U.S. patent application number 12/238751 was filed with the patent office on 2009-01-29 for antiglucocorticoid therapy for the prevention of neurological damage in premature infants.
This patent application is currently assigned to Corcept Therapeutics, Inc.. Invention is credited to Joseph K. Belanoff.
Application Number | 20090029959 12/238751 |
Document ID | / |
Family ID | 34102903 |
Filed Date | 2009-01-29 |
United States Patent
Application |
20090029959 |
Kind Code |
A1 |
Belanoff; Joseph K. |
January 29, 2009 |
Antiglucocorticoid Therapy for the Prevention of Neurological
Damage in Premature Infants
Abstract
This invention pertains to the discovery that agents which
inhibit the binding of cortisol to its receptors can be used in
methods for preventing neurological damage associated with
glucocorticoid therapy in ventilator-dependent low birth weight
preterm infants. Mifepristone, a potent glucocorticoid receptor
antagonist, can be used in these methods.
Inventors: |
Belanoff; Joseph K.;
(Woodside, CA) |
Correspondence
Address: |
TOWNSEND AND TOWNSEND AND CREW, LLP
TWO EMBARCADERO CENTER, EIGHTH FLOOR
SAN FRANCISCO
CA
94111-3834
US
|
Assignee: |
Corcept Therapeutics, Inc.
Menlo Park
CA
|
Family ID: |
34102903 |
Appl. No.: |
12/238751 |
Filed: |
September 26, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10896149 |
Jul 20, 2004 |
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12238751 |
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60489601 |
Jul 23, 2003 |
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Current U.S.
Class: |
514/179 |
Current CPC
Class: |
A61P 25/00 20180101;
A61K 31/567 20130101; A61K 31/569 20130101; A61K 31/569 20130101;
A61K 31/573 20130101; A61K 2300/00 20130101; A61K 31/573 20130101;
A61K 2300/00 20130101; A61K 31/56 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 31/567 20130101; A61K 45/06 20130101;
A61K 31/56 20130101 |
Class at
Publication: |
514/179 |
International
Class: |
A61K 31/573 20060101
A61K031/573; A61P 25/00 20060101 A61P025/00 |
Claims
1. A method for preventing neurological damage in a ventilator
dependent low birth weight preterm infant receiving postnatal
glucocorticoid therapy, comprising: administering a glucocorticoid
receptor antagonist concommitantly with a postnatal glucocorticoid
in a dose effective for preventing neurological damage to the
infant from the postnatal glucocorticoid.
2. The method of claim 1, wherein the concomitant administration of
the glucocorticoid receptor antagonist is by intrathecal
injection.
3. The method of claim 1, wherein the postnatal glucocorticoid
therapy comprises administration of a glucocorticoid selected from
the group consisting of dexamethasone and betamethasone.
4. The method of claim 1, wherein the postnatal glucocorticoid
therapy is initiated within 96 hours of birth.
5. The method of claim 1, wherein the postnatal glucocorticoid
therapy is initiated 3-14 days after birth.
6. The method of claim 1, wherein concomitant administration of the
glucocorticoid receptor antagonist is initiated at the same time as
the postnatal glucocorticoid therapy.
7. The method of claim 1, wherein the low birthweight infant weighs
2500 grams or less at birth.
8. The method of claim 1, wherein the low birthweight infant weighs
1500 grams or less at birth.
9. The method of claim 1, wherein the low birthweight infant weighs
1000 grams or less at birth.
10. The method of claim 1, wherein the glucocorticoid receptor
antagonist comprises a steroidal skeleton with at least one
phenyl-containing moiety in the 11-beta position of the steroidal
skeleton.
11. The method of claim 1, wherein the phenyl-containing moiety in
the 11-beta position of the steroidal skeleton is a
dimethylaminophenyl moiety.
12. The method of claim 11, wherein the glucocorticoid receptor
antagonist comprises mifepristone.
13. The method of claim 11, wherein the glucocorticoid receptor
antagonist is selected from the group consisting of
11.beta.-(4-dimethylaminoethoxyphenyl)-17.alpha.-propynyl-17.beta.-hydrox-
y-4,9 estradien-3-one and
17.beta.-hydroxy-17.alpha.-19-(4-methylphenyl)androsta-4,9(11)-dien-3-one-
.
14. The method of claim 1 wherein the glucocorticoid receptor
antagonist is selected from the group consisting
4.alpha.(S)-Benzyl-2(R)-prop-1-ynyl-1,2,3,4,4.alpha.,9,10,10.alpha.(R)-oc-
tahydro-phenanthrene-2,7-diol and
4.alpha.(S)-Benzyl-2(R)-chloroethynyl-1,2,3,4,4.alpha.,9,10,10.alpha.(R)--
octahydro-phenanthrene-2,7-diol.
15. The method of claim 1, wherein the glucocorticoid receptor
antagonist is
(11.beta.,17.beta.)-11-(1,3-benzodioxol-5-yl)-17-hydroxy-17-(1-propyny-
l)estra-4,9-dien-3-one.
16. A kit for preventing neurological damage in a ventilator
dependent low birth weight preterm infant receiving postnatal
glucocorticoid therapy the kit comprising: (i) a specific
glucocorticoid receptor antagonist; and, (ii) an instructional
material teaching the indications, dosage and schedule of
administration of the glucocorticoid receptor antagonist
concommitantly with a postnatal glucocorticoid in a dose effective
for preventing neurological damage to the infant from the postnatal
glucocorticoid.
17. The kit of claim 16, wherein the glucocorticoid receptor
antagonist is mifepristone.
Description
CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] This application claims the benefit under 35 U.S.C. .sctn.
119(e) of U.S. Provisional Application No. 60/489,601, filed Jul.
23, 2003.
FIELD OF THE INVENTION
[0002] This invention is directed to a method for preventing
neurological damage in a ventilator-dependant low birth weight
preterm infant in need of postnatal glucocorticoid therapy.
BACKGROUND OF THE INVENTION
[0003] Low birth weight (less than 2500 grams) accounts for seven
percent of all births in the United States and is the most
important factor associated with infant mortality (National Center
for Health Statistics, Healthy People 2000: Maternal and Infant
Heath Progress Review, 1999).
[0004] Chronic lung disease (CLD), also known as bronchopulmonary
dysplasia is a frequent and increasing complication in premature
infants, usually presenting within the first 4 weeks after birth.
The incidence and severity of CLD is inversely proportional to
gestational age. Along with respiratory distress syndrome (RDS;
also called hyaline membrane disease), it is one of the leading
causes of infant mortality in developed countries (National Heart
Lung and Blood Institute, NIH Publication No. 98-4081, 1998). CLD
is a common complication in premature infants having RDS, although
any newborn with severe respiratory problems is at risk for CLD.
RDS occurs during the first several hours after birth and is caused
by surfactant deficiency. Lack of surfactant leads to alveoli
collapse, decreased lung capacity and edema. Premature infants with
RDS have difficulty breathing and have an increased oxygen demand,
requiring treatment by supplemental oxygen and mechanical
ventilation. Lack of surfactant leads to pulmonary inflammation,
which is further exacerbated by oxygen toxicity, barotrauma from
mechanical ventilation, and infection (Cole, Exp. Opin. Invest.
Drugs 9:53, 2000). Though the pathogenesis of CLD is not fully
understood, pulmonary inflammation is a common feature in all
infants with the disease. The inflammation and injury leads to
delayed pulmonary growth and development.
[0005] Postnatal treatment with glucocorticoids reduces the
inflammation and swelling of airways in ventilator-dependent low
birth weight preterm infants, and results in observable clinical
changes including increased pulmonary compliance, decreased airway
resistance, and accelerated weaning from mechanical ventilation and
supplemental oxygen (Cole, supra). Recent reports show that
approximately 40% of extremely low birth weight infants receive
such treatment (Barrington, BMC Pediatrics 1:1, 2001). This is
significant because extremely low birth weight infants account for
approximately 1.4% of the 3.5 million babies born in the United
States each year (see, e.g., Barrington, supra).
[0006] In most species, including man, the physiological
glucocorticoid is cortisol (hydrocortisone). Glucocorticoids are
secreted in response to ACTH (adrenocorticotropin), and are
responsive within minutes to many physical and psychological
stresses, including trauma, surgery, exercise, anxiety and
depression. Cortisol acts by binding to an intracellular,
glucocorticoid receptor (GR).
[0007] It has been postulated that high levels of cortisol are
neurotoxic, particularly in the hippocampus, (see, e.g., Sapolsky
et al., Ann. NY Acad Sci. 746:294, 1994; Silva, Annu. Rev. Genet.
31:527, 1997; de Leon et al., J. Clin. Endocrinol & Metab.
82:3251, 1997). Studies of human subjects who have received
treatment with exogenous glucocorticoids at therapeutic levels have
suggested that glucocorticoids may play a role in short-term,
reversible memory impairment. (see, e.g., Wolkowitz et al., Am J.
Psychiatry 147:1297, 1990; Keenan et al., Neurology 47:1396, 1996;
Newcomer et al., Arch Gen. Psychiatry 56:527-533, 1999).
[0008] Thus, despite the success of glucocorticoid therapy for
treating pulmonary inflammation in ventilator-dependent low birth
weight preterm infants, there are growing concerns regarding the
short and long term adverse effects experienced by glucocorticoid
treated premature infants. Short term adverse effects may include
hyperglycemia, hypertension, hypertrophic obstructive
cardiomyopathy, gastrointestinal hemorrhage and perforations,
growth failure and hypothalamic-pituitary-adrenal axis suppression
(see Shah, et al., Cochrane Database Syst. Rev. 1:CD002058, 2003).
The long term neurological disorders are however, the most
disconcerting adverse effects. Studies of preterm infants
demonstrate that in the long term, there are increased rates of
cerebral palsy in those receiving treatment versus those not
receiving treatment, and probable increases in rates of total
neurodevelopmental disability (Barrington, supra). In rats,
glucocorticoid administration in the last days of gestation or
first two weeks of postnatal life at doses mimicking pulmonary
therapy doses, leads to neurological impairment, including
acceleration of differentiation of specific target cells in the
central nervous system (see, e.g., Carlos, et al., Teratology
46:45, 1992).
[0009] Because of the increasing evidence that glucocorticoid
treatment affects neurological development, several experts in the
field have urged abandoning glucocorticoid treatment altogether,
despite its success in reducing inflammation and accelerating the
process of weaning infants off of ventilators (See, e.g.,
Barrington, supra; Shah, supra; Committee on Fetus and Newborn,
Pediatrics 109:330, 2002). Thus, while glucocorticoid therapy is a
rapid and effective treatment for inflammation, the potential risk
for permanent neurological damage threatens to eliminate this
promising treatment.
[0010] Fortunately, it has now been discovered that inhibition of
glucocorticoid receptor activity in the central nervous system of
in ventilator-dependent low birth weight preterm infants by
concomitant intrathecal administration of antiglucocorticoids
during postnatal glucocorticoid therapy can prevent or reverse
neurological damage caused by the postnatal glucocorticoid therapy.
Thus, the invention fulfills a need for effective methods to
prevent damaging neurological side effects of postnatal
glucocorticoid therapy while allowing for the maximum benefit of
the postnatal glucocorticoid therapy to be realized.
SUMMARY OF THE INVENTION
[0011] Accordingly, the present invention provides a method for
preventing neurological damage in ventilator-dependent low birth
weight preterm infants receiving postnatal glucocorticoid therapy.
The method comprises concomitant administration of glucocorticoid
receptor antagonists with postnatal glucocorticoids.
[0012] In one embodiment, the postnatal glucocorticoid is selected
from the group consisting of dexamethasone and betamethasone. In
one embodiment initiation of postnatal glucocorticoid therapy
occurs within 96 hours after birth. In another embodiment
initiation of postnatal glucocorticoid therapy occurs within 3 to
14 days after birth.
[0013] In one embodiment, the glucocorticoid receptor antagonist is
administered intrathecally. In another embodiment administration of
the glucocorticoid receptor antagonist is initiated at the same
time as the postnatal glucocorticoid therapy.
[0014] In one embodiment, the low birth weight preterm infant
weighs 2500 grams or less. In another embodiment, the low birth
weight preterm infant weighs 1500 grams or less. In another
embodiment the the low birth weight preterm infant weighs 1000
grams or less.
[0015] In one embodiment, the glucocorticoid receptor antagonist
comprises a steroidal skeleton with at least one phenyl-containing
moiety in the 11-beta position of the steroidal skeleton. In
another embodiment, the phenyl-containing moiety in the 11-beta
position of the steroidal skeleton is a dimethylaminophenyl moiety.
In a preferred embodiment, the glucocorticoid receptor antagonist
comprises mifepristone. In another embodiment, the glucocorticoid
receptor antagonist is selected from the group consisting of
11-.beta.-(4-dimethyl-aminoethoxyphenyl)-17.alpha.-propynyl-17.beta.-hydr-
oxy-4,9-estradien-3-one, and
17.beta.-hydrox-17.alpha.-19-(4-methyl-phenyl)androsta-4,9
(11)-dien-3-one.
[0016] In one embodiment, the glucocorticoid receptor antagonist is
selected from the group consisting
4.alpha.(S)-Benzyl-2(R)-prop-1-ynyl-1,2,3,4,4.alpha.,9,10,10.alpha.(R)-oc-
tahydro-phenanthrene-2,7-diol and
4.alpha.(S)-Benzyl-2(R)-chloroethynyl-1,2,3,4,4.alpha.,9,10,10.alpha.(R)--
octahydro-phenanthrene-2,7-diol. In an alternative embodiment, the
glucocorticoid receptor antagonist is
(11.beta.,17.beta.)-11-(1,3-benzodioxol-5-yl)-17-hydroxy-17-(1-propynyl)e-
stra-4,9-dien-3-one.
[0017] The invention also provides a kit for preventing
neurological damage in a ventilator dependent low birth weight
preterm infant receiving postnatal glucocorticoid therapy, wherein
the kit comprises a specific glucocorticoid receptor antagonist,
and an instructional material teaching the indications, dosage and
schedule of administration for the glucocorticoid receptor
antagonist concomitantly with a postnatal glucocorticoid, in a dose
effective for preventing neurological damage to the infant from the
postnatal glucocorticoid. In one embodiment the glucocorticoid
receptor antagonist included in the kit is mifepristone.
[0018] Thus, the invention provides a new, effective treatment for
the prevention of neurological damage in ventilator-dependent low
birth weight preterm infants receiving postnatal glucocorticoid
therapy.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0019] The term "cortisol" refers to a family of compositions also
referred to as hydrocortisone, and any synthetic or natural
analogues thereof. This includes glucocorticoids (also known as
glucocorticosteriods or corticoids).
[0020] The term "glucocorticoid receptor" as used herein 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 glucocorticoid
receptors, recombinant glucocorticoid receptors and mutated
glucocorticoid receptors.
[0021] The terms "glucocorticoid receptor antagonist", "GR
antagonist", "antiglucocorticoid", "glucocorticoid blocker" refer
to any composition or compound which at least partially inhibits
(antagonizes) the biological response that results from the binding
of a glucocorticoid receptor agonist, such as cortisol, or cortisol
analogs, synthetic or natural, to a glucocorticoid receptor. A
"glucocorticoid receptor antagonist" may itself bind a
glucocorticoid receptor, or it may inhibit the binding of an
agonist to a glucocorticoid receptor, or it may block the
downstream biological activities that result from the binding of a
glucocorticoid receptor agonist to a glucocorticoid receptor. Thus,
a "glucocorticoid receptor antagonist" or "antiglucocorticoid"
refers to any composition or compound which inhibits any biological
response associated with the binding of a glucocorticoid receptor
to an agonist.
[0022] 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-.alpha.-(1-propyn-
yl)-estra-4,9-dien-3-one), or
11-.beta.-(4dimethylaminophenyl)-17-.beta.-hydroxy-17-.alpha.-(1-propynyl-
)-estra-4,9-dien-3-one), or analogs thereof, which bind to the
glucocorticoid receptor, 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:
11.beta.-[p-(Dimethylamino)phenyl]-17.beta.-hydroxy-17-(1-propynyl)-estra-
-4,9-dien-3-one;
11.beta.-(4-dimethyl-aminophenyl)-17.beta.-hydroxy-17.alpha.-(prop-1-ynyl-
)-estra-4,9-dien-3-one;
17.beta.-hydroxy-11.beta.-(4-dimethylaminophenyl-1)-17.alpha.-(propynyl-1-
)-estra-4,9-diene-3-one;
17.beta.-hydroxy-11.beta.-(4-dimethylaminophenyl-1)-17.alpha.-(propynyl-1-
)-E;
(11.beta.,17.beta.)-11-[4-dimethylamino)-phenyl]-17-hydroxy-17-(1-pro-
pynyl)estra-4,9-dien-3-one; and
11.beta.-[4-(N,N-dimethylamino)phenyl]-17.alpha.-(prop-1-ynyl)-D-4,9-estr-
adiene-17.beta.-ol-3-one.
[0023] The term "neurological damage" as used herein refers to
damage to the nervous system, resulting in structural or functional
abnormalities. By way of example, but not of limitation,
neurological damage may include decreased brain growth, decreased
cell numbers in the cerebrum and cerebellum, decreased cerebellar
DNA, decreased glucocorticoid receptor activity in the hippocampus,
and decreased myelination. Neurological damage may also manifest
itself as reduced premature brain size, cerebral palsy, abnormal
motor activity, retinopathies, or cognitive deficits. Methods for
measuring neurological damage are known in the art.
[0024] The term "cerebral palsy" refers to a group of chronic
disorders impairing control of movement that generally do not
worsen, but may change over time. Symptoms include difficulty with
fine motor tasks, difficulty maintaining balance or walking,
involuntary movements. The exact symptoms differ from person to
person.
[0025] The term "prevention" refers to any indicia of success in
prevention, treatment or amelioration of neurological damage,
injury, pathology or condition, including any objective or
subjective parameter such as abatement; remission; diminishing of
symptoms, prevention or lessening of neurological damage or injury,
making the condition more tolerable to the infant; making the final
point of degeneration less debilitating; improving a patient's
physical or mental well-being. For example, success of treatment by
methods of the invention could be measured by comparison to
ventilator-dependent low birth weight preterm infants who did not
receive concomitant administration of antiglucocorticoids with
postnatal glucocorticoid therapy. The prevention, treatment or
amelioration of symptoms can be based on objective or subjective
parameters; including the results of a physical examination, biopsy
or microscopic examination of a tissue sample, or any other
appropriate means known in the art.
[0026] The term "preterm infant" refers to an infant born before 37
weeks of gestation. This includes terms such as premature infant or
preemie. The term "low birth weight preterm infant" refers to a
preterm infant weighing less than 2,500 grams at birth. This term
includes preterm infants described as low birth weight (less than
2,500 grams), very low birth weight (less than 1,500 grams) and
extremely low birth weight (less than 1,000 grams).
[0027] The term "ventilator" refers a device for maintaining
artificial respiration such as a mechanical ventilator, also called
a respirator. The term "ventilator-dependent" refers to the
requirement for a mechanical means of ventilation to maintain
respiration.
[0028] The term "postnatal glucocorticoid therapy" refers to the
administration of glucocorticoids after birth. The postnatal
glucocorticoid therapy may be administered for the purpose of
preventing chronic lung disease in a preterm infant, or may be
given for any other purpose known in the art. Postnatal
glucocorticoid therapy comprises both inhaled and systemic
treatment, and may be initiated any time between birth and 14 days
after birth. The term "postnatal glucocorticoid therapy" includes,
but is not limited to therapy delivered within 96 hours of birth as
well as that which is initiated 3-14 days after birth. Postnatal
glucocorticoid therapy can be administered prophylactically or
therapeutically. Typically prophylactic therapy is initiated within
3 days or less after birth, before the infant shows any signs of
chronic lung disease or other symptoms that may indicate the need
for postnatal treatment with glucocorticoids. Postnatal
glucocorticoid therapy may also be initiated therapeutically in
response to symptoms. The term "postnatal glucocorticoid" refers to
any glucocorticoid delivered at any time between birth and 14
days.
[0029] The term "concomitant administration" of glucocorticoid
receptor antagonist with a postnatal glucocorticoid refers to
administration of the glucocorticoid receptor antagonist and the
postnatal glucocorticoid at such times that both the postnatal
glucocorticoid and glucocorticoid receptor antagonist can reach a
therapeutically effective amount at an appropriate time relative to
one another. Although concomitant administration typically involves
concurrent (i.e. at the same time), administration of the
antiglucocorticoid with respect to the administration of the
postnatal glucocorticoid, antiglucocorticoid may also be
concomitantly administered prior to or subsequent to the initiation
of glucocorticoid therapy if such timing is required for the
postnatal glucocorticoid and glucocorticoid receptor antagonist to
reach a therapeutically effective amount at an appropriate time
relative to one another. A person of ordinary skill in the art,
based on the information provided herein and having knowledge of
the postnatal glucocorticoid and of central nervous system
administration of glucocorticoid receptor antagonists, will have no
difficulty determining the appropriate timing, sequence, and
dosages for administration of the glucocorticoid receptor
antagonist with respect to the dosage of the postnatal
glucocorticoid.
[0030] The term "intrathecally" refers to introduction into or
occurrence in the space under the arachnoid membrane of the brain
or spinal cord. The term "intrathecal administration" is intended
to include delivering a formulation directly into the cerebrospinal
fluid of a subject, by techniques that include what is understood
in the art to comprise intrathecal injection, as well as lateral
cerebroventricular injection (described in Lazorthes et al.
Advances in Drug Delivery Systems and Applications in Neurosurgery,
143-192 and Omaya et al., Cancer Drug Delivery, 1: 169-179).
Administration can be achieved by direct injection of the
formulation or by the use of infusion pumps. The injection can be,
for example, in the form of a bolus injection or continuous
infusion (e.g., using infusion pumps).
Introduction
[0031] The invention provides a method for preventing neurological
damage in a ventilator dependent low birth weight preterm infant
receiving postnatal glucocorticoid therapy. The method comprises
administering a glucocorticoid receptor antagonist concomitant with
a postnatal glucocorticoid in a dose effective for preventing
neurological damage to the infant from the postnatal
glucocorticoid.
[0032] Glucocorticoids are used in the neonatal period to treat or
prevent chronic lung disease (CLD) in preterm babies. As noted
earlier, glucocorticoid therapy may prevent or treat chronic lung
disease in the preterm infant, but glucocorticoid use may be
associated with certain adverse effects such as neurological damage
and developmental delays.
[0033] It has now been discovered that the neurological damage that
may occur as a result of glucocorticoid administration to preterm
infants can be prevented by administration of an antiglucocorticoid
concomitant with the glucocorticoid therapy. In a preferred
embodiment, the antiglucocorticoid is administered by direct
injection into the cerebrospinal fluid of the infant.
[0034] In humans, glucocorticoid receptors are present in two
forms: a ligand-binding GR-alpha of 777 amino acids; and, a GR-beta
isoform that differs in only the last fifteen amino acids. The two
types of GR have high affnity for their specific ligands, and are
considered to function through the same transduction pathways.
Glucocorticoids bind the receptors thereby acting as agonists to
activate a biological response.
[0035] The biologic effects of glucocorticoids such as
dexamethasone and betamethasone, including pathologies or
dysfunctions that may develop in a preterm infant receiving
glucocorticoid therapy, can be modulated and controlled at the
glucocorticoid receptor 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.sup.-9 M (Cadepond, Annu. Rev. Med 48:129,
1997). Thus, in one embodiment of the invention, mifepristone and
related compounds are administered to low birth weight preterm
infants who are receiving postnatal glucocorticoid therapy, to
prevent neurological damage in the infant.
[0036] 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 and thereby
prevent neurological damage in low birth weight preterm infants
receiving postnatal glucocorticoid therapy are set forth, but these
illustrations are not meant to be limiting. Routine procedures that
can be used to identify further compounds and compositions 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 also set forth below.
Diagnosing Ventilator-Dependant Low Birth Weight Preterm Infants in
Need of Antiglucocorticoid Treatment to Prevent Neurological
Damage
A. Assessing and Diagnosing Preterm Infants in Need of
Anti-Glucocorticoid Treatment
[0037] Any infant receiving glucocorticoid therapy would benefit
from antiglucocorticoid treatment according to the methods of the
invention. However, ventilator-dependent low birth weight preterm
infants receiving postnatal glucocorticoid therapy to treat or
prevent chronic lung disease are preferred candidates.
[0038] The infant may be receiving postnatal glucocorticoid
treatment as prophylactic therapy, wherein the glucocorticoid
therapy was initiated before the infant showed any signs of
respiratory distress syndrome or chronic lung disease, or the
infant may be in early therapy for the treatment of disease
symptoms. In cases where the infant is in early therapy the infant
is typically 3-14 days old. The infant may be receiving postnatal
glucocorticoid therapy by any means known in the art. For example,
the glucocorticoid treatment can be administered systemically in
pulses or by tapering over time or it can be administered by
aerosol inhalation. In some cases the postnatal glucocorticoid
therapy comprises the administration of dexamethasone or
betamethasone.
Treatment of Ventilator-Dependant Low Birth Weight Preterm Infants
Receiving Postnatal Glucocorticoid Therapy with Glucocorticoid
Receptor Antagonists
I. Glucocorticoid Receptor Antagonists to Reduce Neurological
Damage
[0039] The invention provides a method of preventing neurological
damage in ventilator-dependant low birth weight preterm infants who
are receiving postnatal glucocorticoid therapy. The method provides
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.
[0040] A. Steroidal Antiglucocorticoids as GR Antagonists.
[0041] Steroidal glucocorticoid antagonists are administered to
prevent neurological damage in low birth weight preterm infants in
various embodiments of the invention. Steroidal antiglucocorticoids
can be obtained by modification of the basic structure of
glucocorticoid 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).
[0042] Examples of steroidal GR antagonists include androgen-type
steroid compounds as described in U.S. Pat. No. 5,929,058, and the
compounds disclosed in U.S. Pat. Nos. 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;
5,616,458, 5,696,127 and 6,303,591. Such steroidal GR antagonists
include cortexolone, dexamethasone-oxetanone,
19-nordeoxycorticosterone, 19-norprogesterone,
cortisol-21-mesylate; dexamethasone-21-mesylate,
11.beta.-(4-dimethylaminoethoxyphenyl)-17.alpha.-propynyl-17.beta.-hydrox-
y-4,9-estradien-3-one (RU009), and
17.beta.-hydroxy-17.alpha.-19-(4-methylphenyl)androsta-4,9(11)-dien-3-one
(RU044).
[0043] Other examples of steroidal antiglucocorticoids are
disclosed in Van Kampen et al., (2002) Eur. J. Pharmacol.
457(2-3):207, WO 03/043640, EP 0 683 172 B1, and EP 0 763 541 B1,
each of which is incorporated herein by reference. EP 0 763 541 B1
and Hoyberg et al., Int'l J. of Neuro-psychopharmacology, 5:Supp.
1, S148 (2002); disclose the compound
(11.beta.,17.beta.)-11-(1,3-benzodioxol-5-yl)-17-hydroxy-17-(1-propynyl)e-
stra-4,9-dien-3-one (ORG 34517) which in a preferred embodiment, is
administered in an amount effective to prevent neurological damage
in a preterm infant receiving postnatal glucocorticoid therapy.
[0044] 1. Removal or Substitution of the 11-beta Hydroxy Group
[0045] 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 derivatives, and synthetic
compositions, such as mifepristone (Lefebvre, et al. supra).
Preferred embodiments of the invention include all 11-beta-aryl
steroid backbone derivatives because these compounds are devoid of
progesterone receptor (PR) binding activity (Agarwal, FEBS
217:221-226, 1987). Another preferred embodiment comprises an
11-beta phenyl-aminodimethyl steroid backbone derivative, i.e.,
mifepristone, which is both an effective antiglucocorticoid and
anti-progesterone agent. These compositions act as
reversibly-binding steroid receptor antagonists. For example, when
bound to a 11-beta phenyl-arninodimethyl 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).
[0046] Synthetic 11-beta phenyl-aminodimethyl steroids include
mifepristone, also known as RU486, or
17-beta-hydrox-11-beta-(4-dimethyl-aminophenyl)17-alpha-(1-propynyl)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-aminodimethyl steroids shown to
have GR antagonist effects includes RU009 (RU39.009),
11-beta-(4-dimethyl-aminoethoxyphenyl)-17-alpha-(propynyl-17
beta-hydroxy-4,9-estradien-3-one) (see Bocquel, J. Steroid Biochem.
Molec. Biol. 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.
[0047] One embodiment includes compositions containing the basic
glucocorticoid steroid structure which are irreversible
antiglucocorticoids. Such compounds include
alpha-keto-methanesulfonate derivatives of cortisol, including
cortisol-21-mesylate (4-pregnene-11-beta, 17-alpha,
21-triol-3,20-dione-21-methane-sulfonate and
dexamethasone-21-mesylate (16-methyl-9
alpha-fluoro-1,4-pregnadiene-11 beta, 17-alpha,
21-triol-3,20-dione-21-methanesulfonate). See Simons, J. Steroid
Biochem. 24:25-32, 1986; Mercier, J. Steroid Biochem. 25:11-20,
1986; U.S. Pat. No. 4,296,206.
[0048] 2. Modification of the 17-beta Side Chain Group
[0049] Steroidal antiglucocorticoids which can be obtained by
various structural modifications of the 17-beta side chain are also
used in the methods of the invention. This class includes synthetic
antiglucocorticoids such as dexamethasone-oxetanone, various 17,
21-acetonide derivatives and 17-beta-carboxamide derivatives of
dexamethasone (Lefebvre, 1989, supra; Rousseau, Nature 279:158-160,
1979).
[0050] 3. Other Steroid Backbone Modifications
[0051] GR antagonists used in the various embodiments of the
invention include any steroid backbone modification which effects a
biological response resulting from a GR-agonist interaction.
Steroid backbone antagonists can be any natural or synthetic
variation of cortisol, such as adrenal steroids missing the C-19
methyl group, such as 19-nordeoxycorticosterone and
19-norprogesterone (Wynne, Endocrinology 107:1278-1280, 1980).
[0052] In general, the 11-beta side chain substituent, and
particularly the size of that substituent, can play a key role in
determining the extent of a steroid's antiglucocorticoid activity.
Substitutions in the A ring of the steroid backbone can also be
important. 17-hydroxypropenyl side chains generally decrease
antiglucocorticoid activity in comparison to 17-propinyl side chain
containing compounds.
[0053] Additional glucocorticoid receptor antagonists known in the
art and suitable for practice of the invention include
21-hydroxy-6,19-oxidoprogesterone (see Vicent, Mol. Pharm.
52:749-753, 1997), Org31710 (see Mizutani, J Steroid Biochem Mol
Biol 42(7):695-704, 1992), RU43044, RU40555 (see Kim, J Steroid
Biochem Mol Biol. 67(3):213-22, 1998), RU28362, and ZK98299.
[0054] B. Non-Steroidal Antiglucocorticoids as Antagonists.
[0055] Non-steroidal glucocorticoid antagonists are also used in
the methods of the invention to prevent neurological damage in low
birth weight preterm infants. These include synthetic mimetics and
analogs of proteins, including partially peptidic, pseudopeptidic
and non-peptidic molecular entities. For example, oligomeric
peptidomimetics useful in the invention include
(alpha-beta-unsaturated) peptidosulfonamides, N-substituted glycine
derivatives, oligo carbamates, oligo urea peptidomimetics,
hydrazinopeptides, oligosulfones and the like (see, e.g., Amour,
Int. J Pept. Protein Res. 43:297-304, 1994; de Bont, Bioorganic
& Medicinal Chem. 4:667-672, 1996). The creation and
simultaneous screening of large libraries of synthetic molecules
can be carried out using well-known techniques in combinatorial
chemistry, for example, see van Breemen, Anal Chem 69:2159-2164,
1997; and Lam, Anticancer Drug Des 12:145-167, 1997. Design of
peptidomimetics specific for GR can be designed using computer
programs in conjunction with combinatorial chemistry (combinatorial
library) screening approaches (Murray, J. of Computer-Aided Molec.
Design 9:381-395, 1995; Bohm, J. of Computer-Aided Molec. Design
10:265-272, 1996). Such "rational drug design" can help develop
peptide isomerics and conformers including cycloisomers,
retro-inverso isomers, retro isomers and the like (as discussed in
Chorev, TibTech 13:438-445, 1995).
[0056] Examples of non-steroidal 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; and
N-((2,6-dichloro-3-methylphenyl)diphenyl)methylimidazole (see U.S.
Pat. No. 6,051,573); the GR antagonist compounds disclosed in U.S.
Pat. Nos. 5,696,127 and 6,570,020; the GR antagonist compounds
disclosed in U.S. Patent Application 20020077356, the
glucocorticoid receptor antagonists disclosed in Bradley et al., J.
Med Chem. 45, 2417-2424 (2002), e.g.,
4.alpha.(S)-Benzyl-2(R)-chloroethynyl-1,2,3,4,4.alpha.,9,10,10.alpha.(R)--
octahydro-phenanthrene-2,7-diol ("CP 394531") and
4.alpha.(S)-Benzyl-2(R)-prop-1-ynyl-1,2,3,4,4.alpha.,9,10,10.alpha.(R)-oc-
tahydro-phenanthrene-2,7-diol ("CP 409069"); the compounds
disclosed in PCT International Application No. WO 96/19458, which
describes non-steroidal compounds which are high-affinity, highly
selective antagonists for steroid receptors, such as
6-substituted-1,2-dihydro-N-protected-quinolines; and some .kappa.
opioid ligands, such as the .kappa. opioid compounds
dynorphin-1,13-diamide, U50,488
(trans-(1R,2R)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohe-
xyl]benzeneacetamide), bremazocine and ethylketocyclazocine; and
the non-specific opioid receptor ligand, naloxone, as disclosed in
Evans et al., Endocrin., 141:2294-2300 (2000).
Glucocorticoid Receptor Antagonists as Pharmaceutical
Compositions
[0057] Glucocorticoid receptor antagonists can be prepared as
pharmaceutical formulations according to any method known to the
art for the manufacture of pharmaceuticals. Such drugs can contain
coloring agents and preserving agents. Any glucocorticoid receptor
antagonist formulation can be admixtured with nontoxic
pharmaceutically acceptable excipients which are suitable for
manufacture.
[0058] Compositions comprise at least one compound of this
invention in combination with at least one pharmaceutically
acceptable excipient. Suitable excipients are well known to persons
of ordinary skill in the art, and they, and the methods of
formulating the compositions, may be found in such standard
references as Remington's, supra. Suitable liquid carriers,
especially for injectable solutions, include water, aqueous saline
solution, aqueous dextrose solution, and glycols.
[0059] Aqueous suspensions of the invention contain a
glucocorticoid receptor antagonist in admixture with excipients
suitable for the manufacture of aqueous suspensions. Such
excipients include a suspending agent, such as sodium
carboxymethylcellulose, methylcellulose,
hydroxypropylmethylcellulose, sodium alginate,
polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing
or wetting agents such as a naturally occurring phosphatide (e.g.,
lecithin), a condensation product of an alkylene oxide with a fatty
acid (e.g., polyoxyethylene stearate), a condensation product of
ethylene oxide with a long chain aliphatic alcohol (e.g.,
heptadecaethylene oxycetanol), a condensation product of ethylene
oxide with a partial ester derived from a fatty acid and a hexitol
(e.g., polyoxyethylene sorbitol mono-oleate), or a condensation
product of ethylene oxide with a partial ester derived from fatty
acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan
mono-oleate). The aqueous suspension can also contain one or more
preservatives such as ethyl or n-propyl p-hydroxybenzoate or one or
more coloring agents. Formulations can be adjusted for
osmolarity.
[0060] Oil suspensions can be formulated by suspending a
glucocorticoid receptor antagonist in a vegetable oil, such as
arachis oil, olive oil, sesame oil or coconut oil, or in a mineral
oil such as liquid paraffin; or a mixture of these. The oil
suspensions can contain a thickening agent, such as beeswax, hard
paraffin or cetyl alcohol. These formulations can be preserved by
the addition of an antioxidant such as ascorbic acid. As an example
of an injectable oil vehicle, see, e.g., Minto, J. Pharmacol. Exp.
Ther. 281:93-102, 1997. The pharmaceutical formulations of the
invention can also be in the form of oil-in-water emulsions. The
oily phase can be a vegetable oil or a mineral oil, described
above, or a mixture of these. Suitable emulsifying agents include
naturally-occurring gums, such as gum acacia and gum tragacanth,
naturally occurring phosphatides, such as soybean lecithin, esters
or partial esters derived from fatty acids and hexitol anhydrides,
such as sorbitan mono-oleate, and condensation products of these
partial esters with ethylene oxide, such as polyoxyethylene
sorbitan mono-oleate. Such formulations can also contain a
demulcent, a preservative, or a coloring agent.
[0061] In another embodiment, the GR antagonist formulations of the
invention are useful for administration into a body cavity or lumen
of an organ. The formulations for administration will commonly
comprise a solution of the GR antagonist (e.g., mifepristone)
dissolved in a pharmaceutically acceptable carrier. Among the
acceptable vehicles and solvents that can be employed are water and
Ringer's solution, an isotonic sodium chloride. In addition,
sterile fixed oils can conventionally be employed as a solvent or
suspending medium. For this purpose any bland fixed oil can be
employed including synthetic mono- or diglycerides. In addition,
fatty acids such as oleic acid can likewise be used in the
preparation of injectables. These solutions are sterile and
generally free of undesirable matter. These formulations may be
sterilized by conventional, well known sterilization techniques.
The formulations may contain pharmaceutically acceptable auxiliary
substances as required to approximate physiological conditions such
as pH adjusting and buffering agents, toxicity adjusting agents,
e.g., sodium acetate, sodium chloride, potassium chloride, calcium
chloride, sodium lactate and the like. The concentration of GR
antagonist in these formulations can vary widely, and will be
selected primarily based on fluid volumes, viscosities, body
weight, and the like, in accordance with the particular mode of
administration selected and the patient's needs.
[0062] After a pharmaceutical comprising a glucocorticoid receptor
antagonist of the invention has been formulated in a acceptable
carrier, it can be placed in an appropriate container and labeled
for treatment of an indicated condition. For administration of
glucocorticoid receptor antagonists, such labeling would include,
e.g., instructions concerning the amount, frequency and method of
administration. In one embodiment, the invention provides for a kit
for preventing neurological damage in a low birth weight preterm
infant receiving glucocorticoid therapy which includes a
glucocorticoid receptor antagonist and instructional material
teaching the indications, dosage and schedule of administration of
the glucocorticoid receptor antagonist.
Determining Dosing Regimens for Glucocorticoid Receptor
Antagonists
[0063] The methods of the invention prevent neurological damage in
a low birth weight preterm infant receiving postnatal
glucocorticoid therapy. The amount of glucocorticoid receptor
antagonist adequate to accomplish this is defined as a
"therapeutically effective dose", or an "effective dose". The
dosage schedule and amounts effective for this use, i.e., the
"dosing regimen," will depend upon a variety of factors, including
the mode of administration of the antiglucocorticoid, the existence
or severity chronic lung disease, the dose of glucocorticoids, the
birth weight of the infant, as well as the infant's physical
status, age and the like.
[0064] The state of the art allows the clinician to determine the
dosage regimen for each individual infant, taking into
consideration the particular glucocorticoid receptor antagonist to
be used for the prevention of neurological damage, as well as the
particular glucocorticoid being administered as postnatal
glucocorticoid therapy. Indeed, the therapeutically effective
dosage of antiglucocorticoid will take into consideration the
nature, identity and dosage of the postnatal glucocorticoid.
Typically, postnatal glucocorticoid is administered to a preterm
infant in amounts ranging from about 0.5 .mu.g to about 1 mg/kg of
body weight per infant per day, sometimes between about 15 .mu.g to
about 750 .mu.g/kg of body weight per infant per day, or perhaps
about 20 .mu.g to about 500 .mu.g/kg of body weight per infant per
day. The glucocorticoid may be administered in a range of
concentrations over a period of time, and may remain constant over
a period of time or could taper.
[0065] Effective intrathecal doses of antiglucocorticoid are
significantly lower than effective systemic doses (see e.g., De
Kloet E R, et al. (1988) Neuroendocrinology 47:2 109-15; Ratka A,
et al. (1989) Neuroendocrinology 50:2 117-23 and Aemout, D. et al.
(1996) Endocrinology 137(11):4935-4943). Therefore, the precise
dosage for an antiglucocorticoid will typically be lower than the
dosages recited above for postnatal glucocorticoids. Other factors
to be considered in calculating the dose of antiglucocorticoid
include the relative affinities of the glucocorticoid and the
antiglucocorticoid for the glucocorticoid receptor (as reflected in
the relative dissociation constants), the half lives of the
glucocorticoid and the antiglucocorticoid, and the ease with which
the glucocorticoid crosses the blood brain barrier. By evaluating
an infant using the methods described herein, a skilled
practitioner will be able to determine whether a patient is
responding to treatment and will know how to adjust the dosage
levels accordingly.
[0066] The following provides an example of how one of skill can
determine the initial amount of antiglucocorticoid to be
intrathecally administered to the ventilator-dependent preterm
infant. A dose of glucocorticoid for a preterm infant might be 500
.mu.g/kg/day, administered such that the plasma concentration
reaches a peak of 250 ng/ml within 30 minutes of intravenous
systemic dosing. If the glucorticoid traverses the blood brain
barrier readily, but not 100% efficiently, this may correspond to a
peak concentration in the cerebrospinal fluid of 50 ng/ml. However,
the actual concentration can be measured by methods known in the
art. If the rate of dosing is such that the plasma and
cerebrospinal fluid concentrations of the glucocorticoid are
maintained at their peak levels once achieved, and the K.sub.d for
glucocorticoid-glucocorticoid receptor interaction is 10.sup.-8,
then the concentration and dosing rate of the therapeutically
effective dose antiglucocorticoid can readily be calculated.
[0067] To ensure that the antiglucocorticoid is present in the
cerebrospinal fluid at the time the glucocorticoid starts to become
available to the glucocorticoid receptors of the central nervous
system, administration of the antiglucocorticoid should begin
concomitant with glucocorticoid administration. If the
antiglucocorticoid is chosen such that the K.sub.d for dissociation
of the antiglucocorticoid-glucocorticoid receptor complex is at
least 10-fold lower than the K.sub.d for dissociation of the
glucocorticoid-glucocorticoid receptor complex (i.e. the complex is
stronger), then when both the glucocorticoid and the glucocorticoid
receptor antagonist are present at similar concentrations at
equilibrium, at least 90% of the glucocorticoid receptor binding
sites will be occupied by antiglucocorticoid molecules, thus
effectively blocking the action of glucocorticoids in the central
nervous system. In this example, the intrathecal dosage of the
antiglucocorticoid would be adjusted, based on the estimated volume
of the infant's cerebrospinal fluid, to achieve a concentration of
50 ng/ml.
[0068] The antiglucocorticoid may be administered in a range of
concentrations that parallel the dosage of postnatal
glucocorticoid, albeit at a lower level, over a period of time. For
example, an infant could receive an initial concomitant intrathecal
dose ranging from 150 ng/kg/day up to 600 ng/kg/day, over a period
of days, to parallel a dosing schedule of postnatal glucocorticoid
consisting of 45 .mu.g/kg/day to 180 .mu.g/kg/day. The dosage may
remain constant over a period of time or could taper. Other dosages
possible, and can be determined by a skilled practitioner according
to the disclosure provided herein and the needs of a particular
infant.
[0069] In summary, the effective intrathecal dose of
antiglucocorticoid will be small relative to the dosage of
postnatal glucocorticoid. Therefore, systemic plasma glucocorticoid
concentrations will be significantly greater than plasma
antiglucocorticoid concentrations that might arise from leakage of
antiglucocorticoid out of the cerebrospinal fluid. Thus, regardless
of whether or not the antiglucocorticoid readily crosses the blood
brain barrier, intrathecal administration provides an effective
route for administration of the antiglucocorticoid that permits
dosing effective to prevent neurological damage associated with
postnatal glucocorticoids and at the same time allows the maximum
systemic benefit of the postnatal glucocorticoid to be
realized.
Methods of Administration
[0070] In general, antiglucocorticoid compounds may be administered
as pharmaceutical compositions by any method known in the art for
administering therapeutic drugs. However, the glucocorticoid
receptor antagonists used in the methods of the invention are
preferably administered directly into the cerebrospinal fluid by
intrathecal injection.
[0071] Single or multiple administrations of glucocorticoid
receptor antagonist formulations can be administered depending on
the frequency, amount of dosage, and half life of the postnatal
glucocorticoid. Typically the dosage of the glucocorticoid receptor
antagonist formulation will be at a similar frequency, but in a
significantly lower amount than the postnatal glucocorticoid (De
Kloet E R, et al., (1988) Neuroendocrinology 47:2 109-15; Ratka A,
et al., (1989) Neuroendocrinology 50:2 117-23 and Aemout, D. et
al., (1996) Endocrinology 137(11):4935-4943). In general, the
amount of antiglucocorticoid to be administered to the infant will
be at least a 5-fold lower than the amount of postnatal
glucocorticoid, but may be in an amount that is 25-fold, 250-fold,
1000-fold, 100,000-fold or even more fold lower than the postnatal
glucocorticoid. Most importantly, the formulations should provide a
sufficient quantity of active agent, e.g., mifepristone, to
effectively prevent neurological damage caused by postnatal
glucocorticoid therapy in ventilator dependent low birth weight
preterm infants.
[0072] A typical pharmaceutical formulation for intrathecal
administration of an antiglucocorticoid such as mifepristone or ORG
34517 would comprise about 10 ng-4 .mu.g mifepristone or ORG 34517
per kg of body weight per infant per day, more preferably between
about 60 ng to about 3 .mu.g mifepristone or ORG 34517 per kg of
body weight per infant per day, most preferably 500 ng mifepristone
or ORG 34517 per kg of body weight per infant per day, although
dosages of between about 5 ng to about 40 .mu.g mifepristone or ORG
34517 per kg of body weight per infant per day may be used in the
practice of the invention. Such a dose is significantly lower than
the doses of postnatal glucocorticoid typically provided for
postnatal glucocorticoid therapy.
2. General Laboratory Procedures
[0073] 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 a low birth weight preterm infant at risk
for neurological damage, including monitoring of parameters such as
blood and plasma glucocorticoids and antiglucocorticoids, 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 may require different dosage regimens and
formulations. A few illustrative examples are set forth below.
a. Determination of Glucocorticoid or Antiglucocorticoid Levels in
Cerebrospinal Fluid
[0074] It may be necessary to measure levels of glucocorticoid or
antiglucocorticoid in cerebrospinal fluid, as well as in the blood
and plasma. Means for such monitoring are well described in the
scientific and patent literature. An illustrative example of
determining levels of glucocorticoid or antiglucocorticoid in
cerebrospinal fluid is set forth in Example 2 below.
b. Assessing Reduction in Neurological Damage
[0075] Assessing the success of concomitant administration of an
antiglucocorticoid in the prevention of neurological damage in
ventilator-dependent preterm infants receiving postnatal
glucocorticoid therapy may be determined by comparing those infants
with those receiving only glucocorticoid therapy. Methods for
evaluating neurological damage are readily determined by those
skilled in the art. By way of example but not of limitation, the
types of damage that may be expected include decreased premature
brain size, increased rates of cerebral palsy, cognitive deficits
or retinopathies. Methods for evaluating neurological damage could
include, but are not limited to, 3d magnetic resonance imaging to
quantify cerebral tissue, determination of Bayley II Mental
Developmental Index, determination of Psychomotor Developmental
Index, tests for vision or hearing impairment.
d. Other Laboratory Procedures
[0076] 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 methods 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
Pharmacol. and Experimental Therapeutics 241:401-406, 1987.
EXAMPLES
Example 1
Preventing Neurological Damage in a Subject Using Mifepristone
[0077] The following example demonstrates how to practice the
methods of the invention.
Patient Selection:
[0078] Ventilator-dependent low birth weight preterm infants 0-14
days old in need of glucocorticoid therapy using the methods
described herein.
Dosage Regimen and Intrathecal Administration of Mifepristone
Concomitantly with Glucocorticoid Therapy:
[0079] The glucocorticoid receptor (GR) antagonist, mifepristone,
is used concomitantly with the glucocorticoid dexamethasone in this
study. Glucocorticoid therapy is initiated at 0-14 days of age;
with dexamethasone being administered intravenously at a dose of
about 500 .mu.g/kg/day for approximately 5 days.
[0080] Mifepristone administration is initiated intrathecally
within approximately 15 minutes of the start of glucocorticoid
therapy, at a dose that is 1000-fold lower than the dosage of the
postnatal dexamethasone. At this dosage, mifepristone will block
postnatal glucocorticoid action in the central nervous system,
while remaining at very low systemic concentrations (Aernout, D. et
al. (1996) Endocrinology 137(11):4935-4943, and De Kloet E R, et
al. (1988) Neuroendocrinology 47:2 109-15). Dosages will be
adjusted if necessary and further evaluations will be performed
periodically throughout treatment. Infants will receive concomitant
administration of mifepristone for the duration of the postnatal
glucocorticoid therapy, and will be evaluated as described
below.
Assessing Prevention of Neurological Damage:
[0081] To delineate and assess the effectiveness of mifepristone in
preventing neurological damage, the neurological damage is
determined by objective and subjective criteria as described herein
Tests for neurological damage may include tests for cerebral palsy,
cognitive deficits or retinopathies. In addition, neurological
damage could be detected by 3d magnetic resonance imaging to
quantify cerebral tissue, determination of Bayley II Mental
Developmental Index, determination of Psychomotor Developmental
Index, tests for vision or hearing impairment. Tests for
neurological damage will be measured at baseline, 2 weeks, 1 month,
2 months, 3 months, and 6 months.
Example 2
Measuring Levels of Glucocorticoid or Antiglucocorticoid in
Cerebrospinal Fluid
[0082] The concentration of glucocorticoids or antiglucocorticoids
in the cerebrospinal fluid of the infants of Example 1 will be
tested before initiation of postnatal glucocorticoid therapy,
immediately after initiation of postnatal glucocorticoid therapy,
and as necessary during the course of postnatal glucocorticoid
therapy and administration of antiglucocorticoid. A lumbar
reservoir is surgically implanted into the lower back to sample
cerebrospinal fluid and to administer the antiglucocorticoid into
the cerebrospinal fluid.
[0083] Samples of cerebrospinal fluid will be tested for the
absence or presence and of glucocorticoids and antiglucocorticoids
in the cerebrospinal fluid and to measure the concentration of
glucocorticoids and antiglucocorticoids when present. Methods for
measuring the presence and concentration of glucocorticoids and
antiglucocorticoids in samples are well known in the art. For
example, the concentration of glucocorticoids and
antiglucocorticoids can be measured using HPLC, TLC and/or UV
spectroscopy, although and method known in the art for detecting
the presence of glucocorticoids and antiglucocorticoids may be
used.
[0084] It is understood that the examples and embodiments described
herein are for illustrative purposes only and that various
modifications or changes in light thereof will be suggested to
persons skilled in the art and are to be included within the spirit
and purview of this application and scope of the claims.
* * * * *