Patent Application
20230075547
Vascular insufficiency, secondary to occlusive processes in the vasculature, constitutes a disease phenotype of wide applicability in a number of common disease states including among others: coronary insufficiency, cerebrovascular insufficiency, peripheral vascular insufficiency and impaired kidney perfusion. Among the major known predisposing factors causing narrowing of vasculature are: 1) elevated serum cholesterol, 2) elevated serum triglycerides, 3) elevated serum glucose, 4) elevated serum homocysteine, 5) certain inflammatory processes and 6) hypertension.
Ketone bodies cannot be utilized by liver, hence they can not be used to synthesize either triglycerides or cholesterol. Triglycerides and cholesterol are synthesized either from carbohydrates or lipids, which provide acetyl CoA, and thence respectively malonyl CoA or HMG CoA for the two synthetic pathways. The major source of blood cholesterol and triglyceride comes from liver where it is excreted into the blood as VLDL, the fatty acids of which are removed by various tissues to leave LDL in the blood.
The inventors of the subject patent application have found that feeding a subject a diet comprising, in part, esters or oligomers of the ketone body D-β-hydroxybutyrate and lowered dietary fat can reverse a number of the known predisposing factors leading to vascular diseases.
The subject disclosure provides compositions for reducing serum cholesterol and/or triglyceride levels in subjects. These compositions can comprise racemic β-hydroxybutyrate or D-β-hydroxybutyrate (optionally in the acid form), physiologically compatible salts of racemic β-hydroxybutyrate or D-β-hydroxybutyrate (e.g., sodium, potassium, calcium or magnesium salts), esters of D-β-hydroxybutyrate, oligomers of D-β-hydroxybutyrate containing from 2 to 20 (or more) monomeric units in either linear or cyclic form, racemic 1,3 butandiol, R-1,3 butandiol or any combination thereof alone and can be, optionally, administered in conjunction with a low fat diet to a subject. Alternatively, compositions comprising racemic β-hydroxybutyrate or D-β-hydroxybutyrate (optionally in the acid form), physiologically compatible salts of racemic β-hydroxybutyrate or D-β-hydroxybutyrate (e.g., sodium, potassium, calcium or magnesium salts), esters of D-β-hydroxybutyrate, oligomers of D-β-hydroxybutyrate containing from 2 to 20 (or more) monomeric units in either linear or cyclic form, racemic 1,3 butandiol, R-1,3 butandiol or any combination thereof can be formulated as nutritional supplements (also referred to as nutritional compositions) or incorporated into therapeutic compositions (compositions combining racemic β-hydroxybutyrate or D-β-hydroxybutyrate (optionally in the acid form), physiologically compatible salts of racemic β-hydroxybutyrate or D-β-hydroxybutyrate (e.g., sodium, potassium, calcium or magnesium salts), esters of D-β-hydroxybutyrate, oligomers of D-β-hydroxybutyrate containing from 2 to 20 (or more) monomeric units in either linear or cyclic form, racemic 1,3 butandiol, R-1,3 butandiol or any combination thereof and a) anti-hypertensive agents; b) anti-inflammatory agents; c) glucose lowering agents; or d) anti-lipemic agents) which are administered to a subject, optionally in combination with a low fat diet, in order to cause a reduction or lowering of: serum cholesterol levels; triglyceride levels; serum glucose levels, serum homocysteine levels, inflammatory proteins (e.g., C reactive protein) and/or hypertension in treated subjects. Alternatively, racemic β-hydroxybutyrate or D-β-hydroxybutyrate (optionally in the acid form), physiologically compatible salts of racemic β-hydroxybutyrate or D-β-hydroxybutyrate (e.g., sodium, potassium, calcium or magnesium salts), esters of D-β-hydroxybutyrate, oligomers of D-β-hydroxybutyrate containing from 2 to 20 (or more) monomeric units in either linear or cyclic form, racemic 1,3 butandiol, R-1,3 butandiol or any combination thereof can be administered alone, or in combination with other therapeutic agents to prevent or reverse vascular disease.
Table 1 provides details related to the diets fed to experimental animals.
Table 2 relates to plasma metabolite levels in non-fasting rats fed one of three diets for 7 or 66 days. The ketone diet doubled the plasma β-hydroxybutyrate concentrations at both 7 and 66 days. Total cholesterol levels were significantly lower in ketone-fed rats compared with rats fed a Western diet. After 66 days on the diets, plasma HDL and LDL levels were significantly lower, and the HDL/LDL ratios tended to be higher, in the ketone fed rats compared with the Western-diet fed rats. The triacylglycerol levels were significantly lower in the rats fed the ketone diet, compared with rats fed the Western diet. There were no effects of diet on plasma free fatty acid levels, but the rats fed the ketone diet for 66 days had lower plasma glucose levels.
Table 3 provides a listing of combination therapies used for the treatment of hypertension.
The subject disclosure provides compositions for reducing serum cholesterol and/or triglyceride levels in subjects. These compositions can comprise racemic β-hydroxybutyrate or D-β-hydroxybutyrate (optionally in the acid form), physiologically compatible salts of racemic β-hydroxybutyrate or D-β-hydroxybutyrate (e.g., sodium, potassium, calcium or magnesium salts), esters of D-β-hydroxybutyrate, oligomers of D-β-hydroxybutyrate containing from 2 to 20 (or more) monomeric units in either linear or cyclic form, racemic 1,3 butandiol, R-1,3 butandiol, or any combination thereof alone. Alternatively, compositions comprising racemic β-hydroxybutyrate or D-β-hydroxybutyrate (optionally in the acid form), physiologically compatible salts of racemic β-hydroxybutyrate or D-β-hydroxybutyrate (e.g., sodium, potassium, calcium or magnesium salts), esters of D-β-hydroxybutyrate, oligomers of D-β-hydroxybutyrate containing from 2 to 20 (or more) monomeric units in either linear or cyclic form, racemic 1,3 butandiol, R-1,3 butandiol, or any combination thereof can be formulated as nutritional supplements (also referred to as nutritional compositions) or incorporated into therapeutic compositions (compositions combining racemic β-hydroxybutyrate or D-β-hydroxybutyrate (optionally in the acid form), physiologically compatible salts of racemic β-hydroxybutyrate or D-β-hydroxybutyrate (e.g., sodium, potassium, calcium or magnesium salts), esters of D-β-hydroxybutyrate, oligomers of D-β-hydroxybutyrate containing from 2 to 20 (or more) monomeric units in either linear or cyclic form, racemic 1,3 butandiol, R-1,3 butandiol, or any combination thereof and a) anti-hypertensive agents; b) anti-inflammatory agents; c) glucose lowering agents; or d) anti-lipemic agents) which are administered to a subject in order to cause a reduction or lowering of: serum cholesterol levels; triglyceride levels; serum glucose levels, serum homocysteine levels, inflammatory proteins (e.g., C reactive protein) and/or hypertension in treated subjects. Alternatively, racemic β-hydroxybutyrate or D-β-hydroxybutyrate (optionally in the acid form), physiologically compatible salts of racemic β-hydroxybutyrate or D-β-hydroxybutyrate (e.g., sodium, potassium, calcium or magnesium salts), esters of D-β-hydroxybutyrate, oligomers of D-β-hydroxybutyrate containing from 2 to 20 (or more) monomeric units in either linear or cyclic form, racemic 1,3 butandiol, R-1,3 butandiol, or any combination thereof can be administered alone in a normal diet, or in combination with other therapeutic agents to prevent or reverse vascular disease. In any of these embodiments, the compositions can be administered to a subject in combination with a low fat diet.
The subject application provides compositions comprising racemic β-hydroxybutyrate or D-β-hydroxybutyrate (optionally in the acid form), physiologically compatible salts of racemic β-hydroxybutyrate or D-β-hydroxybutyrate (e.g., sodium, potassium, calcium or magnesium salts), esters of D-β-hydroxybutyrate, oligomers of D-β-hydroxybutyrate containing from 2 to 20 (or more) monomeric units in either linear or cyclic form, racemic 1,3 butandiol, R-1,3 butandiol, or any combination thereof in combination with:
Non-limiting examples of anti-hypertensive agents that can be used in the formulation of compositions according to the subject invention include, and are not limited to, captopril (CAPOTEN), benazepril (LOTENSIN), enalapril (VASOTEC), lisinopril (PRINIVIL, ZESTRIL) fosinopril (MONOPRIL), ramipril (ALTACE), perindopril (ACEON), quinapril (ACCUPRIL), moexipril (UNIVASC), trandolapril (MAVIK), candesartan (ATACAND), eprosartan (TEVETAN), irbesartan (AVAPRO), telmisartan (MYCARDIS), valsartan (DIOVAN), losartan (COZAAR), atenolol (TENORMIN), propranolol (INDERAL), metoprolol (TOPROL), nadolol (CORGARD), betaxolol (KERLONE), acebutolol (SECTRAL), pindolol (VISKEN), bisoprolol (ZEBETA), hydrochlorothiazide (IIYDRODIURIL), furosemide (LASIX), torsemide (DEMADEX), the combination of triamterene and hydrochlorothiazide (DYAZIDE), metolazone (ZAROXOLYN), ethacrynic acid, nisoldipine (SULAR), nifedipine (ADALAT, PROCARDIA), nicardipine (CARDENE), bepridil (VASCOR), isradipine (DYNACIRC), nimodipine (NIMOTOP), felodipine (PLENDIL), amlodipine (NORVASC), diltiazem (CARDIZEM), verapamil (CALAN, ISOPTIN), terazosin (HYTRIN), doxazosin (CARDURA), tamsulosin (FLOMAX), alfuzosin (UROXATRAL) or clonidine (CATAPRES) and the combination therapies disclosed in the table below (entitled “Combination Drugs for Treatment of Hypertension” (Table 3)). These agents are formulated with racemic β-hydroxybutyrate or D-β-hydroxybutyrate (optionally in the acid form), physiologically compatible salts of racemic β-hydroxybutyrate or D-β-hydroxybutyrate (e.g., sodium, potassium, calcium or magnesium salts), esters of D-β-hydroxybutyrate, oligomers of D-β-hydroxybutyrate containing from 2 to 20 (or more) monomeric units in either linear or cyclic form, racemic 1,3 butandiol, R-1,3 butandiol, or any combination thereof to provide compositions useful for the reduction or lowering hypertension in treated subjects. These compositions can also be used to prevent or reverse vascular disease in a subject.
With respect to glucose lowering agents, there are four major classes of oral glucose lowering agents. These include the biguanides (e.g., metformin), sulfonylureas (e.g., glyburide), thiazolidinediones and alpha-glucosidase inhibitors. Thus, the subject invention also provides compositions comprising D-β-hydroxybutyrate and esters or precursors thereof in combination with biguanides (e.g., metformin), sulfonylureas (e.g., glyburide), thiazolidinediones and/or alpha-glucosidase inhibitors that are useful for lowering blood glucose levels in a subject.
The subject invention also provides compositions comprising racemic β-hydroxybutyrate or D-β-hydroxybutyrate (optionally in the acid form), physiologically compatible salts of racemic β-hydroxybutyrate or D-β-hydroxybutyrate (e.g., sodium, potassium, calcium or magnesium salts), esters of D-β-hydroxybutyrate, oligomers of D-β-hydroxybutyrate containing from 2 to 20 (or more) monomeric units in either linear or cyclic form, racemic 1,3 butandiol, R-1,3 butandiol, or any combination thereof in combination with anti-lipemic agents (e.g., probucol, niacin, omega 3 ethyl esters or omega 3 fatty acids), bile acid sequesterants (e.g., cholestyramine, cholestyramine-sucrose, cholestyramine-aspartame, colesevelam or colestipol), cholesterol absorption inhibitors (e.g., ezetimibe or ezetimibe-simvastatin), fibric acid derivatives (e.g., fenofibrates or gemfibrozil), and/or HMG-CoA reductase inhibitors (amlodipine-atorvastatin, atorvastatin, fluvastatin, lovastatin, niacin-lovastatin, pravastatin, rosuvastatin, simvastatin). Such compositions can be used to reduce or lower serum cholesterol levels or triglyceride levels in a subject.
Compositions comprising anti-inflammatory agents and racemic β-hydroxybutyrate or D-β-hydroxybutyrate (optionally in the acid form), physiologically compatible salts of racemic β-hydroxybutyrate or D-β-hydroxybutyrate (e.g., sodium, potassium, calcium or magnesium salts), esters of D-β-hydroxybutyrate, oligomers of D-β-hydroxybutyrate containing from 2 to 20 (or more) monomeric units in either linear or cyclic form, racemic 1,3 butandiol, R-1,3 butandiol, or any combination thereof are also provided by the subject application. Anti-inflammatory agents include, but are not limited to: aspirin, salsalate, diflunisal, ibuprofen, ketoprofen, nabumetone, piroxicam, naproxen, diclofenac, indomethacin, sulindac, tolmetin, etodolac, ketorolac, oxaprozin or celecoxib. Thus, the subject invention also provides for the treatment of inflammation comprising the administration of compositions comprising racemic β-hydroxybutyrate or D-β-hydroxybutyrate (optionally in the acid form), physiologically compatible salts of racemic 3-hydroxybutyrate or D-β-hydroxybutyrate (e.g., sodium, potassium, calcium or magnesium salts), esters of D-β-hydroxybutyrate, oligomers of D-β-hydroxybutyrate containing from 2 to 20 (or more) monomeric units in either linear or cyclic form, racemic 1,3 butandiol, R-1,3 butandiol, or any combination thereof alone, or in combination with anti-inflammatory agents.
The subject invention also provides for the use of the aforementioned compositions comprising racemic β-hydroxybutyrate or D-β-hydroxybutyrate (optionally in the acid form), physiologically compatible salts of racemic β-hydroxybutyrate or D-β-hydroxybutyrate (e.g., sodium, potassium, calcium or magnesium salts), esters of D-β-hydroxybutyrate, oligomers of D-β-hydroxybutyrate containing from 2 to 20 (or more) monomeric units in either linear or cyclic form, racemic 1,3 butandiol, R-1,3 butandiol, or any combination thereof for the preparation of a medicament for lowering or reducing serum cholesterol; triglyceride levels; serum glucose levels, serum homocysteine levels, inflammatory proteins (e.g., C reactive protein) and/or hypertension in a subject. The use described in this paragraph can optionally comprise the administration of the aforementioned compositions to a subject in conjunction with the administration of a low fat diet to a subject.
Thus, in one embodiment of the invention, a use of a composition, as described above, comprising racemic β-hydroxybutyrate or D-β-hydroxybutyrate (optionally in the acid form), physiologically compatible salts of racemic β-hydroxybutyrate or D-β-hydroxybutyrate (e.g., sodium, potassium, calcium or magnesium salts), esters of D-β-hydroxybutyrate, oligomers of D-β-hydroxybutyrate containing from 2 to 20 (or more) monomeric units in either linear or cyclic form, racemic 1,3 butandiol, R-1,3 butandiol, or any combination thereof(alone or in combination with other agents (e.g., a) anti-lipemic agents; b) anti-hypertensive agents (including those combination treatments set forth in Table 3, entitled “Combination Drugs for Treatment of Hypertension”); c) glucose lowering agents; or d) anti-inflammatory agents)) to lower or reduce serum cholesterol levels; triglyceride levels; serum glucose levels, serum homocysteine levels, inflammatory proteins (e.g., C reactive protein) and/or hypertension in a subject is provided. These compositions can be administered to a subject orally (e.g., in the form of the diet of the subject (a nutritional composition for example) or via the administration of therapeutic compositions comprising racemic β-hydroxybutyrate or D-β-hydroxybutyrate (optionally in the acid form), physiologically compatible salts of racemic β-hydroxybutyrate or D-β-hydroxybutyrate (e.g., sodium, potassium, calcium or magnesium salts), esters of D-β-hydroxybutyrate, oligomers of D-β-hydroxybutyrate containing from 2 to 20 (or more) monomeric units in either linear or cyclic form, racemic 1,3 butandiol, R-1,3 butandiol, or any combination thereof), parenterally, via injection or rectally. Again, the compositions described herein can be administered alone or in conjunction with a low fat diet to the subject.
In certain preferred embodiments, the methods of the subject application comprise the oral administration of compositions comprising racemic β-hydroxybutyrate or D-β-hydroxybutyrate (optionally in the acid form), physiologically compatible salts of racemic β-hydroxybutyrate or D-β-hydroxybutyrate (e.g., sodium, potassium, calcium or magnesium salts), esters of D-β-hydroxybutyrate, oligomers of D-β-hydroxybutyrate containing from 2 to 20 (or more) monomeric units in either linear or cyclic form, racemic 1,3 butandiol, R-1,3 butandiol, or any combination thereof. These orally administered compositions have the benefit of lowering serum cholesterol, triglyceride and/or glucose levels in a subject, including those instances where the compositions are orally administered as a part of a low fat diet to the subject. For the purposes of this invention, the term “subject” is directed to mammals and, in certain embodiments, humans. “Administering” “administered” or “administer” is defined as the introduction of the disclosed compositions into a subject via oral, nasal, ocular, rectal, vaginal and parenteral routes.
Compositions comprising racemic β-hydroxybutyrate or D-β-hydroxybutyrate (optionally in the acid form), physiologically compatible salts of racemic β-hydroxybutyrate or D-β-hydroxybutyrate (e.g., sodium, potassium, calcium or magnesium salts), esters of D-β-hydroxybutyrate, oligomers of D-β-hydroxybutyrate containing from 2 to 20 (or more) monomeric units in either linear or cyclic form, racemic 1,3 butandiol, R-1,3 butandiol, or any combination thereof may be administered alone (e.g., a composition comprising racemic β-hydroxybutyrate or D-β-hydroxybutyrate (optionally in the acid form), physiologically compatible salts of racemic β-hydroxybutyrate or D-β-hydroxybutyrate (e.g., sodium, potassium, calcium or magnesium salts), esters of D-β-hydroxybutyrate, oligomers of D-β-hydroxybutyrate containing from 2 to 20 (or more) monomeric units in either linear or cyclic form, racemic 1,3 butandiol, R-1,3 butandiol, or any combination thereof and lacking any other therapeutic ingredient) or in combination with other agents (e.g., a) anti-lipemic agents; b) anti-hypertensive agents (including those combination treatments set forth in Table 3, entitled “Combination Drugs for Treatment of Hypertension”); c) glucose lowering agents; or d) anti-inflammatory agents) via any route of administration and, optionally, in conjunction with the administration or intake of a low fat diet by the subject. These routes of administration include, and are not limited to, subcutaneous (SQ), intramuscular (IM), intravenous (IV), intraperitoneal (IP), intradermal (ID), via the nasal, ocular or oral mucosa (IN), or orally (PO). When the compositions disclosed herein are administered orally, the compositions can be provided to the subject in the form of the diet eaten by the subject or in pills or other unit dose forms. A unit dose form can be a packaged preparation, such as packeted tablets, capsules, and powders in paper or plastic containers or in vials or ampoules. Also, the unit dosage can be a liquid based preparation or formulated to be incorporated into solid food products, chewing gum, or lozenge. As described herein, the phrase “in combination” is to be interpreted as the administration of compositions comprising racemic β-hydroxybutyrate or D-β-hydroxybutyrate (optionally in the acid form), physiologically compatible salts of racemic β-hydroxybutyrate or D-β-hydroxybutyrate (e.g., sodium, potassium, calcium or magnesium salts), esters of D-β-hydroxybutyrate, oligomers of D-β-hydroxybutyrate containing from 2 to 20 (or more) monomeric units in either linear or cyclic form, racemic 1,3 butandiol, R-1,3 butandiol, or any combination thereof with other agents either together (in a single composition), separately (i.e., a first composition comprising racemic β-hydroxybutyrate or D-β-hydroxybutyrate (optionally in the acid form), physiologically compatible salts of racemic β-hydroxybutyrate or D-β-hydroxybutyrate (e.g., sodium, potassium, calcium or magnesium salts), esters of D-β-hydroxybutyrate, oligomers of D-β-hydroxybutyrate containing from 2 to 20 (or more) monomeric units in either linear or cyclic form, racemic 1,3 butandiol, R-1,3 butandiol, or any combination thereof and a second composition comprising another agent (e.g., a) anti-lipemic agents; b) anti-hypertensive agents (including those combination treatments set forth in the table entitled “Combination Drugs for Treatment of Hypertension” [Table 3]); c) glucose lowering agents; or d) anti-inflammatory agents)) or sequentially. For the sequential administration of a first and second composition to be considered a combination therapy (e.g., “in combination”), the first and second compositions must be administered separated by a time interval that still permits the first composition to be used during a treatment cycle of the second composition, or that permits the first composition to show enhanced activity, particularly activity, when compared with the single components alone. In the context of this invention, the term “activity” relates to an ability to lower serum cholesterol levels; triglyceride levels; serum glucose levels, blood sugar levels, serum homocysteine levels, inflammatory proteins, inflammation or blood pressure/hypertension.
Racemic β-hydroxybutyrate or D-β-hydroxybutyrate (optionally in the acid form), physiologically compatible salts of racemic β-hydroxybutyrate or D-β-hydroxybutyrate (e.g., sodium, potassium, calcium or magnesium salts), esters of D-β-hydroxybutyrate, oligomers of D-β-hydroxybutyrate containing from 2 to 20 (or more) monomeric units in either linear or cyclic form, racemic 1,3 butandiol, R-1,3 butandiol, or any combination thereof are administered to an individual in an amount that results in blood concentrations of between 0.1 to 25 mM of D-β-hydroxybutyrate plus acetoacetate, or preferably between 0.4 to 10 mM or most preferred between 0.6 and 3 mM blood levels of D-β-hydroxybutyrate plus acetoacetate. Alternatively, the methods may recite the levels of racemic β-hydroxybutyrate or D-β-hydroxybutyrate (optionally in the acid form), physiologically compatible salts of racemic β-hydroxybutyrate or D-β-hydroxybutyrate (e.g., sodium, potassium, calcium or magnesium salts), esters of D-β-hydroxybutyrate, oligomers of D-β-hydroxybutyrate containing from 2 to 20 (or more) monomeric units in either linear or cyclic form, racemic 1,3 butandiol, R-1,3 butandiol, or any combination thereof that are to be administered to an individual in terms of percentages. Thus, racemic β-hydroxybutyrate or D-β-hydroxybutyrate (optionally in the acid form), physiologically compatible salts of racemic β-hydroxybutyrate or D-β-hydroxybutyrate (e.g., sodium, potassium, calcium or magnesium salts), esters of D-β-hydroxybutyrate, oligomers of D-β-hydroxybutyrate containing from 2 to 20 (or more) monomeric units in either linear or cyclic form, racemic 1,3 butandiol, R-1,3 butandiol, or any combination thereof can be administered in amounts that range from 2-100% of the diet of an individual, or preferably 5-70% of the diet of an individual, or most preferred 5-30% of the diet of the individual. These percentages refer to the total caloric intake of the individual. Additionally, any combination of racemic β-hydroxybutyrate or D-β-hydroxybutyrate (optionally in the acid form), physiologically compatible salts of racemic β-hydroxybutyrate or D-β-hydroxybutyrate (e.g., sodium, potassium, calcium or magnesium salts), esters of D-β-hydroxybutyrate, oligomers of D-β-hydroxybutyrate containing from 2 to 20 (or more) monomeric units in either linear or cyclic form, racemic 1,3 butandiol or R-1,3 butandiol can be administered to an individual in accordance with the aforementioned methods.
Animals were fed diets comprising the various components as set forth in Table 1. The animals were then tested to determine total cholesterol levels, low density lipoprotein levels, high density lipoprotein levels, triacylglycerol levels, free fatty acid levels and plasma glucose levels. Table 2 relates to plasma metabolite levels in non-fasting rats fed one of three diets for 7 or 66 days. The ketone diet doubled the plasma β-hydroxybutyrate concentrations at both 7 and 66 days. Total cholesterol levels were significantly lower in ketone-fed rats compared with rats fed a Western diet. After 66 days on the diets, plasma HDL and LDL levels were significantly lower, and the HDL/LDL ratios tended to be higher, in the ketone fed rats compared with the Western-diet fed rats. The triacylglycerol levels were significantly lower in the rats fed the ketone diet, compared with rats fed the Western diet. There were no effects of diet on plasma free fatty acid levels, but the rats fed the ketone diet for 66 days had lower plasma glucose levels.
This application claims the benefit of U.S. Provisional Application Ser. No. 61/018,962, filed Jan. 4, 2008, the disclosure of which is hereby incorporated by reference in its entirety, including all figures, tables and amino acid or nucleic acid sequences.
| Number | Date | Country | |
|---|---|---|---|
| 61018962 | Jan 2008 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 16203748 | Nov 2018 | US |
| Child | 17728600 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 14931265 | Nov 2015 | US |
| Child | 16203748 | US | |
| Parent | 12811648 | Jul 2010 | US |
| Child | 14931265 | US |
