U.S. patent application number 14/064263 was filed with the patent office on 2014-02-20 for methods of treating frontal temporal dementia (ftd) with comprising administering metal chelators to the upper one-third of the nasal cavity.
This patent application is currently assigned to HealthPartners Research Foundation. The applicant listed for this patent is HealthPartners Research Foundation. Invention is credited to Leah Ranae Bresin Hanson, William H. Frey, II.
Application Number | 20140051763 14/064263 |
Document ID | / |
Family ID | 45328905 |
Filed Date | 2014-02-20 |
United States Patent
Application |
20140051763 |
Kind Code |
A1 |
Bresin Hanson; Leah Ranae ;
et al. |
February 20, 2014 |
METHODS OF TREATING FRONTAL TEMPORAL DEMENTIA (FTD) WITH COMPRISING
ADMINISTERING METAL CHELATORS TO THE UPPER ONE-THIRD OF THE NASAL
CAVITY
Abstract
The present invention comprises methods and pharmaceutical
compositions for intranasal delivery of effective amounts of DFO
directly to the CNS, in particular the brain treatments that
inhibit GSK3b in patients with psychiatric disorders including, but
not limited to, bipolar disorder, depression, ADHD and
schizophrenia. In addition a treatment composition is disclosed
which comprises DFO and in certain embodiments combines DFO with
one or more of the psychotropic drug types, i.e., antipsychotics,
mood stabilizers and antidepressants. Moreover, a treatment for
treating impairment of neural plasticity through inhibition of
GSK3b is provided as well as prevention of apoptosis of cells
through inhibition of GSK3b.
Inventors: |
Bresin Hanson; Leah Ranae;
(Vadnais Heights, MN) ; Frey, II; William H.;
(White Bear Lake, MN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
HealthPartners Research Foundation |
Bloomington |
MN |
US |
|
|
Assignee: |
HealthPartners Research
Foundation
Bloomington
MN
|
Family ID: |
45328905 |
Appl. No.: |
14/064263 |
Filed: |
October 28, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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13161934 |
Jun 16, 2011 |
8592485 |
|
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14064263 |
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Current U.S.
Class: |
514/616 |
Current CPC
Class: |
A61K 31/19 20130101;
A61P 25/18 20180101; A61K 45/06 20130101; C07C 259/06 20130101;
A61P 25/24 20180101; A61K 31/16 20130101; A61K 33/00 20130101; A61P
25/00 20180101; A61K 31/16 20130101; A61K 2300/00 20130101; A61K
31/19 20130101; A61K 2300/00 20130101; A61K 33/00 20130101; A61K
2300/00 20130101 |
Class at
Publication: |
514/616 |
International
Class: |
A61K 31/16 20060101
A61K031/16 |
Claims
1-20. (canceled)
21. A method to treat a patient with frontal temporal dementia
comprising: administering at least one effective dose of
deferoxamine (DFO) to the upper one-third of the patient's nasal
cavity, wherein the at least one effective dose of DFO is 0.0001 to
1.0 mg/kg; thereby enabling the at least one effective dose of DFO
to bypass the patient's blood-brain barrier and delivering the at
least one effective dose of DFO to the patient's central nervous
system; and treating the frontal temporal dementia.
22. The method of claim 21, wherein the administration of the at
least one effective dose of DFO treats neurodegeneration in the
patient, wherein the neurodegeneration is caused by frontal
temporal dementia.
23. The method of claim 21, wherein the administration of DFO
inhibits memory loss caused by frontal temporal dementia.
24. The method of claim 21, wherein the administration of the at
least one effective dose of DFO treats physical impairment of the
patient, wherein the physical impairment is caused by frontal
temporal dementia.
25. The method of claim 21, wherein the administration of the at
least one effective dose of DFO treats behavioral impairment of the
patient, wherein the behavioral impairment is caused by frontal
temporal dementia.
26. The method of claim 21, further comprising the at least one
effective dose of DFO having a volume of 0.015 to 1.0 ml.
27. The method of claim 21, wherein the at least one effective dose
of DFO is 0.005 to 1.0 mg/kg.
28. The method of claim 21, further comprising administering the at
least one dose of DFO until the concentration of DFO in the
patient's brain is within the range of 0.1 nM to 50 .mu.M.
29. The method of claim 21, wherein the at least one effective dose
of DFO is administered to the upper one-third of the patient's
nasal cavity as a liquid spray.
30. The method of claim 21, wherein the at least one effective dose
of DFO is administered to the upper one-third of the patient's
nasal cavity as a powdered spray.
31. The method of claim 21, wherein the at least one effective dose
of DFO is administered to the upper one-third of the patient's
nasal cavity as nose drops.
32. The method of claim 21, wherein the at least one effective dose
of DFO is administered to the upper one-third of the patient's
nasal cavity as a gel.
33. The method of claim 21, wherein the at least one effective dose
of DFO is administered to the upper one-third of the patient's
nasal cavity as an ointment.
34. A method to treat a patient with frontal temporal dementia
comprising: administering at least one effective dose of a metal
chelator to the upper one-third of the patient's nasal cavity,
wherein the at least one effective dose of the metal chelator is
0.0001 to 1.0 mg/kg; thereby enabling the at least one effective
dose of the metal chelator to bypass the patient's blood-brain
barrier and delivering the at least one effective dose of the metal
chelator to the patient's central nervous system; and treating the
frontal temporal dementia.
35. The method of claim 34, wherein the metal chelator comprises an
iron chelator or a copper chelator.
36. The method of claim 34, wherein the administration of the at
least one effective dose of the metal chelator treats
neurodegeneration in the patient, wherein the neurodegeneration is
caused by frontal temporal dementia.
37. The method of claim 34, wherein the administration of the at
least one effective dose of the metal chelator inhibits memory loss
caused by frontal temporal dementia.
38. The method of claim 34, wherein the administration of the at
least one effective dose of the metal chelator treats physical
impairment of the patient, wherein the physical impairment is
caused by frontal temporal dementia.
39. The method of claim 34, wherein the administration of the at
least one effective dose of the metal chelator treats behavioral
impairment of the patient, wherein the behavioral impairment is
caused by frontal temporal dementia.
40. The method of claim 34, further comprising the at least one
effective dose of the metal chelator having a volume of 0.015 to
1.0 ml.
41. The method of claim 34, wherein the at least one effective dose
of the metal chelator is 0.005 to 1.0 mg/kg.
42. The method of claim 34, further comprising administering the at
least one dose of the metal chelator until the concentration of the
metal chelator in the patient's brain is within the range of 0.1 nM
to 50 .mu.M.
43. The method of claim 34, wherein the at least one effective dose
of the metal chelator is administered to the upper one-third of the
patient's nasal cavity as one of the group consisting of: a liquid
spray, a powdered spray, nose drops, a gel, and an ointment.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This is a non-provisional application claiming the benefit
of and priority to U.S. provisional patent application No.
61/355,626 filed Jun. 17, 2010, which is incorporated herein by
reference in its entirety.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention is directed to methods and
pharmaceutical compositions for treating the animal central nervous
system for psychiatric disorders, including mood disorders,
depression, schizophrenia and frontal temporal dementia.
[0004] 2. Description of the Related Art
[0005] Certain medical procedures, for example coronary artery
bypass graft (CABG) surgery, are associated with neurological
complications. In the case of CABG, the surgery is performed on
more than 800,000 patients worldwide each year. Many of the CABG
procedures performed are associated with neurological
complications. These complications range from stroke in up to 16%
of the patients to general cognitive decline with 50% of patients
having impairment post-surgery and with progressive decline
occurring in some patients over the next five years. In addition,
physical and behavioral impairment manifest in some CABG patients.
Newman M F et al., N. Eng. J. Med. 344:395-402 (2001); Brillman J.,
Neurol. Clin. 11:475-495 (1993); and Seines, O. A., Ann. Thorac.
Surg. 67:1669-1676 (1999) are instructive.
[0006] Originally, it was hypothesized that the neurological
complications associated with CABG surgery were either procedure or
patient-related. The procedure generally implicated as potentially
harmful was cardiopulmonary bypass using a pump and oxygenator.
However, a recent study reports no difference in cognitive outcome
between groups of patients undergoing CABG surgery performed with,
or without, the pump and oxygenator. Such results suggest that the
neurological impairments following CABG surgery may, in fact, be
patient-related and, as a result, amenable to therapeutic
manipulation.
[0007] In addition, patients at risk for, or diagnosed with
disorders involving neurological impairments, e.g., Alzheimer's
disease, Parkinson's disease, stroke, traumatic brain injury,
spinal cord injury may benefit from similar therapeutic
manipulation. See Crapper McLachlan, D. R., Dalton, A. J., Kruck,
T. P. A., Bell, M. Y., Smith, W. L., Kalow, W., and Andrews, D. F.
Intramuscular desferrioxamine in patients with Alzheimer's disease.
The Lancet 337:1304-1308, 1991. Further, mood disorders such as
bipolar disorder and depression, ADHD, schizophrenia and frontal
temporal dementia are conditions that are generally in the category
of neurological impairment with symptoms that may be amendable to
therapeutic intervention.
[0008] GSK-3.beta. (GSK3b) is a serine/threonine kinase that has
diverse functions in various cellular activities in many cell
types, including glycogen synthesis, cell survival and cell
division. Unlike most protein kinases, GSK3b is constitutively
active and its activity is down-regulated by upstream signals
through inhibitory phosphorylation. The most important and
well-known target of GSK3b is the .beta.-catenin transcriptional
coactivator. Active GSK3b can directly phosphorylate
.beta.-catenin, resulting in ubiquitination-mediated proteasomal
degradation of .beta.-catenin. The NF-AT transcription factor has
been found to be another target of GSK-3.beta., at least in T cells
and neurons. Different from the .beta.-catenin phosphorylation,
NF-AT phosphorylation mediated by GSK3b promotes its export from
the nucleus, therefore terminating NF-AT-dependent transcription.
The NF-AT activation is counterbalanced by GSK3b and
Ca.sup.2+-calcineurin. GSK3b phosphorylates NF-AT, leading to its
nuclear export and transcriptional inactivation, while
Ca.sup.2+-calcineurin dephosphorylates NF-AT, leading to its
nuclear import and transcriptional activation.
[0009] Thus, GSK3b is a unique serine/threonine kinase that is
inactivated by phosphorylation to form phosphorylated GSK3b
(pGSK3b). In response to insulin binding, PKB/AKT phosphorylates
GSK3b on serine 9, which prevents GSKb from phosphorylating
glycogen synthase. Unphosphorylated glycogen synthase is active and
able to synthesize glycogen. GSK3b is also unique in that it
requires a substrate that has been phosphorylated by a distinct
kinase before it can phosphorylate the substrate. The phosphate
priming mechanism explains why phosphorylation of serine 9
inactivates GSK3b. The phosphorylated serine binds to the GSK3b
priming phosphate position and prevents binding of alternative
substrates. In addition to insulin signaling, GSK3b participates in
the Wnt signaling pathway, where it forms a complex with axin,
beta-catenin and adenomatous polyposis coli (APC) protein. In the
presence of Wnt, GSK3b is unable to phosphorylate beta-catenin,
which leads to stabilization of beta-catenin.
[0010] Moreover, the Akt/GSK3 signaling pathway plays a significant
role in responses to dopamine, 5-HT and psychrotropic drugs, e.g.,
lithium, antidepressents and antipsychotics. Thus, this pathway and
its diverse signaling molecules comprise important modulators of
behavior. Regulation of this pathway by dopamine and 5-HT and three
classes of psychotropic drugs (antipsychotics, mood stabilizers and
antidepressants) indicates that Akt and GSK3 can act as signal
integrators, allowing the precise coordination and cooperation of
5-HT and dopamine receptors signaling responses, with each other or
with those related to other neurotransmitters, hormones and/or
growth factors. Thus, inhibition of GSK3b may provide a rationale
for the effects of lithium, antidepressants and antipsychotics,
which are often used in combination for various psychiatric
conditions.
[0011] Studies suggest that inhibition of GSK3b may be a relevant
target for the pathophysiology and treatment of psychiatric
diseases including, e.g., bipolar disorder, also known as manic
depression. A broader category of disease or condition may be
termed mood disorders. Mood disorders include bipolar disorder, as
well as patients experiencing major depression. Lithium is commonly
used to treat mood disorders such as bipolar disorder and major
depression and has been demonstrated to inhibit phosphorylation of
GSK3b. In addition, valproic acid and electroconvulsive therapy
also have been demonstrated to inhibit GSK3b. Studies convincingly
demonstrate that GSK3b plays a critical role in depressive activity
and the counteracting effects of antidepressents. Thus, the
evidence indicates that inhibition of GSK3 contributes to the
therapeutic action of these methods and agents. In addition,
schizophrenia is associated with alterations in GSK3. See, e.g.,
Jope, "Glycogen Synthase Kinase-3 (GSK3) in Psychiatric Diseases
and Therapeutic Interventions", Curr Drug Targets, 2006 November;
7(11): 1421-1434, the contents of which are incorporated in their
entirety. GSK3b clearly plays a role in these psychiatric diseases
and conditions and inhibition of GSK3b, i.e., by phosphorylation,
is of therapeutic value.
[0012] Further, GSK3b inhibitors are of considerable interest
because they mimic the effect of insulin and may reduce the
hyperphosphorylation of Tau that is observed in Alzheimer's
disease. Moreover, GSK3b inhibits the xenobiotic and antioxidant
cell response by direct phosphorylation and nuclear exclusion of
the transcription factor Nrf2, and GSK3b is involved in hydrogen
peroxide-induced suppression of Tcf/Lef-dependent transcriptional
activity.
[0013] Moreover, GSK3b plays a central role in impairment of cell
neural plasticity and cell death or apoptosis. Neural plasticity
includes the capacity of cells to respond to stress or harmful
agents. Experimentally, this may be measured by assessing the
terminal outcome of stress-induced death by apoptosis. Impairment
of neural plasticity and apoptosis driven by GSK3b exposure are
implicated in a wide variety of diseases and/or conditions:
exposure to growth factor withdrawal and inhibition of the
phosphoinositide 3-kiase/Akt signaling pathway, mitochondrial
toxins, hypoxia/ischemia, glutamate excitotoxicity, endoplasmic
reticulum stress, DNA damage, ceramide, oxidative stress,
Alzheimer's disease-related amyloid b-peptide, prion peptide,
polyglutamine toxicity, HIV-associated conditions, hypertonic
stress to name a few. The skilled artisan will recognize the full
depth and breadth of the relevant diseases and/or conditions.
Control of GSK3b by phosphorylation will reduce impairment of cell
neural plasticity as well as apoptosis that may lead, inter alia,
to non-lethal but nevertheless critical and stressful conditions in
psychiatric disorders such as bipolar disorder, depression,
dementia and schizophrenia.
[0014] Certain agents or compounds may increase or promote
phosphorylation of GSK3b. A particular example of such an agent is
deferoxamine (DFO), a hexadentate iron chelator.
[0015] In vivo studies have demonstrated that DFO increases
phosphorylation status of GSK3b in HepG2 cells of the rat liver
supplemented with fetal calf serum wherein DFO-induced iron
depletion improved hepatic insulin resistance. DFO has also been
shown to promote phosphorylation status of GSK3b and increased
b-catenin protein in bone morphogenetic protein-2 (BMP-2)-treated
mesenchymal stem cells (MSC). Such findings demonstrate that, inter
alia, DFO may likewise regulate osteoblast differentiation of MSC
through the b-catenin pathway, which plays a critical role in
BMP-2-induced osteogenic differentiation.
[0016] These studies involving inhibition by DFO of GSK3b through
phosphorylation are in vitro studies involving the liver and bone.
These studies do not make obvious the possibility that DFO could be
used to, e.g., treat psychiatric disorders within the brain and
central nervous system for a variety of reasons.
[0017] For example, problems exist with the administration of DFO
intravenously. DFO is not generally injected intravenously for at
least three reasons. First, it is a small molecule and, as a
result, is eliminated rapidly through the kidney. The typical
plasma half-life in humans is less than 10 minutes. Second, the
injection of an intravenous bolus of DFO causes acute hypotension
that is rapid, may lead to shock and may be lethal. Third,
intravenously or systemically administered DFO does not efficiently
or effectively cross the blood-brain barrier. These characteristics
have limited the utility of DFO in particular as a neuroprotective
agent.
[0018] One published study administered DFO generally intranasally
to iron overloaded patients. G. S. Gordon et al., Intranasal
Administration of Deferoxamine to Iron Overloaded Patients, (1989)
Am. J. Med. Sci. 297(5):280-284. In this particular study, DFO was
administered to the patients as a nasal spray in a volume of 75
microliters per spray. Significantly, such sprays are known to
deposit the drug or other substance in the lower third of the nasal
cavity. This is verified by patient observations stating that a bad
taste in the mouth was resulting from the drug passing through the
nasopharynx and into the mouth. As a result, this study did not
involve delivering the drug to the upper third of the nasal cavity.
Thus, the drug would not have reached the olfactory epithelium or
the olfactory nerves. As a result, delivery of the drug to the CNS
would be less than optimal.
[0019] It is recognized that agent delivery to the CNS may occur
along both the olfactory and trigeminal nerve pathways. See Thorne,
R G (2004), Delivery of Insulin-Like Growth Factor-I to the Rat
Brain and Spinal Cord Along Olfactory and Trigeminal Pathways
Following Intranasal Administration, Neuroscience, Vol. 127, pp.
481-496. Optimal delivery taking advantage of both pathways is
accomplished by administering the substance in the upper third of
the nasal cavity.
[0020] It would be highly desirable to directly deliver an
effective amount or dose of DFO to the upper one-third of the
patient's nasal cavity, thereby bypassing the blood-brain barrier
for treatment of diseases or conditions which are affected by
non-phosphorylated GSK3b. As discussed, DFO stimulates
phosphorylation of GSK3b, thereby inactivating or inhibiting GSK3b
and thus therapeutic for patients suffering from certain
psychiatric mood disorders (bipolar disorder and depression) as
well as patients with schizophrenia and frontal temporal dementia.
Therapy provided by the present invention, i.e., inactivation of
GSK3b by DFO-stimulated phosphorylation of GSK3b may also be used
to treat patients suffering from memory loss in a variety of
conditions, including but not limited to Alzheimer's disease.
BRIEF SUMMARY OF THE INVENTION
[0021] The present invention comprises intranasal delivery of
effective amounts of DFO directly to the CNS, in particular the
brain treatments that inhibit GSK3b in patients with psychiatric
disorders including, but not limited to, bipolar disorder,
depression, ADHD and schizophrenia. In addition a treatment
composition is disclosed which comprises DFO and in certain
embodiments combines DFO with one or more of the psychotropic drug
types, i.e., antipsychotics, mood stabilizers and antidepressants.
Moreover, a treatment for treating impairment of neural plasticity
through inhibition of GSK3b is provided as well as prevention of
apoptosis of cells through inhibition of GSK3b.
[0022] The figures and the detailed description which follow more
particularly exemplify these and other embodiments of the
invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0023] The invention may be more completely understood in
consideration of the following detailed description of various
embodiments of the invention in connection with the accompanying
drawings, which are as follows.
[0024] FIG. 1A is a bar graph illustrating the relative hippocampal
concentrations of phosphorylated GSK3b as compared with total GSK3b
when DFO is delivered to the upper third of the nasal cavity in C57
mice.
[0025] FIG. 1B is a bar graph illustrating the relative hippocampal
concentrations of phosphorylated GSK3b as compared with total GSK3b
when DFO is delivered systemically in C57 mice.
[0026] FIG. 2A is a bar graph illustrating the relative hippocampal
concentrations of beta-Catenin/Actin when DFO is delivered to the
upper third of the nasal cavity in C57 mice.
[0027] FIG. 2B is a bar graph illustrating the relative hippocampal
concentrations of beta-Catenin/Actin when DFO is delivered
systemically in C57 mice.
[0028] FIG. 3 is a bar graph illustrating relative whole brain
concentrations of phosphorylated GSK3b as compared with total GSK3b
when DFO is delivered to the upper third of the nasal cavity in tau
mice (P301L model of accumulating hyperphosphorylated tau).
DETAILED DESCRIPTION OF THE INVENTION, INCLUDING THE BEST MODE
[0029] While the invention is amenable to various modifications and
alternative forms, specifics thereof are shown by way of example in
the drawings and described in detail herein. It should be
understood, however, that the intention is not to limit the
invention to the particular embodiments described. On the contrary,
the intention is to cover all modifications, equivalents, and
alternatives falling within the spirit and scope of the
invention.
DEFINITIONS
[0030] As used herein, "central nervous system" (CNS) refers to the
brain and spinal cord and associated tissues.
[0031] An "effective amount" of agent is an amount sufficient to
prevent, treat, reduce and/or ameliorate the symptoms, neuronal
damage and/or underlying causes of any of the referenced disorders
or diseases. In some instances, an "effective amount" is sufficient
to eliminate the symptoms of those diseases and overcome the
disease itself.
[0032] In the context of the present invention, the terms "treat"
and "treatment" and "therapy" and "therapeutic" and the like refer
to alleviate, slow the progression, prophylaxis, attenuation or
cure the referenced conditions or diseases and/or their associated
symptoms.
[0033] "Prevent", as used herein, refers to putting off, delaying,
slowing, inhibiting, or otherwise stopping, reducing or
ameliorating the onset of the symptoms associated with the
referenced diseases or conditions. The method of the present
invention may be used with any animal, such as a mammal or a bird
(avian), more preferably a mammal. Poultry are a preferred bird.
Exemplary mammals include, but are not limited to rats, mice, cats,
dogs, horses, cows, sheep, pigs, and more preferably humans.
[0034] Thus, methods and pharmaceutical compositions are described
herein that, inter alia, treat patients with psychiatric disorders
including, but not limited to, bipolar disorder, depression and
schizophrenia by inhibition of GSK3b by administration of an
effective amount of deferoxamine (DFO) to directly to the upper
one-third of the patient's nasal cavity, thereby bypassing the
blood-brain barrier. In addition a treatment composition is
disclosed which comprises DFO and in certain embodiments combines
DFO with one or more of the psychotropic drug types, i.e.,
antipsychotics, mood stabilizers and antidepressants. Moreover, a
treatment for treating impairment of neural plasticity through
inhibition of GSK3b is provided as well as prevention of apoptosis
of cells through inhibition of GSK3b by administration of an
effective amount of deferoxamine (DFO) to directly to the upper
one-third of the patient's nasal cavity, thereby bypassing the
blood-brain barrier.
[0035] An alternative to potentially lethal and generally
ineffective intravenous injection of the metal chelator DFO may be
accomplished using an alternative non-invasive method to directly
target the substance to the central nervous system (CNS) and thus
the brain under the present invention. Intranasal delivery allows
substances to be rapidly delivered to the central nervous system,
even those that do not readily cross the blood-brain barrier by
bypassing the blood-brain barrier and directly exposes the CNS to
the delivered substance. In this manner, unwanted systemic side
effects are reduced if not eliminated.
[0036] Since DFO, similar to other metal chelators, has a strong
Fe-III binding constant (10.sup.31), it is rapidly eliminated from
the blood and does not readily cross the blood-brain barrier. Thus,
when metal chelator-based therapeutic agents are administered
intravenously, orally or even intranasally--but not directly to the
upper one-third of the nasal cavity--to target affected tissues
within the brain, the therapeutic effect has been heretofore
minimal. Delivery of intranasal DFO to the upper one-third of the
nasal cavity has been assessed by administering 6 mg DFO bound to 6
.mu.Ci of .sup.59Fe (as .sup.59FeCl.sub.3) to rats under
anesthesia. The IN dose in 60 .mu.L was administered as 6 .mu.L
drops over twenty minutes. Following delivery, tissues were removed
for analysis. Using scintillation counting, labeled ferrioxamine
was detected throughout the brain, with high concentrations
detected in the olfactory bulbs, anterior olfactory nucleus,
hypothalamus, frontal cortex and cervical spinal cord. Even higher
ferrioxamine concentrations were observed in the trigeminal nerves
and ventral dura. Peripheral tissues with the highest ferrioxamine
concentrations included the olfactory epithelium, thyroid and
cervical lymph nodes. By contrast, the blood concentrations of
ferrioxamine, taken at 5 minute intervals from dosing up to 25
minutes post-dose, are quite low, indicating a minimization of
exposure of the therapeutic agent to non-target tissue. The data
provided in Table 1 below, thus illustrates that intranasal DFO,
the concentrations having been calculated based on an extrapolation
of the ferrioxamine concentration, administered to the upper
one-third of the nasal cavity, is effectively delivered to the
brain and upper spinal cord, with minimal systemic exposure.
[0037] Intranasal Delivery of DFO
[0038] (uM Concentrations in Tissues @ 25 Minutes after the Onset
of Delivery)
TABLE-US-00001 TABLE 1 uL delivered 62 65 60 60 64 62 62 62 66 61
uCi delivered 36.55 38.40 35.45 35.35 36.77 35.28 35.30 34.72 35.80
34.31 mg delivered 6.15 6.44 5.95 5.95 6.29 6.05 6.05 6.07 6.45
6.00 nmol delivered 9,361.73 9,801.65 9,063.49 9,053.64 9,583.97
9,218.26 9,207.99 9,237.98 9,824.75 9,128.91 Drug Delivery Time 21
21 20 18 20 22 20 20 20 18 Time of Perfusion 25 25 26 27 25 26 27
26 26 26 Rat weight 303 302 264 281 298 309 336 283 318 315 RAT #
DF09 DF10 DF11 DF12 DF13 DF14 DF15 DF18 DF19 DF20 Blood Sample 1
(5:00) 1.2 1.6 0.6 1.2 0.7 1.5 1.1 0.8 0.3 1.8 Blood Sample 2
(10:00) 1.1 2.1 1.1 1.2 1.2 1.8 1.7 1.0 0.4 1.9 Blood Sample 3
(15:00) 1.1 2.0 0.5 1.8 0.9 1.4 1.7 1.3 0.5 2.6 Blood Sample 4
(20:00) 1.1 1.8 0.3 1.9 1.1 1.6 1.5 1.1 0.4 2.9 Blood Sample 5
(25:00) 1.8 1.6 1.8 1.3 1.5 2.2 1.7 1.3 0.5 2.1 Superficial Nodes
(4) 3.4 0.9 0.6 0.9 2.2 0.6 1.8 0.6 1.1 0.8 Cervical Nodes (2) 12.9
10.9 34.2 40.8 58.2 51.4 65.1 13.2 11.4 8.1 Dorsal Dura 26.5 11.4
7.4 14.1 16.6 32.0 8.0 5.9 35.8 5.1 Ventral Dura 25.3 38.7 70.9
17.7 58.3 44.0 51.5 -- 62.8 11.6 Trigeminal Nerve 33.3 14.7 22.4
8.4 72.8 25.1 26.6 17.4 27.0 9.5 Olfactory Bulbs 12.7 10.6 30.0
14.7 20.5 13.1 28.0 27.5 21.6 6.6 Anterior Olfactory Nucleus 4.4
4.2 -- -- 5.4 2.5 5.5 4.4 7.7 -- Frontal Cortex 4.3 3.3 13.6 -- 2.5
1.1 6.5 1.4 5.0 -- Caudate/Putamen 2.0 1.5 2.1 -- 2.4 0.9 1.6 1.1
2.0 -- Septal Nucleus 2.6 1.6 1.6 -- 3.2 1.9 2.0 1.8 2.9 --
Hippocampus 0.9 0.9 0.9 -- 2.3 1.2 1.2 0.5 1.3 -- Parietal cortex
1.3 1.6 2.3 -- 0.7 1.9 2.8 0.8 1.0 -- Thalamus 1.1 1.2 1.2 -- 1.5
1.0 1.0 0.8 1.2 -- Hypothalamus 5.4 7.3 6.5 -- 3.1 3.0 6.1 2.7 3.8
-- Midbrain 1.3 1.3 1.1 -- 1.8 1.3 1.2 0.6 1.3 -- Pons 2.0 1.5 1.4
-- 1.5 2.0 2.6 0.7 2.4 -- Medulla 1.1 2.3 1.2 -- 1.7 2.2 3.0 1.0
2.0 -- Upper Cervical Spinal Cord 2.1 1.4 3.7 1.5 3.9 6.8 7.3 1.4
4.6 4.6 Cerebellum 0.8 0.9 0.6 -- 0.9 1.4 1.1 0.5 1.1 -- Thyroid
1125.4 2932.7 448.2 814.1 466.7 1285.4 753.3 751.4 3463.9 605.9
Olfactory Epithelium 12016.8 11374.8 11191.7 13841.7 9519.2 10724.4
11764.8 9572.8 9321.0 12205.2 Axillary Nodes (2) 0.5 0.4 0.3 0.3
0.4 0.5 0.3 0.4 1.0 3.1 Liver 0.4 0.8 0.4 0.3 0.3 0.3 0.3 0.4 0.4
0.4 Kidney 1.0 0.4 0.5 0.6 0.4 0.2 0.6 1.0 1.2 0.5 Muscle 0.4 0.3
0.3 0.4 0.4 0.2 0.6 0.6 0.7 0.4 Heart 0.4 0.4 0.5 1.6 0.6 0.3 2.2
0.2 0.2 0.5 Lung 0.6 1.4 0.7 -- 1.0 0.5 2.2 1.5 1.1 0.5 Lower
Cervical Spinal Cord 0.5 5.3 1.0 2.7 0.3 0.1 3.8 0.4 1.8 0.3
Thoracic Spinal Cord 0.1 0.2 0.2 0.4 0.1 0.1 1.2 0.3 0.6 0.1 Lumbar
Spinal Cord 0.1 0.1 0.1 0.1 0.1 0.7 0.1 0.1 0.1 0.1 Spinal Dura 1.9
3.3 1.3 4.2 1.1 2.3 -- 0.4 1.5 0.8
[0039] The method of the invention delivers DFO to the upper third
of the nasal cavity of a mammal. It is preferred that the agent be
delivered to the olfactory area in the upper one-third of the nasal
cavity and, particularly, to the olfactory neuroepithelium in order
to promote rapid and efficient delivery of the agent to the CNS
along the olfactory neural pathway rather than the capillaries
within the respiratory epithelium. The preferred transport of the
DFO to the brain by means of the olfactory and trigeminal neural
pathways rather than the circulatory system so that the harmful
side effects and potentially short half-life of the agent is not an
issue. The preferred method allows direct delivery of DFO to the
brain. The data provided in Table 1 above strongly supports the
increased efficacy of one embodiment of this element of the
inventive method.
[0040] To deliver an effective amount of DFO directly to the brain,
DFO is, either alone or in combination with other substances, e.g.,
psychotropic agents, mood stabilizers such as lithium and/or
antipsychotic agents as a pharmaceutical composition, may be
administered to the olfactory area located in the upper one-third
of the nasal cavity. The composition may be administered
intranasally as a powered or liquid spray, nose drops, a gel or
ointment, through a tube or catheter, by syringe, packtail, pledget
or by submucosal infusion. Optimization of the administration of
DFO is provided by the various embodiments by applying DFO to the
upper third of the nasal cavity.
[0041] The optimal concentration of DFO will necessarily depend
upon the characteristics of the patient and the nature of the
disease or condition for which the agent is being used and the
frequency of administration. In addition, the concentration will
depend upon whether DFO is being employed in a preventive or
treatment capacity. Further, the stage of a particular disease or
disorder may dictate the optimal concentration of the agent.
[0042] Having established that administration of DFO to the upper
one-third of the nasal cavity is a highly effective and efficient
targeting methodology for regions of the brain and CNS as opposed
to systemic exposure, we now turn to further exemplary work
performed according to one embodiment of the inventive method the
results of which are illustrated in FIGS. 1A and 1B. This study
firmly demonstrates that administration of DFO to the upper
one-third of the nasal cavity results in an increase in
phosphorylated GSK-3b as compared with total GSK-3b.
[0043] The study method providing results in FIGS. 1A and 1B
comprised normal C57 mice which were treated with DFO by
administration to the upper third of the nasal cavity, thereby
delivering the DFO directly to the CNS by bypassing the blood-brain
barrier. Treatment groups consisted of 1% DFO, 10% DFO and saline.
Mice were treated five days/week for four weeks. Mice were then
dosed a final time, euthanized after 30 minutes, brain tissues
collected an analyzed for biochemical changes. Protein extraction
was achieved by homogenization of frozen brain tissues in 5 volumes
of ice-cold RIPA buffer supplemented with protease inhibitor
cocktail and phosphatase inhibitor cocktail. Homogenates were
centrifuged at 20,000.times.g for 20 minutes at 4 C. Supernatant
was collected from the cortex, diencephalon and hippocampus and
stored at -70 C until analysis by western blot and ELISA.
[0044] The results of the study are reflected in FIG. 1A. Both
groups of DFO mice (1% and 10%) had a significantly greater ratio
of phosphorylated GSK3b (pGSK3b) to GSK3b. 1% DFO mice had a 99.8%
higher ratio of pGSK3b/GSK3b than PBS mice. 10% DFO mice had a 214%
higher ratio of pGSK3b/GSK3b than PBS mice. Further, the 10% DFO
mice had a significantly higher ratio (57.4%) of pGSK3b/GSK3b than
the 1% DFO mice. Significantly, a dose response of DFO brain
concentration is clearly evident.
[0045] FIG. 1B illustrates the effect of DFO administered
systemically, and provided no statistical change in the ratio of
pGSK3b/GSK3b.
[0046] Turning now to FIG. 2A, beta-Catenin/Actin brain
concentrations are evaluated according to the previously described
method after administration of 1% and 10% DFO to the upper third of
the nasal cavity. The concentrations of beta-Catenin/Actin in the
hippocampus provide a similar dose response to that of the
pGSK3b/GSK3b seen in FIG. 1A. Moreover, the systemic delivery of
DFO did not significantly alter levels of beta-Catenin/Actin as
seen in FIG. 2B.
[0047] FIG. 3 illustrates the ratio of whole brain concentrations
of pGSK3b/GSK3b in tau mice when 1% and 10% DFO is administered to
the upper third of the nasal cavity. The results are consistent
with FIG. 1A, e.g., in that a significant increase is observed with
DFO treatment of tau mice.
[0048] In another embodiment of the present invention, a
pharmaceutical composition comprised of DFO and the group
consisting of: mood stabilizers, e.g., lithium, antidepressants,
and antipsychotics may be administered to treat bipolar disorder,
depression, frontal temporal dementia, ADHD and/or schizophrenia.
The antidepressants in the various embodiments, methods and
pharmaceutical compositions, of the present invention may comprise
drugs in the categories: serotonin reuptake inhibitors;
serotonin-norepinephrine reuptake inhibitors; noradrenergic and
specific serotonergic antidepressants, norepinephrine
(noradrenaline) reuptake inhibitors; norepinephrine-dopamine
reuptake inhibitors; serotonin reuptake enhancers;
norepinephrine-dopamine disinhibitors; tricyclic antidepressants;
monoamine oxidase inhibitors and augmenter drugs. The skilled
artisan will recognize various agents within these categories, each
of which may be candidates for various pharmaceutical compositions
and/or method of the present invention.
[0049] Further, the antipsychotics in the various embodiments,
methods and pharmaceutical compositions of the present invention
may comprise drugs in the following categories: Butyrophenones,
Phenothiazines, Thioxanthenes as well as Clozapine, Olanzapine,
Reisperidone, Quetiapine, Ziprasidone, Amisulpride, Asenapine,
Paliperidone, Iloperidone, Zotepine, Sertindole and others well
known to the skilled artisan.
[0050] In another embodiment of the present invention, a method and
pharmaceutical composition comprising DFO may be provided for
administration to the upper third of the patient's nasal cavity to
treat GSK-3-promoted apoptosis in the CNS, particularly in the
brain wherein the apoptosis results from non-phosphorylated GSK-3b.
The DFO inhibits phosphorylation of GSK3b, thereby inactivating
GSK-3b and preventing apoptosis or cell death as a result.
[0051] In another embodiment of the present invention, a method and
pharmaceutical composition comprising DFO may be administered to
the upper third of the patient's nasal cavity to treat central
nervous system cells of impairment of neural plasticity caused by
GSK-3. The DFO inhibits phosphorylation of GSK3b, thereby
inactivating GSK3b and preventing neural plasticity as a
result.
[0052] An effective amount, as herein defined, of DFO to be
administered pursuant to embodiments of the invention is the most
preferred method of expression of dosage. Such effective amount is
dependent upon many factors, including but not limited to, the type
of disease or condition giving rise to an anticipated cerebral
ischemic episode, the patient's general health, size, age, and the
nature of treatment, i.e., short-term of chronic treatment. For
illustrative purposes only, exemplary treatment regimens relating
generally to DFO as disclosed herein, including dosage ranges,
volumes and frequency are provided below:
[0053] Efficacious dosage range: 0.0001-1.0 mg/kg.
[0054] A more preferred dosage range may be 0.005-1.0 mg/kg.
[0055] The most preferred dosage range may be 0.05-1.0 mg/kg.
[0056] The dosage volume (applicable to nasal sprays or drops)
range may be 0.015 ml-1.0 ml.
[0057] The preferred dosage volume (applicable to nasal sprays or
drops) range may be 0.03 ml-0.6 ml.
[0058] Generally, the treatment may be given in a single dose or
multiple administrations, i.e., once, twice, three or more times
daily over a period of time. The brain concentrations that are
likely to be achieved with the dosage ranges provided above are,
for a single dose: 0.1 nM-50 .mu.M. Over the course of a multi-dose
treatment plan, the maximum brain concentration may be as high as
500 .mu.M.
[0059] The present invention should not be considered limited to
the particular examples described above, but rather should be
understood to cover all aspects of the invention. Various
modifications, equivalent processes, as well as numerous structures
to which the present invention may be applicable will be readily
apparent to those of skill in the art to which the present
invention is directed upon review of the present specification.
* * * * *