Source: http://www.google.com/patents/US8016783?dq=ininventor:oliver+ininventor:steele
Timestamp: 2014-03-12 18:33:17
Document Index: 482599810

Matched Legal Cases: ['art 105', 'art 105', 'art 105', 'art 105', 'art 105', 'art 105']

Patent US8016783 - Method and apparatus for modulating cellular metabolism during post-ischemia ... - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign inAdvanced Patent SearchPatentsA drug delivery system detects a cardiac condition indicative of a need for increasing a cardiac metabolic level and, in response, releases a drug into tissue or blood to shift a source of metabolically synthesized energy fueling cardiac contraction from fatty acid to glucose. One example of such a system...http://www.google.com/patents/US8016783?utm_source=gb-gplus-sharePatent US8016783 - Method and apparatus for modulating cellular metabolism during post-ischemia or heart failureAdvanced Patent SearchPublication numberUS8016783 B2Publication typeGrantApplication numberUS 11/998,969Publication dateSep 13, 2011Filing dateDec 3, 2007Priority dateAug 21, 2003Also published asUS7320675, US20050043675, US20080091138Publication number11998969, 998969, US 8016783 B2, US 8016783B2, US-B2-8016783, US8016783 B2, US8016783B2InventorsJoseph M. Pastore, Julio C. Spinelli, Helen L. Reeve, Jeffrey Ross, Rodney W. Salo, Allan ShurosOriginal AssigneeCardiac Pacemakers, Inc.Export CitationBiBTeX, EndNote, RefManPatent Citations (106), Non-Patent Citations (71), Classifications (22), Legal Events (1) External Links: USPTO, USPTO Assignment, EspacenetMethod and apparatus for modulating cellular metabolism during post-ischemia or heart failureUS 8016783 B2Abstract A drug delivery system detects a cardiac condition indicative of a need for increasing a cardiac metabolic level and, in response, releases a drug into tissue or blood to shift a source of metabolically synthesized energy fueling cardiac contraction from fatty acid to glucose. One example of such a system includes an implantable device detecting an ischemia and a transdermal drug delivery device delivering a drug when an ischemic condition is detected. Another example of such a system includes one or more implantable devices detecting a predefined change in cardiac metabolic level and delivering a drug when the change is detected. Such systems are applied to treat, for example, patients suffering ischemia and/or heart failure and patients having suffered myocardial infarction.
a transdermal drug delivery device adapted to deliver a drug;
an ischemia detector adapted to detect an ischemia and produce an ischemia indicating signal in response to a detection of the ischemia;
a drug level detector including a respiratory sensor adapted to sense a respiratory signal as an indication of whether a blood drug concentration is below a predetermined minimum level after a delivery of the drug; and
a drug delivery controller coupled to the ischemia detector and the drug level detector; and
an external device communicatively coupled to the implantable CRM device, the external device including an external user input to receive an external user command,
wherein the drug delivery controller is adapted to control the transdermal drug delivery device based on at least one of the ischemia indicating signal, the indication of the blood drug concentration, and the external user command.
10. The system of claim 9, wherein the remote device further comprises a remote device controller adapted to generate commands controlling one or more of the transdermal drug delivery device, the implantable CRM device, and the external device based on the received signals and the remote user commands.
11. The system of claim 1, wherein the transdermal drug delivery device comprises a drug reservoir containing one or more pharmaceutical agents shifting a source of metabolically synthesized energy for cardiac contractions from fatty acid to glucose.
12. The system of claim 11, wherein the transdermal drug delivery device further comprises at least one skin contact electrode for transdermal drug delivery.
13. The system of claim 11, wherein the one or more pharmaceutical agents comprise one or more of agents decreasing, inhibiting, and/or reducing fatty acid oxidation and agents increasing, enhancing, and/or stimulating pyruvate, glucose, and/or lactate oxidation.
14. The system of claim 13, wherein the one or more pharmaceutical agents further comprise one or more of anti-hypertensive agents, anti-arrhythmic agents, pressors, vasopressors, vasodilators, anti-hyperlipidemic agents, anti-anginal agents, ionotropic agents, diuretics, volume expanders, thrombolytics, anti-platelet agents, beta-blockers, angiotensin converting enzyme (ACE) inhibitors, and angiotensin receptor blockers.
15. The system of claim 11, wherein the transdermal drug delivery device further comprises a drug delivery status indicator adapted to allow monitoring of whether the one or more pharmaceutical agents are being delivered.
16. The system of claim 11, wherein the transdermal drug delivery device further comprises a drug delivery status indicator adapted to allow monitoring of an amount of the one or more pharmaceutical agents remaining in the drug reservoir.
17. The system of claim 1, wherein the transdermal drug delivery device is configured to be a skin patch.
18. The system of claim 17, wherein the skin patch allows for electrically controlled transdermal drug delivery by iontophoresis, electroporation, electrorepulsion, or electro-osmosis.
19. The system of claim 1, wherein the external user input comprises a push button.
20. The system of claim 1, wherein the external user input comprises a voice controlled switch. Description
CROSS REFERENCE TO RELATED APPLICATION This application is a divisional of U.S. application Ser. No. 10/645,823, filed Aug. 21, 2003, now U.S. Pat. No. 7,320,675, the entirety of which is incorporated herein by reference.
In one embodiment, an implantable CRM device executing an automated ischemia detection algorithm is used to detect an ischemia. The implantable CRM device also detects an external user command directing a drug delivery. The external user command is transmitted from an external device. A drug delivery signal is produced upon a detection of at least one of the ischemia and the external user command. The drug delivery signal is transmitted to a transdermal drug delivery device. In response, a drug is delivered from the transdermal drug delivery device.
In one embodiment, pharmaceutical agents within the scope of the present subject matter include, but are not limited to, those which shift metabolism from fatty acid oxidation to glucose oxidation, e.g., agents which decrease, inhibit (suppress) or reduce fatty acid oxidation (trimetazidine or ranolazine), and/or increase, enhance or stimulate pyruvate, glucose or lactate oxidation, preferably in cardiac cells. Thus, agents which inhibit lipolysis (nicotinic acid, aka niacin, and beta-adrenergic receptor antagonists), the rate of fatty acid release from fat cells, lower plasma fatty acid concentrations, uptake of fatty acids by the heart, entrance of fatty acids into the mitochodrion, for instance, by inhibiting CPT-1 (carnitine, L-propionylcarnitine, perhexyline, etomoxir, or oxfenicine), or inhibit the levels or activity of acyl-CoA dehydrogenase, e.g., long chain or medium chain acyl-CoA dehydrogenase, enoyl-CoA hydratase, 3-hydroxyacyl-CoA dehydrogenase, or beta-ketothiolase, or enhance the levels or activity of pyruvate dehydrogenase, e.g., dichlororacetate inhibits pyruvate dehydrogenase kinase, and increases cytosolic acetyl-CoA, which inhibits fatty acid oxidation, glucose (insulin) and/or lactate transporters or otherwise alter glucose transport (Akt-1) or stimulates insulin secretion (GLP-1). Acetyl CoA is converted to malonyl CoA, which inhibits carnitine palmitoyltransferase-1 (CPT-1), thereby reducing fatty acid uptake into mitochondria.
Those agents may be employed alone or in conjunction with other agents such as anti-hypertensive agents, anti-arrhythmic agents, pressors, vasopressors, vasodilators, anti-hyperlipidemic agents, anti-anginal agents, ionotropic agents, diuretics, volume expanders, thrombolytics, anti-platelet agents, beta-blockers, angiotensin converting enzyme (ACE) inhibitors, and angiotensin receptor blockers, or any combination thereof, including but not limited to diuretics such as thiazides, e.g., hydrochlorothizide, loop duretics, e.g., furosemide, and potassium-sparing agents, e.g., amiloride, sprionolactone and triamterene and hydrochlorothiazide, beta-blockers such as bisoprolol, carvedilol, labetolol and metoprolol, angiotensin-converting enzyme inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, perindopril, quinapril, ramipril, trandolapril, delapril, pentopril, moexipril, spirapril, temocapril, and imidapril, calcium channel blockers, alpha blockers, angiotensin II antagonists, e.g., losartan, statins, e.g., atorvastatin, pitavastatin, and pravastatin, or other lipid lowering agents, moxonidine, dihydropyridines, e.g., amlodipine, class III and IV antiarrhythmics, e.g., amiodarone, azimilide, sotalol, dofetilide, and ibutilide, aspirin, selective non-adrenergic imidazoline receptor inhibitors, nebivolol, vasopeptidase inhibitors, e.g., fasidotritat, omapatrilat, sampatrilat, substrates, inhibitors or inducers of cytochrome P450 enzymes, lidocaine, warfarin, oligonucleotides (sense or antisense), natriuretic peptides such as ANP, BNP, NT pro BNP, CNP, and DNP, colforsin daropate hydrochloride (forskilin derivative), antagonists of platelet integrin IIb/IIIa receptors, e.g., abciximab and trofiblant, reteplase, P2 receptor antagonists, e.g., ticlopidine and clopidogrel, mibefradil, hirudin, acetylcholinesterase inhibitors, cardiac glycosides, e.g., digoxin and digitoxin, bradykinin, neutral endopeptidease inhibitors, e.g., neprilysin, direct-acting vasodilators, e.g., hydralazine, nitroglycerin, sodium nitroprusside, catecholamines, dobutamine and dopamine, phosphodiesterase inhibitors, e.g., aminone and milrinone, TNFα, pentoxifylline, growth hormone, cytokine inhibitors, aldosterone receptor antagonists, calcium sensitizers, nesiritide, 3,5-dicodothyropropionic acid, etomoxir, endothelin receptor antagonists, chlorthiadone, doxazosin, nesiritide, cilostazol, rilmenidine, ticlopidine, dihydropines such as nifedipine and nisoldipine, timolol, propanolol, verapamil, diltiazem, lisinopril, noopept (N-phenylacetyl-L-polyglycine ethylester), cariporide, geldanamycin, radicicol, ibudilast, selective delta (1) agonists such as 2-methyl-4a-alpha-(3-hydroxy-phenyl)-1,2,3,4,4a,5,12,12a-alpha-octahydroquinolinol [2,3,3-g]isoquinoline, monophosphoryl lipid A, RC552, adenosine, adenosine receptor agonists, adenosine triphosphate sensitive channel openers, dipyridamole, fibroblast growth factor, atenolol, ezetimibe, levosimendan, sirolimus, paclitaxel, actinomycin D, dexamethasone, tacrolimeus, everolimus, estradiol, quinapril, tranilast, angiopeptin, trapidil, lacidipine, thiazolidinediones, fenofibrate, lacidipine, nebivolol, nicotinic acid, probucol, rosuvastatin, gemfibrozil, glitazones, indobufen, alpha-tocopherol, dypiridamole, resins, e.g., cholestyramine and colestipol, bezafibrate, or listat, niacin, heparin, e.g., low molecular weight heparins such as dalteparin sodium and nadroparin calcium, bivalirudin, nitroglycerin, nicorandil, denopamine, eptifibatide, xemilofiban, or bofiban, trimetazidine, nicorandil, dalteparin, and isosorbide 5-mononitrate. Additional pharmaceutical agents may be considered based on evidence of their direct or indirect roles in preventing or reducing injury or hemodynamic compromise related to myocardial infarction and/or heart failure. Examples of such pharmaceutical agents include, but are not limited to, L-arginine; nitric oxide (NO); NO derivatives such as nitroxl anion (HNONO�) and peroxynitrite (ONOO�); iNOS, eNOS, and inhibitors such as nitro-L-arginine methyl ester; NO donors such as diethylamine (DEA) NO and nitroglycerin (NTG); and interleukins and interleukin inhibitors.
FIG. 1 is an illustration of an embodiment of a transdermal drug delivery system 100 and portions of an environment in which it is used. System 100 includes, among other things, an implantable cardiac rhythm management (CRM) device 110, a transdermal drug delivery device 130, an external device 150, a remote device 170. As shown in FIG. 1, implantable CRM device is implanted in a body 102. Transdermal drug delivery device 130 is attached to the skin surface of body 102 at a site near heart 105. A lead system 108 provides electrical connection between heart 105 and implantable CRM device 110. A communication link 120 allows signal transmission between implantable CRM device 110 and transdermal drug delivery device 130. A telemetry link 140 provides for bidirectional communication between implantable CRM device 110 and external device 150. A network 160 provides for bidirectional communication between external device 150 and remote device 170.
System 100 allows a drug delivery to be triggered by any one of implantable CRM device 110, external device 150, and remote device 170. In one embodiment, implantable CRM device 110 triggers a drug delivery upon detecting a predetermined signal or condition. External device 150 triggers a drug delivery upon receiving an external user command from the patient wearing implantable CRM device 110 and transdermal drug delivery device 130 or from another person such as a relative, a friend, or a physician/caregiver. The patient enters the external user command when he or she detects an abnormal condition, such as a chest pain indicative of angina. Another person caring for the patient may also enter the external user command upon a request by the patient or an observation of an abnormal condition. Remote device 170 triggers a drug delivery upon receiving a remote user command from a physician/caregiver, who has been notified of the patient's condition. In other embodiments, external device 150 and/or remote device 170 process signals and/or a condition detected by implantable CRM device 110 to determine whether to trigger a drug delivery.
FIG. 2 is a block diagram showing one embodiment of the circuit of portions of system 100. Implantable CRM device 110 as shown in FIG. 2 includes pacing and defibrillation capabilities. In addition to drug delivery, examples of therapies delivered by implantable CRM device 110 include, but are not limited to, bradyarrythmia pacing, anti-tachyarrhythmia pacing, atrial and/or ventricular cardioversion/defibrillation, cardiac resynchronization therapy, and cardiac remodeling control. However, the pacing and defibrillation capabilities are not necessary for system 100 to perform drug delivery, and hence, are not necessary elements of implantable CRM device 110. In other words, implantable CRM device 110 can be an implantable pacemaker and/or defibrillator with additional functions including control of drug delivery, or it can be a dedicated implantable drug delivery processor or controller.
In one embodiment, implantable CRM device 110 includes a sensing circuit 211, an ischemia detector 212, a drug delivery controller 213, a drug level indicator 217, a pacing circuit 218, a defibrillation circuit 219, an implant controller 215, an implant communication module 222, and an implant telemetry module 242. Sensing circuit 211 senses an intracardiac electrogram through a lead of lead system 108. Ischemia detector 212 detects an ischemia and produces an ischemia indicating signal when an ischemic condition is detected. In one embodiment, ischemia detector 212 has an input connected to sensing circuit 211 and an ischemia analyzer running an automatic ischemia detection algorithm to detect an ischemic condition from the electrogram. One specific example of an electrogram-based ischemia detector 212 is discussed in Zhu et al., U.S. patent application Ser. No. 09/962,852, entitled �EVOKED RESPONSE SENSING FOR ISCHEMIA DETECTION,� filed on Sep. 25, 2001, assigned to Cardiac Pacemakers, Inc., which is incorporated herein by reference in its entirety. In another embodiment, ischemia detector 212 includes an electrical impedance based sensor using a low carrier frequency (e.g. 100 Hz) and an ischemia analyzer running an automatic ischemia detection algorithm to detect an ischemic condition from the electrical impedance signal. Tissue electrical impedance has been shown to increase significantly during ischemia, as discussed in Min, et al. International Journal of Bioelectromagnetism, 5(1): 53-56 (2003). Ischemia detector 212 senses low frequency electrical impedance signal between electrodes interposed in the heart, and detects the ischemia as abrupt changes in impedance (such as abrupt increases in value). In yet another embodiment, ischemia detector 212 includes a local heart motion based sensor utilizing an accelerometer located within a lead body positioned on or in the heart and an ischemia analyzer running an automatic ischemia detection algorithm to detect an ischemic condition from the acceleration signal. Ischemia detector 212 detects ischemia as an abrupt decrease in the amplitude of local cardiac accelerations. Upon receiving at least one of the ischemia indicating signal from ischemia detector 212, an external user command from external device 150, and a remote user command from remote device 170, drug delivery controller 213 generates a drug delivery signal. The drug delivery signal is transmitted through communication link 120 to transdermal drug delivery device 130 to trigger a drug delivery. After the drug delivery, drug level indicator 217 measures or estimates a blood drug concentration of the drug delivered to produce an indication of the blood drug concentration. In one embodiment, drug level indicator 217 includes a drug level detector that measures the blood drug concentration. In another embodiment, drug level indicator 217 includes a sensor measuring a physiological parameter indicative of the blood drug concentration. Examples of such a sensor include a respiration sensor and a heart rate detector. If drug level indicator 217 produces an indication of a blood drug concentration that is below a predetermined minimum level, drug delivery controller 213 produces a drug delivery signal to continue the drug delivery or start another drug delivery. Implant controller 215 provides for overall control and signal processing for implantable CRM device 110. Implant communication module 222 provides for a signal transmission interface allowing implantable CRM device 110 to communicate with transdermal drug delivery device 130, such as to transmit the drug delivery signal, via communication link 120. Implant telemetry module 242 provides for a telemetry interface allowing implantable CRM device 110 to communicate with external device 150 via telemetry link 140.
Lead system 108 includes one or more pacing leads, defibrillation leads, pacing-defibrillation leads, or any combination of such leads. It allows sensing of electrical signals from heart 105 and/or delivery of pacing pulses and/or defibrillation shocks to heart 105. In one embodiment, lead system 108 includes one or more transveous leads each having at least one sensing-pacing electrode disposed within heart 105. In one embodiment, lead system 108 includes one or more epicardial leads each having at least one sensing-pacing electrode disposed on heart 105. On one embodiment, lead system 108 includes one or more leads each having at least one sensor such as an accelerometer or a metabolic sensor. In one specific embodiment, lead system 108 includes one or more leads each having a metabolic sensor disposed in a blood pool when the lead is implanted.
Network 160 provides long distance bi-directional communication between external device 150 and remote device 170. It allows management of multiple implantable devices, such as implantable CRM device 110 and transdermal drug delivery device 130, from a central facility at a remote location. In one embodiment, this allows prompt response by a physician/caregiver at the central facility as demanded by the condition of a patient. In one embodiment, network 160 is based on a wireless communications system. In another embodiment, network 160 is based on a wired communications system. In one embodiment, network 160 utilizes portions of a standard communications system such as the Internet, a telephone system, or a radio frequency telemetry system.
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