U.S. patent application number 16/246232 was filed with the patent office on 2019-06-06 for protective effect of dmpc, dmpg, dmpc/dmpg, lysopg and lysopc against drugs that cause channelopathies.
The applicant listed for this patent is SignPath Pharma Inc.. Invention is credited to Annie Bouchard, Lawrence Helson, Muhammed Majeed, George M. Shopp.
Application Number | 20190167585 16/246232 |
Document ID | / |
Family ID | 61241214 |
Filed Date | 2019-06-06 |
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United States Patent
Application |
20190167585 |
Kind Code |
A1 |
Helson; Lawrence ; et
al. |
June 6, 2019 |
Protective Effect of DMPC, DMPG, DMPC/DMPG, LYSOPG and LYSOPC
Against Drugs that Cause Channelopathies
Abstract
The present invention includes compositions and methods for
preventing one or more cardiac channelopathies or conditions
resulting from irregularities or alterations in cardiac patterns
caused by an active agent or a drug in a human or animal subject
comprising: an amount of a phosphatidylglycerol adapted for oral
administration effective to reduce or prevent one or more cardiac
channelopathies or conditions resulting from irregularities or
alterations in cardiac patterns caused by the active agent or drug,
and one or more organoleptic, thixotropic, or both organoleptic and
thixotropic agents.
Inventors: |
Helson; Lawrence;
(Quakertown, PA) ; Shopp; George M.; (Boulder,
CO) ; Bouchard; Annie; (Stoke, CA) ; Majeed;
Muhammed; (East Windsor, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SignPath Pharma Inc. |
Sandy |
UT |
US |
|
|
Family ID: |
61241214 |
Appl. No.: |
16/246232 |
Filed: |
January 11, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15788683 |
Oct 19, 2017 |
10238602 |
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16246232 |
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15297901 |
Oct 19, 2016 |
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15788683 |
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14729940 |
Jun 3, 2015 |
10258691 |
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15297901 |
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15788683 |
Oct 19, 2017 |
10238602 |
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14729940 |
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14575644 |
Dec 18, 2014 |
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15788683 |
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15788683 |
Oct 19, 2017 |
10238602 |
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14575644 |
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15597411 |
May 17, 2017 |
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15788683 |
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15068300 |
Mar 11, 2016 |
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15597411 |
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14268376 |
May 2, 2014 |
9682041 |
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15068300 |
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13487233 |
Jun 3, 2012 |
8753674 |
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14268376 |
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62007244 |
Jun 3, 2014 |
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62035417 |
Aug 9, 2014 |
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62056957 |
Sep 29, 2014 |
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62150059 |
Apr 20, 2015 |
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61917426 |
Dec 18, 2013 |
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61977417 |
Apr 9, 2014 |
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61493257 |
Jun 3, 2011 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
G01N 2800/32 20130101;
A61K 31/12 20130101; G01N 33/6887 20130101; A61K 31/685 20130101;
A61K 31/4545 20130101; A61K 9/0053 20130101; A61K 31/683 20130101;
A61K 31/506 20130101; A61K 31/23 20130101; A61K 31/20 20130101;
A61K 47/24 20130101; G01N 33/5008 20130101; A61K 45/06 20130101;
A61K 9/127 20130101; G01N 33/6872 20130101; A61K 31/445 20130101;
A61K 31/685 20130101; A61K 2300/00 20130101; A61K 31/683 20130101;
A61K 2300/00 20130101; A61K 31/23 20130101; A61K 2300/00 20130101;
A61K 31/20 20130101; A61K 2300/00 20130101; A61K 31/506 20130101;
A61K 2300/00 20130101 |
International
Class: |
A61K 9/127 20060101
A61K009/127; A61K 31/445 20060101 A61K031/445; A61K 31/12 20060101
A61K031/12; A61K 31/4545 20060101 A61K031/4545; A61K 31/685
20060101 A61K031/685; G01N 33/68 20060101 G01N033/68; G01N 33/50
20060101 G01N033/50; A61K 45/06 20060101 A61K045/06; A61K 31/683
20060101 A61K031/683; A61K 31/506 20060101 A61K031/506; A61K 31/23
20060101 A61K031/23; A61K 31/20 20060101 A61K031/20; A61K 47/24
20060101 A61K047/24; A61K 9/00 20060101 A61K009/00 |
Claims
1. A composition for preventing one or more cardiac channelopathies
or conditions resulting from irregularities or alterations in
cardiac patterns caused by an active agent or a drug in a human or
animal subject comprising: an amount of a phosphatidylglycerol
adapted for oral administration effective to reduce or prevent one
or more cardiac channelopathies or conditions resulting from
irregularities or alterations in cardiac patterns caused by the
active agent or drug and one or more organoleptic, thixotropic, or
both organoleptic and thixotropic agents.
2. The composition of claim 1, wherein the phosphatidylglycerol
includes at least one of a lysophosphatidylcholine,
lauroyl-lysophosphatidylcholine, myristoyl-lysophosphatidylcholine,
palmitoyl-lysophosphatidylcholine,
stearoyl-lysophosphatidylcholine,
arachidoyl-lysophosphatidylcholine, oleoyl-lysophosphatidylcholine,
linoleoyl-lysophosphatidylcholine,
linolenoyl-lysophosphatidylcholine or
erucoyl-lysophosphatidylcholine.
3. The composition of claim 1, wherein the one or more organoleptic
agents include one or more flavorants, sweeteners, coolants, dyes,
or combinations and mixtures thereof.
4. The composition of claim 1, wherein the one or more thixotropic
agent forms a thixotrophic matrix and is selected from at least one
of polysaccharides, cellulose, carboxymethylcellulose, gums,
xanthan gum, collagen, gelatin, aerogels, polyacrylamide, alkyd
resins, or silica-lipids.
5. The composition of claim 1, wherein the phosphatidylglycerol is
formed into empty liposomes and have an average diameter of 10, 20,
25, 30, 40, 50, 60, 75, 80, 90, or 100 nM.
6. The composition of claim 1, wherein the phosphatidylglycerol is
1-Myristoyl-2-Hydroxy-sn-Glycero-3-Phosphocholine (DMPC),
12-Mysteroyl-2-Hydroxy-sn-Glycero-3-[Phospho-rac-(glycerol)]
(DMPG), or DMPC/DMPG, formed into liposomes with an average
diameter of 10, 20, 25, 30, 40, 50, 60, 75, 80, 90, or 100 nM.
7. The composition of claim 1, wherein the phosphatidylglycerol
include at least one or
1-Myristoyl-2-Hydroxy-sn-Glycero-3-Phosphocholine (DMPC),
12-Mysteroyl-2-Hydroxy-sn-Glycero-3-[Phospho-rac-(glycerol)]
(DMPG), DMPC/DMPG,
1-myristoyl-2-hydroxy-sn-glycero-3-phospho-(1'-rac-glycerol)
(LysoPG), or 1-myristoyl-2-hydroxy-sn-glycero-3-phosphocholine
(LysoPC).
8. The composition of claim 1, wherein the phosphatidylglycerol is
defined further as a short chain fatty acid is up to 5 carbons, a
medium chain is 6 to 12 carbons, a long chain is 13-21 carbons and
a very long chain fatty acid is greater than 22 carbons, including
both even and odd chain fatty acids.
9. The composition of claim 1, wherein the phosphatidylglycerol has
3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,
21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55 or more
carbons, which are saturated or unsaturated.
10. The composition of claim 1, wherein the cardiac channelopathy
or the condition resulting from the irregularity or alteration in
the cardiac pattern is inhibition of an ion channel responsible for
the delayed-rectifier K+ current in the heart, polymorphic
ventricular tachycardia, prolongation of the QTc, LQT2, LQTS, or
torsades de pointes, or is used for the treatment or prevention of
prolongation of the IKr channel inhibition or QT prolongation
induced by administration of the active agent or drug used in the
treatment of cardiac, allergic, or cancer related diseases.
11. The composition of claim 1, wherein the drug is selected from
Albuterol (salbutamol), Alfuzosin, Amantadine, Amiodarone,
Amisulpride, Amitriptyline, Amoxapine, Amphetamine, Anagrelide,
Apomorphine, Arformoterol, Aripiprazole, Arsenic trioxide,
Astemizole, Atazanavir, Atomoxetine, Azithromycin, Bedaquiline,
Bepridil, Bortezomib, Bosutinib, Chloral hydrate, Chloroquine,
Chlorpromazine, Ciprofloxacin, Cisapride, Citalopram,
Clarithromycin, Clomipramine, Clozapine, Cocaine, Crizotinib,
Dabrafenib, Dasatinib, Desipramine, Dexmedetomidine,
Dexmethylphenidate, Dextroamphetamine (d-Amphetamine),
Dihydroartemisinin+piperaquine, Diphenhydramine, Disopyramide,
Dobutamine, Dofetilide, Dolasetron, Domperidone, Dopamine, Doxepin,
Dronedarone, Droperidol, Ephedrine, Epinephrine (Adrenaline),
Eribulin, Erythromycin, Escitalopram, Famotidine, Felbamate,
Fenfluramine, Fingolimod, Flecainide, Fluconazole, Fluoxetine,
Formoterol, Foscarnet, Fosphenytoin, Furosemide (Frusemide),
Galantamine, Gatifloxacin, Gemifloxacin, Granisetron, Halofantrine,
Haloperidol, Hydrochlorothiazide, Ibutilide, Iloperidone,
Imipramine (melipramine), Indapamide, Isoproterenol, Isradipine,
Itraconazole, Ivabradine, Ketoconazole, Lapatinib, Levalbuterol
(levsalbutamol), Levofloxacin, Levomethadyl, Lisdexamfetamine,
Lithium, Mesoridazine, Metaproterenol, Methadone, Methamphetamine
(methamfetamine), Methylphenidate, Midodrine, Mifepristone,
Mirabegron, Mirtazapine, Moexipril/HCTZ, Moxifloxacin, Nelfinavir,
Nicardipine, Nilotinib, Norepinephrine (noradrenaline),
Norfloxacin, Nortriptyline, Ofloxacin, Olanzapine, Ondansetron,
Oxytocin, Paliperidone, Paroxetine, Pasireotide, Pazopanib,
Pentamidine, Perflutren lipid microspheres, Phentermine,
Phenylephrine, Phenylpropanolamine, Pimozide, Posaconazole,
Probucol, Procainamide, Promethazine, Protriptyline,
Pseudoephedrine, Quetiapine, Quinidine, Quinine sulfate,
Ranolazine, Rilpivirine, Risperidone, Ritodrine, Ritonavir,
Roxithromycin, Salmeterol, Saquinavir, Sertindole, Sertraline,
Sevoflurane, Sibutramine, Solifenacin, Sorafenib, Sotalol,
Sparfloxacin, Sulpiride, Sunitinib, Tacrolimus, Tamoxifen,
Telaprevir, Telavancin, Telithromycin, Terbutaline, Terfenadine,
Tetrabenazine, Thioridazine, Tizanidine, Tolterodine, Toremifene,
Trazodone, Trimethoprim-Sulfa, Trimipramine, Vandetanib,
Vardenafil, Vemurafenib, Venlafaxine, Voriconazole, Vorinostat, or
Ziprasidone.
12. A composition for preventing or treating a diseases with an
active agent or drug that causes one or more adverse reactions
arising from administration of an active agent or drug in a human
that causes at least one of cardiac channelopathies, I.sub.Kr
channel inhibition or QT prolongation comprising: an amount of a
lysophosphatidylglycerol with a basic structure: ##STR00004##
wherein R.sup.1 or R.sup.2 can be any even or odd-chain fatty acid,
and R.sup.3 can be H, acyl, alkyl, aryl, amino acid, alkenes,
alkynes, adapted for oral administration effective to reduce or
prevent the at least one cardiac channelopathies, I.sub.Kr channel
inhibition or QT prolongation caused by the drug; one or more
active agents or drugs that causes at least one of I.sub.Kr channel
inhibition or QT prolongation; and one or more organoleptic,
thixotropic, or both organoleptic and thixotropic agents.
13. The composition of claim 12, wherein the one or more
organoleptic agents include one or more flavorants, sweeteners,
coolants, dyes, or combinations and mixtures thereof.
14. The composition of claim 12, wherein the one or more
thixotropic agent forms a thixotrophic matrix and is selected from
at least one of polysaccharides, cellulose, carboxymethylcellulose,
gums, xanthan gum, collagen, gelatin, aerogels, polyacrylamide,
alkyd resins, or silica-lipids.
15. The composition of claim 12, wherein the phosphatidylglycerol
is formed into empty liposomes and have an average diameter of 10,
20, 25, 30, 40, 50, 60, 75, 80, 90, or 100 nM.
16. The composition of claim 12, wherein the phosphatidylglycerol
is 1-Myristoyl-2-Hydroxy-sn-Glycero-3-Phosphocholine (DMPC),
12-Mysteroyl-2-Hydroxy-sn-Glycero-3-[Phospho-rac-(glycerol)]
(DMPG), or DMPC/DMPG, formed into liposomes with an average
diameter of 10, 20, 25, 30, 40, 50, 60, 75, 80, 90, or 100 nM.
17. The composition of claim 12, wherein the cardiac channelopathy
or the condition resulting from the irregularity or alteration in
the cardiac pattern is inhibition of an ion channel responsible for
the delayed-rectifier K.sup.+ current in the heart, polymorphic
ventricular tachycardia, prolongation of the QTc, LQT2, LQTS, or
torsades de pointes or the composition is used for the treatment or
prevention of prolongation of the I.sub.Kr channel inhibition or QT
prolongation induced by administration of one or more drugs used in
the treatment of cardiac, allergic, or cancer related disease.
18. The composition of claim 12, wherein the liposomes comprises a
lipid or a phospholipid wall, wherein the lipids or the
phospholipids are selected from the group consisting of
phosphatidylcholine (lecithin), lysolecithin,
lysophosphatidylethanol-amine, phosphatidylserine,
phosphatidylinositol, sphingomyelin, phosphatidylethanolamine
(cephalin), cardiolipin, phosphatidic acid, cerebrosides,
dicetylphosphate, phosphatidylcholine, and
dipalmitoyl-phosphatidylglycerol, stearylamine, dodecylamine,
hexadecyl-amine, acetyl palmitate, glycerol ricinoleate, hexadecyl
sterate, isopropyl myristate, amphoteric acrylic polymers, fatty
acid, fatty acid amides, cholesterol, cholesterol ester,
diacylglycerol, and diacylglycerol succinate.
19. The composition of claim 12, wherein the drug is selected from
Albuterol (salbutamol), Alfuzosin, Amantadine, Amiodarone,
Amisulpride, Amitriptyline, Amoxapine, Amphetamine, Anagrelide,
Apomorphine, Arformoterol, Aripiprazole, Arsenic trioxide,
Astemizole, Atazanavir, Atomoxetine, Azithromycin, Bedaquiline,
Bepridil, Bortezomib, Bosutinib, Chloral hydrate, Chloroquine,
Chlorpromazine, Ciprofloxacin, Cisapride, Citalopram,
Clarithromycin, Clomipramine, Clozapine, Cocaine, Crizotinib,
Dabrafenib, Dasatinib, Desipramine, Dexmedetomidine,
Dexmethylphenidate, Dextroamphetamine (d-Amphetamine),
Dihydroartemisinin+piperaquine, Diphenhydramine, Disopyramide,
Dobutamine, Dofetilide, Dolasetron, Domperidone, Dopamine, Doxepin,
Dronedarone, Droperidol, Ephedrine, Epinephrine (Adrenaline),
Eribulin, Erythromycin, Escitalopram, Famotidine, Felbamate,
Fenfluramine, Fingolimod, Flecainide, Fluconazole, Fluoxetine,
Formoterol, Foscarnet, Fosphenytoin, Furosemide (Frusemide),
Galantamine, Gatifloxacin, Gemifloxacin, Granisetron, Halofantrine,
Haloperidol, Hydrochlorothiazide, Ibutilide, Iloperidone,
Imipramine (melipramine), Indapamide, Isoproterenol, Isradipine,
Itraconazole, Ivabradine, Ketoconazole, Lapatinib, Levalbuterol
(levsalbutamol), Levofloxacin, Levomethadyl, Lisdexamfetamine,
Lithium, Mesoridazine, Metaproterenol, Methadone, Methamphetamine
(methamfetamine), Methylphenidate, Midodrine, Mifepristone,
Mirabegron, Mirtazapine, Moexipril/HCTZ, Moxifloxacin, Nelfinavir,
Nicardipine, Nilotinib, Norepinephrine (noradrenaline),
Norfloxacin, Nortriptyline, Ofloxacin, Olanzapine, Ondansetron,
Oxytocin, Paliperidone, Paroxetine, Pasireotide, Pazopanib,
Pentamidine, Perflutren lipid microspheres, Phentermine,
Phenylephrine, Phenylpropanolamine, Pimozide, Posaconazole,
Probucol, Procainamide, Promethazine, Protriptyline,
Pseudoephedrine, Quetiapine, Quinidine, Quinine sulfate,
Ranolazine, Rilpivirine, Risperidone, Ritodrine, Ritonavir,
Roxithromycin, Salmeterol, Saquinavir, Sertindole, Sertraline,
Sevoflurane, Sibutramine, Solifenacin, Sorafenib, Sotalol,
Sparfloxacin, Sulpiride, Sunitinib, Tacrolimus, Tamoxifen,
Telaprevir, Telavancin, Telithromycin, Terbutaline, Terfenadine,
Tetrabenazine, Thioridazine, Tizanidine, Tolterodine, Toremifene,
Trazodone, Trimethoprim-Sulfa, Trimipramine, Vandetanib,
Vardenafil, Vemurafenib, Venlafaxine, Voriconazole, Vorinostat, or
Ziprasidone.
20. A method for preventing or treating one or more cardiac
channelopathies, irregularities or alterations in cardiac patterns,
I.sub.Kr channel inhibition or QT prolongation, in a human or
animal subject caused by an active agent or drug, wherein the
active agent or drug are used to treat a disease in a human or
animal subject comprising the steps of: administering to the human
or animal subject an amount of a lysophosphatidylglycerol adapted
for oral administration effective to reduce or prevent one or
cardiac channelopathies, irregularities or alterations in cardiac
patterns, I.sub.Kr channel inhibition, or QT prolongation caused by
the active agent or drug; an effective amount of the active agent
or drug sufficient to treat the disease, wherein the orally
provided lysophosphatidylglycerol reduces or eliminates the at
least one cardiac channelopathies, irregularities or alterations in
cardiac patterns, I.sub.Kr channel inhibition or QT prolongation;
and one or more organoleptic, thixotropic, or both organoleptic and
thixotropic agents.
21. The method of claim 20, wherein the phosphatidylglycerol
includes at least one of a lysophosphatidylcholine,
lauroyl-lysophosphatidylcholine, myristoyl-lysophosphatidylcholine,
palmitoyl-lysophosphatidylcholine,
stearoyl-lysophosphatidylcholine,
arachidoyl-lysophosphatidylcholine, oleoyl-lysophosphatidylcholine,
linoleoyl-lysophosphatidylcholine,
linolenoyl-lysophosphatidylcholine or
erucoyl-lysophosphatidylcholine.
22.-26. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional patent application of U.S.
patent application Ser. No. 15/788,683 filed on Oct. 19, 2017,
which is a continuation-in-part patent application of U.S. patent
application Ser. No. 15/297,901 filed on Oct. 19, 2016, which is a
continuation-in-part of U.S. patent application Ser. No. 14/729,940
filed on Jun. 3, 2015, which claims priority to U.S. Provisional
Application Ser. No. 62/007,244 filed on Jun. 3, 2014, U.S.
Provisional Application Ser. No. 62/035,417 filed on Aug. 9, 2014,
U.S. Provisional Application Ser. No. 62/056,957 filed on Sep. 29,
2014, and U.S. Provisional Application Ser. No. 62/150,059 filed on
Apr. 20, 2015. This application is also a divisional patent
application of Ser. No. 15/788,683, which is a continuation-in-part
patent application of U.S. patent application Ser. No. 14/575,644
filed on Dec. 18, 2014, which claims priority to U.S. Provisional
Application Ser. No. 61/917,426 filed on Dec. 18, 2013 and U.S.
Provisional Application Ser. No. 61/977,417 filed on Apr. 9, 2014.
This application is also a divisional patent application of Ser.
No. 15/788,683, which is a continuation-in-part application of U.S.
patent application Ser. No. 15/597,411 filed on May 17, 2017, which
is a continuation application of U.S. patent application Ser. No.
15/068,300 filed on Mar. 11, 2016, which is a continuation
application of U.S. patent application Ser. No. 14/268,376 filed on
May 2, 2014, now U.S. Pat. No. 9,682,041 issued on Jun. 20, 2017,
which is a continuation application that claims priority to U.S.
patent application Ser. No. 13/487,233 filed on Jun. 3, 2012, now
U.S. Pat. No. 8,753,674 issued on Jun. 17, 2014, which claims
priority to U.S. Provisional Application Ser. No. 61/493,257 filed
on Jun. 3, 2011, the entire contents of which are incorporated
herein by reference.
STATEMENT OF FEDERALLY FUNDED RESEARCH
[0002] None.
INCORPORATION-BY-REFERENCE OF MATERIALS FILED ON COMPACT DISC
[0003] None.
TECHNICAL FIELD OF THE INVENTION
[0004] The present invention relates in general to the field of
drug treatment, and more particularly, to novel compositions and
methods for reducing or eliminating channelopathies or conditions
resulting from irregularities or alterations in cardiac patterns
caused by an active agent or a drug, and one or more organoleptic,
thixotropic, or both organoleptic and thixotropic agents.
BACKGROUND OF THE INVENTION
[0005] Without limiting the scope of the invention, its background
is described in connection with compositions and methods for
controlling the duration of repolarization of the cardiac ventricle
QT in a subject comprising administering to subject in need thereof
of a modification of or functional interference with a therapeutic
agent, or congenital defect which if unmodified can induce
prolongation of repolarization in the heart myocyte action
potential, torsade de points, and the long QT syndrome.
[0006] The beating of the heart is due to precisely controlled
regularly spaced waves of myocardial excitation and contraction.
The electrical currents during ion-based depolarization and
repolarization can be measured by electrical leads placed on the
body in specific locations (the electrocardiogram) which measure
electrical waves. The P-wave represents a wave of depolarization in
the atrium. When the entire atria becomes depolarized, the wave
returns to zero. After 0.1 seconds the ventricle is entirely
depolarized resulting in the QRS complex. The three peaks are due
to the way the current spreads in the ventricles. This is followed
by the T-wave or repolarization of the ventricle. The QT interval
measured from the beginning of the QRS complex to the end of the T
wave on the standard ECG represents the duration till the
completion of the repolarization phase of the cardiac myocyte (or
the depolarization and repolarization of the ventricle). The
duration of this interval can vary due to genetic variation,
cardiac disease, electrolyte balance, envenomation, and drugs.
Prolongation of the QT interval can result in ventricular
arrhythmias and sudden death.
[0007] Drug induced long QTc Syndrome (LQTS) i.e., a prolongation
of the action potential duration is a common cause of governmental
mandated drug withdrawal. QTc prolongation is an unpredictable risk
factor for Torsades de Pointes (TdP), a polymorphic ventricular
tachycardia leading to ventricular fibrillation. Drug induced LQTS
comprises about 3% of all prescriptions which when followed by TdP
may constitute a lethal adverse reaction. Patients taking one or
more than one QTc-prolonging drug concomitantly, have an enhanced
risk of TdP. While the overall occurrence of TdP is statistically
rare but clinically significant for the affected individual, assay
for this drug effect is a mandatory requirement prior to allowing a
drug to enter clinical trials.
[0008] Common structurally diverse drugs block the human
ether-a-go-go-related gene (KCNH2 or hERG) coded K.sup.+ channel
and the cardiac delayed-rectifier potassium current I.sub.K
(KV11.1) resulting in acquired LQTS. Drug-associated increased risk
of LQTS is a major drug development hurdle and many drugs have been
withdrawn during pre-clinical development, or assigned black box
warnings following approval or withdrawn from the market. Autosomal
recessive or dominant LQTS based upon 500 possible mutations in 10
different genes coding for the potassium channel has an incidence
of 1:3000 or about 100,000 persons in the US. Prolonged QT
intervals, or risk of LQTS occur in 2.5% of the asymptomatic US
population. This syndrome when expressed can lead to severe cardiac
arrhythmia and sudden death in untreated patients. The probability
of cardiac death in patients with asymptomatic congenital LQTS who
are medicated with LQTS-inducing drugs is increased.
[0009] The majority of the acquired LTQS drug withdrawals are due
to obstruction of the potassium ion channels coded by the human
ether-a-go-go related gene (hERG). High concentrations of hERG
blocking drugs generally induce a prolonged QTc interval and
increase the probability of TdP. Up to 10% of cases of drug-induced
TdP can be due to due to 13 major genetic mutations, 471 different
mutations, and 124 polymorphisms (Chig, C 2006).
[0010] Systems and methods for detection of LQTS have been
described previously. For example U.S. Patent Publication No.
2010/0004549 (Kohls et al. 2010) discloses a system and method of
detecting LQTS in a patient by comparing a collected set of ECG
data from the patient to a plurality of databases of collected ECG
data. The plurality of databases will include a database containing
previous ECGs from the patient, a known acquired LQTS
characteristics database, and a known genetic LQTS characteristics
database. Comparing the patient's ECG to these databases will
facilitate the detection of such occurrences as changes in QT
interval from success of ECGs, changes in T-wave morphology,
changes in U-wave morphology, and can match known genetic patterns
of LQTS. The system and method is sensitive to patient gender and
ethnicity, as these factors have been shown to effect LQTS, and is
furthermore capable of matching a QT duration to a database of drug
effects. The system and method is also easily integrated into
current ECG management systems and storage devices.
[0011] A system and method for the diagnosis and treatment of LQTS
is described in U.S.
[0012] Patent Publication No. 2008/0255464 (Michael, 2008). The
Michael invention includes a system for diagnosing Long QT Syndrome
(LQTS) derives a QT/QS2 ratio from an electrical systole (QT) and a
mechanical systole (QS2) to detect a prolonged QT interval in a
patient's cardiac cycle. A processor acquires the systoles from a
microphone and chest electrodes, calculates the QT/QS2 ratio, and
outputs the result to a display. The processor may compare the
QT/QS2 ratio to a threshold value stored in memory for diagnosing
LQTS in the patient. A user interface provides for programming,
set-up, and customizing the display. A mode selector allows the
system to operate alternatively as a phonocardiograph, a 12 lead
electrocardiograph, or a machine for diagnosing LQTS. A related
method for diagnosing cardiac disorders such as LQTS includes
measuring QT and QS2 during a same cardiac cycle, calculating a
QT/QS2 ratio, and comparing the result to a threshold value derived
from empirical data. The method may include measuring systoles both
at rest and during exercise, and may be used for drug efficacy,
dosage optimization, and acquired LQTS causality tests.
[0013] A method for the treatment of cardiac arrhythmias is
provided in U.S. Patent Publication No. 2007/0048284 (Donahue and
Marban, 2007). The method includes administering an amount of at
least one polynucleotide that modulates an electrical property of
the heart. The polynucleotides of the invention may also be used
with a microdelivery vehicle such as cationic liposomes and
adenoviral vectors.
[0014] Methods, compositions, dosing regimes, and routes of
administration for the treatment or prevention of arrhythmias have
been described by Fedida et al. (2010) in U.S. Patent Publication
No. 2001/00120890. In the Fedida invention, early after
depolarizations and prolongation of QT interval may be reduced or
eliminated by administering ion channel modulating compounds to a
subject in need thereof. The ion channel modulating compounds may
be cycloalkylamine ether compounds, particularly cyclohexylamine
ether compounds. Also described are compositions of ion channel
modulating compounds and drugs which induce early after
depolarizations, prolongation of QT interval and/or Torsades de
Pointes. The Fedida invention also discloses antioxidants which may
be provided in combination with the ion channel modulating
compounds, non-limiting examples of the antioxidants include
vitamin C, vitamin E, beta-carotene, lutein, lycopene, vitamin B2,
coenzyme Q10, cysteine as well as herbs, such as bilberry, turmeric
(curcumin), grape seed or pine bark extracts, and ginkgo.
SUMMARY OF THE INVENTION
[0015] In one embodiment, the present invention includes a
composition for preventing one or more cardiac channelopathies or
conditions resulting from irregularities or alterations in cardiac
patterns caused by an active agent or a drug in a human or animal
subject comprising: an amount of a phosphatidylglycerol adapted for
oral administration effective to reduce or prevent one or more
cardiac channelopathies or conditions resulting from irregularities
or alterations in cardiac patterns caused by the active agent or
drug; and one or more organoleptic, thixotropic, or both
organoleptic and thixotropic agents. In one aspect, the
organoleptic agents include one or more flavorants, sweeteners,
coolants, dyes, or combinations and mixtures thereof. Moreover, it
has been found that in a powder dried according to the invention
undesired organoleptic changes have been hardly effected, if
effected at all, and that a powder dried according to the invention
has sufficient solubility for various applications. In one aspect,
the thixotropic agent forms a thixotrophic matrix, e.g.,
polysaccharides such as cellulose (e.g., carboxymethylcellulose) or
gums (e.g., xanthan), collagen, gelatin, aerogels, polyacrylamide,
alkyd resins, and silica-lipids. In one aspect, the composition
includes both organoleptic and thixotropic agents. In one aspect,
the phosphatidylglycerol is provided in the form of empty liposomes
with a diameter of 10, 20, 25, 30, 40, 50, 60, 75, 80, 90, or 100
nM, e.g., 1-Myristoyl-2-Hydroxy-sn-Glycero-3-Phosphocholine (DMPC),
12-Mysteroyl-2-Hydroxy-sn-Glycero-3-[Phospho-rac-(glycerol)]
(DMPG), or DMPC/DMPG liposomes. In one aspect, the
lysophosphatidylglycerol includes at least one of a
lysophosphatidylcholine, lauroyl-lysophosphatidylcholine,
myristoyl-lysophosphatidylcholine,
palmitoyl-lysophosphatidylcholine,
stearoyl-lysophosphatidylcholine,
arachidoyl-lysophosphatidylcholine, oleoyl-lysophosphatidylcholine,
linoleoyl-lysophosphatidylcholine,
linolenoyl-lysophosphatidylcholine or
erucoyl-lysophosphatidylcholine; and one or more organoleptic or
thixotropic agents.
[0016] A method according to the invention is thus suitable for
preparing a product consumable without health risks, optionally
after reconstitution in a suitable liquid. In another aspect, the
lysophosphatidylglycerol include at least one or
1-Myristoyl-2-Hydroxy-sn-Glycero-3-Phosphocholine (DMPC),
12-Mysteroyl-2-Hydroxy-sn-Glycero-3-[Phospho-rac-(glycerol)]
(DMPG), DMPC/DMPG,
1-myristoyl-2-hydroxy-sn-glycero-3-phospho-(1'-rac-glycerol)
(LysoPG), or 1-myristoyl-2-hydroxy-sn-glycero-3-phosphocholine
(LysoPC). In one aspect, the organoleptic agents include one or
more flavorants, sweeteners, coolants, dyes, or combinations and
mixtures thereof. Moreover, it has been found that in a powder
dried according to the invention undesired organoleptic changes
have been hardly effected, if effected at all, and that a powder
dried according to the invention has sufficient solubility for
various applications. In one aspect, the thixotropic agent forms a
thixotrophic matrix, e.g., polysaccharides such as cellulose (e.g.,
carboxymethylcellulose) or gums (e.g., xanthan), collagen, gelatin,
aerogels, polyacrylamide, alkyd resins, and silica-lipids. In one
aspect, the composition includes both organoleptic and thixotropic
agents. In one aspect, the phosphatidylglycerol is provided in the
form of empty liposomes with a diameter of 10, 20, 25, 30, 40, 50,
60, 75, 80, 90, or 100 nM, e.g.,
1-Myristoyl-2-Hydroxy-sn-Glycero-3-Phosphocholine (DMPC),
12-Mysteroyl-2-Hydroxy-sn-Glycero-3-[Phospho-rac-(glycerol)]
(DMPG), or DMPC/DMPG liposomes.
[0017] In another aspect, the drug is selected from Albuterol
(salbutamol), Alfuzosin, Amantadine, Amiodarone, Amisulpride,
Amitriptyline, Amoxapine, Amphetamine, Anagrelide, Apomorphine,
Arformoterol, Aripiprazole, Arsenic trioxide, Astemizole,
Atazanavir, Atomoxetine, Azithromycin, Bedaquiline, Bepridil,
Bortezomib, Bosutinib, Chloral hydrate, Chloroquine,
Chlorpromazine, Ciprofloxacin, Cisapride, Citalopram,
Clarithromycin, Clomipramine, Clozapine, Cocaine, Crizotinib,
Dabrafenib, Dasatinib, Desipramine, Dexmedetomidine,
Dexmethylphenidate, Dextroamphetamine (d-Amphetamine),
Dihydroartemisinin+piperaquine, Diphenhydramine, Disopyramide,
Dobutamine, Dofetilide, Dolasetron, Domperidone, Dopamine, Doxepin,
Dronedarone, Droperidol, Ephedrine, Epinephrine (Adrenaline),
Eribulin, Erythromycin, Escitalopram, Famotidine, Felbamate,
Fenfluramine, Fingolimod, Flecainide, Fluconazole, Fluoxetine,
Formoterol, Foscarnet, Fosphenytoin, Furosemide (Frusemide),
Galantamine, Gatifloxacin, Gemifloxacin, Granisetron, Halofantrine,
Haloperidol, Hydrochlorothiazide, Ibutilide, Iloperidone,
Imipramine (melipramine), Indapamide, Isoproterenol, Isradipine,
Itraconazole, Ivabradine, Ketoconazole, Lapatinib, Levalbuterol
(levsalbutamol), Levofloxacin, Levomethadyl, Lisdexamfetamine,
Lithium, Mesoridazine, Metaproterenol, Methadone, Methamphetamine
(methamfetamine), Methylphenidate, Midodrine, Mifepristone,
Mirabegron, Mirtazapine, Moexipril/HCTZ, Moxifloxacin, Nelfinavir,
Nicardipine, Nilotinib, Norepinephrine (noradrenaline),
Norfloxacin, Nortriptyline, Ofloxacin, Olanzapine, Ondansetron,
Oxytocin, Paliperidone, Paroxetine, Pasireotide, Pazopanib,
Pentamidine, Perflutren lipid microspheres, Phentermine,
Phenylephrine, Phenylpropanolamine, Pimozide, Posaconazole,
Probucol, Procainamide, Promethazine, Protriptyline,
Pseudoephedrine, Quetiapine, Quinidine, Quinine sulfate,
Ranolazine, Rilpivirine, Risperidone, Ritodrine, Ritonavir,
Roxithromycin, Salmeterol, Saquinavir, Sertindole, Sertraline,
Sevoflurane, Sibutramine, Solifenacin, Sorafenib, Sotalol,
Sparfloxacin, Sulpiride, Sunitinib, Tacrolimus, Tamoxifen,
Telaprevir, Telavancin, Telithromycin, Terbutaline, Terfenadine,
Tetrabenazine, Thioridazine, Tizanidine, Tolterodine, Toremifene,
Trazodone, Trimethoprim-Sulfa, Trimipramine, Vandetanib,
Vardenafil, Vemurafenib, Venlafaxine, Voriconazole, Vorinostat, or
Ziprasidone.
[0018] In one embodiment, the present invention includes a
composition for preventing or treating diseases with an active
agent or drug that causes one or more adverse reactions arising
from administration of an active agent or drug in a human that
causes at least one of cardiac channelopathies, I.sub.Kr channel
inhibition or QT prolongation comprising:
an amount of a lysophosphatidylglycerol with a basic structure:
##STR00001##
wherein R.sup.1 or R.sup.2 can be any even or odd-chain fatty acid,
and R.sup.3 can be H, acyl, alkyl, aryl, amino acid, alkenes,
alkynes, adapted for oral administration effective to reduce or
prevent the at least one cardiac channelopathies, I.sub.Kr channel
inhibition or QT prolongation caused by the drug; and one or more
active agents or drugs that cause at least one of I.sub.Kr channel
inhibition or QT prolongation and one or more organoleptic,
thixotropic, or both organoleptic and thixotropic agents. In one
aspect, the organoleptic agents include one or more flavorants,
sweeteners, coolants, dyes, or combinations and mixtures thereof.
Moreover, it has been found that in a powder dried according to the
invention undesired organoleptic changes have been hardly effected,
if effected at all, and that a powder dried according to the
invention has sufficient solubility for various applications. In
one aspect, the thixotropic agent forms a thixotrophic matrix,
e.g., polysaccharides such as cellulose (e.g.,
carboxymethylcellulose) or gums (e.g., xanthan), collagen, gelatin,
aerogels, polyacrylamide, alkyd resins, and silica-lipids. In one
aspect, the composition includes both organoleptic and thixotropic
agents. In one aspect, the phosphatidylglycerol is provided in the
form of empty liposomes with a diameter of 10, 20, 25, 30, 40, 50,
60, 75, 80, 90, or 100 nM, e.g.,
1-Myristoyl-2-Hydroxy-sn-Glycero-3-Phosphocholine (DMPC),
12-Mysteroyl-2-Hydroxy-sn-Glycero-3-[Phospho-rac-(glycerol)]
(DMPG), or DMPC/DMPG liposomes. In one aspect, the
lysophosphatidylglycerol includes at least one of a
lysophosphatidylcholine, lauroyl-lysophosphatidylcholine,
myristoyl-lysophosphatidylcholine,
palmitoyl-lysophosphatidylcholine,
stearoyl-lysophosphatidylcholine,
arachidoyl-lysophosphatidylcholine, oleoyl-lysophosphatidylcholine,
linoleoyl-lysophosphatidylcholine,
linolenoyl-lysophosphatidylcholine or
erucoyl-lysophosphatidylcholine. In another aspect, the liposome or
liposome precursors are selected from at least one or
1-Myristoyl-2-Hydroxy-sn-Glycero-3-Phosphocholine (DMPC),
12-Mysteroyl-2-Hydroxy-sn-Glycero-3-[Phospho-rac-(glycerol)]
(DMPG), DMPC/DMPG,
1-myristoyl-2-hydroxy-sn-glycero-3-phospho-(1'-rac-glycerol)
(LysoPG), or 1-myristoyl-2-hydroxy-sn-glycero-3-phosphocholine
(LysoPC). In another aspect, the short chain fatty acid is up to 5
carbons, a medium chain is 6 to 12 carbons, a long chain is 13-21
carbons and a very long chain fatty acid is greater than 22
carbons, including both even and odd chain fatty acids. In another
aspect, the short chain fatty acid has 3, 4, 5, 6, 7, 8, 9, 10, 11,
12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,
29, 30, 35, 40, 45, 50, 55 or more carbons, which are saturated or
unsaturated. In another aspect, the cardiac channelopathy or the
condition resulting from the irregularity or alteration in the
cardiac pattern is inhibition of an ion channel responsible for the
delayed-rectifier K.sup.+ current in the heart, polymorphic
ventricular tachycardia, prolongation of the QTc, LQT2, LQTS, or
torsades de pointes. In another aspect, the composition is used for
the treatment or prevention of prolongation of the I.sub.Kr channel
inhibition or QT prolongation induced by administration of one or
more drugs used in the treatment of cardiac, allergic, or cancer
related disease. In another aspect, the one or more active agents
is selected from at least one of crizotinib, nilotinib,
terfenadine, astemizole, gripafloxacin, terodilene, droperidole,
lidoflazine, levomethadyl, sertindoyle or cisapride. In another
aspect, the active agent or drug is provided enterally,
parenterally, intravenously, intraperitoneally, or orally. In
another aspect, the liposomes comprises a lipid or a phospholipid
wall, wherein the lipids or the phospholipids are selected from the
group consisting of phosphatidylcholine (lecithin), lysolecithin,
lysophosphatidylethanol-amine, phosphatidylserine,
phosphatidylinositol, sphingomyelin, phosphatidylethanolamine
(cephalin), cardiolipin, phosphatidic acid, cerebrosides,
dicetylphosphate, phosphatidylcholine, and
dipalmitoyl-phosphatidylglycerol, stearylamine, dodecylamine,
hexadecyl-amine, acetyl palmitate, glycerol ricinoleate, hexadecyl
sterate, isopropyl myristate, amphoteric acrylic polymers, fatty
acid, fatty acid amides, cholesterol, cholesterol ester,
diacylglycerol, and diacylglycerolsuccinate. In another aspect, the
drug is selected from Albuterol (salbutamol), Alfuzosin,
Amantadine, Amiodarone, Amisulpride, Amitriptyline, Amoxapine,
Amphetamine, Anagrelide, Apomorphine, Arformoterol, Aripiprazole,
Arsenic trioxide, Astemizole, Atazanavir, Atomoxetine,
Azithromycin, Bedaquiline, Bepridil, Bortezomib, Bosutinib, Chloral
hydrate, Chloroquine, Chlorpromazine, Ciprofloxacin, Cisapride,
Citalopram, Clarithromycin, Clomipramine, Clozapine, Cocaine,
Crizotinib, Dabrafenib, Dasatinib, Desipramine, Dexmedetomidine,
Dexmethylphenidate, Dextroamphetamine (d-Amphetamine),
Dihydroartemisinin+piperaquine, Diphenhydramine, Disopyramide,
Dobutamine, Dofetilide, Dolasetron, Domperidone, Dopamine, Doxepin,
Dronedarone, Droperidol, Ephedrine, Epinephrine (Adrenaline),
Eribulin, Erythromycin, Escitalopram, Famotidine, Felbamate,
Fenfluramine, Fingolimod, Flecainide, Fluconazole, Fluoxetine,
Formoterol, Foscarnet, Fosphenytoin, Furosemide (Frusemide),
Galantamine, Gatifloxacin, Gemifloxacin, Granisetron, Halofantrine,
Haloperidol, Hydrochlorothiazide, Ibutilide, Iloperidone,
Imipramine (melipramine), Indapamide, Isoproterenol, Isradipine,
Itraconazole, Ivabradine, Ketoconazole, Lapatinib, Levalbuterol
(levsalbutamol), Levofloxacin, Levomethadyl, Lisdexamfetamine,
Lithium, Mesoridazine, Metaproterenol, Methadone, Methamphetamine
(methamfetamine), Methylphenidate, Midodrine, Mifepristone,
Mirabegron, Mirtazapine, Moexipril/HCTZ, Moxifloxacin, Nelfinavir,
Nicardipine, Nilotinib, Norepinephrine (noradrenaline),
Norfloxacin, Nortriptyline, Ofloxacin, Olanzapine, Ondansetron,
Oxytocin, Paliperidone, Paroxetine, Pasireotide, Pazopanib,
Pentamidine, Perflutren lipid microspheres, Phentermine,
Phenylephrine, Phenylpropanolamine, Pimozide, Posaconazole,
Probucol, Procainamide, Promethazine, Protriptyline,
Pseudoephedrine, Quetiapine, Quinidine, Quinine sulfate,
Ranolazine, Rilpivirine, Risperidone, Ritodrine, Ritonavir,
Roxithromycin, Salmeterol, Saquinavir, Sertindole, Sertraline,
Sevoflurane, Sibutramine, Solifenacin, Sorafenib, Sotalol,
Sparfloxacin, Sulpiride, Sunitinib, Tacrolimus, Tamoxifen,
Telaprevir, Telavancin, Telithromycin, Terbutaline, Terfenadine,
Tetrabenazine, Thioridazine, Tizanidine, Tolterodine, Toremifene,
Trazodone, Trimethoprim-Sulfa, Trimipramine, Vandetanib,
Vardenafil, Vemurafenib, Venlafaxine, Voriconazole, Vorinostat, or
Ziprasidone.
[0019] In one embodiment, the present invention includes a method
for preventing or treating one or more cardiac channelopathies,
irregularities or alterations in cardiac patterns, I.sub.Kr channel
inhibition or QT prolongation, in a human or animal subject caused
by an active agent or drug, wherein the active agents or drugs are
used to treat a disease in a human or animal subject comprising the
steps of: administering to the human or animal subject an amount of
a lysophosphatidylglycerol adapted for oral administration
effective to reduce or prevent one or cardiac channelopathies,
irregularities or alterations in cardiac patterns, I.sub.Kr channel
inhibition, or QT prolongation caused by the active agent or drug;
and an effective amount of the active agent or drug sufficient to
treat the disease, wherein the orally provided
lysophosphatidylglycerol reduces or eliminates the at least one
cardiac channelopathies, irregularities or alterations in cardiac
patterns, I.sub.Kr channel inhibition or QT prolongation and one or
more organoleptic, thixotropic, or both organoleptic and
thixotropic agents. In one aspect, the organoleptic agents include
one or more flavorants, sweeteners, coolants, dyes, or combinations
and mixtures thereof. Moreover, it has been found that in a powder
dried according to the invention undesired organoleptic changes
have been hardly effected, if effected at all, and that a powder
dried according to the invention has sufficient solubility for
various applications. In one aspect, the thixotropic agent forms a
thixotrophic matrix, e.g., polysaccharides such as cellulose (e.g.,
carboxymethylcellulose) or gums (e.g., xanthan), collagen, gelatin,
aerogels, polyacrylamide, alkyd resins, and silica-lipids. In one
aspect, the composition includes both organoleptic and thixotropic
agents. In one aspect, the phosphatidylglycerol is provided in the
form of empty liposomes with a diameter of 10, 20, 25, 30, 40, 50,
60, 75, 80, 90, or 100 nM, e.g.,
1-Myristoyl-2-Hydroxy-sn-Glycero-3-Phosphocholine (DMPC),
12-Mysteroyl-2-Hydroxy-sn-Glycero-3-[Phospho-rac-(glycerol)]
(DMPG), or DMPC/DMPG liposomes. In one aspect, the
lysophosphatidylglycerol includes at least one of a
lysophosphatidylcholine, lauroyl-lysophosphatidylcholine,
myristoyl-lysophosphatidylcholine,
palmitoyl-lysophosphatidylcholine,
stearoyl-lysophosphatidylcholine,
arachidoyl-lysophosphatidylcholine, oleoyl-lysophosphatidylcholine,
linoleoyl-lysophosphatidylcholine,
linolenoyl-lysophosphatidylcholine or
erucoyl-lysophosphatidylcholine. In another aspect, the liposome or
liposome precursor are selected from at least one or
1-Myristoyl-2-Hydroxy-sn-Glycero-3-Phosphocholine (DMPC),
12-Mysteroyl-2-Hydroxy-sn-Glycero-3-[Phospho-rac-(glycerol)]
(DMPG), DMPC/DMPG,
1-myristoyl-2-hydroxy-sn-glycero-3-phospho-(1'-rac-glycerol)
(LysoPG), or 1-myristoyl-2-hydroxy-sn-glycero-3-phosphocholine
(LysoPC). In another aspect, the short chain fatty acid is up to 5
carbons, a medium chain is 6 to 12 carbons, a long chain is 13-21
carbons and a very long chain fatty acid is greater than 22
carbons, including both even and odd chain fatty acids. In another
aspect, the short chain fatty acid has 3, 4, 5, 6, 7, 8, 9, 10, 11,
12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,
29, 30, 35, 40, 45, 50, 55 or more carbons, which are saturated or
unsaturated. In another aspect, the cardiac channelopathy or the
condition resulting from the irregularity or alteration in the
cardiac pattern is inhibition of an ion channel responsible for the
delayed-rectifier K.sup.+ current in the heart, polymorphic
ventricular tachycardia, prolongation of the QTc, LQT2, LQTS, or
torsades de pointes. In another aspect, the one or more active
agents is selected from at least one of crizotinib, nilotinib,
terfenadine, astemizole, gripafloxacin, terodilene, droperidole,
lidoflazine, levomethadyl, sertindoyle or cisapride. In another
aspect, the drug is selected from Albuterol (salbutamol),
Alfuzosin, Amantadine, Amiodarone, Amisulpride, Amitriptyline,
Amoxapine, Amphetamine, Anagrelide, Apomorphine, Arformoterol,
Aripiprazole, Arsenic trioxide, Astemizole, Atazanavir,
Atomoxetine, Azithromycin, Bedaquiline, Bepridil, Bortezomib,
Bosutinib, Chloral hydrate, Chloroquine, Chlorpromazine,
Ciprofloxacin, Cisapride, Citalopram, Clarithromycin, Clomipramine,
Clozapine, Cocaine, Crizotinib, Dabrafenib, Dasatinib, Desipramine,
Dexmedetomidine, Dexmethylphenidate, Dextroamphetamine
(d-Amphetamine), Dihydroartemisinin+piperaquine, Diphenhydramine,
Disopyramide, Dobutamine, Dofetilide, Dolasetron, Domperidone,
Dopamine, Doxepin, Dronedarone, Droperidol, Ephedrine, Epinephrine
(Adrenaline), Eribulin, Erythromycin, Escitalopram, Famotidine,
Felbamate, Fenfluramine, Fingolimod, Flecainide, Fluconazole,
Fluoxetine, Formoterol, Foscarnet, Fosphenytoin, Furosemide
(Frusemide), Galantamine, Gatifloxacin, Gemifloxacin, Granisetron,
Halofantrine, Haloperidol, Hydrochlorothiazide, Ibutilide,
Iloperidone, Imipramine (melipramine), Indapamide, Isoproterenol,
Isradipine, Itraconazole, Ivabradine, Ketoconazole, Lapatinib,
Levalbuterol (levsalbutamol), Levofloxacin, Levomethadyl,
Lisdexamfetamine, Lithium, Mesoridazine, Metaproterenol, Methadone,
Methamphetamine (methamfetamine), Methylphenidate, Midodrine,
Mifepristone, Mirabegron, Mirtazapine, Moexipril/HCTZ,
Moxifloxacin, Nelfinavir, Nicardipine, Nilotinib, Norepinephrine
(noradrenaline), Norfloxacin, Nortriptyline, Ofloxacin, Olanzapine,
Ondansetron, Oxytocin, Paliperidone, Paroxetine, Pasireotide,
Pazopanib, Pentamidine, Perflutren lipid microspheres, Phentermine,
Phenylephrine, Phenylpropanolamine, Pimozide, Posaconazole,
Probucol, Procainamide, Promethazine, Protriptyline,
Pseudoephedrine, Quetiapine, Quinidine, Quinine sulfate,
Ranolazine, Rilpivirine, Risperidone, Ritodrine, Ritonavir,
Roxithromycin, Salmeterol, Saquinavir, Sertindole, Sertraline,
Sevoflurane, Sibutramine, Solifenacin, Sorafenib, Sotalol,
Sparfloxacin, Sulpiride, Sunitinib, Tacrolimus, Tamoxifen,
Telaprevir, Telavancin, Telithromycin, Terbutaline, Terfenadine,
Tetrabenazine, Thioridazine, Tizanidine, Tolterodine, Toremifene,
Trazodone, Trimethoprim-Sulfa, Trimipramine, Vandetanib,
Vardenafil, Vemurafenib, Venlafaxine, Voriconazole, Vorinostat, or
Ziprasidone.
[0020] In one embodiment, the present invention includes a method
for preventing or treating one or more adverse reactions arising
from administration of a therapeutically active agent or a drug in
a human or animal subject comprising the steps of: administering to
the human or animal subject an amount of an amount of a
lysophosphatidylglycerol with a basic structure:
##STR00002##
wherein R.sup.1 or R.sup.2 can be any even or odd-chain fatty acid,
and R.sup.3 can be H, acyl, alkyl, aryl, amino acid, alkenes,
alkynes, adapted for oral administration effective to reduce or
prevent the at least one cardiac channelopathies, I.sub.Kr channel
inhibition or QT prolongation caused by the drug; and adapted for
oral administration effective to reduce or prevent one or more
cardiac channelopathies or conditions resulting from irregularities
or alterations in cardiac patterns caused by the drug; and
measuring the effect of the combination of the
lysophosphatidylglycerol and the therapeutically active agent or
the drug on the drug-induced channelopathy, wherein the composition
reduces or eliminated the channelopathy induced by the
therapeutically active agent or the drug, and one or more
organoleptic, thixotropic, or both organoleptic and thixotropic
agents. In one aspect, the organoleptic agents include one or more
flavorants, sweeteners, coolants, dyes, or combinations and
mixtures thereof. Moreover, it has been found that in a powder
dried according to the invention undesired organoleptic changes
have been hardly effected, if effected at all, and that a powder
dried according to the invention has sufficient solubility for
various applications. In one aspect, the thixotropic agent forms a
thixotrophic matrix, e.g., polysaccharides such as cellulose (e.g.,
carboxymethylcellulose) or gums (e.g., xanthan), collagen, gelatin,
aerogels, polyacrylamide, alkyd resins, and silica-lipids. In one
aspect, the composition includes both organoleptic and thixotropic
agents. In one aspect, the phosphatidylglycerol is provided in the
form of empty liposomes with a diameter of 10, 20, 25, 30, 40, 50,
60, 75, 80, 90, or 100 nM, e.g.,
1-Myristoyl-2-Hydroxy-sn-Glycero-3-Phosphocholine (DMPC),
12-Mysteroyl-2-Hydroxy-sn-Glycero-3-[Phospho-rac-(glycerol)]
(DMPG), or DMPC/DMPG liposomes.
BRIEF DESCRIPTION OF THE DRAWINGS
[0021] For a more complete understanding of the features and
advantages of the present invention, reference is now made to the
detailed description of the invention along with the accompanying
figures and in which:
[0022] FIG. 1 is a graph that shows the effect of DMPC,
DMPC+Nilotinib and Nilotinib on hERG current density from
transfected HEK 293 cells.
[0023] FIG. 2 is a graph that shows the effect of DMPG,
DMPG+Nilotinib and Nilotinib on hERG current density from
transfected HEK 293 cells.
[0024] FIG. 3 is a graph that shows the effect of DMPC/DMPG,
DMPC/DMPG+Nilotinib and Nilotinib on hERG current density from
transfected HEK 293 cells.
[0025] FIG. 4 is a graph that shows the effect of LysoPC,
LysoPC+Nilotinib and Nilotinib on hERG current density from
transfected HEK 293 cells.
[0026] FIG. 5 is a graph that shows the effect of LysoPG,
LysoPG+Nilotinib and Nilotinib on hERG current density from
transfected HEK 293 cells.
[0027] FIG. 6 is a graph that shows the effect of DMPC,
DMPC+Nilotinib, DMPC+Nilotinib (in DMSO) and Nilotinib on hERG
current density from transfected HEK 293 cells.
[0028] FIG. 7 is a graph that shows the effect of DMPG,
DMPG+Nilotinib, DMPG+Nilotinib (in DMSO) and Nilotinib on hERG
current density from transfected HEK 293 cells.
DETAILED DESCRIPTION OF THE INVENTION
[0029] While the making and using of various embodiments of the
present invention are discussed in detail below, it should be
appreciated that the present invention provides many applicable
inventive concepts that can be embodied in a wide variety of
specific contexts. The specific embodiments discussed herein are
merely illustrative of specific ways to make and use the invention
and do not delimit the scope of the invention.
[0030] To facilitate the understanding of this invention, a number
of terms are defined below. Terms defined herein have meanings as
commonly understood by a person of ordinary skill in the areas
relevant to the present invention. Terms such as "a", "an" and
"the" are not intended to refer to only a singular entity, but
include the general class of which a specific example may be used
for illustration. The terminology herein is used to describe
specific embodiments of the invention, but their usage does not
delimit the invention, except as outlined in the claims.
[0031] As used herein, the term "thixotropic" is used to describe
one or more agents, e.g., certain gels, which liquefy when
subjected to vibratory forces like simple shaking, and then
solidify again when left standing. Thixotropic behavior is observed
when long-chain molecules tend to orient themselves in the
direction of flow; as the applied force is increased, the
resistance to flow is decreased. Yet when high shear stress is
removed, the solution will quickly revert to its original viscous
state. Some celluloses exhibit thixotropic behavior wherein the
solution returns to its viscous state over a period of time.
Examples of thixotropic agents for use with, e.g., food,
pharmaceuticals, are well known in the art, e.g., "A time-dependent
expression for thixotropic areas. Application to Aerosil 200
hydrogels," M. Dolz, F. Gonzalez, J. Delegido, M. J. Hernandez, J.
Pellicer, J. Pharm. Sci., Vol. 89, No. 6, pages 790-797 (2000),
relevant portions incorporated herein by reference. Numerous
examples of thixotropic agents, such as cellulose (e.g.,
carboxymethylcellulose), gums (e.g., xanthan), collagen, gelatin,
aerogels and others are well known in the art and may be used with
the present invention, e.g., U.S. Pat. Nos. 6,709,675; 6,838,449;
6,818,018, relevant portions incorporated herein by reference.
[0032] As used herein, an "organoleptic agent" refers to an
additive with sensory attributes of a food or beverage, in
particular the oral compositions provided herein. Those of skill in
the art understand such properties and they can be quantitated if
needed. Organoleptic properties include, but are not limited to,
taste, odor and/or appearance. "Desirable" organoleptic properties
include those organoleptic properties that make a food or beverage
composition desirable for consumption by an average human subject,
such as a desirable odor, taste and/or appearance, or the lack of
an undesirable odor, taste and/or appearance. Undesirable
organoleptic properties include the presence of, for example, an
undesirable taste, odor or appearance attribute, such as the
presence of an "off-taste" or "off-odor," for example a fishy,
grassy, metal or iron, sharp or tingling taste or odor, or the
presence of an undesirable appearance attribute, such as separation
or precipitation. In one example, the provided beverage
compositions retain the same or about the same taste, odor and/or
appearance as the same beverage composition that does not contain
the provided concentrates, that is, the provided beverage
compositions retain organoleptic properties desirable for
consumption by an average human subject. Desirable and undesirable
organoleptic properties can be measured by a variety of methods
known to those skilled in the art, including, for example,
organoleptic evaluation methods by which undesirable properties are
detectable by sight, taste and/or smell and chemical tests, as well
as by chemical analytical methods. For example, the provided
beverage compositions retain the same or about the same
organoleptic properties as the same beverage composition that does
not contain the provided concentrates over a period of time, for
example, at least or over 1, 2, 3, 4, 5, 6, or more days, at least
or over 1, 2, 3, 4, or more weeks, at least or over 1, 2, 3, 4, 5,
6, 7, 8, 9, 10, 11, 12, or more months, or at least or over 1, 2,
3, 4, or more years. As used herein, "retaining the organoleptic
properties" refers to retention of these properties upon storage
for a recited period of time, typically at room temperature.
[0033] Examples of suitable liquid dosage forms include solutions
or suspensions in water, pharmaceutically acceptable fats and oils,
alcohols or other organic solvents, including esters, emulsions,
syrups or elixirs, suspensions, solutions and/or suspensions
reconstituted from non-effervescent granules and effervescent
preparations reconstituted from effervescent granules. Such liquid
dosage forms may contain, for example, suitable solvents,
preservatives, emulsifying agents, suspending agents, diluents,
sweeteners, thickeners, and melting agents. Oral dosage forms
optionally contain flavorants and coloring agents. Parenteral and
intravenous forms may also include minerals and other materials to
make them compatible with the type of injection or delivery system
chosen.
[0034] Non-limiting exemplary lysophosphatidylglycerols for use
with the present invention include lysophosphatidylcholines,
lauroyl-lysophosphatidylcholine, myristoyl-lysophosphatidylcholine,
palmitoyl-lysophosphatidylcholine,
stearoyl-lysophosphatidylcholine,
arachidoyl-lysophosphatidylcholine, oleoyl-lysophosphatidylcholine,
linoleoyl-lysophosphatidylcholine,
linolenoyl-lysophosphatidylcholine or
erucoyl-lysophosphatidylcholine. Asymmetric phosphatidylcholines
are referred to as 1-acyl, 2-acyl-sn-glycero-3-phosphocholines,
wherein the acyl groups are different from each other. Symmetric
phosphatidylcholines are referred to as
1,2-diacyl-sn-glycero-3-phosphocholines. As used herein, the
abbreviation "PC" refers to phosphatidylcholine. The
phosphatidylcholine 1,2-dimyristoyl-sn-glycero-3-phosphocholine is
abbreviated herein as "DMPC." The phosphatidylcholine
1,2-dioleoyl-sn-glycero-3-phosphocholine is abbreviated herein as
"DOPC." The phosphatidylcholine
1,2-dipalmitoyl-sn-glycero-3-phosphocholine is abbreviated herein
as "DPPC." The single fatty acid chain version of these short or
long chain fatty acids are referred to as the "lyso" forms when
only a single fatty acid chain is attached to the glyceryl
backbone. In certain non-limiting examples, the
phosphatidylglycerols form liposomes that are empty and have a
diameter of 10, 20, 25, 30, 40, 50, 60, 75, 80, 90, or 100 nM.
[0035] As used herein, the term "additive" refers to a food,
beverage, or other human consumable that enhances one or more of
its nutritional, pharmaceutical, dietary, health, nutraceutical,
health benefit, energy-providing, treating, holistic, or other
properties such as dosing compliance. In certain embodiments of the
present invention users of the composition will need one or more
additional nutrients with the present invention. For example, the
additives can be oil-based additives (e.g., non-polar compounds),
such as nutraceuticals; pharmaceuticals; vitamins, for example,
oil-soluble vitamins, e.g., vitamin D, vitamin E and vitamin A;
minerals; fatty acids, such as essential fatty acids, for example,
polyunsaturated fatty acids, e.g., omega-3 fatty acids and omega-6
fatty acids, such as alpha-linolenic acid (ALA), docosahexaenoic
acid (DHA), eicosapentaenoic acid (EPA), gamma-linolenic acid GLA,
CLA, saw palmetto extract, flaxseed oil, fish oil and algae oil;
phytosterols; coenzymes, such as coenzyme Q10; and any other
oil-based additives. Furthermore, in certain embodiments, the
composition may have reduced dosing compliance as a result of the
taste or smell of the active agents and/or the
phosphatidylglycerol.
[0036] In one embodiment, the lysophosphatidylglycerol has a basic
structure:
##STR00003##
[0037] wherein R.sup.1 or R.sup.2 can be any even or odd-chain
fatty acid, and R.sup.3 can be H, acyl, alkyl, aryl, amino acid,
alkenes, alkynes, and wherein a short chain fatty acid is up to 5
carbons, a medium chain is 6 to 12 carbons, a long chain is 13-21
carbons and a very long chain fatty acid is greater than 22
carbons, including both even and odd chain fatty acids. In one
example, the fatty acids have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,
14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,
35, 40, 45, 50, 55 or long fatty acids, which can be saturated or
unsaturated.
[0038] The present invention can be used with any QT prolonging
drug, including but not limited to those listed at:
www.crediblemeds.org, Albuterol (salbutamol), Alfuzosin,
Amantadine, Amiodarone, Amisulpride, Amitriptyline, Amoxapine,
Amphetamine, Anagrelide, Apomorphine, Arformoterol, Aripiprazole,
Arsenic trioxide, Astemizole, Atazanavir, Atomoxetine,
Azithromycin, Bedaquiline, Bepridil, Bortezomib, Bosutinib, Chloral
hydrate, Chloroquine, Chlorpromazine, Ciprofloxacin, Cisapride,
Citalopram, Clarithromycin, Clomipramine, Clozapine, Cocaine,
Crizotinib, Dabrafenib, Dasatinib, Desipramine, Dexmedetomidine,
Dexmethylphenidate, Dextroamphetamine (d-Amphetamine),
Dihydroartemisinin+piperaquine, Diphenhydramine, Disopyramide,
Dobutamine, Dofetilide, Dolasetron, Domperidone, Dopamine, Doxepin,
Dronedarone, Droperidol, Ephedrine, Epinephrine (Adrenaline),
Eribulin, Erythromycin, Escitalopram, Famotidine, Felbamate,
Fenfluramine, Fingolimod, Flecainide, Fluconazole, Fluoxetine,
Formoterol, Foscarnet, Fosphenytoin, Furosemide (Frusemide),
Galantamine, Gatifloxacin, Gemifloxacin, Granisetron, Halofantrine,
Haloperidol, Hydrochlorothiazide, Ibutilide, Iloperidone,
Imipramine (melipramine), Indapamide, Isoproterenol, Isradipine,
Itraconazole, Ivabradine, Ketoconazole, Lapatinib, Levalbuterol
(levsalbutamol), Levofloxacin, Levomethadyl, Lisdexamfetamine,
Lithium, Mesoridazine, Metaproterenol, Methadone, Methamphetamine
(methamfetamine), Methylphenidate, Midodrine, Mifepristone,
Mirabegron, Mirtazapine, Moexipril/HCTZ, Moxifloxacin, Nelfinavir,
Nicardipine, Nilotinib, Norepinephrine (noradrenaline),
Norfloxacin, Nortriptyline, Ofloxacin, Olanzapine, Ondansetron,
Oxytocin, Paliperidone, Paroxetine, Pasireotide, Pazopanib,
Pentamidine, Perflutren lipid microspheres, Phentermine,
Phenylephrine, Phenylpropanolamine, Pimozide, Posaconazole,
Probucol, Procainamide, Promethazine, Protriptyline,
Pseudoephedrine, Quetiapine, Quinidine, Quinine sulfate,
Ranolazine, Rilpivirine, Risperidone, Ritodrine, Ritonavir,
Roxithromycin, Salmeterol, Saquinavir, Sertindole, Sertraline,
Sevoflurane, Sibutramine, Solifenacin, Sorafenib, Sotalol,
Sparfloxacin, Sulpiride, Sunitinib, Tacrolimus, Tamoxifen,
Telaprevir, Telavancin, Telithromycin, Terbutaline, Terfenadine,
Tetrabenazine, Thioridazine, Tizanidine, Tolterodine, Toremifene,
Trazodone, Trimethoprim-Sulfa, Trimipramine, Vandetanib,
Vardenafil, Vemurafenib, Venlafaxine, Voriconazole, Vorinostat, or
Ziprasidone.
[0039] Human ether-a-go-go-related gene (hERG) Potassium channel
anti-blockade by liposome and fragments.
[0040] Potassium channels conduct the rapid component of the
delayed rectifier potassium current, Kir, which is crucial for
repolarization of cardiac action potentials. A reduction in hERG
currents due to either genetic defects or adverse drug effects can
lead to hereditary or acquired long QT syndromes characterized by
action potential prolongation, lengthening of the QT interval on
the surface ECG, and an increased risk for "torsade de pointes"
arrhythmias and sudden death. This undesirable side effect of
non-antiarrhythmic compounds has prompted the withdrawal of drugs
from the market. Studies on mechanisms of hERG channel inhibition
provide significant insights into the molecular factors that
determine state-, voltage-, and use-dependency of hERG current
block. Mutations altering properties of the high-affinity drug
binding site in hERG and its interaction with drug molecules cause
current increase and hereditary short QT syndrome with a high risk
for life-threatening arrhythmias. (Thomas D1, 2006).
[0041] Anatomical Characteristics of the K+ channel. The types and
distributions of inwardly rectifying potassium (Kir) channels are
one of the major determinants of the electrophysiological
properties of cardiac myocytes. Inward rectifier potassium (Kir)
channels regulate cell excitability and transport of K+ ions across
cell membranes.
[0042] The potassium channel from Streptomyces lividans is an
integral membrane protein with sequence similarity to all known
K.sup.+ channels, particularly in the pore region. X-ray analysis
with data to 3.2 angstroms reveals that four identical subunits
create an inverted teepee, or cone, cradling the selectivity filter
of the pore in its outer end. The narrow selectivity filter is only
12 angstroms long, whereas the remainder of the pore is wider and
lined with hydrophobic amino acids. A large water-filled cavity and
helix dipoles are positioned so as to overcome electrostatic
destabilization of an ion in the pore at the center of the bilayer.
Main chain carbonyl oxygen atoms from the K.sup.+ channel signature
sequence line the selectivity filter, which is held open by
structural constraints to coordinate K.sup.+ ions but not smaller
Na.sup.+ ions. The selectivity filter contains two K.sup.+ ions
about 7.5 angstroms apart. Ion channels exhibit ion selectivity
through pore architecture that conducts specific ions. This
configuration promotes ion conduction by exploiting electrostatic
repulsive forces to overcome attractive forces between K.sup.+ ions
and the selectivity filter. The architecture of the pore
establishes the physical principles underlying selective K.sup.+
conduction. (Doyle D A, 1998).
[0043] Another member of the inward-rectifier family of potassium
channels is the prokaryotic KirBac1.1 channel. The structure of the
Kir channel assembly in the closed state, when refined to a
resolution of 3.65 angstroms contains a main activation gate and
structural elements involved in gating. On the basis of structural
evidence, gating involves coupling between the intracellular and
membrane domains suggesting that initiation of gating by membrane
or intracellular signals represents different entry points to a
common mechanistic pathway. (Kuo, A 2003).
[0044] Kir channels in the cardiac myocytes may be actively
regulated by means of the change in PIP(2) level rather than by
downstream signal transduction pathways. The classical inward
rectifier K(+) channel), Kir2.1, Kir6.2/SUR2A (ATP-sensitive K(+)
channel) and Kir3.1/3.4 (muscarinic K(+) channels) in cardiac
myocytes are commonly upregulated by a membrane lipid,
phosphatidylinositol 4,5-bisphosphates (PIP(2)). PIP(2) interaction
sites appear to be conserved by positively charged amino acid
residues and the putative alpha-helix in the C-terminals of Kir
channels. PIP(2) level in the plasma membrane is regulated by
tagonist stimulation (Takano M I 2003).
[0045] Inward rectifier potassium channels are characterized by two
transmembrane helices per subunit, plus an intracellular C-terminal
domain that controls channel gating in response to changes in
concentration of various ligands. Based on the crystal structure of
the tetrameric C-terminal domain of Kir3.1, it is possible to build
a homology model of the ATP-binding C-terminal domain of Kir6.2.
Molecular dynamics simulations are used to probe the dynamics of
Kir C-terminal domains and to explore the relationship between
their dynamics and possible mechanisms of channel gating. Multiple
simulations, each of 10 ns duration, were performed for Kir3.1
(crystal structure) and Kir6.2 (homology model), in both their
monomeric and tetrameric forms. The Kir6.2 simulations were
performed with and without bound ATP. The results of the
simulations reveal comparable conformational stability for the
crystal structure and the homology model. There is decrease in
conformational flexibility when comparing the monomers with the
tetramers, corresponding mainly to the subunit interfaces in the
tetramer. The beta-phosphate of ATP interacts with the side chain
of K185 in the Kir6.2 model and simulations. The flexibility of the
Kir6.2 tetramer is not changed greatly by the presence of bound
ATP, other than in two loop regions. Principal components analysis
of the simulated dynamics suggests loss of symmetry in both the
Kir3.1 and Kir6.2 tetramers, consistent with "dimer-of-dimers"
motion of subunits in C-terminal domains of the corresponding Kir
channels. This is suggestive of a gating model in which a
transition between exact tetrameric symmetry and dimer-of-dimers
symmetry is associated with a change in transmembrane helix packing
coupled to gating of the channel. Dimer-of-dimers motion of the
C-terminal domain tetramer is also supported by coarse-grained
(anisotropic network model) calculations. Loss of exact rotational
symmetry is suggested to play a role in gating in the bacterial Kir
homolog, KirBac1.1, and in the nicotinic acetylcholine receptor
channel. (Haider S I, 2005).
[0046] Homotetrameric models of three mammalian Kir channels
(Kir1.1, Kir3.1, and Kir6.2) have been generated, using the
KirBac3.1 transmembrane and rat Kir3.1 intracellular domain
structures as templates. All three models were explored by 10 ns
molecular dynamics simulations in phospholipid bilayers. Analysis
of the initial structures revealed conservation of potential lipid
interaction residues (Trp/Tyr and Arg/Lys side chains near the
lipid headgroup-water interfaces). Examination of the intracellular
domains revealed key structural differences between Kir1.1 and
Kir6.2 which may explain the difference in channel inhibition by
ATP. The behavior of all three models in the MD simulations
revealed that they have conformational stability similar to that
seen for comparable simulations of, for example, structures derived
from cryoelectron microscopy data. Local distortions of the
selectivity filter were seen during the simulations, as observed in
previous simulations of KirBac and in simulations and structures of
KcsA. These may be related to filter gating of the channel. The
intracellular hydrophobic gate does not undergo any substantial
changes during the simulations and thus remains functionally
closed. Analysis of lipid-protein interactions of the Kir models
emphasizes the key role of the MO (or "slide") helix which lies
approximately parallel to the bilayer-water interface and forms a
link between the transmembrane and intracellular domains of the
channel (Haider S I, 2007).
[0047] The potassium-selective transmembrane pore in
voltage-activated K+ channels is gated by changes in the membrane
potential. Activation gating (opening) occurs in milliseconds and
involves a gate at the cytoplasmic side of the pore. Substituting
cysteine at a particular position in the last transmembrane region
(S6) of the homotetrameric Shaker K+ channel creates metal binding
sites at which Cd2+ ions can bind with high affinity. The bound
Cd2+ ions form a bridge between the introduced cysteine in one
channel subunit and a native histidine in another subunit, and the
bridge traps the gate in the open state. These results suggest that
gating involves a rearrangement of the intersubunit contacts at the
intracellular end of S6. The structure of a bacterial K+ channel
shows that the S6 homologs cross in a bundle, leaving an aperture
at the bundle crossing. In the context of this structure, the metal
ions form a bridge between a cysteine above the bundle crossing and
a histidine below the bundle crossing in a neighboring subunit.
results suggest that gating occurs at the bundle crossing, possibly
through a change in the conformation of the bundle itself (Holmgren
M L 2002).
[0048] Activated gating in voltage-activated K+ channels are a
potassium-selective transmembrane pore gated by changes in the
membrane potential. This activation gating (opening) occurs in
milliseconds and involves a gate at the cytoplasmic side of the
pore. Substituting cysteine at a particular position in the last
transmembrane region (S6) of the homotetrameric Shaker K+ channel
creates metal binding sites at which Cd2+ ions can bind with high
affinity. The bound Cd2+ ions form a bridge between the introduced
cysteine in one channel subunit and a native histidine in another
subunit, and the bridge traps the gate in the open state. These
results suggest that gating involves a rearrangement of the
intersubunit contacts at the intracellular end of S6. The structure
of a bacterial K+ channel shows that the S6 homologs cross in a
bundle, leaving an aperture at the bundle crossing. In the context
of this structure, the metal ions form a bridge between a cysteine
above the bundle crossing and a histidine below the bundle crossing
in a neighboring subunit. results suggest that gating occurs at the
bundle crossing, possibly through a change in the conformation of
the bundle itself (Holmgren M L 2002).
[0049] Channelopathies
[0050] The human ether-a-go-go gene related cardiac tetrameric
potassium channel. when mutated can render patients sensitive to
over 163 drugs which may inhibit ion conduction and deregulate
action potentials. (Credible Meds) Prolongation of the action
potential follows effects in the potassium channel. Ion channel
active drugs may directly increase the QTc interval, and increase
the risk of torsade de point and sudden cardiac death. (Table 1)
Exacerbation of cardiomyocyte potassium channel sensitivity to
drugs may also be associated with metabolic diseased states
including diabetes (Veglio M, 2002) or may be of idiopathic
origin.
[0051] For these reasons, evaluation of drug effects on
cardiomyocyte potassium channel function is a critical step during
drug development, and when serious, may be an obstacle to
regulatory approval. In whole-cell patch-clamp experiments,
curcumin inhibited hERG K.sup.+ currents in HEK293 cells stably
expressing hERG channels in a dose-dependent manner, with IC.sub.50
value of 5.55 .mu.M. The deactivation, inactivation and the
recovery time from inactivation of hERG channels were significantly
changed by acute treatment of 10 .mu.M curcumin. Incubation of 20
.mu.M curcumin for 24 h reduced the HEK293 cell viability.
Intravenous injection of 20 mg of curcumin in rabbits did not
affect the cardiac repolarization manifested by QTc values. (Hu C W
2012). However, SignPath Pharma has discovered specific molecules
which antagonize QTc prolonging drugs (Helson L, 2002 Ranjan A,
2014, Shopp G, 2014). These molecules are specific liposomes, or
components of liposomes which were initially bound to lipophilic
drugs to permit intravenous solubility at physiological conditions,
and reduce adverse events. The loci of action appears to be in
intra-channel ion selectivity or gating site(s) controlling
potassium ion movement: a key functional component of regulation of
action potentials which lead downstream to myocyte contraction.
[0052] The mechanism of human ether-a-go-go related gene channels
blocade may be analogous to the effects of externally applied
quaternary ammonium derivatives which indirectly may suggest the
mechanism of action of the anti-blockading effect of the DMPC/DMPG
liposome or its metabolites. The inhibitory constants and the
relative binding energies for channel inhibition indicate that more
hydrophobic quaternary ammoniums have higher affinity blockade
while cation-.pi. interactions or size effects are not a
deterministic factor in channel inhibition by quaternary ammoniums.
Also hydrophobic quaternary ammoniums either with a longer tail
group or with a bigger head group than tetraethylammonium permeate
the cell membrane to easily access the high-affinity internal
binding site in the gene channel and exert a stronger blockade.
[0053] Although these data suggest that the basis for the
ameliorating effect liposome, or its components is the higher
competitive affinity for binding sites by the, DMPC and DMPG
compared to QTc prolonging drugs( ), its constitutive lack of ion
transport modulation, i.e. liposome or its fragments do not impede
K+ ion transport indicates that
[0054] By way of explanation, and in no way a limitation of these
claims, these data suggest that the basis for the ameliorating
effect liposome, or its components, is the higher competitive
affinity for binding sites by the DMPC and DMPG compared to QTc
prolonging drugs, its constitutive lack of ion transport
modulation, i.e., liposome, or its fragments, do not impede K+ ion
transport and indicates that the site of the mechanism of DMPC or
DMPG protection may be in the selectivity segment of the channel or
in the hydration surrounding the ion.
[0055] Additionally, based upon these hERG channel data the
structures of these liposome components may be informative for
designing or selecting other molecules to prevent drug induced
cardiac arrhythmias.
[0056] This study provides additional information as to the QTc
modulating effects by drugs, induced in cardiac myocyte potassium
channels, and mitigation by liposomes and liposomal constituents.
The latter molecules present an opportunity to probe the K.sup.+
channels as targets for pharmacological mitigation of drug-induced
channelopathies.
[0057] Evaluation of the protective effect of DMPC, DMPG,
DMPC/DMPG, LysoPG and LysoPC against hERG inhibition by
Nilotinib.
[0058] Purpose of the study: The purpose of this study is to
evaluate in vitro the protective effect of DMPC, DMPG, DMPC/DMPG,
LysoPG and LysoPC on the rapidly activating delayed-rectifier
potassium selective current GO generated under normoxic conditions
in stably transfected Human Embryonic Kidney cells (HEK 293 cells).
This study was designed as a screen and does not require QA
involvement (non-GLP-compliant).
[0059] Test Articles:
1--DMPC
2--DMPG
3--DMPC/DMPG 90:9
4--14:0 LysoPC
5--14:0 LysoPG
6--DMPC+Nilotinib (0.1 .mu.M)
7--DMPG+Nilotinib (0.1 .mu.M)
8--DMPC/DMPG 90:9+Nilotinib (0.1 .mu.M)
9--14:0 LysoPC+Nilotinib (0.1 .mu.M)
10--14:0 LysoPG+Nilotinib (0.1 .mu.M)
[0060] Test System: hERG-expressing HEK 293 transfected cell line.
Test performed: Whole-cell patch-clamp current acquisition and
analysis. Experimental Temperature: 35.+-.2.degree. C.
[0061] Application of test articles:
[0062] 5 minutes of exposure to each concentration in presence of
closed circuit perfusion (2 mL/min). 5 minutes for washout periods
in presence of a flow-through perfusion (2 mL/min) in addition to a
closed circuit perfusion (2 mL/min). The positive control
(Nilotinib, 0.05 .mu.g/mL) was added to naive cells obtained from
the same cell line and same passage for a period of 5 minutes in
presence of a closed circuit perfusion (2 mL/min).
[0063] Cells were under continuous stimulation of the pulses
protocol throughout the experiments and cell currents were recorded
after 5 minutes of exposure to each condition.
[0064] Original data acquisition design: Acquisition Rate(s): 1.0
kHz.
[0065] Design for acquisition when testing the compound or the
vehicle/solvent equivalent:
1 recording made in baseline condition 1 recording made in the
presence of concentration 1
[0066] Design for acquisition when testing the positive
control:
1 recording made in baseline condition 1 recording made in the
presence of the positive control n=number of responsive cells
patched on which the whole protocol above could be applied.
[0067] Statistical analysis: Statistical comparisons were made
using paired Student's t-tests. The currents recorded obtained on
day 2, 3 and 4 were statistically compared to the currents recorded
on day 1.
[0068] The currents recorded after the positive control (nilotinib
alone) exposure were compared to the currents recorded in baseline
conditions.
[0069] Differences were considered significant when
p.ltoreq.0.05.
[0070] Exclusion criteria:
1. Timeframe of drug exposure not respected 2. Instability of the
seal 3. No tail current generated by the patched cell 4. No
significant effect of the positive control 5. More than 10%
variability in capacitance transient amplitude over the duration of
the Study.
[0071] Effect of the Test Articles on whole-cell I.sub.Kr hERG
currents. Whole-cell currents elicited during a voltage pulse were
recorded in baseline conditions and following the application of
the selected concentration of test article. The cells were
depolarized for one second from the holding potential (-80 mV) to a
maximum value of +40 mV, starting at -40 mV and progressing in 10
mV increments. The membrane potential was then repolarized to -55
mV for one second, and finally returned to -80 mV.
[0072] Whole-cell tail current amplitude was measured at a holding
potential of -55 mV, following activation of the current from -40
to +40 mV. Current amplitude was measured at the maximum (peak) of
this tail current. Current density was obtained by dividing current
amplitude by cell capacitance measured prior to capacitive
transient minimization.
[0073] Current run-down and solvent effect correction. All data
points presented in this Study Report have been corrected for
solvent effect and time-dependent current run-down. Current
run-down and solvent effects were measured simultaneously by
applying the experimental design in test-article free conditions
over the same time frame as was done with the test article. The
loss in current amplitude measured during these so-called vehicle
experiments (representing both solvent effects and time-dependent
run-down) was subtracted from the loss of amplitude measured in the
presence of the test article to isolate the effect of the test
article, apart from the effect of the solvent and the inevitable
run-down in current amplitude over time.
TABLE-US-00001 TABLE 1 Effect of DMPC, DMPC + Nilotinib and
Nilotinib on hERG current density from transfected HEK 293 cells.
Normalized Corrected Current Normalized p Density Current Density
SEM value n = Baseline 1.000 1.000 n/a n/a 3 DMPC 0.863 1.056 0.056
0.423 3 Nilotinib, 0.1 .mu.M 0.308 0.459* 0.070 0.016 3 DMPC +
Nilotinib, 0.836 1.029 0.023 0.328 3 0.1 .mu.M
[0074] FIG. 1 is a graph that shows the effect of DMPC,
DMPC+Nilotinib and Nilotinib on hERG current density from
transfected HEK 293 cells.
TABLE-US-00002 TABLE 2 Effect of DMPG, DMPG + Nilotinib and
Nilotinib on hERG current density from transfected HEK 293 cells.
Normalized Corrected Current Normalized p Density Current Density
SEM value n = Baseline 1.000 1.000 n/a n/a 3 DMPG 0.800 0.994 0.044
0.901 3 Nilotinib, 0.1 .mu.M 0.308 0.459* 0.070 0.016 3 DMPG +
Nilotinib, 0.743 0.936 0.067 0.437 3 0.1 .mu.M
[0075] FIG. 2 is a graph that shows the effect of DMPG,
DMPG+Nilotinib and Nilotinib on hERG current density from
transfected HEK 293 cells.
TABLE-US-00003 TABLE 3 Effect of DMPC/DMPG, DMPC/DMPG + Nilotinib
and Nilotinib on hERG current density from transfected HEK 293
cells. Normalized Corrected Current Normalized Density Current
Density SEM p value n = Baseline 1.000 1.000 n/a n/a 3 DMPC-DMPG
0.871 1.064 0.127 0.647 4 Nilotinib, 0.1 .mu.M 0.308 0.459* 0.070
0.016 3 DMPC/DMPG + 0.773 0.966 0.098 0.754 4 Nilotinib, 0.1
.mu.M
[0076] FIG. 3 is a graph that shows the effect of DMPC/DMPG,
DMPC/DMPG+Nilotinib and Nilotinib on hERG current density from
transfected HEK 293 cells.
TABLE-US-00004 TABLE 4 Effect of LysoPC, LysoPC + Nilotinib and
Nilotinib on hERG current density from transfected HEK 293 cells.
Normalized Corrected Current Normalized Density Current Density SEM
p value n = Baseline 1.000 1.000 n/a n/a 3 LysoPC 0.647 0.840*
0.040 0.028 4 Nilotinib, 0.1 .mu.M 0.308 0.459* 0.070 0.016 3
LysoPC + 0.865 1.097 0.055 0.553 3 Nilotinib, 0.1 .mu.M
[0077] FIG. 4 is a graph that shows the effect of LysoPC,
LysoPC+Nilotinib and Nilotinib on hERG current density from
transfected HEK 293 cells.
TABLE-US-00005 TABLE 5 Effect of LysoPG, LysoPG + Nilotinib and
Nilotinib on hERG current density from transfected HEK 293 cells.
Normalized Corrected Current Normalized Density Current Density SEM
p value n = Baseline 1.000 1.000 n/a n/a 3 14:0 LysoPG, 0.930 1.124
0.128 0.435 3 0.45 .mu.g/mL Nilotinib, 0.1 .mu.M 0.308 0.459* 0.070
0.016 3 14:0 LysoPG + 0.743 0.936 0.067 0.437 3 Nilotinib, 0.1
.mu.M
[0078] FIG. 5 is a graph that shows the effect of LysoPG,
LysoPG+Nilotinib and Nilotinib on hERG current density from
transfected HEK 293 cells.
[0079] This study aimed at quantifying the protective effect of
DMPC, DMPG, DMPC/DMPG, LysoPG and LysoPC against the inhibition of
the rapidly activating delayed-rectifier potassium selective
current (I.sub.Kr) generated under normoxic conditions in stably
transfected Human Embryonic Kidney (HEK) 293 cells caused by the
Nilotinib.
[0080] All data points presented in this study have been corrected
for solvent effects and time-dependent current run-down. These two
parameters were evaluated by applying exactly the same experimental
design to the vehicle as that done with the test articles. The
currents were measured over the same time course as was done in the
presence of the test article. The values obtained, representing
both solvent effects and time-dependent run-down, were used to
correct the effect of the test articles, if any. This ensures that
changes attributable to time or the solvent are not mistakenly
attributed to the test articles.
[0081] DMPC, DMPG, DMPC/DMPG and LysoPG alone did not cause any
inhibition of the hERG tail current density (n=3). LysoPC alone
caused 16% of inhibition of the hERG tail current density
(n=4).
[0082] Nilotinib alone, formulated in DMSO at 0.1 .mu.M, caused
54.1% of inhibition of the hERG tail current (n=3). The inhibition
observed is in line with previous data generated in identical
conditions, and agrees with reported inhibition values for this
compound.
[0083] Nilotinib when formulated in an aqueous solution containing
DMPC, DMPG, DMPC/DMPC, LysoPG or LysoPC (ratio 1:9) did not cause
any inhibition of the hERG tail current.
[0084] These data suggest that co-formulating Nilotinib with DMPC,
DMPG, DMPC/DMPC, LysoPG and LysoPC protects against hERG inhibition
caused by Nilotinib.
[0085] In this study, the DMPC+Nilotinib, DMPG+Nilotinib,
DMPC/DMPC+Nilotinib, LysoPG+Nilotinib or LysoPC+Nilotinib were all
formulated using the same method. The appropriate amount of
Nilotinib powder was dissolved in an aqueous solution containing
either DMPC, DMPG, DMPC/DMPC, LysoPG or LysoPC (ratio 9:1). The
solution was vortexed for 10 minutes before being used in the
patch-clamp assay.
[0086] In contrast, the Nilotinib used for the cells exposed to
Nilotinib alone was dissolved in DMSO. Additional studies were
conducted to determine whether the difference in hERG inhibition
between DMSO-formulated Nilotinib and lipid-co-formulated Nilotinib
resulted from the different formulations (aqueous or
DMSO-based).
[0087] Steps for the study:
TABLE-US-00006 Step 1 Step 2 Step 3 Step 4 Baseline TA* added into
the 5 minutes exposure TA recording recording experimental chamber
time *TA = 1- DMPC (in aqueous solution) 2- DMPG (in aqueous
solution) 3- DMPC/DMPG 90:0 (in aqueous solution) 4- 14:0 LysoPC
(in aqueous solution) 5- 14:0 LysoPG (in aqueous solution) 6- DMPC
+ Nilotinib (0.1 .mu.M) (in aqueous solution) 7- DMPG + Nilotinib
(0.1 .mu.M) (in aqueous solution) 8- DMPC/DMPG 90:9 + Nilotinib
(0.1 .mu.M) (in aqueous solution) 9- 14:0 LysoPC + Nilotinib (0.1
.mu.M) (in aqueous solution) 10- 14:0 LysoPG + Nilotinib (0.1
.mu.M) (in aqueous solution) 11- Nilotinib alone (in DMSO)
[0088] Amongst the mechanisms considered to explain the protection
of hERG currents were the possibility that DMPC/DMPG or the
Lyso-variants quenched the Nilotinib at the moment of formulation,
essentially preventing it from getting into the channel at its
receptor site. Another possibility was that Nilotinib was less
soluble in an aqueous solution, and therefore was incompletely
solubilized at 0.1 .mu.M.
[0089] To test both hypotheses, Nilotinib was formulated in DMSO
and added into the experimental chamber following the addition of
the DMPC or DMPG. This was based on the principle that 1--adding
DMPC/DMPG alone, followed by DMSO-formulated Nilotinib, would
eliminate the possibility of early quenching of Nilotinib by the
lysosome; and 2-that DMSO would maintain the solubility of
Nilotinib (the "Nilotinib-only" inhibition of hERG was observed
when DMSO-formulated Nilotinib was added to the cells).
[0090] Steps for the following Data
TABLE-US-00007 Step 1 Step 2 Step 3 Step 4 Step 5 Step 6 Baseline
DMPC or 5 minutes DMPC or Nilotinib in DMPC or recording DMPG
exposure DMPG DMSO DMPG + added time recording added Nilotinib into
the into the (in experi- experimental DMSO) mental chamber
recording chamber
TABLE-US-00008 TABLE 6 Effect of DMPC, DMPC + Nilotinib, DMPC +
Nilotinib (in DMSO) and Nilotinib on hERG current density from
transfected HEK 293 cells. Corrected Normalized Normalized Current
Current Density Density SEM p value n = Baseline 1.000 1.000 n/a
n/a 3 DMPC 0.863 1.056 0.056 0.423 3 Nilotinib, 0.1 .mu.M 0.308
0.459* 0.070 0.016 3 DMPC + Nilotinib, 0.836 1.029 0.023 0.328 3
0.1 .mu.M (Aqueous) DMPC + Nilotinib 0.164 0.358* 0.020 0.019 2 (in
DMSO), 0.1 .mu.M
[0091] FIG. 6 is a graph that shows the effect of DMPC,
DMPC+Nilotinib, DMPC+Nilotinib (in DMSO) and Nilotinib on hERG
current density from transfected HEK 293 cells.
TABLE-US-00009 TABLE 7 Effect of DMPG, DMPG + Nilotinib, DMPG +
Nilotinib (in DMSO) and Nilotinib on hERG current density from
transfected HEK 293 cells. Normalized Corrected Current Normalized
p Density Current Density SEM value n = Baseline 1.000 1.000 n/a
n/a 3 DMPG 0.800 0.994 0.044 0.901 3 Nilotinib, 0.1 .mu.M 0.308
0.459* 0.070 0.016 3 DMPG + Nilotinib, 0.743 0.936 0.067 0.437 3
0.1 .mu.M DMPG + Nilotinib 0.630 0.823 0.290 0.651 2 (in DMSO), 0.1
.mu.M
[0092] FIG. 7 is a graph that shows the effect of DMPG,
DMPG+Nilotinib, DMPG+Nilotinib (in DMSO) and Nilotinib on hERG
current density from transfected HEK 293 cells.
[0093] Active Agent-empty liposomes suspensions. A suspension
formulated having a dose of active agent, the empty liposomes
(e.g., DMPG, DMPC, or both DMOG and DMPC, and an organoleptic
agent, may be formed in suspension and may further includes Xanthan
gum (Rhodia Inc.) as the suspending agent and several other
ingredients such as, e.g., color, flavor, parabens (e.g.,
methylparaben and propylparaben) (preservatives), high fructose
corn syrup (viscosity builder and sweetener), propylene glycol
(solvent and dispersing agent), and ascorbic acid (to adjust the pH
of the suspension) were used to achieve a stable suspension. The
suspension can be studies for release profiles in 0.1 N HCl at pH
1.2 using USP dissolution apparatus II with 900 ml of dissolution
medium. Briefly, samples are withdrawn at predetermined time
intervals and were analyzed for active agent content using HPLC
analysis. The release of the active agent against time can be
plotted.
[0094] Different amounts of thixotropic agents (and if necessary
salts) can be added to three suspensions to obtain suspensions with
varying thixotropic agent, e.g., 0.1, 0.3, and 0.5 weight percent.
The suspensions can be mixed and held for 24 hours to achieve
equilibrium.
[0095] In certain embodiments, the active agents can also be coated
and formed into mini-caps, mini-tabs, or just small particles (1.0
micrometer (uM), 10 uM, 100 uM, to 1 millimeter) and mixed in
solution with the empty liposomes and the organoleptic and/or
thixotropic agent.
[0096] It is contemplated that any embodiment discussed in this
specification can be implemented with respect to any method, kit,
reagent, or composition of the invention, and vice versa.
Furthermore, compositions of the invention can be used to achieve
methods of the invention.
[0097] It will be understood that particular embodiments described
herein are shown by way of illustration and not as limitations of
the invention. The principal features of this invention can be
employed in various embodiments without departing from the scope of
the invention. Those skilled in the art will recognize, or be able
to ascertain using no more than routine experimentation, numerous
equivalents to the specific procedures described herein. Such
equivalents are considered to be within the scope of this invention
and are covered by the claims.
[0098] All publications and patent applications mentioned in the
specification are indicative of the level of skill of those skilled
in the art to which this invention pertains. All publications and
patent applications are herein incorporated by reference to the
same extent as if each individual publication or patent application
was specifically and individually indicated to be incorporated by
reference.
[0099] The use of the word "a" or "an" when used in conjunction
with the term "comprising" in the claims and/or the specification
may mean "one," but it is also consistent with the meaning of "one
or more," "at least one," and "one or more than one." The use of
the term "or" in the claims is used to mean "and/or" unless
explicitly indicated to refer to alternatives only or the
alternatives are mutually exclusive, although the disclosure
supports a definition that refers to only alternatives and
"and/or." Throughout this application, the term "about" is used to
indicate that a value includes the inherent variation of error for
the device, the method being employed to determine the value, or
the variation that exists among the study subjects.
[0100] As used in this specification and claim(s), the words
"comprising" (and any form of comprising, such as "comprise" and
"comprises"), "having" (and any form of having, such as "have" and
"has"), "including" (and any form of including, such as "includes"
and "include") or "containing" (and any form of containing, such as
"contains" and "contain") are inclusive or open-ended and do not
exclude additional, unrecited elements or method steps. In
embodiments of any of the compositions and methods provided herein,
"comprising" may be replaced with "consisting essentially of" or
"consisting of". As used herein, the phrase "consisting essentially
of" requires the specified integer(s) or steps as well as those
that do not materially affect the character or function of the
claimed invention. As used herein, the term "consisting" is used to
indicate the presence of the recited integer (e.g., a feature, an
element, a characteristic, a property, a method/process step or a
limitation) or group of integers (e.g., feature(s), element(s),
characteristic(s), propertie(s), method/process steps or
limitation(s)) only.
[0101] The term "or combinations thereof" as used herein refers to
all permutations and combinations of the listed items preceding the
term. For example, "A, B, C, or combinations thereof" is intended
to include at least one of: A, B, C, AB, AC, BC, or ABC, and if
order is important in a particular context, also BA, CA, CB, CBA,
BCA, ACB, BAC, or CAB. Continuing with this example, expressly
included are combinations that contain repeats of one or more item
or term, such as BB, AAA, AB, BBC, AAABCCCC, CBBAAA, CABABB, and so
forth. The skilled artisan will understand that typically there is
no limit on the number of items or terms in any combination, unless
otherwise apparent from the context.
[0102] As used herein, words of approximation such as, without
limitation, "about", "substantial" or "substantially" refers to a
condition that when so modified is understood to not necessarily be
absolute or perfect but would be considered close enough to those
of ordinary skill in the art to warrant designating the condition
as being present. The extent to which the description may vary will
depend on how great a change can be instituted and still have one
of ordinary skilled in the art recognize the modified feature as
still having the required characteristics and capabilities of the
unmodified feature. In general, but subject to the preceding
discussion, a numerical value herein that is modified by a word of
approximation such as "about" may vary from the stated value by at
least .+-.1, 2, 3, 4, 5, 6, 7, 10, 12 or 15%.
[0103] All of the compositions and/or methods disclosed and claimed
herein can be made and executed without undue experimentation in
light of the present disclosure. While the compositions and methods
of this invention have been described in terms of preferred
embodiments, it will be apparent to those of skill in the art that
variations may be applied to the compositions and/or methods and in
the steps or in the sequence of steps of the method described
herein without departing from the concept, spirit and scope of the
invention. All such similar substitutes and modifications apparent
to those skilled in the art are deemed to be within the spirit,
scope and concept of the invention as defined by the appended
claims.
REFERENCES
[0104] U.S. Patent Publication No. 2010/0004549: System and Method
of Serial Comparison for Detection of Long QT Syndrome (LQTS).
[0105] U.S. Patent Publication No. 2008/0255464: System and Method
for Diagnosing and Treating Long QT Syndrome. [0106] U.S. Patent
Publication No. 2007/0048284: Cardiac Arrhythmia Treatment Methods.
[0107] U.S. Patent Publication No. 2001/00120890: Ion Channel
Modulating Activity I.
* * * * *
References