U.S. patent application number 15/618239 was filed with the patent office on 2017-09-28 for antitussive compositions and methods.
The applicant listed for this patent is Attenua, Inc.. Invention is credited to Brendan CANNING, Robert DEVITA, Peter DICPINIGAITIS, Jing LIANG.
Application Number | 20170273957 15/618239 |
Document ID | / |
Family ID | 57886252 |
Filed Date | 2017-09-28 |
United States Patent
Application |
20170273957 |
Kind Code |
A1 |
LIANG; Jing ; et
al. |
September 28, 2017 |
ANTITUSSIVE COMPOSITIONS AND METHODS
Abstract
Disclosed herein are compositions which include nicotinic
receptor agonists, specifically of the .alpha.7 nAChR subtype, and
methods for suppressing cough.
Inventors: |
LIANG; Jing; (New York,
NY) ; DICPINIGAITIS; Peter; (Armonk, NY) ;
CANNING; Brendan; (Baltimore, MD) ; DEVITA;
Robert; (Westfield, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Attenua, Inc. |
New York |
NY |
US |
|
|
Family ID: |
57886252 |
Appl. No.: |
15/618239 |
Filed: |
June 9, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15208266 |
Jul 12, 2016 |
9724340 |
|
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15618239 |
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62199353 |
Jul 31, 2015 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/439 20130101;
A61K 31/465 20130101; A61P 11/14 20180101; A61K 31/444 20130101;
A61K 9/0073 20130101; A61K 45/06 20130101; A61K 31/444 20130101;
A61K 2300/00 20130101; A61K 31/465 20130101; A61K 2300/00
20130101 |
International
Class: |
A61K 31/444 20060101
A61K031/444; A61K 31/439 20060101 A61K031/439; A61K 45/06 20060101
A61K045/06 |
Claims
1.-20. (canceled)
21. A method of suppressing cough in a subject comprising
administering to the subject in need thereof a therapeutically
effective amount of an .alpha.7 nicotinic receptor agonist.
22. The method of claim 21, wherein the .alpha.7 nicotinic receptor
agonist is chosen from
Octahydro-2-methyl-5-(6-phenyl-3-pyridazinyl)-pyrrolo[3,4-c]pyrrole
(A 582941),
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[2-(methoxy)phenyl]-1-ben-
zofuran-2-carboxamide (ABBF), ABT-418 hydrochloride (CAS
147388-83-8), acetylcholine, anabaseine,
(2S)-2'H-spiro[4-azabicyclo[2.2.2]octane-2,5'-[1,3]oxazolidin]-2'-one
(AR-R17779),
3'H-4-Azaspiro[bicyclo[2.2.2]octane-2,2'-furo[2,3-b]pyridine]
(AZD0328), choline, cytosine,
3-(2,4-dimethoxybenzylidene)anabaseine (DMXB-A; DMBX-anabaseine,
GTS-21 dihydrochloride), epibatidine, imidacloprid, lobeline,
(S)-(1-aza-bicyclo[2.2.2]oct-3-yl)carbamic acid
(S)-1-(2-fluorophenyl)ethyl ester HCl salt (JN403), R3487/MEM 3454,
nicotine,
N-(3R)-1-Azabicyclo[2.2.2]oct-3-yl-furo[2,3-c]pyridine-5-carbox-
amide hydrochloride (PHA-543613),
N-(3R)-1-Azabicyclo[2.2.2]oct-3-yl-4-chlorobenzamide (PNU-282987),
pyridol, N-[4-(3-pyridinyl)phenyl]-4-morpholinepentanamide
(SEN12333, WAY 317538), 1,4-Diazabicyclo[3.2.2]nonane-4-carboxylic
acid, 4-bromophenyl ester (SSR180711), (R,R; R,S; S,R; and
S,S)--N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-
-carboxamide (TC-5619),
(2S,3R)--N-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3,5-diflu-
orobenzamide (TC-6987),varenicline,
4-(4-Bromophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfon-
amide (4BP-TQS),
2-(Hexahydro-5-methylpyrrolo[3,4-c]pyrrol-2(1H)-yl)-9H-xanthen-9-one
(A 844606),
(2S)-2'H-spiro[4-azabicyclo[2.2.2]octane-2,5'-[1,3]oxazolidin]-2-
'-one (AR-R 17779), 3-Bromocytisine,
4-[(5,6-Dihydro[2,3'-bipyridin]-3
(4H)-ylidene)methyl]-N,N-dimethylbenzenamine dihydrochloride
(DMAB-anabaseine dihydrochloride),
N-(3R)-1-Azabicyclo[2.2.2]oct-3-yl-furo[2,3-c]pyridine-5-carboxamide
hydrochloride (PHA 543613 hydrochloride),
N-(3R)-1-Azabicyclo[2.2.2]oct-3-yl-2,3-dihydro-1,4-benzodioxin-6-carboxam-
ide fumarate (PHA 568487),
2-[2-(4-Bromophenyl)-2-oxoethyl]-1-methylpyridinium iodide (S
24795), N-[4-(3-pyridinyl)phenyl]-4-morpholinepentanamide (SEN
12333, WAY 317538), h2-(3-Pyridinyl)-1-azabicyclo[3.2.2]nonane
dihydrochloride (TC-1698 dihydrochloride).
23. The method of claim 21 further comprising administering to said
subject one or more additional pharmaceutically active ingredients
chosen from antitussives other than nicotine or a derivative
thereof, antipyretics, expectorants, mucolytics, nasal
decongestants, antihistamines, opioid analgesics, or non-opiate
analgesics.
24. The method of claim 23 wherein the antitussive is chosen from
ambroxol, apomorphine hydrochloride, beechwood creosote,
benzonatate, camphor ethanedisulfonate, caramiphen edisylate,
carbetapentane citrate, chlophendianol hydrochloride, codeine,
codeine phosphate, codeine sulfate, dextromethorphan,
dextromethorphan hydrobromide, diphenhydramine, diphenhydramine
hydrochloride, fentanyl, fentanyl citrate, hydrocodone,
hydromorphone hydrochloride, levorphanol tartrate, menthol,
methadone hydrochloride, morphine, morphine sulfate, noscapine,
noscapine hydrochloride, oxycodone hydrochloride, oxymorphone
hydrochloride or zinc gluconate.
25. The method of claim 23 wherein the expectorant is chosen from
acetylcysteine, ammonium carbonate, ammonium chloride, antimony
potassium tartrate, glycerin, guaifenesin, potassium iodide, sodium
citrate, terpin hydrate, or tolu balsam.
26. The method of claim 23 wherein the mucolytic is chosen from
acetylcysteine, ambroxol, bromhexine, carbocisteine, domiodol,
dornase alfa, eprazinone, erdosteine, letosteine, mesna,
neltenexine, sobrerol, stepronin, or tiopronin.
27. The method of claim 23 wherein the nasal decongestant is chosen
from ephedrine, ephedrine hydrochloride, ephedrine sulfate,
epinephrine bitartrate, hydroxyamphetamine hydrobromide,
mephentermine sulfate, methoxamine hydrochloride, naphazoline
hydrochloride, oxymetalozine hydrochloride, phenylpropanolamine
hydrochloride, propylhexedrine, psuedoephedrine hydrochloride,
tetrahydrozoline hydrochloride, or xylometazoline
hydrochloride.
28. The method of claim 23 wherein the antihistamine is chosen from
antazoline, azatadine, brompheniramine, brompheniramine mepyramine,
carbinoxamine, chlorcyclizine, chlorpheniramine, chlorpheniramine,
clemastine, cyclizine, cyproheptadine, dexchlorpheniramine,
dimenhydrinate, dimetindene, diphenhydramine, diphenhydramine,
doxylamine, doxylamine, hydroxyzine, ketotifen, meclizine,
pheniramine, promethazine, trimeprazine, or triprolidine.
29. The method of claim 23 wherein the opioid analgesic is chosen
from codeine, diphenoxylate, fentanyl, hydrocodone, hydromorphone,
levorphanol, meperidine, methadone, morphine, oxycodone,
oxymorphone, or propoxyphene.
30. The method of claim 23 wherein the non-opioid analgesic is
chosen from memantine, acetaminophen, aspirin, ibuprofen, or
naproxen.
31. The method of claim 21 wherein the nicotinic receptor agonist
is administered in the form of a capsule, elixir, fast-melt strip,
gum, lozenge, liquid, lotion, nasal-inhaled spray, oral-inhaled
spray, orally disintegrating tablet, syrup, tablet, or transdermal
patch.
32. The method of claim 21 wherein the subject is a human.
33. The method of claim 21 wherein the nicotinic receptor agonist
is administered once a day.
34. The method of claim 21 wherein the nicotinic receptor agonist
is administered twice a day.
35. The method of claim 21 wherein the nicotinic receptor agonist
is administered at least three times a day.
36. The method of claim 21 wherein the cough is a symptom of one or
more conditions chosen from sneezing, rhinorrhea, nasal
obstruction, nasal congestion, nasal pruritus, rhinorrhea,
allergies, allergic vasomotor rhinitis (hay fever), seasonal
allergic vasomotor rhinitis, perennial allergic vasomotor rhinitis,
a respiratory disease, a cold, acute bronchitis, chronic
bronchitis, asthmatic bronchitis, bronchiectasis, pneumonia, lung
tuberculosis, silicosis, silicotuberculosis, pulmonary cancer,
upper respiratory inflammation, pharyngitis, laryngitis, nasal
catarrh, asthma, bronchial asthma, infantile asthma, pulmonary
emphysema, pneumoconiosis, pulmonary fibrosis, pulmonary silicosis,
pulmonary suppuration, pleuritis, tonsillitis, cough hives,
post-viral cough, gastreoesophageal reflux disease, post-nasal
drip, nasal congestion, sinusitis, whooping cough or the cough
results from a procedure chosen from a bronchography or a
bronchoscopy.
37. The method of claim 21 wherein the cough is acute.
38. The method of claim 21 wherein the cough is subacute.
39. The method of claim 21 wherein the cough is chronic.
40. The method of claim 21 wherein the nicotinic receptor agonist
is administered orally or by intramuscular injection, subcutaneous
injection, intraperitoneal injection, intrathecal, sublingual.
41. A method of suppressing or reducing cough by orally consuming a
cough suppressing or reducing amount of a nicotinic receptor
agonist.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of priority of U.S.
provisional application Ser. No. 62/199,353, filed on Jul. 31,
2015, the contents of which is hereby incorporated by reference as
if written herein in its entirety.
FIELD OF THE DISCLOSURE
[0002] The present disclosure relates to pharmaceutical
compositions (i.e., antitussives) incorporating compounds capable
of affecting nicotinic acetylcholinergic receptors (nAChRs), for
example, as modulators of specific nicotinic receptor subtypes
(specifically, the .alpha.7 nAChR subtype). The present disclosure
also relates to methods for treating a wide variety of conditions
and disorders, particularly those associated with suppressing
cough.
BACKGROUND OF THE DISCLOSURE
[0003] Cough is the most common symptom for which patients seek
medical advice from primary health care providers. Current
antitussive therapies are minimally effective and have side effects
that limit their utility. In the United States alone over 2 billion
dollars are spent annually on over the counter cough remedies with
questionable efficacy, potential toxicity, and abuse potential,
with billions more spent annually in sick days and doctor's visits.
Cough is the primary mechanism of transmission of airborne
infections, including all forms of influenza, tuberculosis, and
Bordetella pertussis, the gram negative bacterium causing whooping
cough. As such, cough represents a major public health issue that
is poorly treated with currently existing therapies. Currently
existing cough medications include dextromethorphan and codeine;
however these afford limited efficacy effects in clinical trials
with significant side effects and are not suitable for chronic use.
People suffering from coughing generally take throat lozenges,
cough syrups, and cough drops, using these medications for
symptomatic relief. While such medications presently exist, there
is room for significant improvement in the efficacy of these
treatments. Thus, there is a need for new antitussive compositions
that are efficacious in suppressing cough.
SUMMARY OF THE DISCLOSURE
[0004] The present disclosure relates to to pharmaceutical
compositions (i.e., antitussives) incorporating compounds capable
of affecting nicotinic acetylcholinergic receptors (nAChRs), for
example, as modulators (e.g., agonist and/or partial agonist) of
specific nicotinic receptor subtypes (specifically, the .alpha.7
nAChR subtype).
[0005] The compounds disclosed herein are of the azabicycloalkane
category, and generally are azabicyclooctanes. The aryl group in
the arylalkyl moiety is a 6-membered ring heteroaromatic,
preferably 3-pyridinyl moieties, and the alkyl group is typically a
C.sub.1-4 alkyl. The substituent at the 3-position of the
1-azabicycloalkane is a carbonyl-containing functional group,
preferably an amide, or similar functionality.
[0006] Accordingly, the inventors herein disclose methods that can
provide relief or suppression of cough. Provided is an antitussive
composition comprising a nicotinic receptor agonist (e.g., agonist
and/or partial agonist) of specific nicotinic receptor subtypes
(specifically, the .alpha.7 nAChR subtype). Provided is a method of
suppressing cough in subjects in need thereof, comprising the step
of administering to the subject a therapeutically effective amount
of a composition comprising a nicotinic receptor agonist,
specifically, the .alpha.7 nAChR subtype. Provided is an
antitussive composition comprising a nicotinic receptor agonist,
specifically, the .alpha.7 nAChR subtype, for use in human therapy.
Provided is an antitussive composition comprising a nicotinic
receptor agonist, specifically, the .alpha.7 nAChR subtype, for use
in inducing suppression of cough. Provided is an antitussive
composition comprising a nicotinic receptor agonist, specifically,
the .alpha.7 nAChR subtype, for the manufacture of a medicament to
treat cough.
BRIEF DESCRIPTION OF THE DRAWINGS
[0007] FIG. 1. Shows the change in cough reflex sensitivity
(C.sub.5) from baseline after electronic cigarette exposure (30
puffs delivered 30 seconds apart) in 30 healthy adult nonsmokers.
Significant inhibition of cough reflex sensitivity (increase in
C.sub.5) occurred 15 minutes after exposure (p<0.0001). This
effect was transient, as C.sub.5 returned to baseline 24 hours
after exposure (p=0.0002 vs. post-15-minute value).
C.sub.5=concentration of capsaicin inducing .gtoreq.5 coughs.
[0008] FIG. 2. Shows a comparison of the effect of
nicotine-containing and non-nicotine-containing electronic
cigarette exposure on cough reflex sensitivity (C.sub.5) in a
subgroup of 8 subjects who had demonstrated the largest increments
in C.sub.5 (greatest degree of inhibition of cough reflex
sensitivity) after nicotine-containing electronic cigarette use.
The non-nicotine-containing electronic cigarette exposure did not
affect cough reflex sensitivity as did the nicotine-containing
product (p=0.0078 for difference in change in C.sub.5).
C.sub.5=concentration of capsaicin inducing .gtoreq.5 coughs.
[0009] FIG. 3. Guinea pigs were pretreated intraperitoneally with
drug vehicle (saline), .alpha.7 PHA543613 (10 mg/kg). Respiration
and cough reflexes were measured using a Buxco inhalation chamber
connected to a Biopac data acquisition system. Thirty minutes after
vehicle or drug administration, animals were challenged in sequence
with ascending aerosol concentrations of citric acid (0.01M-0.3M),
with each aerosol delivered for 5 minutes and with 5 minutes
interval in between challenges. The cumulative coughs evoked were
quantified and results are presented as a mean.+-.standard error of
the mean (SEM) of n experiments, where n refers to a single
animal). The compound markedly inhibited citric acid evoked
coughs.
[0010] FIG. 4. Guinea pigs were pretreated intraperitoneally with
drug vehicle (saline) or
(2S,3R)--N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofura-
n-2-carboxamide (30 mg/kg). Respiration and cough reflexes were
measured using a Buxco inhalation chamber connected to a Biopac
data acquisition system. Thirty minutes after vehicle or drug
administration, animals were challenged in sequence with ascending
aerosol concentrations of citric acid (0.01M-0.3M), with each
aerosol delivered for 5 minutes and with 5 minutes interval in
between challenges. The cumulative coughs evoked were quantified
and results are presented as a mean.+-.standard error of the mean
(SEM) of n experiments, where n refers to a single animal). The
compound markedly inhibited citric acid evoked coughs. The compound
markedly inhibited citric acid evoked coughing.
DETAILED DESCRIPTION OF THE DISCLOSURE
[0011] The compound described herein have the structure that is
represented by Formula I:
##STR00001##
[0012] For this compound, individual isomers thereof, mixtures
thereof, including racemic mixtures, enantiomers, diastereomers,
and tautomers thereof, and the pharmaceutically acceptable salts
thereof, are intended to be within the scope of the present
disclosure.
Abbreviations and Definitions
[0013] To facilitate understanding of the disclosure, a number of
terms and abbreviations as used herein are defined below as
follows:
[0014] When introducing elements of the present disclosure or the
preferred embodiment(s) thereof, the articles "a", "an", "the" and
"said" are intended to mean that there are one or more of the
elements. The terms "comprising", "including" and "having" are
intended to be inclusive and mean that there may be additional
elements other than the listed elements.
[0015] The term "and/or" when used in a list of two or more items,
means that any one of the listed items can be employed by itself or
in combination with any one or more of the listed items. For
example, the expression "A and/or B" is intended to mean either or
both of A and B, i.e. A alone, B alone or A and B in combination.
The expression "A, B and/or C" is intended to mean A alone, B
alone, C alone, A and B in combination, A and C in combination, B
and C in combination or A, B, and C in combination. When ranges of
values are disclosed, and the notation "from n.sub.1 . . . to
n.sub.2" or "between n.sub.1 . . . and n.sub.2" is used, where
n.sub.1 and n.sub.2 are the numbers, then unless otherwise
specified, this notation is intended to include the numbers
themselves and the range between them. This range may be integral
or continuous between and including the end values. By way of
example, the range "from 2 to 6 carbons" is intended to include
two, three, four, five, and six carbons, since carbons come in
integer units. Compare, by way of example, the range "from 1 to 3
.mu.M (micromolar)," which is intended to include 1 .mu.M, 3 .mu.M,
and everything in between to any number of significant figures
(e.g., 1.255 .mu.M, 2.1 .mu.M, 2.9999 .mu.M, etc.).
[0016] The term "about," as used herein, is intended to qualify the
numerical values that it modifies, denoting such a value as
variable within a margin of error. When no particular margin of
error, such as a standard deviation to a mean value given in a
chart or table of data, is recited, the term "about" should be
understood to mean that range which would encompass the recited
value and the range which would be included by rounding up or down
to that figure as well, taking into account significant
figures.
[0017] The term "combination therapy" means the administration of
two or more therapeutic agents to treat a therapeutic condition or
disorder described in the present disclosure. Such administration
encompasses co-administration of these therapeutic agents in a
substantially simultaneous manner, such as in a single capsule
having a fixed ratio of active ingredients or in multiple, separate
capsules for each active ingredient. In addition, such
administration also encompasses use of each type of therapeutic
agent in a sequential manner. In either case, the treatment regimen
will provide beneficial effects of the drug combination in treating
the conditions or disorders described herein.
[0018] The phrase "therapeutically effective" is intended to
qualify the amount of active ingredients used in the treatment of a
disease or disorder or on the effecting of a clinical endpoint. The
term "therapeutically acceptable" refers to those compounds (or
salts, prodrugs, tautomers, zwitterionic forms, etc.) which are
suitable for use in contact with the tissues of patients without
undue toxicity, irritation, and allergic response, are commensurate
with a reasonable benefit/risk ratio, and are effective for their
intended use.
[0019] As used herein, reference to "treatment" of a patient is
intended to include prophylaxis. Treatment may also be preemptive
in nature, i.e., it may include prevention of disease. Prevention
of a disease may involve complete protection from disease, for
example as in the case of prevention of infection with a pathogen,
or may involve prevention of disease progression. For example,
prevention of a disease may not mean complete foreclosure of any
effect related to the diseases at any level, but instead may mean
prevention of the symptoms of a disease to a clinically significant
or detectable level. Prevention of diseases may also mean
prevention of progression of a disease to a later stage of the
disease.
[0020] As used herein, an "agonist" is a substance that stimulates
its binding partner, typically a receptor. Stimulation is defined
in the context of the particular assay, or may be apparent in the
literature from a discussion herein that makes a comparison to a
factor or substance that is accepted as an "agonist" or an
"antagonist" of the particular binding partner under substantially
similar circumstances as appreciated by those of skill in the art.
Stimulation may be defined with respect to an increase in a
particular effect or function that is induced by interaction of the
agonist or partial agonist with a binding partner and can include
allosteric effects.
[0021] As used herein, an "antagonist" is a substance that inhibits
its binding partner, typically a receptor. Inhibition is defined in
the context of the particular assay, or may be apparent in the
literature from a discussion herein that makes a comparison to a
factor or substance that is accepted as an "agonist" or an
"antagonist" of the particular binding partner under substantially
similar circumstances as appreciated by those of skill in the art.
Inhibition may be defined with respect to a decrease in a
particular effect or function that is induced by interaction of the
antagonist with a binding partner, and can include allosteric
effects.
[0022] As used herein, a "partial agonist" is a substance that
provides a level of stimulation to its binding partner that is
intermediate between that of a full or complete antagonist and an
agonist defined by any accepted standard for agonist activity. It
will be recognized that stimulation, and hence, inhibition is
defined intrinsically for any substance or category of substances
to be defined as agonists, antagonists, or partial agonists.
[0023] As used herein, "intrinsic activity", or "efficacy,"relates
to some measure of biological effectiveness of the binding partner
complex. With regard to receptor pharmacology, the context in which
intrinsic activity or efficacy should be defined will depend on the
context of the binding partner (e.g.,receptor/ligand) complex and
the consideration of an activity relevant to a particular
biological outcome. For example, in some circumstances, intrinsic
activity may vary depending on the particular second messenger
system involved. See Hoyer, D. and Boddeke, H., Trends Pharmacol
Sci. 14(7):270-5 (1993). Where such contextually specific
evaluations are relevant, and how they might be relevant in the
context of the present invention, will be apparent to one of
ordinary skill in the art.
[0024] The compounds disclosed herein can exist as therapeutically
acceptable salts. The present disclosure includes compounds listed
above in the form of salts, including acid addition salts. Suitable
salts include those formed with both organic and inorganic acids.
Such acid addition salts will normally be pharmaceutically
acceptable. However, salts of non-pharmaceutically acceptable salts
may be of utility in the preparation and purification of the
compound in question. Basic addition salts may also be formed and
be pharmaceutically acceptable. For a more complete discussion of
the preparation and selection of salts, refer to Pharmaceutical
Salts: Properties, Selection, and Use. (Stahl, P. Heinrich.
Wiley-VCHA, Zurich, Switzerland, 2002).
[0025] The term "therapeutically acceptable salt," as used herein,
represents salts or zwitterionic forms of the compounds disclosed
herein which are water or oil-soluble or dispersible and
therapeutically acceptable as defined herein. The salts can be
prepared during the final isolation and purification of the
compounds or separately by reacting the appropriate compound in the
form of the free base with a suitable acid. Representative acid
addition salts include acetate, adipate, alginate, L-ascorbate,
aspartate, benzoate, benzenesulfonate (besylate), bisulfate,
butyrate, camphorate, camphorsulfonate, citrate, digluconate,
formate, fumarate, gentisate, glutarate, glycerophosphate,
glycolate, hemisulfate, heptanoate, hexanoate, hippurate,
hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate
(isethionate), lactate, maleate, malonate, DL-mandelate,
mesitylenesulfonate, methanesulfonate, naphthylenesulfonate,
nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate,
persulfate, 3-phenylproprionate, phosphonate, picrate, pivalate,
propionate, pyroglutamate, succinate, sulfonate, tartrate,
L-tartrate, trichloroacetate, trifluoroacetate, phosphate,
glutamate, bicarbonate, para-toluenesulfonate (p-tosylate), and
undecanoate. Also, basic groups in the compounds disclosed herein
can be quaternized with methyl, ethyl, propyl, and butyl chlorides,
bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl
sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides,
and iodides; and benzyl and phenethyl bromides. Examples of acids
which can be employed to form therapeutically acceptable addition
salts include inorganic acids such as hydrochloric, hydrobromic,
sulfuric, and phosphoric, and organic acids such as oxalic, maleic,
succinic, and citric. Salts can also be formed by coordination of
the compounds with an alkali metal or alkaline earth ion. Hence,
the present disclosure contemplates sodium, potassium, magnesium,
and calcium salts of the compounds disclosed herein, and the like.
Basic addition salts can be prepared during the final isolation and
purification of the compounds by reacting a carboxy group with a
suitable base such as the hydroxide, carbonate, or bicarbonate of a
metal cation or with ammonia or an organic primary, secondary, or
tertiary amine. The cations of therapeutically acceptable salts
include lithium, sodium, potassium, calcium, magnesium, and
aluminum, as well as nontoxic quaternary amine cations such as
ammonium, tetramethylammonium, tetraethylammonium, methylamine,
dimethylamine, trimethylamine, triethylamine, diethylamine,
ethylamine, tributylamine, pyridine, N,N-dimethylaniline,
N-methylpiperidine, N-methylmorpholine, dicyclohexylamine,
procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine,
and N,N'-dibenzylethylenediamine. Other representative organic
amines useful for the formation of base addition salts include
ethylenediamine, ethanolamine, diethanolamine, piperidine, and
piperazine. A salt of a compound can be made by reacting the
appropriate compound in the form of the free base with the
appropriate acid.
Nicotinic Receptor Agonists
[0026] Provided herein are antitussive compositions for suppressing
cough comprising a nicotinic receptor agonist. Nicotinic receptor
agonists are ligands that mimic the action of acetylcholine at
nicotinic acetylcholine receptors. Provided herein is a list of
nicotinic receptor agonists, specifically, the .alpha.7 nAChR
subtype: A-582941, ABBF, ABT-418, ABT-594, acetylcholine,
anabaseine, AR-R17779, AZD0328, choline, cytosine, DMBX-anabaseine,
DMXB-A, epibatidine, GTS-21, imidacloprid, lobeline, JN403, MEM
3454, nicotine, PHA-543613, PNU-282987, pyridol, SEN12333,
SSR18071, SSR180711, TC-5619, TC-6987, varenicline, 4BP-TQS, A
582941, A 844606, AR-R 17779 hydrochloride, 3-Bromocytisine,
DMAB-anabaseine dihydrochloride, GTS 21 dihydrochloride, PHA-543613
hydrochloride, PHA 568487, PNU 282987, S 24795, SEN 12333, SSR
18071 hydrochloride, TC-1698 dihydrochloride, and pharmaceutically
acceptable salts thereof. The nicotinic receptor agonists may be
present in the form of their pharmaceutically acceptable salts,
such as, but not limited to, an acid salt such as acetates,
tartrates, chloride, phosphate, sulfates, sulfites, carbonates,
bicarbonate and citrates.
[0027] An embodiment of the pharmaceutical compositions described
herein is the (2R,3R; 2R,3S; 2S,3R; and
2S,3S)--N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-
-2-carboxamide and/or pharmaceutically acceptable salts
thereof.
[0028] For this chiral compound, individual isomers thereof,
mixtures thereof, including racemic mixtures, pure enantiomers,
diastereomers, and tautomers thereof, and the pharmaceutically
acceptable salts thereof, are intended to be within the scope of
the present disclosure.
[0029] Another embodiment as described herein, is the pure
enantiomer,
(2S,3R)--N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofura-
n-2-carboxamide and/or pharmaceutically acceptable salts
thereof.
[0030] In yet another embodiment as described herein, the
pharmaceutically acceptable salt of the pure enantiomer,
(2S,3R)--N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofura-
n-2-carboxamide is the hydrochloride salt.
Additional Antitussives
[0031] In certain embodiments, the antitussive composition
comprises an additional antitussive chosen from ambroxol,
apomorphine hydrochloride, beechwood creosote, benzonatate, camphor
ethanedisulfonate, caramiphen edisylate, carbetapentane citrate,
chlophendianol hydrochloride, codeine, codeine phosphate, codeine
sulfate, dextromethorphan, dextromethorphan hydrobromide,
diphenhydramine, diphenhydramine hydrochloride, fentanyl, fentanyl
citrate, hydrocodone, hydromorphone hydrochloride, levorphanol
tartrate, menthol, methadone hydrochloride, morphine, morphine
sulfate, noscapine, noscapine hydrochloride, oxycodone
hydrochloride, and oxymorphone hydrochloride, zinc gluconate.
Expectorants In certain embodiments, the antitussive composition
comprises an expectorant chosen from acetylcysteine, ammonium
carbonate, ammonium chloride, antimony potassium tartrate,
glycerin, guaifenesin, potassium iodide, sodium citrate, terpin
hydrate, tolu balsam.
Mucolytics
[0032] In certain embodiments, the antitussive composition
comprises a mucolytic chosen from acetylcysteine, ambroxol,
bromhexine, carbocisteine, domiodol, dornase alfa, eprazinone,
erdosteine, letosteine, mesna, neltenexine, sobrerol, stepronin,
and tiopronin.
Nasal Decongestants
[0033] In certain embodiments, the antitussive composition
comprises a nasal decongestant chosen from ephedrine, ephedrine
hydrochloride, ephedrine sulfate, epinephrine bitartrate,
hydroxyamphetamine hydrobromide, mephentermine sulfate, methoxamine
hydrochloride, naphazoline hydrochloride, oxymetalozine
hydrochloride, phenylpropanolamine hydrochloride, propylhexedrine,
psuedoephedrine hydrochloride, tetrahydrozoline hydrochloride, and
xylometazoline hydrochloride. AntihistaminesIn certain embodiments,
the antitussive composition comprises an antihistamine chosen from
antazoline, azatadine, brompheniramine, brompheniramine mepyramine,
carbinoxamine, chlorcyclizine, chlorpheniramine, chlorpheniramine,
clemastine, cyclizine, cyproheptadine, dexchlorpheniramine,
dimenhydrinate, dimetindene, diphenhydramine, diphenhydramine,
doxylamine, doxylamine, hydroxyzine, ketotifen, meclizine,
pheniramine, promethazine, trimeprazine, and triprolidine.
Opioid Analgesics
[0034] In certain embodiments, the antitussive composition
comprises an opioid analgesic chosen from codeine, diphenoxylate,
fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine,
methadone, morphine, oxycodone, oxymorphone, and propoxyphene.
[0035] Non-opioid Analgesics In certain embodiments, the
antitussive composition comprises a non-opioid analgesic is chosen
from acetaminophen, aspirin, ibuprofen and naproxen.
[0036] I. Pharmaceutical Compositions
[0037] The compounds described herein can be incorporated into
pharmaceutical compositions and used to prevent a condition or
disorder in a subject susceptible to such a condition or disorder,
and/or to treat a subject suffering from the condition or
disorder.
[0038] In one embodiment, such condition or disorder is suppressing
cough.
[0039] The pharmaceutical compositions described herein include
nicotinic receptor agonists, specifically of the .alpha.7 nAChR
subtype.
[0040] An embodiment of the pharmaceutical compositions described
herein is the (2R,3R; 2R,3S; 2S,3R; and
2S,3S)--N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-
-2-carboxamide and/or pharmaceutically acceptable salts
thereof.
[0041] For this chiral compound, individual isomers thereof,
mixtures thereof, including racemic mixtures, pure enantiomers,
diastereomers, and tautomers thereof, and the pharmaceutically
acceptable salts thereof, are intended to be within the scope of
the present disclosure.
[0042] Another embodiment as described herein, is the pure
enantiomer,
(2S,3R)--N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofura-
n-2-carboxamide and/or pharmaceutically acceptable salts
thereof.
[0043] In yet another embodiment, the pharmaceutically acceptable
salt of the pure enantiomer,
(2S,3R)--N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofura-
n-2-carboxamide is the hydrochloride salt.
[0044] The manner in which the compounds are administered can vary.
The compositions are preferably administered orally (e.g., in
liquid form within a solvent such as an aqueous or non-aqueous
liquid, or within a solid carrier). Preferred compositions for oral
administration include pills, tablets, capsules, caplets, syrups,
and solutions, including hard gelatin capsules and time-release
capsules. Compositions can be formulated in unit dose form, or in
multiple or subunit doses. Preferred compositions are in liquid or
semisolid form. Compositions including a liquid pharmaceutically
inert carrier such as water or other pharmaceutically compatible
liquids or semisolids can be used. The use of such liquids and
semisolids is well known to those of skill in the art. The
compositions can also be administered via injection, i.e.,
intravenously, intramuscularly, subcutaneously, intraperitoneally,
intraarterially, intrathecally; and intracerebroventricularly.
Intravenous administration is the preferred method of injection.
Suitable carriers for injection are well known to those of skill in
the art and include 5% dextrose solutions, saline, and
phosphate-buffered saline. The compounds can also be administered
as an infusion or injection (e.g., as a suspension or as an
emulsion in a pharmaceutically acceptable liquid or mixture of
liquids).
[0045] The formulations can also be administered using other means,
for example, rectal administration. Formulations useful for rectal
administration, such as suppositories, are well known to those of
skill in the art. The compounds can also be administered by
inhalation (e.g., in the form of an aerosol either nasally or using
delivery articles of the type set forth in U.S. Pat. No. 4,922,901
to Brooks et al., the disclosure of which is incorporated herein in
its entirety); topically (e.g., in lotion form); or transdermally
(e.g., using a transdermal patch, using technology that is
commercially available from Novartis and Alza Corporation).
Although it is possible to administer the compounds in the form of
a bulk active chemical, it is preferred to present each compound in
the form of a pharmaceutical composition or formulation for
efficient and effective administration.
[0046] Exemplary methods for administering such compounds will be
apparent to the skilled artisan. The usefulness of these
formulations can depend on the particular composition used and the
particular subject receiving the treatment. These formulations can
contain a liquid carrier that can be oily, aqueous, emulsified or
contain certain solvents suitable to the mode of
administration.
[0047] The compositions can be administered intermittently or at a
gradual, continuous, constant or controlled rate to a warm-blooded
animal (e.g., a mammal such as a mouse, rat, cat, rabbit, dog, pig,
cow, or monkey), but advantageously are administered to a human
being. In addition, the time of day and the number of times per day
that the pharmaceutical formulation is administered can vary.
[0048] Preferably, upon administration, the active ingredients
interact with receptor sites within the body of the subject that
affect suppressing cough. More specifically, in suppressing cough,
preferable administration is designed to optimize the effect upon
those relevant nicotinic acethylcholine receptor (nAChR) subtypes,
e.g., specifically of the .alpha.7 nAChR subtype, that have an
effect upon suppressing cough, while minimizing the effects upon
muscle-type receptor subtypes. Other suitable methods for
administering the compounds of the present disclosure are described
in U.S. Pat. No. 5,604,231 to Smith et al., the contents of which
are hereby incorporated by reference.
[0049] In certain circumstances, the compounds described herein can
be employed as part of a pharmaceutical composition with other
compounds intended to prevent or treat a particular disorder. In
addition to effective amounts of the compounds described herein,
the pharmaceutical compositions can also include various other
components as additives or adjuncts. Exemplary pharmaceutically
acceptable components or adjuncts which are employed in relevant
circumstances include antioxidants, free-radical scavenging agents,
peptides, growth factors, antibiotics, bacteriostatic agents,
immunosuppressives, anticoagulants, buffering agents,
antiinflammatoryagents, anti-pyretics, time-release binders,
anesthetics, steroids, vitamins, minerals and corticosteroids. Such
components can provide additional therapeutic benefit, act to
affect the therapeutic action of the pharmaceutical composition, or
act towards preventing any potential side effects that can be
imposed as a result of administration of the pharmaceutical
composition.
[0050] The appropriate dose of the compound is that amount
effective to prevent occurrence of the symptoms of the disorder or
to treat some symptoms of the disorder from which the patient
suffers. By "effective amount", "therapeutic amount" or"effective
dose" is meant that amount sufficient to elicit the desired
pharmacological or therapeutic effects, thus resulting in effective
prevention or treatment of the disorder. When treating a cough, an
effective amount of compound is an amount sufficient to pass across
the blood-brain barrier of the subject, to bind to relevant
receptor sites in the brain of the subject and to modulate the
activity of relevant nAChR subtypes (e.g., specifically of the the
.alpha.7 nAChR subtype, that have an effect upon suppressing
cough). Prevention of the disorder is manifested by delaying the
onset of the symptoms of the disorder. Treatment of the disorder is
manifested by a decrease in the symptoms associated with the
disorder or an amelioration of the recurrence of the symptoms of
the disorder. Preferably, the effective amount is sufficient to
obtain the desired result, but insufficient to cause appreciable
side effects.
[0051] The effective dose can vary, depending upon factors such as
the condition of the patient, the severity of the symptoms of the
disorder, and the manner in which the pharmaceutical composition is
administered. For human patients, the effective dose of typical
compounds generally requires administering the compound in an
amount sufficient to modulate the activity of relevant nAChRs
subtypes (e.g., specifically of the .alpha.7 nAChR subtype, that
have an effect upon suppressing cough), but the amount should be
insufficient to induce effects on skeletal muscles and ganglia to
any significant degree. The effective dose of compounds will of
course differ from patient to patient, but in general includes
amounts starting where desired therapeutic effects occur but below
the amount where muscular effects are observed.
[0052] The compounds, when employed in effective amounts in
accordance with the method described herein, are selective to
certain relevant nAChRs subtypes (e.g., specifically of the
.alpha.7 nAChR subtype, that have an effect upon suppressing
cough), but do not significantly activate receptors associated with
undesirable side effects at concentrations at least greater than
those required for eliciting the release of dopamine or other
neurotransmitters. By this is meant that a particular dose of
compound effective in preventing and/or treating a cough is
essentially ineffective in eliciting activation of certain
ganglionic-type nAChRs at concentration higher than 5 times
(5.times.), preferably higher than 100 times (100.times.), and more
preferably higher than 1,000 times (1000.times.) than those
required for modulation of neurotransmitter release.
[0053] The compounds described herein, when employed in effective
amounts in accordance with the methods described herein, can
provide some degree of preventing and/or suppressing cough, the
progression of cough, ameliorate symptoms of cough, and ameliorate
to some degree of the recurrence of cough. The effective amounts of
those compounds are typically below the threshold concentration
required to elicit any appreciable side effects, for example those
effects relating to skeletal muscle. The compounds can be
administered in a therapeutic window in which certain cough
disorders are treated and certain side effects are avoided.
Ideally, the effective dose of the compounds described herein is
sufficient to provide the desired effects upon the cough but is
insufficient (i.e., is not at a high enough level) to provide
undesirable side effects. Preferably, the compounds are
administered at a dosage effective for treating a cough disorder
but less than 1/5, and often less than 1/10, the amount required to
elicit certain side effects to any significant degree.
[0054] Compounds may be administered orally at a dose of from 0.1
mg to 1 g/kg per day. The dose range for adult humans is generally
from 5 mg to 2 g/day. Tablets or other forms of presentation
provided in discrete units may conveniently contain an amount of
one or more compounds which is effective at such dosage or as a
multiple of the same, for instance, units containing 5 mg to 500
mg, usually around 10 mg to 200 mg.
II. Methods of Using the Compounds and/or Pharmaceutical
Compositions
[0055] Provided is a method of suppressing cough in a subject
comprising administering to the subject in need thereof a
therapeutically effective amount of
(2S,3R)--N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl-
)benzofuran-2-carboxamide or a pharmaceutically acceptable salt
thereof.
[0056] In another embodiment, wherein the pharmaceutically
acceptable salt of
(2S,3R)--N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzof-
uran-2-carboxamide is the hydrochloride salt.
[0057] In another embodiment, wherein the method comprises
administering to said subject one or more additional
pharmaceutically active ingredients chosen from antitussives other
than nicotine or a derivatives thereof, antihistamines,
antipyretics, expectorants, mucolytics, nasal decongestants,
non-opiate analgesics or opioid analgesics.
[0058] In another embodiment, wherein the antitussive is chosen
from ambroxol, apomorphine hydrochloride, beechwood creosote,
benzonatate, camphor ethanedisulfonate, caramiphen edisylate,
carbetapentane citrate, chlophendianol hydrochloride, codeine,
codeine phosphate, codeine sulfate, dextromethorphan,
dextromethorphan hydrobromide, diphenhydramine, diphenhydramine
hydrochloride, fentanyl, fentanyl citrate, hydrocodone,
hydromorphone hydrochloride, levorphanol tartrate, menthol,
methadone hydrochloride, morphine, morphine sulfate, noscapine,
noscapine hydrochloride, oxycodone hydrochloride or oxymorphone
hydrochloride.
[0059] In another embodiment, wherein the expectorant is chosen
from acetylcysteine, ammonium carbonate, ammonium chloride,
antimony potassium tartrate, glycerin, guaifenesin, potassium
iodide, sodium citrate, terpin hydrate, tolu balsam.
[0060] In another embodiment, wherein the mucolytic is chosen from
acetylcysteine, ambroxol, bromhexine, carbocisteine, domiodol,
dornase alfa, eprazinone, erdosteine, letosteine, mesna,
neltenexine, sobrerol, stepronin or tiopronin.
[0061] In another embodiment, wherein the nasal decongestant is
chosen from ephedrine, ephedrine hydrochloride, ephedrine sulfate,
epinephrine bitartrate, hydroxyamphetamine hydrobromide,
mephentermine sulfate, methoxamine hydrochloride, naphazoline
hydrochloride, oxymetalozine hydrochloride, phenylpropanolamine
hydrochloride, propylhexedrine, psuedoephedrine hydrochloride,
tetrahydrozoline hydrochloride, or xylometazoline
hydrochloride.
[0062] In another embodiment, wherein the antihistamine is chosen
from antazoline, azatadine, brompheniramine, brompheniramine
mepyramine, carbinoxamine, chlorcyclizine, chlorpheniramine,
chlorpheniramine, clemastine, cyclizine, cyproheptadine,
dexchlorpheniramine, dimenhydrinate, dimetindene, diphenhydramine,
diphenhydramine, doxylamine, doxylamine, hydroxyzine, ketotifen,
meclizine, pheniramine, promethazine, trimeprazine or
triprolidine.
[0063] In another embodiment, wherein the opioid analgesic is
chosen from codeine, diphenoxylate, fentanyl, hydrocodone,
hydromorphone, levorphanol, meperidine, methadone, morphine,
oxycodone, oxymorphone or propoxyphene.
[0064] In another embodiment, the non-opioid analgesic is chosen
from acetaminophen, aspirin, ibuprofen or naproxen.
[0065] In yet another embodiment, wherein
(2S,3R)--N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofura-
n-2-carboxamide is administered in the form of a capsule, elixir,
fast-melt strip, gum, lozenge, liquid, lotion, nasal-inhaled spray,
oral-inhaled spray, orally disintegrating tablet, syrup, tablet, or
transdermal patch.
[0066] In another embodiment, the subject is a human.
[0067] In yet another embodiment, wherein
(2S,3R)--N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofura-
n-2-carboxamide is administered once a day.
[0068] In yet another embodiment, wherein
(2S,3R)--N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofura-
n-2-carboxamide is administered twice a day.
[0069] In yet another embodiment, wherein
(2S,3R)--N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofura-
n-2-carboxamide is administered at least three times a day.
[0070] In another embodiment, the cough is a symptom of one or more
conditions chosen from sneezing, rhinorrhea, nasal obstruction,
nasal congestion, nasal pruritus, rhinorrhea, allergies, allergic
vasomotor rhinitis (hay fever), seasonal allergic vasomotor
rhinitis, perennial allergic vasomotor rhinitis, a respiratory
disease, a cold, acute bronchitis, chronic bronchitis, asthmatic
bronchitis, bronchiectasis, pneumonia, lung tuberculosis,
silicosis, silicotuberculosis, pulmonary cancer, upper respiratory
inflammation, pharyngitis, laryngitis, nasal catarrh, asthma,
bronchial asthma, infantile asthma, pulmonary emphysema,
pneumoconiosis, pulmonary fibrosis, pulmonary silicosis, pulmonary
suppuration, pleuritis, tonsillitis, cough hives, post-viral cough,
gastreoesophageal reflux disease, post-nasal drip, nasal
congestion, sinusitis, whooping cough or the cough results from a
procedure chosen from a bronchography or a bronchoscopy.
[0071] In an embodiment, wherein the cough is acute.
[0072] In an embodiment, wherein the cough is subacute.
[0073] In an embodiment, wherein the cough is chronic.
[0074] In an embodiment, wherein
(2S,3R)--N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofura-
n-2-carboxamide is administered orally or by intramuscular
injection, subcutaneous injection, intraperitoneal injection,
intrathecal, sublingualmal.
[0075] In an embodiment, wherein the method of suppressing or
reducing cough by orally consuming a cough suppressing or reducing
amount of
(2S,3R)--N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofura-
n-2-carboxamide or a pharmaceutically acceptable salt thereof.
EXAMPLES
Example 1
Cough Reflex Sensitivity Study
[0076] Capsaicin, the pungent extract of red peppers, has been
shown in over three decades of clinical experience to
experimentally induce cough in a safe, dose-dependent and
reproducible manner. Thus, capsaicin cough challenge testing has
become an important tool in clinical research, allowing for the
accurate measurement of the effect of a pharmacological or other
intervention on the sensitivity of the cough reflex. The standard
endpoint measured in capsaicin cough challenge testing is the
concentration of capsaicin inducing 5 or more coughs (C.sub.5). In
healthy volunteers, this endpoint has been demonstrated to be
highly reproducible, in the short-term (20 minutes to 14 days) and
long term (months to years). Standard capsaicin challenge
methodology was used in this study to assess the effect of e-cig
vapor exposure on cough reflex sensitivity. Electronic cigarettes
are electronic nicotine delivery devices. A cartridge within the
e-cig contains nicotine in a vehicle of distilled water, as well as
either vegetable glycerin or propylene glycol. A lithium battery
within the e-cig generates heat, thus vaporizing the nicotine
solution. No combustion is involved in the creation of the
nicotine-containing vapor that is inhaled by the user and promptly
absorbed from the respiratory tract into the bloodstream.
Capsaicin Cough Challenge
[0077] Subjects inhaled single, vital-capacity breaths of
ascending, doubling concentrations (range 0.49 .mu.M to 1,000
.mu.M) of aerosolized capsaicin solution, administered via a
compressed air-driven nebulizer controlled by a dosimeter, with
1-minute intervals between inhalations, until 5 or more coughs
resulted in the 15 seconds following an inhalation. Placebo saline
breaths were randomly interspersed between capsaicin doses to
increase challenge blindness. The end point of capsaicin challenge
testing is the concentration of capsaicin inducing 5 or more coughs
(C.sub.5).
Subjects
[0078] Thirty adult lifetime nonsmokers were enrolled after
providing written, informed consent for this study, which was
approved by the Institutional Review Board of the Albert Einstein
College of Medicine, Bronx, N.Y. (IRB #2014-3288). Subjects were
without history of asthma, gastroesophageal reflux disease, or
symptoms suggestive of acute viral upper respiratory tract
infection (common cold) or allergies within 4 weeks of enrollment.
Subjects were not receiving medication known to affect cough reflex
sensitivity.
Study Design
[0079] Upon enrollment, subjects underwent capsaicin challenge
testing on Day 1 to establish their baseline cough reflex
sensitivity. On study Day 2 subjects underwent an electronic
cigarette vaping session. While in a relaxed, seated position,
subjects inhaled a total of 30 puffs (one puff every 30 seconds)
from a disposable electronic cigarette (Blu, Classic Tobacco
flavor, Lorillard Technologies, Greensboro, N.C., USA). A
disposable Blu electronic cigarette contains 20-24 mg of nicotine,
and delivers approximately 400 puffs of nicotine-containing vapor.
The ingredients of the vapor include distilled water, nicotine,
vegetable glycerin, natural flavors, artificial flavors and citric
acid (from Blu website, accessed January 2, 2015). Thus, 30 puffs
of the e-cigarette delivered approximately 1.5-1.8 mg of nicotine.
In comparison, the estimated nicotine intake from a tobacco
cigarette is in the range of 1.07-2.6 mg, depending on the brand.
Fifteen minutes after the conclusion of the e-cigarette session,
subjects underwent capsaicin cough challenge. On study Day 3,
approximately 24 hours after the vaping session, subjects underwent
repeat capsaicin challenge. In addition, the number of coughs
induced by each of the 30 puffs of the e-cig was tabulated. A cough
number of 5 was assigned for .gtoreq.5 coughs. A subgroup of 8
subjects who demonstrated large degrees of cough reflex sensitivity
inhibition after e-cig exposure, (defined as .gtoreq.2
doubling-concentration increase in C.sub.5), underwent a repeat
protocol identical to the above but with a disposable non-nicotine
containing e-cigarette with similar vehicle (BlueStar, Full Tobacco
Flavor, Las Vegas, Nev., USA). Subjects were unaware that the e-cig
used in this portion of the study was nicotine free. Cough reflex
sensitivity (C.sub.5) was analyzed employing mixed-effects
modeling, with subsequent post-hoc analysis correcting for multiple
comparisons using the Tukey-Kramer approach. Pre and post e-cig
exposure differences in C.sub.5 response and number of coughs
between nicotine and non-nicotine containing e-cigs were compared
using Wilcoxon's signed-rank test. Statistical analyses were
performed using SAS version 9.3 software (Cary, N.C., USA).
Results
[0080] Thirty subjects (15 female; age 29.8.+-.4.5) were enrolled
and completed the study. After electronic cigarette exposure, cough
reflex sensitivity was significantly diminished (i.e., C.sub.5 was
significantly increased) compared to baseline. This effect was
transient, as demonstrated by the enhancement of cough reflex
sensitivity back to baseline levels 24 hours after the e-cig
exposure. Mean log C.sub.5 at baseline was 0.50.+-.0.09 (SEM); 15
minutes after electronic cigarette exposure 0.79.+-.0.11; and 24
hours subsequently 0.55.+-.0.10. Employing mixed-effects modeling,
with subsequent post-hoc analysis correcting for multiple
comparisons using the Tukey-Kramer approach, the difference between
log C.sub.5 at baseline and post e-cig exposure was significant
(difference in mean log C.sub.5 -0.29, 95% CI -0.43 to -0.15,
p<0.0001) as was the difference between post e-cig use and 24
hours later (difference in mean log C.sub.5 0.24, 95% CI 0.10-0.38,
p=0.0002) (FIG. 1). In terms of individual responses, 23 of 30
subjects demonstrated an inhibition of cough reflex sensitivity
(increased C.sub.5) after e-cig exposure; 5 subjects had no change;
and 2 subjects had a one-doubling concentration decrease in
C.sub.5. Twenty six of the 30 subjects coughed to some degree in
response to inhalation of the 30 puffs of the e-cig. The median
number of coughs for the study group was 15.5 with a range of 0-114
coughs. There was no correlation between the number of coughs
induced by e-cig inhalation and subsequent change in cough reflex
sensitivity (C.sub.5), as demonstrated by computation of the
Spearman correlation coefficient, with Fisher's z-transformation.
The point estimate of this correlation was -0.20 with 95% CI
(-0.62, 0.23) and was not significantly different from zero
(p=0.453). To further investigate the role of nicotine in our
observations, we performed an additional exploratory analysis by
repeating an identical protocol of cough reflex sensitivity
measurement before and after exposure to a non-nicotine-containing
disposable electronic cigarette in a subgroup of subjects. All 8
subjects who had demonstrated large degrees of inhibition of cough
reflex sensitivity after exposure to the nicotine-containing e-cig,
defined as a .gtoreq.2 doubling-concentration increase in C.sub.5,
agreed to participate in a follow-up study of a different brand of
e-cigarette. Subjects were not aware that the e-cig being evaluated
in the second phase of the study did not contain nicotine. No
inhibition of cough reflex sensitivity was observed after exposure
to the non-nicotine-containing e-cig, in contrast to the change in
C.sub.5 after use of the nicotine-containing e-cig (median
difference in .DELTA.C.sub.5 0.6, range 0.6-0.9, p=0.0078,
Wilcoxon's signed-ranks test) (FIG. 2). In addition, significantly
less coughing was observed after 30 puffs of the
non-nicotine-containing e-cig compared with the nicotine-containing
product; median difference in A number of coughs 6, range 0-21,
p=0.0156. The results indicate that a single exposure to electronic
cigarette vapor, approximating the nicotine delivery of one tobacco
cigarette, significantly inhibits cough reflex sensitivity in a
group of healthy adult nonsmokers as measured by capsaicin
inhalation cough challenge testing. The effect is transient, as
cough reflex sensitivity returned to baseline 24 hours after e-cig
use. These findings are consistent with observations in healthy
smokers of tobacco cigarettes, whose cough reflex sensitivity is
suppressed relative to nonsmokers. The demonstration that cough
reflex sensitivity is significantly enhanced as soon as two weeks
after smoking cessation supports the hypothesis that inhibition of
cough reflex sensitivity is due to desensitization of cough
receptors within the airway epithelium caused by chronic exposure
to tobacco smoke. Furthermore, as this effect is promptly
reversible even after years of tobacco smoking, cough reflex
sensitivity is apparently a dynamic phenomenon, able to be
modulated by the presence or absence of stimuli such as tobacco
smoke. Given that these previous studies were performed in chronic
tobacco cigarette smokers, the observations of the present study
are perhaps more remarkable in that significant inhibition of cough
reflex sensitivity was demonstrated after a single brief exposure
to an electronic cigarette. In an attempt to gain insight as to the
causative agent within the electronic cigarette vapor that led to
significant inhibition of cough reflex sensitivity, we performed an
exploratory analysis of a subgroup of our 30 subjects. Eight of the
30 subjects with the greatest degree of cough reflex suppression
(defined as an elevation of capsaicin C.sub.5.gtoreq.2 doubling
concentrations) after nicotine-containing e-cig exposure were
subsequently exposed in a similar manner to a
non-nicotine-containing e-cig with similar flavoring and vehicle.
The absence of an effect on cough reflex sensitivity implicates
nicotine as the agent within the e-cig vapor causing the inhibition
of cough reflex sensitivity that we observed. Nicotine has been
demonstrated in animals and man to have a peripheral, rapid-onset,
cough-inducing effect, probably through stimulation of nicotinic
acetylcholine receptors (nAChRs) expressed on sensory terminals of
cough receptors within the airway mucosa. These observations may be
relevant to the findings of the present study, since most of our
subjects did cough immediately and transiently in response to e-cig
inhalation, yet demonstrated inhibition of cough reflex sensitivity
when measured 15 minutes after completion of the e-cig vaping
session. In the subgroup of subjects who also underwent an exposure
to a non-nicotine-containing electronic cigarette, less cough
occurred during the vaping session, and inhibition of cough reflex
sensitivity was absent. Thus, the results of our study may be an
illustration of a dual action of nicotine: an acute, peripheral
tussive effect, and a delayed, central antitussive effect. The
putative action of nicotine as a centrally acting inhibitor of
cough reflex sensitivity introduces the concept of nicotinic
receptor agonists as potential therapeutic antitussive agents.
Example 2
(2S,3R)--N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-
-2-carboxamide
Inhibits Citric Acid Evoked Coughing in Guinea Pigs
[0081] Cough suppression was evaluated in conscious guinea pigs
using a citric acid inhalation model (Smith et al., 2012). Guinea
pigs were pretreated intraperitoneally with drug vehicle (saline),
.alpha.7 PHA543613 (10 mg/kg) (FIG. 3), or
(2S,3R)--N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofura-
n-2-carboxamide (30 mg/kg) (FIG. 4). Respiration and cough reflexes
were measured using a Buxco inhalation chamber connected to a
Biopac data acquisition system. Thirty minutes after vehicle or
drug administration, animals were challenged in sequence with
ascending aerosol concentrations of citric acid (0.01M-0.3M), with
each aerosol delivered for 5 minutes and with 5 minutes interval in
between challenges. The cumulative coughs evoked were quantified
and results are presented as a mean.+-.standard error of the mean
(SEM) of n experiments, where n refers to a single animal). Studies
were performed using a nonpaired parallel group design. Differences
amongst group means were evaluated by t-test or ANOVA, with a
p<0.05 considered statistically significant which is represented
by an asterisk (*) in FIG. 3 and FIG. 4.
[0082] The detailed description set-forth above is provided to aid
those skilled in the art in practicing the present disclosure.
However, the disclosure described and claimed herein is not to be
limited in scope by the specific embodiments herein disclosed
because these embodiments are intended as illustration of several
aspects of the disclosure. Any equivalent embodiments are intended
to be within the scope of this disclosure. Indeed, various
modifications of the disclosure in addition to those shown and
described herein will become apparent to those skilled in the art
from the foregoing description, which do not depart from the spirit
or scope of the present inventive discovery. Such modifications are
also intended to fall within the scope of the appended claims.
* * * * *