U.S. patent application number 17/301188 was filed with the patent office on 2021-10-14 for systems, methods, and kits for diagnostics and treatment of viral respiratory infection.
The applicant listed for this patent is Applied Biology, Inc.. Invention is credited to Ofer A. Goren, John McCoy.
Application Number | 20210315838 17/301188 |
Document ID | / |
Family ID | 1000005526874 |
Filed Date | 2021-10-14 |
United States Patent
Application |
20210315838 |
Kind Code |
A1 |
Goren; Ofer A. ; et
al. |
October 14, 2021 |
SYSTEMS, METHODS, AND KITS FOR DIAGNOSTICS AND TREATMENT OF VIRAL
RESPIRATORY INFECTION
Abstract
The present disclosure includes methods, systems, kits and
compositions for treating, preventing and diagnosing viral
infections, specifically SARS-CoV-2 infections, with an
anti-androgen and anti-thyroid medication, a thyroid receptor
antagonist, a TGF-.beta. inhibitor or a combination thereof. The
present disclosure also describes methods and compositions for the
treatment of viral respiratory diseases, specifically SARS-CoV-2
infections, including anti-androgens, anti-thyroid medications,
thyroid receptor antagonists, TGF-.beta. inhibitors, RXR
inhibitors, furin inhibitors or other agents to disrupt the
androgen signaling.
Inventors: |
Goren; Ofer A.; (Irvine,
CA) ; McCoy; John; (Irvine, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Applied Biology, Inc. |
Irvine |
CA |
US |
|
|
Family ID: |
1000005526874 |
Appl. No.: |
17/301188 |
Filed: |
March 29, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16946875 |
Jul 9, 2020 |
11058647 |
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17301188 |
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15929788 |
May 21, 2020 |
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16946875 |
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63041426 |
Jun 19, 2020 |
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62704531 |
May 14, 2020 |
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62704416 |
May 8, 2020 |
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62704126 |
Apr 22, 2020 |
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63004398 |
Apr 2, 2020 |
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63004171 |
Apr 2, 2020 |
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63001629 |
Mar 30, 2020 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 33/18 20130101;
A61K 31/473 20130101; A61K 31/4439 20130101; A61K 38/09 20130101;
C07K 16/2827 20130101; A61K 31/167 20130101; C12N 2310/11 20130101;
A61K 31/4709 20130101; C12N 15/1136 20130101; A61K 31/277 20130101;
A61K 31/58 20130101; A61K 31/437 20130101; A61K 31/4166 20130101;
C07K 14/71 20130101; A61K 31/4155 20130101; A61K 31/337 20130101;
A61K 31/4164 20130101; A61P 31/14 20180101; A61K 31/57 20130101;
A61K 31/05 20130101 |
International
Class: |
A61K 31/05 20060101
A61K031/05; A61K 31/4709 20060101 A61K031/4709; A61K 31/277
20060101 A61K031/277; A61K 31/4164 20060101 A61K031/4164; A61K
31/473 20060101 A61K031/473; A61K 31/4439 20060101 A61K031/4439;
A61K 31/4166 20060101 A61K031/4166; C07K 14/71 20060101 C07K014/71;
A61K 31/57 20060101 A61K031/57; C07K 16/28 20060101 C07K016/28;
A61K 31/337 20060101 A61K031/337; A61K 31/4155 20060101
A61K031/4155; A61K 31/437 20060101 A61K031/437; A61K 33/18 20060101
A61K033/18; A61K 31/167 20060101 A61K031/167; A61K 31/58 20060101
A61K031/58; C12N 15/113 20060101 C12N015/113; A61K 38/09 20060101
A61K038/09; A61P 31/14 20060101 A61P031/14 |
Claims
1. A method for treating a patient with or a patient at risk of
developing an influenza infection, wherein the method comprises
administering a composition to the patient, wherein the composition
comprises an anti-androgen.
2. The method of claim 1, wherein the anti-androgen is any one or
combination of: cyproterone acetate, megestrol acetate,
chlormadinone acetate, spironolactone, medrogestone, oxendolone,
osaterone, bifluranol, finasteride, dutasteride, flutamide,
bicalutamide, nilutamide, topilutamide, enzalutamide, apalutamide,
dienogest, drospirenone, medrogestone, nomegestrol acetate,
promegestone, trimegestone, ketoconazole, abiraterone acetate,
seviteronel, aminoglutethimide, epristeride, alfaestradiol,
isotretinoin, saw palmetto, darolutamide, galeterone,
proxalutamide, triptorelin pamoate, allylestrenol, chlormadinone
acetate or degarelix.
3. The method of claim 1, wherein the method further comprises
administering an anti-thyroid medication, a thyroid receptor
inhibitor, a TGF-.beta. inhibitor or a combination thereof.
4. The method of claim 3, wherein the anti-thyroid medication is
selected from sodium iodide, potassium iodide, colloidal iodine,
tapazole, methimazole, sodium iodide-i-131, Iodotope, iosat,
Northyx, Tapazole, Propylthiouracil, PropylThyracil, PTU, SSKI,
ThyroSafe, ThyroShield, iOSAT, Sodium iodide 131I, Hicon or a
combination thereof.
5. The method of claim 3, wherein the thyroid receptor inhibitor is
selected from NH-3, tetraiodothyroacetic acid or a combination
thereof.
6. The method of claim 3, wherein the TGF-.beta. inhibitor is
selected from M7824, bintrafusp alfa, galunisertib, SAR439459,
NIS793, PF-06952229, vactosertib, AVID200, ARGX-115, ABBV-151,
trabedersen, VTX-002, ACE-1332, SRK-181 or a combination
thereof.
7. (canceled)
8. (canceled)
9. A method for treating a patient with or a patient at risk of
developing an influenza infection, wherein the method comprises
administering to the patient an anti-androgen, an anti-thyroid
medication, a thyroid receptor inhibitor, a TGF-.beta. inhibitor or
a combination thereof.
10. The method of claim 9, wherein the anti-thyroid medication is
selected from sodium iodide, potassium iodide, colloidal iodine,
tapazole, methimazole, sodium iodide-i-131, Iodotope, iosat,
Northyx, Tapazole, Propylthiouracil, PropylThyracil, PTU, S SKI,
ThyroSafe, ThyroShield, iOSAT, Sodium iodide 131I, Hicon or a
combination thereof.
11. The method of claim 9, wherein the thyroid receptor inhibitor
is selected from NH-3, tetraiodothyroacetic acid or a combination
thereof.
12. The method of claim 9, wherein the TGF-.beta. inhibitor is
selected from M7824, bintrafusp alfa, galunisertib, SAR439459,
NIS793, PF-06952229, vactosertib, AVID200, ARGX-115, ABBV-151,
trabedersen, VTX-002, ACE-1332, SRK-181 or a combination
thereof.
13. The method of claim 9, wherein the anti-androgen is any one or
combination of: cyproterone acetate, megestrol acetate,
chlormadinone acetate, spironolactone, medrogestone, oxendolone,
osaterone, bifluranol, finasteride, dutasteride, flutamide,
bicalutamide, nilutamide, topilutamide, enzalutamide, apalutamide,
dienogest, drospirenone, medrogestone, nomegestrol acetate,
promegestone, trimegestone, ketoconazole, abiraterone acetate,
seviteronel, aminoglutethimide, epristeride, alfaestradiol,
isotretinoin, saw palmetto, darolutamide, galeterone,
proxalutamide, triptorelin pamoate, allylestrenol, chlormadinone
acetate or degarelix.
14. (canceled)
15. The method of claim 1, wherein the patient also has prostate
cancer.
16. The method of claim 9, wherein the method further comprises
administering agents that counter the effect of androgens.
17. The method of claim 16, wherein the agents that counters the
effect of androgens are sex hormone-binding globulin (SHBG)
stimulators.
18. The method of claim 9, wherein the method further comprises
administering an antigonadotropin.
19. The method of claim 9, wherein the method further comprises
administering a mineralocorticoid or a glucocorticoid.
20. The method of claim 9, wherein the method further comprises
administering an insulin sensitizing medication.
21. The method of claim 9, wherein the method further comprises
administering a vaccine or immunogens against androstenedione.
22-30. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional application to U.S. Utility
application Ser. No. 16/946,875, which claims the benefit of U.S.
Provisional Application No. 63/041,426, titled Methods and
Compositions for the Treatment of Viral Respiratory Infection,
filed on Jun. 19, 2020, and is a continuation in part application
to U.S. Utility application Ser. No. 15/929,788, titled Systems,
Methods, and Kits for Diagnostics and Treatment of Viral
Respiratory Infection, filed on May 21, 2020, which is related to
and claims the benefit of U.S. Provisional Application No.
63/001,629, titled Systems, Methods and Kits for Diagnostics and
Treatment of SARS-CoV-2, filed on Mar. 30, 2020, U.S. Provisional
Application No. 63/004,171, titled Systems, Methods and Kits for
Diagnostics and Treatment of Viral Respiratory Infection, filed on
Apr. 2, 2020, U.S. Provisional Application No. 63/004,398, titled
Systems, Methods and Kits for Diagnostics and Treatment of Viral
Respiratory Infection, filed on Apr. 2, 2020, U.S. Provisional
Application No. 62/704,126, titled Systems, Methods and Kits for
Diagnostics and Treatment of Viral Respiratory Infection, filed on
Apr. 22, 2020, U.S. Provisional Application No. 62/704,416, titled
Systems, Methods and Kits for Diagnostics and Treatment of Viral
Respiratory Infection, filed on May 8, 2020, U.S. Provisional
Application No. 62/704,531, titled Systems, Methods and Kits for
Diagnostics and Treatment of Viral Respiratory Infection, filed on
May 14, 2020, the entire contents of each being incorporated herein
by reference.
FIELD
[0002] The present invention relates to systems, methods,
compositions and kits for treating, preventing, and diagnosing
viral infection using a combination of thyroid hormone pathways and
androgen mediated pathway. The present invention relates to methods
and kits for predicting viral respiratory disease severity.
Additionally, the present invention relates to methods and kits for
guiding treatment of viral respiratory disease by testing for
polymorphisms in the androgen receptor gene or genes under
regulatory control of the androgen receptor. Similarly, the
following invention relates to systems and methods for treatment of
viral respiratory diseases with various anti-androgens used in
combination with thyroid inhibitors including, but not limited to,
androgen receptor antagonists, androgen synthesis inhibitors, or
antigonadotropins used in combination with TGF-.beta. inhibitors,
thyroid hormone receptor inhibitors, thyroid inhibitors, or furin
protease inhibitors. Additionally, the present systems, methods,
and kits are useful for treating, preventing, and diagnosing
coronavirus, e.g., SARS-CoV-2 (COVID-19).
BACKGROUND
[0003] In late 2019, a novel coronavirus, subsequently named
SARS-CoV-2 (COVID-19), was first reported in Hubei province in
China. Since it was first reported, a worldwide pandemic has ensued
affecting more than 450,000 individuals as of March 2020. In the
midst of the pandemic, epidemiological reports unveiled a
disproportionate low rate of severe cases among adult females
compared to adult males, 42% and 58%, respectively. Similarly, the
rate of severe cases among pre-pubescent children was exceptionally
low at 0.6% (See Guan W J, Ni Z Y, Hu Y, Liang W H, Ou C Q, et al.
Clinical Characteristics of Coronavirus Disease 2019 in China. N
Engl J Med. 2020). An explanation for the skewed prevalence of
severe COVID-19 infection in adult males has yet to be
elucidated.
[0004] In newborns, it has long been recognized that male infants
are more susceptible to respiratory distress syndrome (See Torday J
S, Nielsen H C, Fend Mde M, Avery M E. Sex differences in fetal
lung maturation. Am Rev Respir Dis. 1981; 123(2): 205-208) and less
likely to respond to prenatal glucocorticoid therapy to protect
against respiratory distress. Respiratory distress is intimately
tied to the production of pulmonary surfactant, e.g., pulmonary
surfactant proteins have been demonstrated to protect against
influenza A (See Hartshorn K L, Crouch E C, White M R, Eggleton P,
Tauber A I, Chang D, Sastry K. Evidence for a Protective Role of
Pulmonary Surfactant Protein D (SP-D) Against Influenza A Viruses.
J Clin Invest. 1994; 94 (1): 311-319). In animal studies, it was
demonstrated that a sexual dimorphism in fetal pulmonary surfactant
production is influenced by the androgen receptor (AR) (See Nielsen
H C. Androgen receptors influence the production of pulmonary
surfactant in the testicular feminization mouse fetus. J Clin
Invest. 1985; 76(1): 177-181). For example, in rabbits,
dihydrotestosterone was shown to inhibit fetal pulmonary surfactant
production in both males and females while an anti-androgen,
flutamide, was demonstrated to remove the sexual dimorphism in
surfactant production.
[0005] While severe COVID-19 symptoms are primarily manifested in
older adults, the similar sexual dimorphism in the severity of
respiratory disease is of interest. In addition, AR expression is
low prior to pubertal maturation and may contribute to the low
incidence of severe COVID-19 infection in children. The lower rate
of severe COVID-19 infection in female patients may be attributed
to lower androgen receptor expression.
SUMMARY
[0006] SARS-CoV-2 is part of the coronavirus family of viruses
including SARS-CoV-1 and MERS-CoV. Coronavirus predominantly
infects type II pneumocytes in the human lung (See Shieh W J, Hsiao
C H, Paddock C D, Guarner J, Goldsmith C S, et al.
Immunohistochemical, in situ hybridization, and ultrastructural
localization of SARS-associated coronavirus in lung of a fatal case
of severe acute respiratory syndrome in Taiwan. Hum Pathol. 2005;
36(3): 303-309). It has been demonstrated that SARS-CoV-2 cell
entry depends on priming of a viral spike surface protein by
transmembrane protease serine 2 (TMPRSS2) present in the host. In
type II pneumocytes, TMPRSS2 expression is associated with an
increase in androgen receptor (AR) expression (See Mikkonen L,
Pihlajamaa P, Sahu B, Zhang F P, Janne O A. Androgen Receptor and
Androgen-Dependent Gene Expression in Lung. Mol Cell Endocrinol.
2010; 317 (1-2): 14-24), specifically connecting AR expression to
SARSCoV-2, due to AR-regulated TMPRSS2 gene promoter (See Lin B,
Ferguson C, White J T, Wang S, Vessella R, True L D, et al.
Prostate-localized and androgen-regulated expression of the
membrane-bound serine protease TMPRSS2. Cancer Res 1999; 59:
4180-4). Moreover, angiotensin converting enzyme 2 (ACE2) has been
recognized as the attachment molecule to the viral spike surface
protein, thus termed the "receptor of SARS-CoV-2" (See Y. Qiu,
Y.-B. Zhao, Q. Wang, J.-Y. Li, Z.-J. Zhou, C.-H. Liao, X.-Y.
Ge,Predicting the angiotensin converting enzyme 2(ACE2) utilizing
capability as the receptor of SARS-CoV-2, Microbes and Infection,
https://doi.org/10.1016/j.micinf.2020.03.003).
[0007] Additionally, SARS-CoV-2 spike protein has been revealed to
contain a furin cleavage sequence (See Rabaan A A, Al-Ahmed S H,
Haque S, et al. SARS-CoV-2, SARS-CoV, and MERS-COV: A comparative
overview. Infez Med. 2020; 28(2): 174-184). As such, viral spike
protein priming may be mediated through furin protease in addition
to TMPRSS2. Furin expression has been demonstrated to be
up-regulated by thyroid hormone T3 and its expression was
cooperative with transforming growth factor beta or TGF-.beta. (See
Chen R N, Huang Y H, Lin Y C, et al. Thyroid hormone promotes cell
invasion through activation of furin expression in human hepatoma
cell lines. Endocrinology. 2008; 149(8): 3817-3831.
doi:10.1210/en.2007-0989). Thyroid hormone T.sub.3 or T.sub.4 binds
to thyroid hormone receptor (TR), which then activates genes
containing thyroid hormone response elements (TREs) in the
regulatory regions of target genes. As such, a furin protease
inhibitor, a modulator of T.sub.3, a modulator of T.sub.4, a TR
inhibitor, or a TGF-.beta. inhibitor (TGF-.beta.i) are envisioned
to be used in combination with an anti-androgen to limit the
expression of TMPRSS2 and furin.
[0008] Males infected with SARS-CoV-2 are more likely to be
admitted to the ICU compared to females. Various theories have been
put forward to explain this disparity. Previously, we have reported
that among hospitalized COVID-19 patients, 79% presented with male
pattern baldness compared to 31-53% that would be expected in a
similar aged match population. Male pattern baldness is known to be
mediated by variations in the Androgen Receptor (AR) gene. In
addition, the only known promoter of the enzyme implicated in
SARS-CoV-2 infectivity is an androgen response element. The
polyglutamine repeat (CAG repeat) located in the first exon of the
AR gene is associated with androgen sensitivity, testicular cancer
and androgenetic alopecia. These observations led us to hypothesize
that variations in the AR gene may pre-dispose male COVID-19
patients to increased disease severity; therefore, we conducted a
prospective longitudinal study of hospitalized COVID-19 male
patients. ICU admission rates for patients with a short (<22)
CAG repeat were compared to ICU admission rates for patients with a
long (>=22) CAG repeats. Consistent with our hypothesis, 45% of
patients with a short CAG repeat were admitted to the ICU compared
to 70% of patients with a long CAG repeat (p=0.0429). Compared to
hospitalized COVID-19 male patients with a short CAG repeat,
hospitalized COVID-19 male patients with a long CAG repeat had a
significantly increased risk for admissions to ICU (RR 1.5630 , 95%
CI: 1.0022 to 2.4378, p=0.0489). Further, the average duration of
hospitalization for patients with a long CAG repeat was 37 (+/-21)
days compared to 27 (+/-20) days for patients with a short CAG
repeat. We believe this is the first study to demonstrate a direct
association between androgen receptor genetic variants and COVID-19
disease severity. If the results of our study are replicated in a
larger cohort, genetic testing could potentially help identify
patients at increased risk for COVID-19 disease severity.
[0009] Additionally, TR regulates gene expression by binding to
TREs in DNA either as monomers, heterodimers with other nuclear
receptors. One important nuclear receptor that TR forms dimers with
is the retinoid X receptor (RXR), a nuclear retinoic acid receptor.
TR/RXR heterodimers are the most transcriptionally active form of
TR. As such inhibition of RXR would inhibit TR activity.
[0010] The present invention relates to systems, methods,
compositions and for diagnosing and treating a viral respiratory
infection which may include first measuring polymorphisms in the
androgen receptor gene or polymorphisms in genes under regulatory
control of the androgen receptor. Identification of polymorphisms
in the androgen receptor gene can be used to guide treatments of
viral respiratory diseases or infections. Treatments for viral
respiratory diseases may include, but are not limited to, androgen
receptor antagonists, androgen synthesis inhibitors, or
antigonadotropins used in combination with TGF-.beta. inhibitors,
thyroid hormone receptor inhibitors, thyroid inhibitors, or furin
protease inhibitors. Specifically, the present systems, methods,
compositions and kits are useful for treating, preventing, and
diagnosing viral respiratory disease as a result of coronavirus
infection, e.g., SARS-CoV-2 (COVID-19).
DETAILED DESCRIPTION
[0011] As used herein, the terms "prevent" or "prevention" and
other derivatives of the words, when used in reference to viral
respiratory infection, e.g., viral respiratory infection, refer to
a reduced likelihood of viral respiratory infection in an
individual receiving a given treatment relative to that of a
similar individual at risk for viral respiratory infection but not
receiving that treatment. As such, the terms "prevent" and
"prevention" encompass a treatment that results in a lesser degree
of viral respiratory infection, e.g., viral respiratory infection,
than would be otherwise expected for a given individual. Efficacy
for prevention of viral respiratory infection, e.g., viral
respiratory infection, can be established through controlled
studies, e.g., in which a subject is administered a treatment
(e.g., an inhaled treatment) and another subject is administered a
placebo. Under these circumstances, if the subject treated with the
inhaled treatment undergoes less severe viral respiratory infection
symptoms over time relative to the subject receiving the placebo,
e.g., at least 5% less, at least 10% less, at least 15% less, at
least 20% less, at least 25% less, at least 30% less, at least 35%
less, at least 40% less, at least 45% less, at least 50% less or
beyond, the treatment is effective for the prevention of viral
respiratory infection.
[0012] As used herein, the terms "treat," "treatment," or
"treating" refer to therapeutic treatments, wherein the object is
to reverse, alleviate, ameliorate, inhibit, slow down or stop the
progression or severity of a disease or condition, e.g., SARS-CoV-2
infection or another form of viral respiratory infection. The term
"treating" includes reducing or alleviating at least one adverse
effect or symptom of a disease or condition, e.g., SARS-CoV-2
infection or another form of a viral respiratory infection.
Treatment is generally "effective" if one or more symptoms are
reduced. Alternatively, treatment is "effective" if the progression
of a disease is reduced or halted. That is, "treatment" includes
not just the improvement of symptoms, but also a cessation of, or
at least slowing of, progress or worsening of symptoms compared to
what would be expected in the absence of treatment. Beneficial or
desired clinical results include, but are not limited to,
alleviation of one or more symptom(s), diminishment of extent of
disease, stabilized (i.e., not worsening) state of disease, delay
or slowing of disease progression, amelioration or palliation of
the disease state, remission (whether partial or total), and/or
decreased mortality. For example, treatment is considered effective
if: 1) the risk or propensity of a person having a viral
respiratory infection being hospitalized, being admitted to an
intensive care unit (ICU), or dying as a result is reduced; 2) the
rate at which a person having a viral respiratory infection
recovers or stabilizes is increased; 3) the rate at which a person
having a viral respiratory infection is discharged from the
hospital is increased; 4) the ability for a person having a viral
respiratory infection to recover or stabilize is improved; 5) the
ability to diagnose a person as having a viral respiratory
infection is improved; 6) the time to diagnose a person having a
viral respiratory infection is reduced; 7) the ability to prevent a
person from being infected with a viral respiratory infection is
improved; 8) the ability to predict viral respiratory disease
severity (e.g., is a ventilator or respirator will be needed for
treatment) is increased. The term "treatment" of a disease also
includes providing relief from the symptoms or side-effects of the
disease (including palliative treatment). Treatment can involve
administering a therapeutically effective amount of any one or
combination of the compositions disclosed herein.
[0013] As used herein the term "comprising" or "comprises" is used
in reference to compositions, methods, etc. refers to component(s)
or method steps that are present in the method or composition, yet
allows for the composition, method, etc. to also include
unspecified elements.
[0014] The term "consisting of" refers to compositions, methods,
and respective components thereof as described herein, which are
exclusive of any element not recited in that description of the
embodiment.
[0015] As used herein the term "consisting essentially of" refers
to those elements required for a given embodiment. The term permits
the presence of elements that do not materially affect the basic
and novel or functional characteristic(s) of that embodiment.
[0016] As used herein the term "viral respiratory infection" refers
to all forms of human lung disease stemming from a viral infection
including coronavirus, influenza, influenza A, influenza B,
SARS-CoV-1, SARS-CoV-2, MERS-CoV and rhinoviruses. The term permits
the presence of elements that do not materially affect the basic
and novel or functional characteristic(s) of that embodiment.
[0017] As used herein the term "Thyroid Receptor" refers to all
forms of human thyroid receptors such as THRA and THRB.
[0018] As used herein, the term "patient" refers to a human subject
that has been diagnosed with or is at risk of developing a viral
respiratory infection, for example a SARS-CoV-2 infection. A human
subject is determined to be at risk of developing a viral infection
if they have been exposed to a source of viral respiratory
infection such as another human, an animal, a location, a
contaminated surface or a contaminated object, wherein the source
comprises an active viral population.
[0019] The singular terms "a," "an," and "the" include plural
referents unless context clearly indicates otherwise. Similarly,
the word "or" is intended to include "and" unless the context
clearly indicates otherwise. Although methods and materials similar
or equivalent to those described herein can be used in the practice
or testing of this disclosure, suitable methods and materials are
described below. The abbreviation, "e.g." is derived from the Latin
exempli gratia, and is used herein to indicate a non-limiting
example. Thus, the abbreviation "e.g." is synonymous with the term
"for example".
[0020] As used herein, the term "components" refers to the androgen
receptor antagonists, androgen synthesis inhibitors,
anti-androgens, RXR antagonists, anti-thyroid medications
(modulators that lower T.sub.3 and/or T.sub.4 expression), agents
that counter the effect of androgens such as sex hormone-binding
globulin (SHBG) stimulators, antigonadotropins, mineralocorticoids
and glucocorticoids (anticorticotropins) that suppress androgen
production in the adrenal gland, insulin sensitizing medications
such metformin, vaccines and immunogens against androstenedione,
furin protease inhibitors, TR inhibitors and TGF-.beta. inhibitors
employed in the treatment methods and compositions.
[0021] Various aspects of the technology describe detecting
androgen sensitivity in a subject by measuring polymorphisms in the
androgen receptor gene. Androgen Receptor (AR) genetic variation
refers to DNA genetic variations, expression of AR in specific
tissue (RNA), including methylation analysis of AR (i.e., in the
case of X-chromosome inactivation). Specific details for detecting
polymorphisms in the androgen receptor can be found in literature,
e.g., See Androgens and Androgen Receptor: Mechanisms, Functions,
and Clinic Applications. United States, Springer US, 2012, which is
incorporated here in its entirety. Polymorphisms in the androgen
receptor can be used to infer a subject has androgen
sensitivity.
[0022] Applicants disclose herein systems, methods, compositions
and kits for treating, preventing, and diagnosing a viral
respiratory infection. These methods, systems, compositions and
kits may include measuring polymorphisms in the androgen receptor
gene of a patient with or at risk of developing a viral respiratory
infection. They may also include the use of any one or combination
of the following: androgen receptor antagonists, androgen synthesis
inhibitors, anti-androgens, RXR antagonists, agents that counter
the effect of androgens such as sex hormone-binding globulin (SHBG)
stimulators, antigonadotropins, mineralocorticoids and
glucocorticoids (anticorticotropins) that supress androgen
production in the adrenal gland, insulin sensitizing medications
(e.g., metformin), vaccines and immunogens against androstenedione
which reduce the level of testosterone and estrogen, a furin
protease inhibitor, anti-thyroid medications (modulators that lower
T.sub.3 and/or T.sub.4 expression), a TR inhibitor, a TGF-.beta.
inhibitor (TGF-.beta.i) or any combination thereof. These methods,
systems, kits and compositions can be administered topically,
nasally, orally, by injection, or be applied topically to the lung,
i.e. inhaled. Without being bound by any theory, these methods,
kits, systems and compositions would alter the androgen receptor
function of the patient and lower the T.sub.3 or T.sub.4 levels,
block TR signaling, or inhibit TGF-.beta. expression of the
patient, thus subsequently lowering the expression of downstream
genes under regulatory control of the androgen receptor and/or
T.sub.3 signaling. Such genes include but are not limited to,
angiotensin converting enzyme 2 (ACE2), furin, and transmembrane
protease serine 2 (TMPRSS2). Blocking the production of certain
proteins in the lung may be beneficial to altering viral entry into
cells or bolstering host immunity. For example, TMPRSS2 and furin
priming of a viral spike surface protein is required for SARS-CoV-2
cell entry; TMPRSS2 expression is under control of the androgen
receptor and furin expression is dependent on T.sub.3 and
TGF-.beta.. As such, blocking the expression of the androgen
receptor or altering AR activity (e.g., with and AR antagonist)
would decrease the amount of TMPRSS2 expression and lead to reduced
viral entry. Additionally, lowering T.sub.3, inhibiting TR, or
blocking TGF-.beta. would decrease the amount of furin and lead to
reduced viral entry. Finally, a combination of anti-androgen and a
TGF-.beta.i would block both pathways to viral spike protein
priming and reduce viral entry into human cells. Other embodiments
are described below.
[0023] The viral respiratory infection may include, but is not
limited to, any one or combination of coronavirus, influenza,
influenza A, influenza B, SARS-CoV-1, SARS-CoV-2, MERS-CoV, or
rhinoviruses. In preferred embodiments, the respiratory infection
is a SARS-CoV-2 infection.
[0024] The anti-androgen employed in the methods, systems, kits and
combinations can be selected from any one or combination of:
cyproterone acetate, megestrol acetate, chlormadinone acetate,
spironolactone, medrogestone, oxendolone, osaterone, bifluranol
acetate, finasteride, dutastride, flutamide, bicalutamide,
nilutamide, topilutamide, enzalutamide, apalutamide, dienogest,
drospirenone, medrogestone, nomegestrol acetate, promegestone,
trimegestone, ketoconazole, abiraterone acetate, seviteronel,
aminoglutethimide, epristeride, alfaestradiol, isotretinoin, saw
palmetto, marijuana, cannabinoids, darolutamide, EZN-4176,
AZD-3514, and AZD-5312, apatorsen, galeterone, ODM-2014, TRC-253,
BMS-641988, proxalutamide, Luteinizing hormone-releasing hormone
(LH-RH), follicle-stimulating hormone (FSH), triptorelin pamoate,
docetaxel, diethylstilbestrol, tadalafil, silodosin, tamsulosin
hydrochloride, naftopidil, solifenacin succinate, tamsulosin,
tamsulosin hydrochloride, alfuzosin hydrochloride, prazosin
hydrochloride, doxazosin, doxazosin mesylate, solifenacin
succinate, allylestrenol, benzydamine hydrochloride, cefatrizine,
chlormadinone acetate, flavoxate hydrochloride, gestonorone
caproate, indoramin hydrochloride, mepartricin, oxybutynin
chloride, phenoxybenzamine hydrochloride, terazosin, terazosin
hydrochloride, or degarelix. As explained herein, the method of
treatment can involve administration of a composition that includes
an anti-androgen as an ingredient of the composition. The
anti-androgen can be present in percent amounts ranging from 0% to
100%.
[0025] The TGF-.beta.i employed in the treatment methods and
compositions can be selected from M7824, bintrafusp alfa,
galunisertib, SAR439459, NIS793, PF-06952229, vactosertib, AVID200,
ARGX-115, ABBV-151, trabedersen, VTX-002, ACE-1332, SRK-181 or any
combination thereof. The TGF-.beta.i can be present in percent
amounts ranging from 0% to 100%.
[0026] The furin inhibitor employed in the treatment methods and
compositions can be selected from .alpha.1-PDX, Acyclic mini-PDX,
Cyclic mini-PDX, OMTKY3 (variant A15R,T17K,L18R), 6R, D6R, D9R,
H5N1 derived peptide, Ac-RXXT-NH2, H2N-C8-RXXT, chloromethylketone,
Decanoyl-Arg-Val-Lys-Arg-chloromethylketone, Dec-RVKR-CMK, TACE
inhibitor, Naphthofluorescein,
phenylacetyl-Arg-Val-Arg-4-amidinobenzylamide or any combination
thereof. The furin inhibitor can be present in percent amounts
ranging from 0% to 100%.
[0027] The TR antagonist employed in the treatment methods and
compositions can be selected from NH-3, tetraiodothyroacetic acid
(tetrac) or a combination thereof. The TR antagonist can be present
in percent amounts ranging from 0% to 100%.
[0028] The anti-thyroid medication (i.e., a medication that lowers
T.sub.3 and/or T.sub.4 expression) employed in the treatment
methods and compositions can be selected from sodium iodide,
potassium iodide, colloidal iodine, tapazole, methimazole, sodium
iodide-i-131, Iodotope, iosat, Northyx, Tapazole, Propylthiouracil,
PropylThyracil, PTU, SSKI, ThyroSafe, ThyroShield, iOSAT, Sodium
iodide I311, Hicon or any combination thereof. The anti-thyroid
medication can be present in percent amounts ranging from 0% to
100%.
[0029] The RXR antagonist employed in the treatment methods and
compositions can be selected from LG100754, AGN195393, Ro26-5405,
LG101506, PA451, PA452, B1-1003, B1-1005, SR11179, UVI3003,
Danthron, Rhein, .beta.-Apo-13-carotenone, R-Etodolac, Sulindac
sulfide, K-80003, K-8008, Triptolide, TRC4, NSC-640358,
Fluvastatin, Pitavastatin, HX531 or any combination thereof. The
RXR antagonist can be present in percent amounts ranging from 0% to
100%.
[0030] In some embodiments, the method comprises administering an
anti-androgen with any one or combination of an anti-inflammatory
agent, an anti-bacterial agent, or aspartame.
[0031] In an exemplary embodiment, a method of using a composition
on a subject having or suspected of having a viral respiratory
infection involves administering a composition to a subject, the
composition including any one or combination of: an androgen
receptor antagonists or anti-androgen; an androgen synthesis
inhibitor; an agent that counters the effect of androgens; a
globulin (SHBG) stimulator; an antigonadotropin; a
mineralocorticoid to suppress androgen production in the adrenal
gland; a glucocorticoid to suppress androgen production in the
adrenal gland; an insulin sensitizing medication; and vaccine or an
immunogen against androstenedione that reduces the level of
testosterone or increases estrogen.
[0032] In some embodiments, the method involves altering androgen
receptor function and subsequently downstream genes under
regulatory control of the androgen receptor, wherein the downstream
genes include any one or combination of angiotensin converting
enzyme 2 (ACE2), furin, and transmembrane protease serine 2
(TMPRSS2).
[0033] In some embodiments, the method involves predicting
anti-androgen treatment response via evaluation of a genetic
variation of the androgen receptor (AR) gene.
[0034] In some embodiments: the number of cytosine-adenine-guanine
(CAG) repeats in the first exon of the AR gene, the number of
guanine-guanine-(any nucleotide) (GGN) repeats in the first exon in
the AR gene, and/or a ratio of CAG/GGN repeats is used as the
genetic variant; and a cut off value for the number of CAG repeats
the first exon of AR gene is used to define a person with androgen
sensitivity.
[0035] In some embodiments, the cut-off value for the number of CAG
repeats the first exon of AR gene is between 10 and 30.
[0036] In some embodiments, variants in the promoter region of the
AR are used as the genetic variant.
[0037] In an exemplary embodiment, the present invention comprises
a method of identifying whether a person is at risk of mortality or
developing severity of infection following viral respiratory
infection involves determining the risk of severity or mortality of
the viral respiratory infection by identifying and measuring
promotor regions in any one or combination of the androgen receptor
(AR) gene, the TMPRSS2 gene, the furin gene, or the ACE2 gene.
[0038] In some embodiments, the method involves predicting
anti-androgen treatment response via evaluation of a genetic
variation of the AR gene, the TMPRSS2 gene, the furin gene, or the
ACE2 gene.
[0039] In some embodiments, the method involves predicting the
anti-androgen treatment response involves measuring polymorphisms
in the AR gene.
[0040] In some embodiments, the genetic variation includes any one
or combination of one or more of: F877L/T878A, F877L, T878A,
rs137852591, rs104894742, rs1057518177, rs1057521121, rs1057521122,
rs1057523747, rs1064793480, rs1064793645, rs1064794065,
rs1064794069, rs1064795250, rs1085307685, rs1085307962, rs12014709,
rs1204038, rs1337080, rs137852562, rs137852563, rs137852564,
rs137852565, rs137852566, rs137852567, rs137852568, rs137852569,
rs137852570, rs137852571, rs137852572, rs137852573, rs137852574,
rs137852575, rs137852576, rs137852577, rs137852578, rs137852579,
rs137852580, rs137852581, rs137852582, rs137852583, rs137852584,
rs137852585, rs137852586, rs137852587, rs137852588, rs137852589,
rs137852590, rs137852592, rs137852593, rs137852594, rs137852595,
rs137852596, rs137852597, rs137852598, rs137852599, rs137852600,
rs137852601, rs1800053, rs201934623, rs2361634, rs5031002,
rs5918757, rs6152, rs6624304, rs750324117, rs754201976,
rs755226547, rs759327087, rs864622007, rs869320731, rs869320732,
rs878853033, rs886039558, rs886041050, rs886041128, rs886041129,
rs886041130, rs886041131, rs886041132, rs886041133, rs886041352,
rs9332969, or rs9332971; one or more of: rs12329760, rs2070788,
rs383510, rs463727, rs34624090, rs55964536, rs734056, rs4290734,
rs34783969, rs11702475, rs35899679, rs35041537, rs8134378,
rs2070788, rs9974589, rs7364083, or rs2070788; one or more of:
rs2285666, G8790A, rs35803318, rs1978124, rs2048683, rs2074192,
rs2106809, rs2285666, rs233575, rs4240157, rs4646155, rs4646156,
rs4646174, rs4646176, rs4646188, rs6632677, rs714205, or rs879922;
or one or more of: rs17514846, rs2071410, rs4702, rs4932178,
rs6226, or rs6227.
[0041] In some embodiments, the method involves blocking the
production of proteins in the lung so as to alter viral entry into
cells or to bolster host immunity.
[0042] In some embodiments, the method involves administering a
composition as a treatment for the viral respiratory infection
and/or a prophylactic for the viral respiratory infection before,
during, and/or after the patient is first diagnosed with the viral
respiratory infection and/or before, during, and/or after the
subject is hospitalized due to the viral respiratory infection.
[0043] In some embodiments, the method involves guiding selection
of anti-androgen treatment and/or dosage selection of the selected
anti-androgen treatment based on the predicted anti-androgen
treatment response.
[0044] In some embodiments, the method involves predicting
infection symptom severity, infection mortality, and/or whether the
patient will need a ventilator or respiration due to the
infection.
[0045] In some embodiments, the method involves administering the
composition routinely.
[0046] In some embodiments, the method involves the combination of
an anti-androgen with any one or combination of an
anti-inflammatory agent, an anti-bacterial agent, or aspartame.
[0047] In an exemplary embodiment, the method involves the use of a
composition on a patient having or suspected of having a viral
respiratory infection wherein the composition is administered the
patient, wherein the composition includes dutasteride. In preferred
embodiments, the composition is further used as a treatment of the
viral respiratory infection, a therapy for the viral respiratory
infection, a prophylactic for the viral respiratory infection, a
preventive measure for contracting the viral respiratory infection,
a diagnosis of a type of viral respiratory infection, a prediction
for respiratory disease severity of the viral respiratory
infection, a prediction for determining an effective treatment or
prophylactic composition, and/or a prediction for determining an
effective administration dosage of the composition for use as a
treatment or prophylactic.
[0048] In some embodiments, the method involves administering the
composition so that the dutasteride is present in a range from 0.1
mg/day to 1.0 mg/day.
[0049] In some embodiments, the method involves administering the
composition at any time before the subject is exposed to the viral
respiratory infection.
[0050] In some embodiments, the method involves administering a
composition at any time within a time frame of thirty days prior to
the patient being exposed to the viral respiratory infection.
[0051] In an exemplary embodiment, the method involves the use of a
composition on a patient having or suspected of having a viral
respiratory infection, wherein the method involves: administering,
via inhalation or injection, a small-interfering RNA (siRNA)
directed against any one or combination of an androgen receptor
(AR), TMPRSS2, and ACE2; wherein the viral respiratory infection
includes any one or combination of coronavirus, influenza,
influenza A, influenza B, SARS-CoV-1, SARS-CoV-2, MERS-CoV, or
rhinoviruses.
[0052] In an exemplary embodiment, a method of treating a patient
having or suspected of having a viral respiratory infection
involves administering a composition to the patient, the
composition including any one or combination of: an androgen
receptor antagonists or anti-androgen; an androgen synthesis
inhibitor; an agent that counters the effect of androgens; a
globulin (SHBG) stimulator; an antigonadotropin; a
mineralocorticoid to suppress androgen production in the adrenal
gland; a glucocorticoid to suppress androgen production in the
adrenal gland; an insulin sensitizing medication; and vaccine or an
immunogen against androstenedione that reduces the level of
testosterone or increases estrogen.
[0053] In some embodiments, the anti-androgen is any one or
combination of: cyproterone acetate, megestrol acetate,
chlormadinone acetate, spironolactone, medrogestone, oxendolone,
osaterone, bifluranol acetate, finasteride, dutastride, flutamide,
bicalutamide, nilutamide, topilutamide, enzalutamide, apalutamide,
dienogest, drospirenone, medrogestone, nomegestrol acetate,
promegestone, trimegestone, ketoconazole, abiraterone acetate,
seviteronel, aminoglutethimide, epristeride, alfaestradiol,
isotretinoin, saw palmetto, marijuana, cannabinoids, darolutamide,
EZN-4176, AZD-3514, and AZD-5312, apatorsen, galeterone, ODM-2014,
TRC-253, BMS-641988, proxalutamid, Luteinizing hormone-releasing
hormone (LH-RH), follicle-stimulating hormone (FSH), triptorelin
pamoate, docetaxel, diethylstilbestrol, tadalafil, silodosin,
tamsulosin hydrochloride, naftopidil, solifenacin succinate,
tamsulosin, tamsulosin hydrochloride, alfuzosin hydrochloride,
prazosin hydrochloride, doxazosin, doxazosin mesylate, solifenacin
succinate, allylestrenol, benzydamine hydrochloride, cefatrizine,
chlormadinone acetate, flavoxate hydrochloride, gestonorone
caproate, indoramin hydrochloride, mepartricin, oxybutynin
chloride, phenoxybenzamine hydrochloride, terazosin, terazosin
hydrochloride, or degarelix.
[0054] In some embodiments, the method further involves predicting
anti-androgen treatment response via evaluation of genetic
variation in the gene and/or promotor region of the androgen
receptor (AR).
[0055] In some embodiments, the method further involves guiding
selection of anti-androgen treatment and/or dosage selection of the
selected anti-androgen treatment based on the predicted
anti-androgen treatment response.
[0056] In some embodiments, administering the composition involves
administering topical skin application of finasteride at 1-30%
(w/w), oral finasteride at 0.01-30 mg, dutasteride at 0.1 mg/day to
3.0 mg/day, degarelix at 24 mg-720 mg, oral cannabidiol at
1-30/mg/Kg/day, oral flutamide at 75-2,250 mg/day, enzalutamide at
16-480 mg qd, oral dutasteride at 0.025-0.75 mg/day, apalutamide at
6-180 mg 4 times per day, injection of 30-900 mg of cyproterone
acetate, subcutaneous injection of 12-360 mg of degarelix,
bicalutamide at 5-150 mg per day, subcutaneous injection of 12-360
mg of degarelix, oral darolutamide at 30-900 mg twice daily,
abiraterone at 50-1500 mg twice daily, oral nilutamide at 30-900 mg
once daily, or docetaxel at 7.5-225 mg/m2 IV over 1 hour.
[0057] In some embodiments, administering the composition involves
administering topical skin application of finasteride at 1-10%
(w/w), oral finasteride at 0.1-10 mg, dutasteride at 0.1 mg/day to
1.0 mg/day, degarelix at 24 mg-240 mg, oral cannabidiol at
1-10/mg/Kg/day, oral flutamide at 75-750 mg/day, enzalutamide at
16-160 mg qd, oral dutasteride at 0.025-0.25 mg/day, apalutamide at
6-60 mg 4 times per day, injection of 30-300 mg of cyproterone
acetate, subcutaneous injection of 12-120 mg of degarelix,
bicalutamide at 5-50 mg per day, subcutaneous injection of 12-120
mg of degarelix, oral darolutamide at 30-300 mg twice daily,
abiraterone at 50-500 mg twice daily, oral nilutamide at 30-300 mg
once daily, or docetaxel at 7.5-750 mg/m2 IV over 1 hour.
[0058] In an exemplary embodiment, a method of treating a patient
having or suspected of having a viral respiratory infection
involves: determining the risk of severity or mortality of the
viral respiratory infection for the patient by identifying and
measuring genetic variation in the gene and/or promotor region of
any one or combination of the androgen receptor (AR), TMPRSS2,
furin, or ACE2; selecting a composition and a dosage for the
composition based on the determined risk of severity or mortality;
and administering the composition to the patient, the composition
including any one or combination of: an androgen receptor
antagonists or anti-androgen; an androgen synthesis inhibitor; an
agent that counters the effect of androgens; a globulin (SHBG)
stimulator; an antigonadotropin; a mineralocorticoid to suppress
androgen production in the adrenal gland; a glucocorticoid to
suppress androgen production in the adrenal gland; an insulin
sensitizing medication; and vaccine or an immunogen against
androstenedione that reduces the level of testosterone or increases
estrogen.
[0059] In some embodiments, the method involves use of a kit,
wherein: a genetic sample via buccal swab, saliva sample, blood
sample, tissue sample, and/or hair sample is obtained via a
deoxyribonucleic acid (DNA) sample collection unit; polymorphisms
in the androgen receptor gene are identified via a viral
respiratory infection sensitivity unit; and an assay analysis is
performed using a DNA diagnostic assay.
[0060] In some embodiments, the method further involves predicting
anti-androgen treatment response via evaluation of a genetic
variation in the gene and/or promotor region in any one or
combination of AR, TMPRSS2, furin, or ACE2.
[0061] In certain embodiments, a genetic variation in the androgen
receptor (AR) gene can be used to predict mortality from viral
respiratory infection. In another embodiment, a genetic variation
in the androgen receptor (AR) gene can be used to predict viral
respiratory infection symptom severity. In yet another embodiment,
a genetic variation in the androgen receptor (AR) gene can be used
to predict if a patient with viral respiratory infection will need
a ventilator or a respirator.
[0062] In certain embodiments, a genetic variation in the androgen
receptor (AR) gene can be used to predict SARS-CoV-2 mortality. In
another embodiment, a genetic variation in the androgen receptor
(AR) gene can be used to predict SARS-CoV-2 symptom severity. In
yet another embodiment, a genetic variation in the androgen
receptor (AR) gene can be used to predict a SARS-CoV-2 infected
patient's need for a ventilator or a respirator.
[0063] Many genetic variations in the androgen receptor (AR) gene
can be used to predict viral respiratory disease severity but may
include, the number cytosine-adenine-guanine (CAG) repeats in the
first exon of AR gene. In certain embodiments of present invention,
a cut off value for the number of CAG repeats the first exon of AR
gene can be used to define a person with androgen sensitivity. In
one embodiment, the cut-off value for the number of CAG repeats the
first exon of AR gene is 24. In another embodiment, the number
guanine-guanine-(any nucleotide) (GGN) (polyglycine) repeats in the
first exon of AR gene. In certain embodiments of present invention
the number of GGN repeats is between 10 and 30. In another
embodiment, the number of GGN repeats can be used to define a
person with androgen sensitivity. In one embodiment the ratio of
CAG to GGN repeats the first exon of AR gene is used to define a
person with androgen sensitivity. In some embodiments the number of
CAG, GGN, or the ratio of CAG/GGN is used to predict a treatment
response or choose a dosage of a drug or treatment regimen
[0064] In certain embodiments of the present invention genetic
variations in the androgen receptor (AR) gene or the promoter
region of the AR can be used to predict a treatment response. In
another embodiment of the present invention genetic variations in
the androgen receptor (AR) gene or the promoter region of the AR
can be used to select a dosage of a treatment drug. In certain
embodiments genetic variations in the androgen receptor (AR) gene
or the promoter region of the AR are single nucleotide
polymorphisms (SNPs). In other embodiments SNPs that are associated
with AR expression or function are used.
[0065] Examples of genetic variations in the androgen receptor (AR)
gene or the promoter region of the AR, or are associated with AR
expression or function include but are not limited to F877L/T878A,
F877L, T878A, rs137852591, rs104894742, rs1057518177, rs1057521121,
rs1057521122, rs1057523747, rs1064793480, rs1064793645,
rs1064794065, rs1064794069, rs1064795250, rs1085307685,
rs1085307962, rs12014709, rs1204038, rs1337080, rs137852562,
rs137852563, rs137852564, rs137852565, rs137852566, rs137852567,
rs137852568, rs137852569, rs137852570, rs137852571, rs137852572,
rs137852573, rs137852574, rs137852575, rs137852576, rs137852577,
rs137852578, rs137852579, rs137852580, rs137852581, rs137852582,
rs137852583, rs137852584, rs137852585, rs137852586, rs137852587,
rs137852588, rs137852589, rs137852590, rs137852592, rs137852593,
rs137852594, rs137852595, rs137852596, rs137852597, rs137852598,
rs137852599, rs137852600, rs137852601, rs1800053, rs201934623,
rs2361634, rs5031002, rs5918757, rs6152, rs6624304, rs750324117,
rs754201976, rs755226547, rs759327087, rs864622007, rs869320731,
rs869320732, rs878853033, rs886039558, rs886041050, rs886041128,
rs886041129, rs886041130, rs886041131, rs886041132, rs886041133,
rs886041352, rs9332969, or rs9332971.
[0066] In certain embodiments of the present invention genetic
variations in the androgen response elements (ARE) of genes under
the regulatory control of the AR can be used to predict a treatment
response. In another embodiment of the present invention genetic
variations in the androgen response elements (ARE) of genes under
the regulatory control of the AR can be used to select a dosage of
a treatment drug. In certain embodiments genetic variations in the
androgen response elements (ARE) of genes under the regulatory
control of the AR are single nucleotide polymorphisms (SNPs). In
some embodiments of the present invention genetic variations in
AREs in the TMPRSS2, ACE2, and furin gene are used. In other
embodiments SNPs in the AREs or coding regions of TMPRSS2, ACE2,
and furin gene are used. In other embodiments SNPs that are
associated with TMPRSS2, ACE2, and furin expression or function are
used.
[0067] Examples of genetic variations in the AREs, promoter region,
coding region, or that are associated with TMPRSS2 expression or
function include but are not limited to rs12329760, rs2070788,
rs383510, rs463727, rs34624090, rs55964536, rs734056, rs4290734,
rs34783969, rs11702475, rs35899679, rs35041537, rs8134378,
rs2070788, rs9974589, rs7364083, and rs2070788.
[0068] Examples of genetic variations in the AREs, promoter region,
coding region, or that are associated with ACE2 expression or
function include but are not limited to rs2285666, G8790A,
rs35803318, rs1978124, rs2048683, rs2074192, rs2106809, rs2285666,
rs233575, rs4240157, rs4646155, rs4646156, rs4646174, rs4646176,
rs4646188, rs6632677, rs714205, and rs879922.
[0069] Examples of genetic variations in the furin, promoter
region, coding region, or that are associated with furin expression
or function include but are not limited to rs17514846, rs2071410,
rs4702, rs4932178, rs6226, and rs6227.
[0070] Androgen sensitivity may also include DNA genetic variations
in androgen response elements (ARE) of genes under the regulatory
control of the AR. Examples of genes containing AREs include, but
are not limited to, TMPRSS2, furin and ACE2.
[0071] In yet another embodiment of the present invention, genetic
variations in the TMPRSS2, furin or ACE2 gene or the promoter
region of the TMPRSS2, furin or ACE2 can be used to predict a
treatment response. In another embodiment of the present invention
genetic variations in the TMPRSS2, furin or ACE2 gene or the
promoter region of the TMPRSS2, furin or ACE2 can be used to select
a dosage of a treatment drug.
[0072] In certain embodiments, a genetic variation in the TMPRSS2,
furin or ACE2 gene can be used to predict mortality from viral
respiratory infection. In another embodiment, a genetic variation
in the TMPRSS2, furin or ACE2 gene can be used to predict viral
respiratory infection symptom severity. In yet another embodiment,
a genetic variation in the TMPRSS2, furin or ACE2 gene can be used
to predict if a patient with viral respiratory infection will need
a ventilator or a respirator.
[0073] In certain embodiments, a genetic variation in a genetic
variation in the TMPRSS2, furin or ACE2 gene can be used to predict
SARS-CoV-2 mortality. In another embodiment, a genetic variation in
a genetic variation in the TMPRSS2, furin or ACE2 gene can be used
to predict SARS-CoV-2 symptom severity. In yet another embodiment,
a genetic variation in a genetic variation in the TMPRSS2, furin or
ACE2 gene can be used to predict a SARS-CoV-2 infected patient's
need for a ventilator or a respirator.
[0074] In certain embodiments, a genetic variation in the TMPRSS2,
furin or ACE2 gene is used as a predictor of anti-androgen
treatment response for viral respiratory infection. In certain
embodiments, a genetic variation in the TMPRSS2, furin or ACE2 gene
is used to guide selection of the appropriate anti-androgen
treatment for viral respiratory infection. In certain embodiments,
a genetic variation in the TMPRSS2, furin or ACE2 gene is used as a
predictor of anti-androgen treatment response for SARS-CoV-2. In
certain embodiments, a genetic variation in the TMPRSS2, furin or
ACE2 gene is used to guide selection of the appropriate
anti-androgen treatment for SARS-CoV-2. In certain embodiments, a
genetic variation in the TMPRSS2, furin or ACE2 gene is used to
guide dosage selection of the appropriate anti-androgen treatment
for SARS-CoV-2.
[0075] In certain embodiments, a genetic variation in the AR gene
and either the TMPRSS2, furin or ACE2 gene is used as a predictor
of anti-androgen treatment response for viral respiratory
infection. In certain embodiments, a genetic variation in the AR
gene and either the TMPRSS2, furin or ACE2 gene is used to guide
selection of the appropriate anti-androgen treatment for viral
respiratory infection. In certain embodiments, a genetic variation
in the AR gene and either the TMPRSS2, furin or ACE2 gene is used
as a predictor of anti-androgen treatment response for SARS-CoV-2.
In certain embodiments, a genetic variation in the AR gene and
either the TMPRSS2, furin or ACE2 gene is used to guide selection
of the appropriate anti-androgen treatment for SARS-CoV-2. In
certain embodiments, a genetic variation in the AR gene and either
the TMPRSS2, furin or ACE2 gene is used to guide dosage selection
of the appropriate anti-androgen treatment for SARS-CoV-2.
[0076] In certain embodiments, the number of CAG repeats in the
first exon of the AR gene is used as a genetic variant. In other
embodiments, the variants in the promoter region of the AR are used
as a genetic variant. In another embodiment, a shorter CAG repeat
(compared to normal) may predispose patients to more severe viral
respiratory infections. In another embodiment, a shorter CAG repeat
(compared to normal) may predispose patients to more severe
infection for COVID-19. In another embodiment, the length of the
CAG repeat determines anti-androgen dosing for the treatment of
viral respiratory infections.
[0077] In certain embodiments, the methods of treatment are used to
treat a patient with or a patient at risk of developing a
SARS-CoV-2 infection. In preferred embodiments, the method of
treatment for a patient or a patient at risk of developing a
SARS-CoV-2 infection comprises administering an anti-androgen to
the patient with an anti-thyroid medication, a TR inhibitor, a
TGF-.beta.i or a combination thereof.
[0078] In certain embodiments, the method of treatment for a
patient with or a patient at risk of developing a SARS-CoV-2
infection comprises administering an anti-androgen to the patient
with a furin inhibitor.
[0079] In certain embodiments, the method of treatment for a
patient with or a patient at risk of developing a SARS-CoV-2
infection comprises administering an anti-androgen to the patient
with a TGF-.beta.i.
[0080] In certain embodiments, the method of treatment for a
patient with or a patient at risk of developing a SARS-CoV-2
infection comprises administering an anti-androgen to the patient
with a TR antagonist.
[0081] In certain embodiments, the method of treatment for a
patient with or a patient at risk of developing a SARS-CoV-2
infection comprises administering an anti-androgen to the patient
with an anti-thyroid medication.
[0082] In certain embodiments, the method of treatment for a
patient with or a patient at risk of developing a SARS-CoV-2
infection comprises administering a TGF-.beta.i to the patient. In
certain embodiments, the method of treatment is administered to a
patient with or at risk of developing a SARS-CoV-2 infection,
wherein the patient also suffers from prostate cancer and wherein
the patient is administered a TGF-.beta.i.
[0083] In certain embodiments, the method of treatment for a
patient with or a patient at risk of developing a SARS-CoV-2
infection comprises administering a TR antagonist to the patient.
In certain embodiments, the method of treatment is administered to
a patient with or at risk of developing a SARS-CoV-2 infection,
wherein the patient also suffers from prostate cancer and wherein
the patient is administered a TR antagonist.
[0084] In certain embodiments, the method of treatment for a
patient with or a patient at risk of developing a SARS-CoV-2
infection comprises administering an anti-thyroid medication (i.e.,
a medication that lowers T.sub.3 or T.sub.4) to the patient. In
certain embodiments, the method of treatment is administered to a
patient with or at risk of developing a SARS-CoV-2 infection,
wherein the patient also suffers from prostate cancer and wherein
the patient is administered an anti-thyroid medication.
[0085] In certain embodiments, the method of treatment for a
patient with or a patient at risk of developing a SARS-CoV-2
infection comprises administering a TGF-.beta.i and an RXR
antagonist to the patient.
[0086] In certain embodiments, the method of treatment for a
patient with or a patient at risk of developing a SARS-CoV-2
infection comprises administering a TR antagonist and an RXR
antagonist to the patient.
[0087] In certain embodiments, the method of treatment for a
patient with or a patient at risk of developing a SARS-CoV-2
infection comprises administering an anti-thyroid medication and an
RXR antagonist to the patient.
[0088] In certain embodiments, the method of treatment for a
patient with or a patient at risk of developing a SARS-CoV-2
infection comprises administering an RXR antagonist.
[0089] In certain embodiments, the method of treatment for a
patient with or a patient at risk of developing a SARS-CoV-2
infection comprises administering an agent that counters the effect
of androgens such as sex hormone-binding globulin (SHBG)
stimulators. In preferred embodiments, the method further comprises
administering sex hormone-binding globulin (SHBG) stimulators with
an anti-thyroid medication, a TR inhibitor, a TGF-.beta.i or any
combination thereof. The agents or components can be present in
percent amounts ranging from 0% to 100%.
[0090] In certain embodiments, the method of treatment for a
patient with or a patient at risk of developing a SARS-CoV-2
infection comprises administering antigonadotropins. In preferred
embodiments, the method further comprises administering
antigonadotropins with an anti-thyroid medication, a TR antagonist,
a TGF-.beta.i or any combination thereof. As explained herein, the
method of treatment can involve administration of a composition
that includes an antigonadotropin as an ingredient of the
composition. The antigonadotropin can be present in percent amounts
ranging from 0% to 100%. The word antigonadotropin includes
Gonadotropin-releasing hormone antagonists (GnRH antagonists). Some
GnRH antagonist are: Elagolix, Cetrorelix, Relugolix, Degarelix
[0091] In certain embodiments, the method of treatment for a
patient with or a patient at risk of developing a SARS-CoV-2
infection comprises administering a mineralocorticoid or a
glucocorticoid (anticorticotropins) that suppresses androgen
production in the adrenal gland. In preferred embodiments, the
method further comprises administering a mineralocorticoid or a
glucocorticoid with an anti-thyroid medication, a TR antagonist, a
TGF-.beta.i or any combination thereof. As explained herein, the
method of treatment can involve administration of a composition
that includes a mineralocorticoid and/or a glucocorticoid as an
ingredient of the composition. The mineralocorticoid and/or a
glucocorticoid can be present in percent amounts ranging from 0% to
100%.
[0092] In certain embodiments, the method of treatment for a
patient with or a patient at risk of developing a SARS-CoV-2
infection comprises administering an insulin sensitizing medication
such as metformin. In preferred embodiments, the method further
comprises administering an insulin sensitizing medication with an
anti-thyroid medication, a TR antagonist, a TGF-.beta.i or any
combination thereof. As explained herein, the method of treatment
can involve administration of a composition that includes an
insulin sensitizing medication as an ingredient of the composition.
The insulin sensitizing medication can be present in percent
amounts ranging from 0% to 100%.
[0093] In certain embodiments, the method of treatment for a
patient with or a patient at risk of developing a SARS-CoV-2
infection comprises administering a vaccine or immunogens against
androstenedione to reduce the level of testosterone and estrogen in
the patient, wherein the immunogens include ovandrotone albumin,
androstenedione albumin or a combination thereof. In preferred
embodiments the method further comprises administering a vaccine or
immunogen with an anti-thyroid medication, a TR antagonist, a
TGF-.beta.i or any combination thereof. As explained herein, the
method of treatment can involve administration of a composition
that includes said vaccine or immunogen as an ingredient of the
composition. The vaccine or immunogen can be present in percent
amounts ranging from 0% to 100%.
[0094] In certain embodiments, the method of treatment for a
patient with or a patient at risk of developing a SARS-CoV-2
infection comprises administering an anti-androgen, wherein the
anti-androgen is used as a prophylactic treatment for a viral
respiratory infection with an anti-thyroid medication, a TR
antagonist a TGF-.beta.i or a combination thereof.
[0095] In certain embodiments, the methods of treatment for a
patient with or a patient at risk of developing a viral infection
comprise administering an anti-androgen, wherein the anti-androgen
is used as a prophylactic treatment for a SARS-CoV-2 infection with
an anti-thyroid medication, a TR antagonist, a TGF-.beta.i or a
combination thereof.
[0096] In certain embodiments, the methods of treatment for a
patient with or a patient at risk of developing a viral infection
comprises RNA interference therapy. RNA interference (RNAi) is a
biological process in which RNA molecules inhibit gene expression
or translation, by neutralizing targeted mRNA molecules. RNAi
selectively knocks down target genes. RNAi can also mean other
names, including co-suppression, post-transcriptional gene
silencing (PTGS), siRNA, quelling, or gene knock-down. In one
embodiment of the present invention RNAi is used to knock down the
AR. In one embodiment of the present invention RNAi is used to
knock down the AR in type II pneumocytes. In one embodiment of the
present invention RNAi is used to knock down the TMPRSS2. In one
embodiment of the present invention RNAi is used to knock down the
TMPRSS2 in type II pneumocytes. In another embodiment, RNAi is used
to knock down ACE2. In one embodiment the RNAi treatment is inhaled
in another embodiment the RNAi treatment is administered (e.g., via
injection). In one embodiment the RNAI treatment is used to treat
upper respiratory disease or any viral infection disclosed herein
(e.g., coronavirus, influenza, influenza A, influenza B,
SARS-CoV-1, SARS-CoV-2, MERS-CoV and rhinoviruses). In one
embodiment, a small-interfering RNA (siRNA) directed against
androgen receptor (AR) is administered. In one embodiment, a
small-interfering RNA (siRNA) directed against TMPRSS2 is
administered. In one embodiment, a small-interfering RNA (siRNA)
directed against ACE2 is administered. Upon administration of
anti-AR siRNA, for example, SXL01, the siRNAs bind to AR mRNAs,
which may result in the inhibition of translation of the AR protein
and by preventing AR expression, AR-mediated signaling is
decreased, which leads to inhibition of TMPRSS2 or ACE2. In one
embodiment, anti-AR siRNA, for example, SXL01, is administered
(e.g., inhaled) to treat any viral infection disclosed herein
(e.g., coronavirus, influenza, influenza A, influenza B,
SARS-CoV-1, SARS-CoV-2, MERS-CoV and rhinoviruses). In one
embodiment, anti-AR siRNA, for example, SXL01, is inhaled to treat
SARS-CoV-2.
[0097] In certain embodiments, use of an anti-androgen for
treatment can mean a treatment that promotes the production of
estrogen. In another embodiment use of estrogen is the treatment.
Examples of drugs that promote the production of estrogen include,
but are not limited to, estrogen, estradiol, Premarin (conjugated
estrogens), medroxyprogesterone acetate, Provera,
medroxyprogesterone, Vivelle-Dot (estradiol patch).
[0098] In certain embodiments, use of degarelix can be used in the
method of treatment and/or prophylactic treatment. For instance,
degarelix can be administered for a predetermined period of time
(e.g., 1 week, 2, weeks, 1 month, 2 months, etc.). The
administration of degarelix can be in single or multiple doses per
day over the predetermined time period. For instance, the
administration of degarelix can involve a 240 mg dose comprising a
first injection of 120 mg and a second injection of 120 mg every 24
hours. This first and second injection routine can be administered
for 1 month. The administration of degarelix can be for treatment
and/or prophylactic use before, during, and/or after a patient is
first diagnosed with the viral respiratory infection and/or before,
during, and/or after a patient is hospitalized due to the viral
respiratory infection.
[0099] In certain embodiments, an anti-androgen is used as a
prophylactic treatment for viral respiratory infection.
[0100] In certain embodiments, an anti-androgen is prescribed to a
patient believed to be infected with SARS-CoV-2 as a prophylactic
for viral respiratory infection, i.e. severe SARS-CoV-2 disease. In
another embodiment an anti-androgen is prescribed to a patient to
prevent COVID disease symptoms from developing. In certain
embodiments, apalutamide is prescribed to patients who are
diagnosed with SARS-CoV-2 infection but have yet to demonstrate
symptoms. It is specifically envisioned that hospitalization rates
of populations given an anti-androgen or a placebo at early
diagnosis SARS-CoV-2 can be used as a clinical endpoint for
determining the efficacy of an anti-androgen for preventing the
progression of SARS-CoV-2 disease. It is specifically envisioned
that hospitalization rates of populations given apalutamide or a
placebo at early diagnosis SARS-CoV-2 can be used as a clinical
endpoint for determining the efficacy of apalutamide for preventing
the progression of SARS-CoV-2 disease.
[0101] In certain embodiments, dutasteride
(Bis(trifluoromethyl)phenyl]-3-oxo-4-aza-5a-androst-1-ene-17.beta.-carbox-
amide) is used as treatment for SARS-CoV-2 . In certain
embodiments, dutasteride can be administered orally. In certain
embodiments, the dutasteride is used as a prophylactic treatment
for SARS-CoV-2. The treatment can involve administration of
dutasteride ranging from 0.1 mg/day to 1.0 mg/day. The treatment
can involve administration of dutasteride before being exposed to
the viral respiratory infection. This can include administration of
dutasteride at any time before being exposed to the viral
respiratory infection up to and including 30 days prior to being
exposed.
[0102] In certain embodiments, a genetic variation in the AR gene
is used as a predictor of anti-androgen treatment response for
viral respiratory infection. In certain embodiments, a genetic
variation in the AR gene is used to guide selection of the
appropriate anti-androgen treatment for viral respiratory
infection. In certain embodiments, a genetic variation in the AR
gene is used as a predictor of anti-androgen treatment response for
SARS-CoV-2. In certain embodiments, a genetic variation in the AR
gene is used to guide selection of the appropriate anti-androgen
treatment for SARS-CoV-2. In certain embodiments, a genetic
variation in the AR gene is used to guide dosage selection of the
appropriate anti-androgen treatment for SARS-CoV-2.
[0103] The various treatment methods for patients with or a patient
at risk of developing a SARS-CoV-2 infection described above may
also be used to treat patients with or at risk of developing other
viral respiratory infections, wherein the other viral infections
include, but are not limited to, influenza, influenza A, influenza
B, SARS-CoV-1, MERS-CoV and rhinoviruses.
[0104] The components of the treatment methods can be administered
by inhalation, orally, nasally, or by injection. In preferred
embodiments, the treatments can be administered by vaping. In other
embodiments, the treatments can be administered systemically via
intravenous injection, or subcutaneous injection. In other
embodiments, the treatments are administered topically.
[0105] In an exemplary embodiment, the composition administered to
a patient having or suspected of having a viral respiratory
infection includes any one or combination of: an androgen receptor
antagonists or anti-androgen; an androgen synthesis inhibitor; an
agent that counters the effect of androgens; a globulin (SHBG)
stimulator; an antigonadotropin; a mineralocorticoid to suppress
androgen production in the adrenal gland; a glucocorticoid to
suppress androgen production in the adrenal gland; an insulin
sensitizing medication; and a vaccine or an immunogen against
androstenedione that reduces the level of testosterone or increases
estrogen levels.
[0106] In some embodiments, the composition is used as a treatment
of the viral respiratory infection, a therapy for the viral
respiratory infection, a prophylactic for the viral respiratory
infection, a preventive measure for contracting the viral
respiratory infection, a diagnosis of a type of viral respiratory
infection, a prediction for respiratory disease severity of the
viral respiratory infection, a prediction for determining an
effective treatment or prophylactic composition, and/or a
prediction for determining an effective administration dosage of
the composition for use as a treatment or prophylactic.
[0107] In one embodiment of the present invention, a composition
including an anti-androgen is used to treat patients with any one
or combination of benign prostatic hyperplasia (BPH), prostate
cancer, castration-resistant prostate cancer, metastatic
castration-sensitive prostate cancer, or non-metastatic
castration-resistant prostate cancer. In some embodiments, the
composition including an anti-androgen can be used to treat
patients with any viral infection disclosed herein (e.g.,
coronavirus, influenza, influenza A, influenza B, SARS-CoV-1,
SARS-CoV-2, MERS-CoV and rhinoviruses) and/or any one or
combination of benign prostatic hyperplasia (BPH), prostate cancer,
castration-resistant prostate cancer, metastatic
castration-sensitive prostate cancer, or non-metastatic
castration-resistant prostate cancer.
[0108] In some embodiments, the composition is used to treat a
patient with or a patient at risk of developing a SARS-CoV-2
infection comprising an anti-androgen with an anti-thyroid
medication, a TR antagonist, a TGF-.beta.i or a combination
thereof, wherein the composition may be formulated with a carrier
or delivery vehicle. In preferred embodiments, the composition is
formulated with a carrier or delivery vehicle optimized for
delivery to the lung.
[0109] In an exemplary embodiment, the composition is administered
to a subject having or suspected of having a viral respiratory
infection comprises dutasteride, wherein the composition is
formulated for use as a treatment of the viral respiratory
infection, a therapy for the viral respiratory infection, a
prophylactic for the viral respiratory infection, a preventive
measure for contracting the viral respiratory infection, a
diagnosis of a type of viral respiratory infection, a prediction
for respiratory disease severity of the viral respiratory
infection, a prediction for determining an effective treatment or
prophylactic composition, and/or a prediction for determining an
effective administration dosage of the composition for use as a
treatment or prophylactic.
[0110] In some embodiments, the composition is formulated to alter
androgen receptor function and subsequently downstream genes under
regulatory control of the androgen receptor.
[0111] In some embodiments, the composition is formulated to block
the production of proteins in the lung so as to alter viral entry
into cells or to bolster host immunity.
[0112] In some embodiments, the administration of the composition
involves any one or combination of topical application to the skin,
nasal application, oral application, via injection, via inhalation,
or ocular application.
[0113] In some embodiments, the composition is formulated to
facilitate administration of the composition topically to the skin,
nasally, sub-lingually orally, by injection, via inhalation, or
ocular application.
[0114] In some embodiments the composition is further formulated
for use as a treatment for prostate cancer, castration-resistant
prostate cancer, metastatic castration-sensitive prostate cancer,
non-metastatic castration-resistant prostate cancer and/or benign
prostatic hyperplasia.
[0115] In some embodiments, the composition is used as a treatment
for prostate cancer, castration-resistant prostate cancer,
metastatic castration-sensitive prostate cancer, non-metastatic
castration-resistant prostate cancer and/or benign prostatic
hyperplasia.
[0116] In some embodiments, the composition comprises an
anti-androgen.
[0117] In other embodiments, the composition comprises an
anti-thyroid medication.
[0118] In some embodiments, the composition comprises a
TGF-.beta.i.
[0119] In other embodiments, the composition comprises a TR
antagonist.
[0120] In some embodiments, the composition comprises a furin
inhibitor.
[0121] In some embodiments, the composition further comprises a RXR
antagonist.
[0122] In some embodiments, the composition further comprises
agents that counter the effect of androgens such as sex
hormone-binding globulin (SHBG) stimulators.
[0123] In some embodiments, the composition further comprises an
antigonadotropin.
[0124] In some embodiments, the composition further comprises a
vaccine or immunogens against androstenedione.
[0125] Any of the compositions disclosed herein can include other
ingredients (e.g., carrier agents) to facilitate use or
administration of the composition via injection, oral
administration, nasal administration, topological administration,
etc. For instance, a composition can include a carrier or delivery
vehicle optimized for delivery of the composition to the lung. As
another example, a composition can be formulated to be released
using several different formulations or release methods including
time release, creams, ointments, sprays, capsules, or other release
methods. Capsules or vehicles that encapsulate the composition can
include, but are not limited to, liposomes, non-ionic liposomes,
niosomes, novasome I, erythromycin-Zn complex, microspheres,
nanoparticles, solid lipid nanoparticles, and nanoemulsions. In
some embodiments, this can include a gel or foam.
[0126] In preferred embodiments, the composition comprises an
anti-androgen with an anti-thyroid medication, a TR antagonist, a
TGF-.beta.i or a combination thereof, wherein the composition is
formulated to be administered orally.
[0127] In preferred embodiments, the composition comprises an
anti-androgen with an anti-thyroid medication, a TR antagonist, a
TGF-.beta.i or a combination thereof, wherein the composition is
formulated to be administered nasally.
[0128] In preferred embodiments, the composition comprises an
anti-androgen with an anti-thyroid medication, a TR antagonist, a
TGF-.beta.i or a combination thereof, wherein the composition is
formulated to be administered by inhalation.
[0129] In preferred embodiments, the composition comprises an
anti-androgen with an anti-thyroid medication, a TR antagonist, a
TGF-.beta.i or a combination thereof, wherein the composition is
formulated to be administered topically via the skin.
[0130] In preferred embodiments, the composition comprises an
anti-androgen with an anti-thyroid medication, a TR antagonist, a
TGF-.beta.i or a combination thereof, wherein the composition is
formulated to be administered intramuscularly or intravenously.
[0131] Any of the aforementioned compositions may be administered
routinely, e.g., once daily, twice daily, every other day, once a
week.
[0132] In certain embodiments, the uses (e.g., treatment, therapy,
prophylactic treatment, prevention, diagnosis, prediction,
selection of a drug, selection of a dosage, etc.) of the
composition(s) disclosed herein can be administered by inhalation,
oral, nasal, injection, topological application, ocular
application, etc. In certain embodiments, the uses of the
composition can involve being administered by nebulization or
vaping. In certain embodiments, the uses can involve being
administered systemically in oral, intravenous injection,
subcutaneous injection. In certain embodiments, the uses can
involve being administered topically.
[0133] In one embodiment of the present invention a therapy
involving the use of a composition is delivered as a topical ocular
solution, i.e., eye drop, spray, solution, lotion, gel,
ointment.
[0134] In another embodiment of the present invention, a topically
applied ocular anti-androgen solution, is used as a prophylactic
treatment against any viral infection disclosed herein (e.g.,
coronavirus, influenza, influenza A, influenza B, SARS-CoV-1,
SARS-CoV-2, MERS-CoV and rhinoviruses).
[0135] In another embodiment of the present invention, a topically
applied ocular anti-androgen solution, is used as a prophylactic
treatment against any viral infection disclosed herein (e.g.,
coronavirus, influenza, influenza A, influenza B, SARS-CoV-1,
SARS-CoV-2, MERS-CoV and rhinoviruses). The anti-androgen can be
applied every 1 hr, 2 hrs, 4 hrs, 8 hrs, 12 hrs, once per day,
twice daily, three times a day or every other day.
[0136] In another embodiment of the present invention, a topically
applied ocular anti-androgen solution, is used as a treatment
against any viral infection disclosed herein (e.g., coronavirus,
influenza, influenza A, influenza B, SARS-CoV-1, SARS-CoV-2,
MERS-CoV and rhinoviruses).
[0137] In another embodiment of the present invention, a topically
applied ocular anti-androgen solution, is used as a treatment
against any viral infection disclosed herein (e.g., coronavirus,
influenza, influenza A, influenza B, SARS-CoV-1, SARS-CoV-2,
MERS-CoV and rhinoviruses) and benign prostatic hyperplasia and/or
androgenetic alopecia.
[0138] In another embodiment of the present invention, a topically
applied ocular anti-androgen solution, is used as a treatment
against any viral infection disclosed herein (e.g., coronavirus,
influenza, influenza A, influenza B, SARS-CoV-1, SARS-CoV-2,
MERS-CoV and rhinoviruses) and hirsutism.
[0139] In another embodiment of the present invention, a topically
applied ocular anti-androgen solution, is used as a treatment
against any viral infection disclosed herein (e.g., coronavirus,
influenza, influenza A, influenza B, SARS-CoV-1, SARS-CoV-2,
MERS-CoV and rhinoviruses) and polycystic ovary syndrome.
[0140] It should be noted that any of the ingredients disclosed
herein can be used in combination with any one or combination of
other ingredients (e.g., an anti-androgen can be used with an agent
that counters the effect of androgens, an antigonadotropin can be
used with a mineralocorticoid, an insulin sensitizing medication
can be used with an anti-androgen and a mineralocorticoid, etc.).
Thus, it should be understood that a reference to a composition can
(to the extent it is not impossible to do so) include a single
composition, a combination of compositions, and/or a combination of
a composition with another ingredient.
[0141] It should also be understood that a reference to a use of a
composition can (to the extent it is not impossible to do so)
involve use of any one or combination of uses (e.g., treatment,
therapy, prophylactic treatment, prevention, diagnosis, prediction,
selection of a drug, selection of a dosage, etc.).
[0142] It should also be understood that a reference to an
administration of a composition can (to the extent it is not
impossible to do so) involve any one or combination of
administrations (e.g., inhalation, oral, nasal, injection,
topological application, ocular application, etc.).
[0143] In some embodiments, provided herein is an anti-androgen
formulated with a carrier or delivery vehicle optimized for
delivery of the anti-androgen treatment to the lung. An
anti-androgen can be released using several different formulations
or release methods including time release, creams, ointments,
sprays, capsules, or other release methods. Capsules or vehicles
that encapsulate the anti-androgen can include, but are not limited
to, liposomes, non-ionic liposomes, niosomes, novasome I,
erythromycin-Zn complex, microspheres, nanoparticles, solid lipid
nanoparticles, and nanoemulsions. In some embodiments, this can
include a gel or foam.
[0144] In some embodiments, the anti-androgen is combined with an
anti-inflammatory agent, such as an NSAID.
[0145] In some embodiments, the anti-androgen is combined with an
anti-bacterial agent, such as an azithromycin.
[0146] In some embodiments, the anti-androgen is combined with
aspartame.
[0147] In some embodiments, the anti-androgen treatment is
administered orally.
[0148] In other embodiments, the anti-androgen treatment is
administered nasally.
[0149] In other embodiments, the anti-androgen treatment is
administered by inhalation.
[0150] In other embodiments, the anti-androgen treatment is
administered topically via the skin.
[0151] In other embodiments, the anti-androgen treatment is
administered intramuscularly or intravenously.
[0152] Any of the anti-androgens, thyroid inhibitors, or other
ingredients disclosed herein can be present in compositions used
for treating, preventing, and diagnosing viral infection in amounts
ranging from 1-500 mgs.
[0153] Any of the aforementioned compositions can be used
routinely, e.g., once daily, twice daily, every other day, once a
week.
[0154] In certain embodiments of the present invention, a kit
containing a DNA sample collection tool is envisioned. The genetic
sample can be obtained by buccal swab, saliva, blood, or tissue
samples. The genetic sample can also be obtained from a plucked
hair sample. For example, a kit is disclosed for detecting COVID-19
androgen sensitivity; the kit is an in-vitro diagnostic medical
device intended to identify polymorphisms in the androgen receptor
gene. The kit includes a collection device (buccal swab) and a DNA
diagnostic assay (laboratory based). DNA samples are collected from
a patient and mailed to a laboratory for processing.
[0155] In an exemplary embodiment, the present invention comprises
a kit that includes a deoxyribonucleic acid (DNA) sample collection
unit configured to obtain a genetic sample via buccal swab, saliva
sample, blood sample, tissue sample, and/or hair sample; a viral
respiratory infection sensitivity unit configured to identify
polymorphisms in the androgen receptor gene; and a DNA diagnostic
assay.
[0156] As noted herein, any of the compositions disclosed herein
can be used as a treatment for a viral respiratory infection and/or
a prophylactic for a viral respiratory infection. The viral
respiratory infection can include any one or combination of
coronavirus, influenza, influenza A, influenza B, SARS-CoV-1,
SARS-CoV-2, MERS-CoV and rhinoviruses. Any of the compositions can
be used as a treatment and/or a prophylactic before, during, and/or
after a patient is first diagnosed with the viral respiratory
infection and/or before, during, and/or after a patient is
hospitalized due to the viral respiratory infection.
[0157] As described herein, efficacy of treatment to treat or
prevent viral respiratory infection can be categorized via patient
conditions related to: being discharged from the hospital, being
hospitalized, being admitted to and intensive care unit (ICU), or
dying as a result of the viral respiratory infection. Efficacy may
also be determined by the hospitalization rates of populations
given an anti-androgen or a placebo at early diagnosis of
COVID-19.
[0158] The various methods, compositions and techniques described
herein provide a number of ways to carry out the invention. Of
course, it is to be understood that not necessarily all objectives
or advantages described can be achieved in accordance with any
particular embodiment described herein. Thus, for example, those
skilled in the art will recognize that the methods and compositions
can be performed in a manner that achieves or optimizes one
advantage or group of advantages as taught herein without
necessarily achieving other objectives or advantages as taught or
suggested herein. A variety of alternatives are mentioned herein.
It is to be understood that some embodiments specifically include
one, another, or several features, while others specifically
exclude one, another, or several features, while still others
mitigate a particular feature by inclusion of one, another, or
several advantageous features.
[0159] Furthermore, the skilled artisan will recognize the
applicability of various features from different embodiments.
Similarly, the various elements, features and steps discussed
herein, as well as other known equivalents for each such element,
feature or step, can be employed in various combinations by one of
ordinary skill in this art to perform methods in accordance with
the principles described herein. Among the various elements,
features, and steps some will be specifically included and others
specifically excluded in diverse embodiments.
[0160] Although the application has been disclosed in the context
of certain embodiments and examples, it will be understood by those
skilled in the art that the embodiments of the application extend
beyond the specifically disclosed embodiments to other alternative
embodiments and/or uses and modifications and equivalents
thereof.
[0161] The recitation of ranges of values herein is merely intended
to serve as a shorthand method of referring individually to each
separate value falling within the range (the range including the
end points of the range). Unless otherwise indicated herein, each
individual value is incorporated into the specification as if it
were individually recited herein. All methods described herein can
be performed in any suitable order unless otherwise indicated
herein or otherwise clearly contradicted by context. The use of any
and all examples, or exemplary language (for example, "such as")
provided with respect to certain embodiments herein is intended
merely to better illuminate the application and does not pose a
limitation on the scope of the application otherwise claimed. No
language in the specification should be construed as indicating any
non-claimed element essential to the practice of the
application.
[0162] Certain embodiments of this application are described
herein. Variations on those embodiments will become apparent to
those of ordinary skill in the art upon reading the foregoing
description. It is contemplated that skilled artisans can employ
such variations as appropriate, and the application can be
practiced otherwise than specifically described herein.
Accordingly, many embodiments of this application include all
modifications and equivalents of the subject matter recited in the
claims appended hereto as permitted by applicable law. Moreover,
any combination of the herein-described elements in all possible
variations thereof is encompassed by the application unless
otherwise indicated herein or otherwise clearly contradicted by
context.
[0163] All patents, patent applications, publications of patent
applications, and other material, such as articles, books,
specifications, publications, documents, things, and/or the like,
referenced herein are hereby incorporated herein by this reference
in their entirety for all purposes, excepting any prosecution file
history associated with same, any of same that is inconsistent with
or in conflict with the present document, or any of same that can
have a limiting affect as to the broadest scope of the claims now
or later associated with the present document. By way of example,
should there be any inconsistency or conflict between the
descriptions, definitions, and/or the use of terms associated with
any of the incorporated material and that associated with the
present document, the description, definition, and/or the use of
the term in the present document shall prevail.
EXAMPLES
Example 1
[0164] In-vitro Diagnostic Test to Predict COVID-19 Mortality and
Disease Severity.
[0165] Investigational Device
[0166] Device Name: COVID-19 Androgen Sensitivity Test (CoVAST)
[0167] Device Background:
[0168] The COVID-19 Androgen Sensitivity Test is a non-invasive
In-Vitro Diagnostic device that utilizes qualitative DNA
genotyping. The COVID-19 Androgen Sensitivity Test requires a
health care professional to collect a DNA sample using an FDA
cleared DNA sample collection kit. The sample collection kit is an
ORAcollectDx OCD-100A device manufactured by DNA Genotek, Inc
(previously cleared under K152464). The COVID-19 Androgen
Sensitivity Test is intended to be performed at a Clinical
Laboratory Improvement Amendments (CLIA) certified laboratory. The
reagents used in performing the COVID-19 Androgen Sensitivity Test
are manufactured in a GMP facility. COVID-19 Androgen Sensitivity
Test reports the results of the DNA genotyping.
[0169] Trial Conduct
[0170] The following describes how the methods and compositions
disclosed herein may be implemented.
[0171] It is contemplated for a trial study to be conducted in
compliance with the protocol approved by the Institutional Review
Board (IRB), and according to Good Clinical Practice standards. The
CoVAST Test used in this study can be manufactured according to GMP
and the specimens are analyzed at a CLIA laboratory. It is
contemplated that no deviation from the protocol will be
implemented without the prior review and approval of the IRB except
where it may be necessary to eliminate an immediate hazard to a
research subject. In such case, the deviation should reported to
the IRB as soon as possible.
[0172] Population
[0173] In an exemplary implementation, the trial study can be a
multi-center study. For instance, the study may be conducted in at
least 2 countries--Spain and the US. It is contemplated for the
protocol disclosed herein to be followed without deviation in each
country. It is contemplated for there to be a minimum of 2 separate
sites and 2 separate PIs (if not deviating from the protocol then
there will be a minimum of 2 separate sites and 2 separate PIs). In
the US, the study should be approved by an IRB and in the other
countries by the appropriate Ethics Committees (if not deviating
from the protocol then the study will be approved by an IRB in the
US and by the appropriate Ethics Committees in other
countries).
[0174] The population for this study can be subjects recruited from
each site (e.g., hospital) (if not deviating from the protocol then
the subjects will be recruited from each site (hospital)). Subjects
can be males requesting a SARS-CoV-2 test following respiratory
symptoms (if not deviating from the protocol then the subjects will
be males requesting a SARS-CoV-2 test following respiratory
symptoms). Subjects can be males 18 years and older of any
ethnicity (if not deviating from the protocol then the subjects
will be males 18 years and older of any ethnicity).
[0175] Trial Objectives
[0176] The primary purpose of the study can be to determine the
predictive value of the CoVAST Test (if not deviating from the
protocol then the primary purpose of the study will be to determine
the predictive value of the CoVAST Test). The predictive value can
be calculated based on the positive percent agreement and negative
percent agreement of the CoVAST Test (if not deviating from the
protocol then the predictive value will be calculated based on the
positive percent agreement and negative percent agreement of the
CoVAST Test). The results can be presented in 2.times.2 tables (if
not deviating from the protocol then the results will be presented
in 2.times.2 tables).
[0177] Trial Design
[0178] Primary Study Endpoints/Secondary Endpoints
[0179] Primary Outcome Measures:
[0180] Severity of Disease (discharged, hospitalization, admission
to intensive care unit [ICU], or death) [Baseline, Day 7, Day 14,
Day 21, Day 28]
[0181] Study Design/Type
[0182] The study can be (or will be) a prospective cross-sectional
observational study. The study can (or will) have 2 arms:
[0183] Arm 1: Males first tested positive for SARS-CoV-2 at the
site (hospital) with CAG length <24 (based on the CoVAST
Test)
[0184] Arm 2: Males first tested positive for SARS-CoV-2 at the
site (hospital) with CAG length >=24 (based on the CoVAST
Test)
[0185] Study Environment:
[0186] This can be (or will be) a multi-center study to be
conducted in at least 2 countries--Spain and the US. Again, it is
contemplated for the following protocol to be followed without
deviation. The protocol can (or will) be followed in each country.
There can (or will) be a minimum of 2 separate sites and 2 separate
PIs. In the US, the study can (or will) be approved by an IRB and
in the other countries by the appropriate Ethics Committees.
[0187] The study can (or will) be conducted at the site(s) listed
herein i.e., the PI's hospital. All data collection including
sample collection can (or will) be performed at the site.
[0188] Study Design:
[0189] Study Phase Ia: Screening (first site visit)
[0190] The PI can (or will) screen each potential subject for the
inclusion and exclusion criteria.
[0191] Study Phase Ib: Enrollment (first site visit)
[0192] Each qualified subject can (or will) complete and sign the
informed consent form.
[0193] Each subject can (or will) be assigned a subject study
number.
[0194] Study Phase Ic: Sample Collection (first site visit)
[0195] For each subject, the PI can (or will) collect the saliva
DNA sample using the CoVAST Test Sample Collection Kit. The sample
collection can (or will) be performed in accordance with IFU for
the collection kit.
[0196] The sample collection kit can (or will) be sent to the
hospital laboratory.
[0197] All information can (or will) be recorded in the appropriate
CRFs.
[0198] Study Phase Id: Hospital Laboratory (first site visit)
[0199] The hospital laboratory can (or will) extract the DNA from
the sample collection kit utilizing the DNA extraction kit provided
with the CoVAST Test kit.
[0200] The laboratory can (or will) ship the extracted DNA to the
CLIA laboratory.
[0201] Study Phase II: Primary Outcome (Days: 0, 7, 14, 21, 28):
[0202] 1. For each subject, the PI or PI assistant can (or will)
record the subject's severity of disease. [0203] 2. All information
can (or will) be recorded in the appropriate CRF.
[0204] Inclusion Criteria [0205] 1. Male over the age of 18 [0206]
2. First time present at the site [0207] 3. Laboratory confirmed
SARS-CoV-2 infection [0208] 4. Able to give informed consent
[0209] Exclusion Criteria [0210] 1. Unable to give informed consent
[0211] 2. Diagnosed with an additional respiratory co-infection
[0212] 3. XXY male
[0213] Assessment of Efficacy
[0214] Efficacy Parameters
[0215] Severity of Disease
[0216] Clinical assessment of disease severity can (or will) be
made by attending physician and reported to the PI or PI assistant.
Disease severity can (or will) be categorized as: discharged,
hospitalization, admission to intensive care unit [ICU] or
death.
[0217] Method and Timing
[0218] All assessments can (or will) be recorded on paper forms
(CRFs) and stored with each subject's clinical study record.
[0219] The timing to complete the assessment of efficacy can (or
will) be at Baseline, Day 7, Day 14, Day 21 and Day 28. After
baseline assessment, the additional assessment can be performed by
computerized hospital record search by the PI or PI assistant.
[0220] Primary Outcome Measures:
[0221] 1. COVID Ordinal Outcomes Scale on Day 15 [Time Frame:
assessed on study day 15]. The COVID Ordinal Scale for all patients
can (or will) be determined on study day 15.
[0222] COVID Ordinal Scale can (or will) be defined as: [0223] a.
Death [0224] b. Hospitalized on invasive mechanical ventilation or
ECMO (extracorporeal membrane oxygenation) [0225] c. Hospitalized
on non-invasive ventilation or high flow nasal cannula [0226] d.
Hospitalized on supplemental oxygen [0227] e. Hospitalized not on
supplemental oxygen [0228] f. Not hospitalized with limitation in
activity (continued symptoms) [0229] g. Not hospitalized without
limitation in activity (no symptoms)
[0230] Secondary Outcome Measures:
[0231] 1. COVID Ordinal Outcomes Scale on Study Day 3 [Time Frame:
assessed on study day 3]. The COVID Ordinal Scale for all patients
can (or will) be determined on study day 3.
[0232] 2. COVID Ordinal Outcomes Scale on Study Day 8 [Time Frame:
assessed on study day 8]. COVID Ordinal Scale can (or will) be
determined on study day 8.
[0233] 3. Hospital-free days to Day 28 [Time Frame: 28 days]. This
is defined as 28 days minus the number of days from randomization
to discharge home. If a patient has not been discharged home prior
to day 28 or dies prior to day 28, hospital free days will be
zero.
Example 2
[0234] A double-blinded placebo controlled study was conducted on
97 male and female health care workers working at two hospital
emergency room departments.
[0235] At baseline, all subjects were tested negative for
SARS-CoV-2 infection. 50 subjects were given a daily dose of 10
mg/Kg/day oral cannabidiol. The reminder 47 subjects were given a
placebo oral pill. At day 28 all subjects were tested for
SARS-CoV-2 infection. Among the subjects that were administered the
cannabidiol, 2 subjects were tested positive for SARS-CoV-2. Among
the subjects administered the placebo, 9 subjects were tested
positive for SARS-CoV-2.
Example 3
[0236] A double-blinded placebo controlled study was conducted on
28 male health care workers working at two hospital emergency room
departments.
[0237] At baseline, all subjects were tested and found to be
negative for SARS-CoV-2 infection. 18 subjects were given a daily
dose of 750 mg/day oral flutamide. The reminder 10 subjects were
given a placebo oral pill. At day 28 all subjects were tested again
for SARS-CoV-2 infection. Among the subjects that were administered
oral flutamide, 1 subject tested positive for SARS-CoV-2. Among the
subjects administered the placebo, 3 subjects tested positive for
SARS-CoV-2.
Example 4
[0238] A double-blinded placebo controlled study was conducted on
30 hospitalized male patients with average age of 61 years old.
[0239] All subjects were tested and found to be positive for
SARS-CoV-2 infection. 15 subjects were assigned to enzalutamide
treatment 160 mg qd. The other 15 subjects received standard
treatment. Following 15 days of treatment, 20% of the subjects in
the enzalutamide survived while 7% of the control group
survived.
Example 5
[0240] A double-blinded placebo controlled study was conducted on
121 male health care workers working at two hospital emergency room
departments.
[0241] At baseline, all subjects were tested and found to be
negative for SARS-CoV-2 infection. 68 subjects were given a daily
dose of 0.25 mg/day of oral dutasteride
(Bis(trifluoromethyl)phenyl]-3-oxo-4-aza-5.alpha.-androst-1-ene-17.beta.--
carboxamide). The reminder 53 subjects were given a placebo oral
pill. At day 28 all subjects were tested again for SARS-CoV-2
infection. Among the subjects that were administered oral
dutasteride, 3 (4.4%) subject tested positive for SARS-CoV-2. Among
the subjects administered the placebo, 9 (17%) subjects tested
positive for SARS-CoV-2.
Example 6
[0242] A double-blinded placebo controlled study was conducted on
400 male patients with average age of 43.2 years old.
[0243] Patients were diagnosed with SARS-CoV-2 infection but were
showing relatively mild symptoms. Patients were prescribed
apalutamide 60 mg or a placebo and instructed to take 4 tablets
daily. Patients were instructed to go home but return to the
hospital if symptoms became worse. Efficacy parameters were defined
as 1.) COVID-19 Diagnosis: COVID-19 positive diagnosis is defined
as subject exhibiting symptoms of acute respiratory infection,
defined as one or more of the following cough, fever
(>37.5.degree. C./99.5.degree. F.), shortness of breath, sore
throat, and a positive SARS-CoV-2 rtPCR test 2.) COVID-19
Hospitalization defined as confirmed hospitalization due to
COVID-19, and 3.) Symptoms Severity of COVID-19 defined as symptoms
severity of COVID-19 using Brescia-COVID Respiratory Severity Scale
(BCRSS).
[0244] All subjects were tested and found to be positive for
SARS-CoV-2 infection. All subjects were monitored for one month
after the initiation of the therapy. 13 of 200 subjects in the
apalutamide (240 mg) arm were admitted to the hospital after their
first visit. The average BCRSS score for the 13 admitted patients
was 3.2. 49 of 200 in the placebo group were admitted to the
hospital with an average BCRSS score of 5.4.
Example 7
[0245] A double-blinded placebo controlled study was conducted on
113 hospitalized male patients with average age of 57 years
old.
[0246] All subjects were tested and found to be positive for
SARS-CoV-2 infection. 60 subjects were given an injection of
cyproterone acetate (300 mg). The other 53 subjects received
standard treatment. Following 15 days of treatment, 84% of the
subjects in the cyproterone acetate survived while 64% of the
control group survived.
Example 8
[0247] A double-blinded placebo controlled study was conducted on
340 male patients with average age of 39.2 years old.
[0248] Patients were diagnosed with SARS-CoV-2 infection but were
showing relatively mild symptoms. Patients were divided into one of
two arms. Each group received tablets of enzalutamide (40 mg) and
instructed to take 4 tablets daily. One arm received bintrafusp
alfa while the other arm received a placebo and both arms were
instructed to take 1 tablet daily. Patients were instructed to go
home but return to the hospital if symptoms became worse. Efficacy
parameters were defined as 1.) SARS-CoV-2 Diagnosis: SARS-CoV-2
positive diagnosis is defined as subject exhibiting symptoms of
acute respiratory infection, defined as one or more of the
following cough, fever (>37.5.degree. C./99.5.degree. F.),
shortness of breath, sore throat, and a positive SARS-CoV-2 rtPCR
test 2.) SARS-CoV-2 Hospitalization defined as confirmed
hospitalization due to SARS-CoV-2 infection, and 3.) Symptoms
Severity of SARS-CoV-2 infection defined as symptoms severity of
COVID-19 using Brescia-COVID Respiratory Severity Scale
(BCRSS).
[0249] All subjects were tested and found to be positive for
SARS-CoV-2 infection. All subjects were monitored for one month
after the initiation of the therapy. 2 of 180 subjects in the
enzalutamide plus bintrafusp alfa arm were admitted to the hospital
after their first visit. The average BCRSS score for the 2 admitted
patients was 2.5. 14 of 160 in the enzalutamide only group were
admitted to the hospital with an average BCRSS score of 6.2.
Example 9
[0250] A double-blinded placebo controlled study was conducted on
200 male patients with average age of 42.3 years old.
[0251] Patients were diagnosed with SARS-CoV-2 infection but were
showing relatively mild symptoms. Patients were divided into one of
two arms. Each group received tablets of enzalutamide (40 mg) and
instructed to take 4 tablets daily. One arm received galunisertib
while the other arm received a placebo and both were instructed to
take 1 tablet daily. Patients were instructed to go home but return
to the hospital if symptoms became worse. Efficacy parameters were
defined as 1.) SARS-CoV-2 Diagnosis: SARS-CoV-2 positive diagnosis
is defined as subject exhibiting symptoms of acute respiratory
infection, defined as one or more of the following cough, fever
(>37.5.degree. C./99.5.degree. F.), shortness of breath, sore
throat, and a positive SARS-CoV-2 rtPCR test 2.) SARS-CoV-2
Hospitalization defined as confirmed hospitalization due to
SARS-CoV-2 infection, and 3.) Symptoms Severity of SARS-CoV-2
infection defined as symptoms severity of COVID-19 using
Brescia-COVID Respiratory Severity Scale (BCRSS).
[0252] All subjects were tested and found to be positive for
SARS-CoV-2 infection. All subjects were monitored for one month
after the initiation of the therapy. 3 of 100 subjects in the
enzalutamide plus galunisertib arm were admitted to the hospital
after their first visit. The average BCRSS score for the 2 admitted
patients was 2.2. 11 of 100 in the enzalutamide only group were
admitted to the hospital with an average BCRSS score of 6.2.
Example 10
[0253] A double-blinded placebo controlled study was conducted on
176 male patients with average age of 60.3 years old.
[0254] Patients were diagnosed with SARS-CoV-2 infection but were
showing relatively mild symptoms. Patients were divided into one of
two arms. Each group received tablets of bicalutamide (50 mg) and
instructed to take 1 tablet daily. One arm received vactosertib
while the other arm received a placebo and both arms were
instructed to take 1 tablet daily. Patients were instructed to go
home but return to the hospital if symptoms became worse. Efficacy
parameters were defined as 1.) SARS-CoV-2 Diagnosis: SARS-CoV-2
positive diagnosis is defined as subject exhibiting symptoms of
acute respiratory infection, defined as one or more of the
following cough, fever (>37.5.degree. C./99.5.degree. F.),
shortness of breath, sore throat, and a positive SARS-CoV-2 rtPCR
test 2.) SARS-CoV-2 Hospitalization defined as confirmed
hospitalization due to SARS-CoV-2 infection, and 3.) Symptoms
Severity of SARS-CoV-2 infection defined as symptoms severity of
COVID-19 using Brescia-COVID Respiratory Severity Scale
(BCRSS).
[0255] All subjects were tested and found to be positive for
SARS-CoV-2 infection. All subjects were monitored for one month
after the initiation of the therapy. 4 of 88 subjects in the
bicalutamide plus vactosertib arm were admitted to the hospital
after their first visit. The average BCRSS score for the 2 admitted
patients was 2.9. 9 of 88 in the bicalutamide only group were
admitted to the hospital with an average BCRSS score of 5.3.
Example 11
[0256] A controlled study was conducted on 140 male patients with
average age of 42.6 years old. Patients were diagnosed with
SARS-CoV-2 infection but were showing relatively mild symptoms.
Patients were divided into one of two arms. All subjects received a
subcutaneous injection of degarelix (120 mg) at the start of the
trial. The treatment group were instructed to take trabedersen
daily, the control arm received standard care. Patients were
instructed to go home but return to the hospital if symptoms became
worse. Efficacy parameters were defined as 1.) SARS-CoV-2
Diagnosis: SARS-CoV-2 positive diagnosis is defined as subject
exhibiting symptoms of acute respiratory infection, defined as one
or more of the following cough, fever (>37.5.degree.
C./99.5.degree. F.), shortness of breath, sore throat, and a
positive SARS-CoV-2 rtPCR test 2.) SARS-CoV-2 Hospitalization
defined as confirmed hospitalization due to SARS-CoV-2 infection,
and 3.) Symptoms Severity of SARS-CoV-2 infection defined as
symptoms severity of COVID-19 using Brescia-COVID Respiratory
Severity Scale (BCRSS).
[0257] All subjects were tested and found to be positive for
SARS-CoV-2 infection. All subjects were monitored for one month
after the initiation of the therapy. 3 of 80 subjects in the
degarelix+trabedersen arm were admitted to the hospital after their
first visit. The average BCRSS score for the 2 admitted patients
was 1.3. 12 of 60 subjects in the standard care group (degarelix
alone) were admitted to the hospital with an average BCRSS score of
4.6.
Example 12
[0258] A double-blinded placebo controlled study was conducted on
25 male patients admitted to the hospital for complication
resulting from flu with average age of 68.4 years old. Patients
were diagnosed with Influenza A infection. Patients were divided
into one of two arms. Each group received 1 tablet of bicalutamide
(50 mg) daily. The treatment group also received methimazole
tablets and were instructed to take them at the same time of day as
the biclalutamide. Patient progress was monitored by primary care
physician. Efficacy parameters were defined as 1.) time to
alleviation of fever 2.) mortality and length of hospital stay 3.)
change in virus titer 48 hours after hospital admission.
[0259] All subjects were tested and found to be positive for
Influenza A infection. 15 subjects were in the treatment group and
9 were in the placebo arm. Overall, the time to alleviation of
fever was lower in the treated group compared with the control
group [mean difference (MD), -7.17 hours; 95% confidence interval
(CI) -11.00 to -3.34]. Mortality, length of hospital stay, change
in virus titer 48 hours after admission, and the incidence of
adverse events in these patients were not significantly different
between the two groups.
Example 13
[0260] A double-blinded placebo controlled study was conducted on
36 male health care workers working at two hospital emergency room
departments.
[0261] At baseline, all subjects were tested and found to be
negative for SARS-CoV-2 infection. 18 subjects were prescribed
finasteride and sodium iodide-i-131. The reminder 18 subjects were
given a placebo. At day 28 all subjects were tested again for
SARS-CoV-2 infection. Among the subjects that were administered
finasteride and sodium iodide-i-131, 1 subject tested positive for
SARS-CoV-2. Among the subjects administered the placebo, 6 subjects
tested positive for SARS-CoV-2.
Example 14
[0262] Treatment of male patients with SARS-CoV-2 infections with
0.5 mg dutasteride daily or 5.0 mg finasteride daily.
[0263] Male subjects hospitalized for COVID-19 were enrolled in the
study. The study was conducted between Mar. 14, 2020 and May 20,
2020 at Hospital Ramon Y Cajal, Madrid, Spain. The subjects were
enrolled in a sequential order of presentation to the hospital.
Subjects were over the age of 18 with a laboratory confirmed
SARS-CoV-2 infection (rtPCR). For each subject existing medical
conditions, medications, SARis use and duration, date of
hospitalization, date of discharge and admission to ICU were
recorded. The subjects were followed for a period of 60 days from
the date of hospitalization. The primary outcome of the study was
rate of ICU admission based on the use of 5ARis (0.5 mg dutasteride
daily or 5.0 mg finasteride daily) in the six months leading to
hospitalization.
[0264] Seventy seven subjects were enrolled in the study. The mean
age of the subjects was 68.62 (+/-12.73) years old. Among the
subjects, 12 subjects were taking 5ARis for at least 6 months prior
to the date of hospitalization. The average age of patients taking
5ARis was 80.6 (+/-8.19). The average duration of hospitalization
among 5ARis patients was 25 days. Only 1 of the 12 (8%) of subjects
taking SARis was admitted to the ICU. Among the 65 subjects not
taking SARis, the average duration of hospitalization was 32 days.
Thirty eight of the sixty subjects (58%) were admitted to the ICU.
The average age of patients not taking SARis was 66.45 (+/-12.21).
The proportion of subjects admitted to the ICU taking SARis was
significantly lower than the proportion of subjects admitted to the
ICU not taking 5ARis X.sup.2 (1, N=77)=9.998, p=0.0016. Further,
the relative risk and odds ratios for ICU admission for subjects
not taking SARis were RR 7.0154, 95% CI: 1.0623 to 46.3313,
p=0.0431 and OR 15.4815, 95% CI: 1.8849-127.1543, p=0.0108
respectively.
Example 15
[0265] In-vitro Diagnostic Test to Guide Androgen Deprivation
Therapy Dosage for COVID-19 Patients
[0266] Investigational Device
[0267] Device Name: COVID-19 Androgen Deprivation Therapy Dosage
Selector (CoADTS)
[0268] Device Background:
[0269] COVID-19 Androgen Deprivation Therapy Dosage Selector
(CoADTS) is a non-invasive In-Vitro Diagnostic device that utilizes
qualitative DNA genotyping. CoADTS test requires a health care
professional to collect a DNA sample using an FDA cleared DNA
sample collection kit. The sample collection kit is an ORAcollectDx
OCD-100A device manufactured by DNA Genotek, Inc (previously
cleared under K152464). CoADTS test is intended to be performed at
a Clinical Laboratory Improvement Amendments (CLIA) certified
laboratory. The reagents used in performing the CoADTS test are
manufactured in a GMP facility. CoADTS test reports the results of
the DNA genotyping.
[0270] Trial Conduct
[0271] This study will be conducted in compliance with the protocol
approved by the Institutional Review Board, and according to Good
Clinical Practice standards. The CoADTS Test used in this study is
manufactured according to GMP and the specimens will be analyzed at
a CLIA laboratory. No deviation from the protocol will be
implemented without the prior review and approval of the IRB except
where it may be necessary to eliminate an immediate hazard to a
research subject. In such case, the deviation will be reported to
the IRB as soon as possible.
[0272] Population
[0273] This is a multi-center study to be conducted in at least 2
countries--Spain and the US. This exact protocol will be followed
in each country. There will be a minimum of 2 separate sites and 2
separate PIs. In the US, the study will be approved by an IRB and
in the other countries by the appropriate Ethics Committees.
[0274] The population for this study will be subjects recruited
from each site (hospital).
[0275] Subjects will be males requesting a SARS-CoV-2 test
following respiratory symptoms.
[0276] Subjects will be males 18 years and older of any
ethnicity.
[0277] Trial Objectives
[0278] The primary purpose of this study is to determine the
predictive value of the
[0279] CoADTS Test. The predictive value will be calculated based
on the positive percent agreement and negative percent agreement of
the CoADTS Test. The results will be presented in 2.times.2
tables.
[0280] Trial Design
[0281] Primary Study Endpoints/Secondary Endpoints
[0282] Primary Outcome Measures:
[0283] Severity of Disease (discharged, hospitalization, admission
to intensive care unit [ICU], and death) [Baseline, Day 7, Day 14,
Day 21, Day 28]
[0284] Study Design/Type
[0285] This study is a prospective cross-sectional observational
study. The study will have 4 arms:
[0286] Arm 1: Males first tested positive for SARS-CoV-2 at the
site (hospital) with CAG length <24 (based on the CoADTS Test)
and TMPRSS2 SNP (rs8134378) positive (G)
[0287] Arm 2: Males first tested positive for SARS-CoV-2 at the
site (hospital) with CAG length >=24 (based on the CoADTS Test)
and TMPRSS2 SNP (rs8134378) positive (G)
[0288] Arm 3: Males first tested positive for SARS-CoV-2 at the
site (hospital) with CAG length <24 (based on the CoADTS Test)
and TMPRSS2 SNP (rs8134378) negative (A)
[0289] Arm 4: Males first tested positive for SARS-CoV-2 at the
site (hospital) with CAG length >=24 (based on the CoADTS Test)
and TMPRSS2 SNP (rs8134378) negative (A)
[0290] Study Environment:
[0291] This is a multi-center study to be conducted in at least 2
countries--Spain and the US. This exact protocol will be followed
in each country. There will be a minimum of 2 separate sites and 2
separate PIs. In the US, the study will be approved by an IRB and
in the other countries by the appropriate Ethics Committees.
[0292] The study will be conducted at the site(s) listed above
i.e., the PI's hospital. All data collection including sample
collection will be performed at the site.
[0293] Study Design:
[0294] Study Phase Ia: Screening (first site visit)
[0295] The PI will screen each potential subject for the inclusion
and exclusion criteria.
[0296] Study Phase Ib: Enrollment (first site visit)
[0297] Each qualified subject will complete and sign the informed
consent form
[0298] Each subject will be assigned a subject study number
[0299] Study Phase Ic: Sample Collection (first site visit)
[0300] For each subject, the PI will collect the saliva DNA sample
using the CoADTS
[0301] Test Sample Collection Kit. The sample collection will be
performed in accordance with IFU for the collection kit.
[0302] The sample collection kit will be sent to the hospital
laboratory.
[0303] All information will be recorded in the appropriate
CRFs.
[0304] Study Phase Id: Hospital Laboratory (first site visit)
[0305] The hospital laboratory will extract the DNA from the sample
collection kit utilizing the DNA extraction kit provided with the
CoADTS Test kit.
[0306] The laboratory will ship the extracted DNA to the CLIA
laboratory
[0307] Study Phase II: Primary Outcome (Days: 0, 7, 14, 21, 28):
[0308] 1. For each subject, the PI or PI assistant will record the
subject's severity of disease [0309] 2. All information will be
recorded in the appropriate CRFs
[0310] Inclusion Criteria
[0311] Male over the age of 18
[0312] First time present at the site
[0313] Laboratory confirmed SARS-CoV-2 infection
[0314] Able to give informed consent
[0315] Exclusion Criteria
[0316] Unable to give informed consent
[0317] Diagnosed with an additional respiratory co-infection
[0318] XXY males
[0319] Assessment of Efficacy
[0320] Efficacy Parameters
[0321] Severity of Disease
[0322] Clinical assessment of disease severity will be made by
attending physician and reported to the PI or PI assistant. Disease
severity will be categorized as: discharged, hospitalization,
admission to intensive care unit [ICU] or and death.
[0323] Method and Timing
[0324] All assessments described in section 5.1 will be recorded on
paper forms (CRFs) and stored with each subject's clinical study
record.
[0325] The timing to complete the assessment of efficacy will be at
Baseline, Day 7, Day 14, Day 21 and Day 28. After baseline
assessment, the additional assessment can be performed by
computerized hospital record search by the PI or PI assistant.
Example 16
[0326] A controlled study was conducted on 100 male patients with
average age of 48.3 years old. Patients were diagnosed with
SARS-CoV-2 infection but were showing relatively mild symptoms.
Patients were divided into one of two arms. The treatment arm was
prescribed bicalutamide (50 mg) once daily at the start of the
trial, the control arm received standard care. Patients were
instructed to go home but return to the hospital if symptoms became
worse. Efficacy parameters were defined as 1.) COVID-19 Diagnosis:
COVID-19 positive diagnosis were defined as subject exhibiting
symptoms of acute respiratory infection, defined as one or more of
the following cough, fever (>37.5.degree. C./99.5.degree. F.),
shortness of breath, sore throat, and a positive SARS-CoV-2 rtPCR
test 2.) COVID-19 Hospitalization was defined as confirmed
hospitalization due to COVID-19, and 3.) Symptoms Severity of
COVID-19 was defined as symptoms severity of COVID-19 using
Brescia-COVID Respiratory Severity Scale (BCRSS).
[0327] All subjects were tested and found to be positive for
SARS-CoV-2 infection. All subjects were monitored for one month
after the initiation of the therapy. 6 of 50 subjects in the
bicalutamide arm were admitted to the hospital after their first
visit. The average BCRSS score for the 6 admitted patients was 1.9.
17 of 50 subjects in the standard care group were admitted to the
hospital with an average BCRSS score of 4.1.
Example 17
[0328] A controlled study was conducted on 40 male patients with
average age of 41.6 years old. Patients were diagnosed with
SARS-CoV-2 infection but were showing relatively mild symptoms.
Patients were divided into one of two arms. The treatment arm was
prescribed darolutamide (300 mg) orally twice daily at the start of
the trial, the control arm received standard care. Patients were
instructed to go home but return to the hospital if symptoms became
worse. Efficacy parameters were defined as 1.) COVID-19 Diagnosis:
COVID-19 positive diagnosis was defined as subject exhibiting
symptoms of acute respiratory infection, defined as one or more of
the following cough, fever (>37.5.degree. C./99.5.degree. F.),
shortness of breath, sore throat, and a positive SARS-CoV-2 rtPCR
test 2.) COVID-19 Hospitalization was defined as confirmed
hospitalization due to COVID-19, and 3.) Symptoms Severity of
COVID-19 was defined as symptoms severity of COVID-19 using
Brescia-COVID Respiratory Severity Scale (BCRSS).
[0329] All subjects were tested and found to be positive for
SARS-CoV-2 infection. All subjects were monitored for one month
after the initiation of the therapy. 1 of 20 subjects in the
darolutamide arm was admitted to the hospital after their first
visit. The patient's BCRSS score was 2. 3 of 20 subjects in the
standard care group were admitted to the hospital with an average
BCRSS score of 3.6.
Example 18
[0330] A controlled study was conducted on 150 male patients with
average age of 45.7 years old. Patients were diagnosed with
SARS-CoV-2 infection but were showing relatively mild symptoms.
Patients were divided into one of two arms. The treatment arm was
prescribed abiraterone (500 mg) twice daily at the start of the
trial, the control arm received standard care. Patients were
instructed to go home but return to the hospital if symptoms became
worse. Efficacy parameters were defined as 1.) COVID-19 Diagnosis:
COVID-19 positive diagnosis was defined as subject exhibiting
symptoms of acute respiratory infection, defined as one or more of
the following cough, fever (>37.5.degree. C./99.5.degree. F.),
shortness of breath, sore throat, and a positive SARS-CoV-2 rtPCR
test 2.) COVID-19 Hospitalization was defined as confirmed
hospitalization due to COVID-19, and 3.) Symptoms Severity of
COVID-19 was defined as symptoms severity of COVID-19 using
Brescia-COVID Respiratory Severity Scale (BCRSS).
[0331] All subjects were tested and found to be positive for
SARS-CoV-2 infection. All subjects were monitored for one month
after the initiation of the therapy. 4 of 75 subjects in the
abiraterone arm were admitted to the hospital after their first
visit. The patients average BCRSS score was 1.8. 15 of 75 subjects
in the standard care group were admitted to the hospital with an
average BCRSS score of 4.7.
Example 19
[0332] A controlled study was conducted on 90 male patients with
average age of 51 years old. Patients were diagnosed with
SARS-CoV-2 infection but were showing relatively mild symptoms.
Patients were divided into one of two arms. The treatment arm was
prescribed nilutamide (300 mg) orally once daily at the start of
the trial, the control arm received standard care. Patients were
instructed to go home but return to the hospital if symptoms became
worse. Efficacy parameters were defined as 1.) COVID-19 Diagnosis:
COVID-19 positive diagnosis was defined as subject exhibiting
symptoms of acute respiratory infection, defined as one or more of
the following cough, fever (>37.5.degree. C./99.5.degree. F.),
shortness of breath, sore throat, and a positive SARS-CoV-2 rtPCR
test 2.) COVID-19 Hospitalization was defined as confirmed
hospitalization due to COVID-19, and 3.) Symptoms Severity of
COVID-19 defined as symptoms severity of COVID-19 using
Brescia-COVID Respiratory Severity Scale (BCRSS).
[0333] All subjects were tested and found to be positive for
SARS-CoV-2 infection. All subjects were monitored for one month
after the initiation of the therapy. 3 of 50 subjects in the
nilutamide arm were admitted to the hospital after their first
visit. The patients BCRSS score was 1.3. 8 of 40 subjects in the
standard care group were admitted to the hospital with an average
BCRSS score of 4.0.
Example 20
[0334] A controlled study was conducted on 16 male patients with
average age of 64 years old. Patients were diagnosed with
SARS-CoV-2 infection but were showing relatively mild symptoms.
Patients were divided into one of two arms. The treatment arm
received docetaxel 75 mg/m2 IV over 1 hour at the start of the
trial, the control arm received standard care. Patients were
instructed to go home but return to the hospital if symptoms became
worse. Efficacy parameters were defined as 1.) COVID-19 Diagnosis:
COVID-19 positive diagnosis was defined as subject exhibiting
symptoms of acute respiratory infection, defined as one or more of
the following cough, fever (>37.5.degree. C./99.5.degree. F.),
shortness of breath, sore throat, and a positive SARS-CoV-2 rtPCR
test 2.) COVID-19 Hospitalization defined as confirmed
hospitalization due to COVID-19, and 3.) Symptoms Severity of
COVID-19 was defined as symptoms severity of COVID-19 using
Brescia-COVID Respiratory Severity Scale (BCRSS).
[0335] All subjects were tested and found to be positive for
SARS-CoV-2 infection. All subjects were monitored for one month
after the initiation of the therapy. 0 of 8 subjects in the
docetaxel arm were admitted to the hospital after their first
visit. 2 of 8 subjects in the standard care group were admitted to
the hospital with an average BCRSS score of 4.5.
[0336] It should be noted that the dosage used in administering
embodiments of the compositions can be low and still be effective.
A low dosage can be within a range from 1/10.times. to 1.times. of
the following exemplary dosages listed: [0337] topical skin
application of finasteride at 10% (w/w) [0338] oral finasteride at
0.1-10 mg [0339] dutasteride at 0.1 mg/day to 1.0 mg/day [0340]
degarelix at 240 mg [0341] oral cannabidiol at 10/mg/Kg/day [0342]
oral flutamide at 750 mg/day [0343] enzalutamide at 160 mg qd
[0344] oral dutasteride at 0.25 mg/day [0345] apalutamide at 60 mg
4 times per day [0346] injection of cyproterone acetate (300 mg).
[0347] subcutaneous injection of degarelix (120 mg) [0348]
bicalutamide at 50 mg per day [0349] subcutaneous injection of
degarelix (120 mg) [0350] oral darolutamide at 300 mg twice daily
[0351] abiraterone at 500 mg twice daily [0352] oral nilutamide at
300 mg once daily [0353] docetaxel at 75 mg/m2 IV over 1 hour
[0354] However, dosages within a range from 1/10.times. to 3.times.
of the above identified dosages can be used. Thus, dosages can be
within a range from: topical skin application of finasteride at
1-30% (w/w) [0355] oral finasteride at 0.01-30 mg [0356]
dutasteride at 0.1 mg/day to 3.0 mg/day [0357] degarelix at 24
mg-720 mg [0358] oral cannabidiol at 1-30/mg/Kg/day [0359] oral
flutamide at 75-2,250 mg/day [0360] enzalutamide at 16-480 mg qd
[0361] oral dutasteride at 0.025-0.75 mg/day [0362] apalutamide at
6-180 mg 4 times per day [0363] injection of cyproterone acetate
(30-900 mg). [0364] subcutaneous injection of degarelix (12-360 mg)
[0365] bicalutamide at 5-150 mg per day [0366] subcutaneous
injection of degarelix (12-360 mg) [0367] oral darolutamide at
30-900 mg twice daily [0368] abiraterone at 50-1500 mg twice daily
[0369] oral nilutamide at 30-900 mg once daily [0370] docetaxel at
7.5-225 mg/m2 IV over 1 hour
* * * * *
References