(Diagnostic Products Corporation, Los Angeles, Calif.),
`(Acta Psychiatr. Scand. 70:239-247, 1984). This test is a
`competitive radioimmunoassay in which 125I-labeled corti(cid:173)
`sol competes with cortisol from an clinical sample for
`antibody sites. In this test, due to the specificity of the
`antibody and lack of any significant protein effect, serum
`and plasma samples require neither preextraction nor pre(cid:173)
`dilution. This assay is described in further detail in Example
`2, below.
`
`[0040] b. Determination of Blood/Urine Mifepristone
`Levels
`
`[0041] Because a patient's metabolism, clearance rate,
`toxicity levels, etc. differs with variations in underlying
`primary or secondary disease conditions, drug history, age,
`general medical condition and the like, it may be necessary
`to measure blood and urine levels of GR antagonist. Means
`for such monitoring are well described in the scientific and
`patent literature. As in one embodiment of the invention
`mifepristone is administered to treat delirium, an illustrative
`example of determining blood and urine mifepristone levels
`is set forth in the Example below.
`
`[0042] c. Other Laboratory Procedures
`
`[0043] Because the presentation of delirium may be com(cid:173)
`plex, a number of additional laboratory tests can be used
`adjunctively in the methods of the invention to assist in
`diagnosis, treatment efficacy, prognosis, toxicity and the
`like. For example, as increased hypercortisolemia has also
`been associated with delirium, diagnosis and treatment
`assessment can be augmented by monitoring and measuring
`glucocorticoid-sensitive variables, including but limited to
`fasting blood sugar, blood sugar after oral glucose admin(cid:173)
`istration, plasma concentrations thyroid stimulating hor(cid:173)
`mone (TSH), corticosteroid-binding globulin, luteinizing
`hormone (LH), testosterone-estradiol-binding globulin, and/
`or total and free testosterone.
`
`[0044] Laboratory tests monitoring and measuring GR
`antagonist metabolite generation, plasma concentrations and
`clearance rates, including urine concentration of antagonist
`and metabolites, may also be useful in practicing the meth(cid:173)
`ods of the invention. For example, mifepristone has two
`hydrophilic, N-monomethylated
`and N-dimethylated,
`metabolites. Plasma and urine concentrations of these
`metabolites (in addition to RU486) can be determined using,
`for example, thin layer chromatography, as described in
`Kawai Pharmacal. and Experimental Therapeutics 241:401-
`406, 1987.
`
`[0045] 3. Glucocorticoid Receptor Antagonists to Treat
`Delirium
`
`[0046] The invention provides for methods of treating
`delirium utilizing any composition or compound that can
`block a biological response associated with the binding of
`cortisol or a cortisol analogue to a GR. Antagonists of GR
`activity utilized in the methods of the invention are well
`described in the scientific and patent literature. A few
`illustrative examples are set forth below.
`
`[0047]
`nists.
`
`a. Steroidal Anti-Glucocorticoids as GR Antago(cid:173)
`
`[0048] Steroidal glucocorticoid antagonists are adminis(cid:173)
`tered for the treatment of delirium in various embodiments
`of the
`invention. Steroidal antiglucocorticoids can be
`
`

`

`US 2004/0029848 Al
`
`Feb. 12,2004
`
`5
`
`obtained by modification of the basic structure of glucocor(cid:173)
`ticoid agonists, i.e., varied forms of the steroid backbone.
`The structure of cortisol can be modified in a variety of
`ways. The two most commonly known classes of structural
`modifications of the cortisol steroid backbone to create
`glucocorticoid antagonists include modifications of the
`11-beta hydroxy group and modification of the 17 -beta side
`chain (see, e.g., Lefebvre, J. Steroid Biochem. 33:557-563,
`1989).
`
`[0049]
`Group
`
`i) Removal or Substitution of the 11-beta Hydroxy
`
`[0050] Glucocorticoid agonists with modified steroidal
`backbones comprising removal or substitution of the 11-beta
`hydroxy group are administered in one embodiment of the
`invention This class includes natural antiglucocorticoids,
`including cortexolone, progesterone and testosterone deriva(cid:173)
`tives, and synthetic compositions, such as mifepristone
`(Lefebvre, et al. supra). Preferred embodiments of the inven(cid:173)
`tion include all 11-beta-aryl steroid backbone derivatives
`because these compounds are devoid of progesterone recep(cid:173)
`tor (PR) binding activity (Agarwal, FEES 217:221-226,
`1987). Another preferred embodiment comprises an 11-beta
`phenyl-aminodimethyl steroid backbone derivative, i.e.,
`mifepristone, which is both an effective anti -glucocorticoid
`and anti-progesterone agent. These compositions act as
`reversibly-binding
`steroid
`receptor
`antagonists. For
`example, when bound to a 11-beta phenyl-aminodimethyl
`steroid, the steroid receptor is maintained in a conformation
`that cannot bind its natural ligand, such as cortisol in the case
`of GR (Cadepond, 1997, supra).
`
`[0051] Synthetic 11-beta phenyl-aminodimethyl steroids
`include mifepristone, also known as RU486, or 17-beta(cid:173)
`hydrox -11-beta -( 4-dimethy 1-aminopheny 1) 17 -alpha-( 1-pro(cid:173)
`pynyl)estra-4,9-dien-3-one ). Mifepristone has been shown
`to be a powerful antagonist of both the progesterone and
`glucocorticoid (GR) receptors. Another 11-beta phenyl-ami(cid:173)
`nodimethyl steroids shown to have GR antagonist effects
`includes R U009 (R U39 .009), 11-beta -( 4-dimethyl-amnino(cid:173)
`ethoxyphenyl)-17 -alpha -(propynyl-17 beta -hydroxy-4,9-es(cid:173)
`tradien-3-one) (see Bocquel, J. Steroid Biochem. Malec.
`Bioi. 45:205-215, 1993). Another GR antagonist related to
`RU486 is RU044 (RU43.044) 17-beta-hydrox-17-alpha-19-
`( 4-methyl-phenyl)-androsta-4,9 (11)-dien-3-one) (Bocquel,
`1993, supra). See also Teutsch, Steroids 38:651-665, 1981;
`U.S. Pat. Nos. 4,386,085 and 4,912,097.
`
`[0052] One embodiment includes compositions contain(cid:173)
`ing the basic glucocorticoid steroid structure which are
`irreversible anti-glucocorticoids. Such compounds include
`alpha-keto-methanesulfonate derivatives of cortisol, includ(cid:173)
`ing cortisol-21-mesylate ( 4-pregnene-11-beta, 17-alpha,
`21-triol-3, 20-dione-21-methane-sulfonate and dexametha(cid:173)
`sone-21-mesylate (16-