WO2001093951A1 - Dispositif d'administration de medicaments - Google Patents

Dispositif d'administration de medicaments Download PDF

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Publication number
WO2001093951A1
WO2001093951A1 PCT/IL2000/000832 IL0000832W WO0193951A1 WO 2001093951 A1 WO2001093951 A1 WO 2001093951A1 IL 0000832 W IL0000832 W IL 0000832W WO 0193951 A1 WO0193951 A1 WO 0193951A1
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WO
WIPO (PCT)
Prior art keywords
molecule
effect
electrode
transport
tissue
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Application number
PCT/IL2000/000832
Other languages
English (en)
Inventor
Nissim Darvish
Itsik Shemer
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Impulse Dynamics Nv
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Impulse Dynamics Nv filed Critical Impulse Dynamics Nv
Priority to AU18815/01A priority Critical patent/AU1881501A/en
Priority to US10/048,803 priority patent/US7171263B2/en
Priority to AU18820/01A priority patent/AU1882001A/en
Priority to US10/048,802 priority patent/US7092753B2/en
Priority to PCT/IL2001/000056 priority patent/WO2001052931A1/fr
Priority to AU27023/01A priority patent/AU2702301A/en
Publication of WO2001093951A1 publication Critical patent/WO2001093951A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/325—Applying electric currents by contact electrodes alternating or intermittent currents for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/20—Applying electric currents by contact electrodes continuous direct currents
    • A61N1/30—Apparatus for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body, or cataphoresis
    • A61N1/303—Constructional details
    • A61N1/306—Arrangements where at least part of the apparatus is introduced into the body

Definitions

  • the present invention relates to electrically mediated transport of drugs into cardiac tissue and/or into cells of the tissues.
  • Electroporation is a technique used for introducing molecules across a cell membrane and into a cell, h a typical application, an in-vitro cell culture is mixed with a target molecule and a brief electrical field is applied to the mixture. The electrical field causes a transient porosity of the cell membranes, allowing the molecules to enter the cell.
  • U.S. Patent 5,501,662 the disclosure of which is incorporated herein by reference, describes an electroporation system for blood, in which an electric field is applied to a vessel having blood cells mixed with a target gene (or other molecules) and the electric field causes the genes to be transported into the cells.
  • Electroporation is especially useful for large molecules, such as proteins, and for other molecules which do not have a biological mechanism for crossing the cell barrier.
  • Iontophoresis is a method of transporting drugs into a body tissue, from outside the body tissue, usually from the skin. The drug is provided in a charged form and, when an electric field is applied, the electric field moves the charged drug along the gradient of the field.
  • One aspect of some exemplary embodiments of the invention relates to using a non- excitatory pulse to control molecule availability at or near excitable tissue, such as the heart, the uterus or the GI tract, which might be activated in an undesirable manner by an applied electric field.
  • the exerted control may include, for example, one or more of causing a molecule to exit a reservoir, iontophoresis of the molecule into tissues, release of the molecule from a circulating reservoir, such as electrically-opened liposomes and/or electroporation of the molecule into individual tissue cells.
  • An optional second non-excitatory pulse may be provided to interact with the first pulse (e.g., to control the tissue) and/or the molecule.
  • the molecule availability pulse is excitatory and adverse effects of the pulse are prevented by the second pulse.
  • non-excitatory pulse means an applied electric field which does not induce an additional propagating action potential in the heart (or other relevant excitable tissue), for example due to its frequency, polarity, waveform, duration, amplitude and/or its being applied at a time in the electrical activation cycle when the nearby tissue does not respond to the pulse.
  • the term molecule means any type of molecule, including, especially, genetic material, such as DNA and RNA, genetic vectors, such as viruses and plasmids, polypeptides, hormones and small molecule drugs, hi addition, the molecules may include ATP, cAMP and/or particles having the molecule adsorbed thereto or located inside a volume of a hollow particle, such as a liposome, which can be transported into the tissue or trapped in a matrix, such as a hydrogel matrix reservoir on the electrode.
  • genetic material such as DNA and RNA
  • genetic vectors such as viruses and plasmids, polypeptides, hormones and small molecule drugs
  • the molecules may include ATP, cAMP and/or particles having the molecule adsorbed thereto or located inside a volume of a hollow particle, such as a liposome, which can be transported into the tissue or trapped in a matrix, such as a hydrogel matrix reservoir on the electrode.
  • Exemplary pharmaceuticals include: ⁇ -Blockers, anti-cancer drugs, specific antibodies, SERCA, VEGF and Nitro components such as Nitroglycerine, i particular, some molecules may have a systemic toxic effect and/or may damage some organs of the body, another example, the provided molecule is an antagonist for a different molecule, also present in the body, for example antagonists e.g. Protamine which antagonizes Heparin.
  • an arrhythmia knowledge of what types of pulses will not cause an ectopic excitation and or other arrhythmia, (herein referred to as an arrhythmia) in any particular excitable tissue organ and/or methods for controlling such arrhythmia should they occur are used to apply pulses having larger voltages, currents and/or durations than previously thought possible, to the excitable tissue, for the purpose of transporting drugs.
  • a variety of waveforms becomes available.
  • apparatus designed for non- excitatory pulses is used (e.g., not a pacemaker), making possible various programmable pulse forms and larger amounts of power.
  • a modified pacemaker/simulator may be used, for example a pacemaker with modified programming, to provide a non-excitatory pulse.
  • the type of electrode used is a point electrode.
  • a line electrode, a wide area electrode, a vascular electrode which is inserted into a vessel and/or a one- or two- dimensional matrix electrode may be used.
  • the molecules are provided by the electrode, for example using a drug-eluting electrode of one of various types as known in the art.
  • the molecule is provided in other ways. For example the molecule is injected systemically or locally or applied using an implanted pump (possibly with output ports at the region to be treated or in a vascular bed thereof or adjacent thereto where the electrical pulse can transport it).
  • a decomposing or other matrix having the molecule embedded therein is used to supply the molecule.
  • the molecule is ingested, inhaled or applied topically, h some cases, a plurality of molecules and/or molecule provision methods are used simultaneously in a single patient, for example both systemic and local provision of two different molecules.
  • such two or more molecules may interact, for example the local molecule blocking the activity of the systemic one or enhancing it, or vice versa, for example, the systemic molecule blocking the effect of the local molecule outside of the targeted area, where the concentration of the local molecule is lower.
  • An aspect of some embodiments of the invention relates to an interaction between non- excitatory signals applied and the molecule transport.
  • the transport pulse and/or an optionally provided second non-excitatory pulse prevent and/or counteract adverse affects of the transport pulse and/or of the transported molecule, for example by preventing the propagation of undesirable action potentials.
  • the transport pulse is applied at a location spatially displaced from the location of the second non-excitatory pulse.
  • the adverse effect that is contracted by the second non-excitatory pulse is caused by a non-transport electrical signal, for example an electrical or optical signal used to stimulate cells in or near the excitable tissue to perform angiogenesis.
  • the molecule and the non-excitatory signal cooperate to have a desired, synergistic effect on the excitable tissue, for example the molecule enhancing a contractility increasing effect of the signal or the signal enhancing a contractility increasing effect of the molecule.
  • the signal may be selected to have a minimal (e.g., functional and/or sensory) effect on the excitable tissue.
  • non-ionized/charged molecules are used for electrically mediated transport in the excitable tissue.
  • the effect of electroporation is achieved by the electric field of the non-excitatory signal momentarily opening pores in the cardiac cell membranes.
  • dipole charges are formed on the molecules, for transport, by using suitable electric field frequencies.
  • required field intensities, waveforms or frequencies are provided by virtue of using non- excitatory fields.
  • An aspect of some exemplary embodiments of the invention relates to a method of treating a dysfunction in an excitable organ.
  • a patient is temporarily connected to a device that electrically transports molecules into excitable tissue.
  • the device also performs monitoring functions and/or provides other treatment, such as applying electrical fields that prevent arrhythmia or pacing the excitable tissue.
  • An aspect of some exemplary embodiments of the invention relates to treating coronary blood vessels or other blood vessels that are near or inside the heart or other excitable tissue, using electrically mediated molecule transport.
  • the timing and/or other parameters of application of electric fields for transporting the molecules are selected to not have a pro-arrhythmic effect on the excitable tissue.
  • the molecule transported is one which causes breakdown of clots or other occlusions, one which causes angiogenesis and/or one which prevents stenosis or re-stenosis of the vessel.
  • the therapy may be effected using a non-transport pulse, for example a vessel spasm relaxation pulse. It is noted that pacemaker lead placement usually avoids placing the lead over a coronary vessel, in order to provide better electrical contact with the excitable tissue.
  • An aspect of some exemplary embodiments of the invention relates to using a non- excitatory pulse generating device to both transport a molecule and detect and/or measure an effect of the molecule, for example an effect on conduction velocity, contractility or action potential propagation.
  • the device can be used to counteract or block pro-arrhythmic effects of the molecule and/or of the pulse used to transport the molecule.
  • the device is used to control the type, timing and/or dosage of molecule to be applied.
  • An aspect of some exemplary embodiments of the invention relates to providing one or more types of molecules at a plurality of locations on the excitatory tissue.
  • the amount of molecule transported and the type of molecule transported at each point is individually controllable.
  • the application regimen of the molecule may be pre determined.
  • the application regimen may be varied, for example in response to needs of the excitatory tissue or in response to the effect of a previous application.
  • a non-excitatory pulse is used to transport the molecule.
  • An aspect of some exemplary embodiments of the invention relates to synchronizing the transport of a molecule with activity of the excitable tissue, for example the cardiac cycle or cardiac output variations caused by activity, to achieve desirable effects, for example transport effects.
  • the synchronization is with on-off (or high-low) activation cycles of the tissue.
  • Three types of synchronization may be distinguished. First is synchronization with the activity of a single cell (or a region) from depolarization to depolarization. The synchronization may be with any part of the electrical cycle, including, for example, an onset of depolarization or a plateau. Second is synchronization with the activity of the excitatory tissue within a cycle.
  • the non-excitatory device can also control the above excitable tissue activities, alternatively or additionally to synchronizing with them.
  • the molecule is transported at a time when it will have the greatest effect on the heart.
  • the molecule is transported when travel through the uterine tissue is easiest, for example when the muscles of the uterus are relaxed.
  • the non-excitatory pulse is used to extend the refractory time of all or part of the tissue to allow the molecule to travel further in one cycle.
  • An aspect of some embodiments of the invention relates to releasing a molecule from a circulating reservoir, using a field applied by an electrode associated with a particular blood vessel.
  • the particular blood vessel feeds a particular organ or part of an organ to be treated.
  • the electrode is mounted on a stent-like device, on the inside of the blood vessel.
  • the device is mounted outside the blood vessel, for example being a wire implanted electrode.
  • the circulating reservoir comprises a liposome of a type that releases its contents when a sufficiently strong electric field is applied to it.
  • the stent also includes a reservoir of a same or different molecule.
  • the electrode (or a different electrode) also applies a transport field, for example to release a drug from the reservoir or to transport a molecule from the blood flow to the surrounding tissue.
  • electrical treatment apparatus for use with an associated molecule source, comprising: at least one electrode; a power source for electrifying said at least one electrode; and a controller, which is programmed to activate the power source to selectively electrify said at least one electrode to apply at least one electric field including a transport effect for transporting a molecule in a desired manner and a non-excitatory control effect for controlling the activity of at least a part of a non-cardiac excitable tissue, said programming selected to achieve a desired provision of said molecule into said at least a part of an excitable tissue or associated vasculature, said desired provision being at least assisted by an interaction between the transport effect and the control effect.
  • said controller is hardware programmable.
  • said controller is software programmable.
  • said apparatus comprises a wireless programming input.
  • said programming comprises programming adapted for said patient.
  • said programming comprises a setting of at least one operational parameter of said apparatus.
  • said programming comprises a selection or at least one operational protocol from a set of available protocols in said apparatus.
  • said controller is operable in a testing mode, in which mode a test treatment of a molecule is provided to the patient and the response of the patient to the test is monitored by said controller.
  • said apparatus comprises a synchronization connection to a molecule source containing said at least one type of molecule.
  • said synchronization connection comprises an informative connection that provides at least one informative signal to said controller, informing of a state of molecule release.
  • said synchronization connection comprises a control connection that provides at least one control signal from said controller, to control a state of molecule release.
  • said molecule source is an electric-field mediated molecule source and wherein said control signal generates an electric field that releases said molecule from said source.
  • said synchronization connection is comprised in said at least one electrode used for applying a transport effect.
  • said molecule source is integral with said electrode.
  • said molecule source comprises blood dispersed molecules.
  • said molecule source is external to said apparatus.
  • said molecule source comprises a catheter, coupled to said apparatus outside said patient.
  • said molecule source comprises a source of a plurality of molecule types.
  • said controller controls said molecule source to selectively release at least a particular one of said plurality of molecule types.
  • said apparatus comprises at least one sensor that senses a functional tissue parameter and provides said sensed parameter to said controller.
  • said sensor measures a functional tissue parameter relating to the entire excitable tissue.
  • said sensor measures a functional tissue parameter relating to a portion of the excitable tissue.
  • said controller analyses said sensed parameter to detect an effect of said molecule on said excitable tissue.
  • said controller analyses said sensed parameter to detect an activity of the excitable tissue and wherein said controller synchronizes said provision to said sensed activity.
  • said controller analyses said sensed parameter to detect an effect of said transport field on said excitable tissue.
  • said controller modifies said at least one electric field to modify said transport effect responsive to said sensed parameter.
  • said controller modifies said at least one electric field to modify said control effect responsive to said sensed parameter.
  • said apparatus comprises a watchdog that detects an abnormal effect of said applied fields.
  • said apparatus comprises a watchdog that detects an abnormal effect of said molecule.
  • said apparatus comprises a user input for receiving an indication of an effect of said apparatus from said patient.
  • a single electric field applies both of said transport effect and said control effect.
  • said at least one electric field comprises at least one transport field and at least one control field.
  • said transport effect and said control effect are provided simultaneously. Alternatively, said transport effect and said control effect are applied sequentially. Alternatively or additionally, said control effect is selectively applied in association with only some of said transport effects.
  • said apparatus comprises at least one pacing electrode that is controlled by said controller to apply a pacing pulse.
  • said at least one pacing electrode is comprised in said at least one electrode.
  • said transport effect is provided by an excitatory field.
  • said transport effect is provided by a non-excitatory field.
  • said control effect is selected to prevent an adverse effect of said transport pulse. Alternatively or additionally, said control effect is selected to prevent an adverse effect of said molecule. Alternatively or additionally, said molecule is selected to counteract an adverse effect of said control effect. Alternatively or additionally, said control effect is selected to counteract an adverse effect of said molecule. Alternatively or additionally, said control effect is selected to prepare said tissue for said transport. Alternatively or additionally, said control effect is selected to extend a period of time suitable for provision of said molecule. Alternatively or additionally, said control effect and said molecule are selected to cooperate and effect a desired treatment of said tissue. Alternatively or additionally, said at least one electrode comprises at least one transport electrode for applying a transport effect of said at least one field and at least one control electrode for applying said control effect of said at least one field.
  • said transport effect and said control effect of said at least one electric field are applied using at least one common electrode of said at least one electrode.
  • said at least one control electrode is spatially displaced from said at least one transport electrode.
  • said at least one electrode comprises a point electrode.
  • said at least one electrode comprises a spiral electrode.
  • said at least one electrode comprises a linear electrode.
  • said at least one electrode comprises a mesh electrode.
  • said at least one electrode comprises a plate electrode.
  • said electrode comprises a plurality of independently electrifiable contacts.
  • said controllers selectively electrifies said independent contacts to achieve a desired, non-uniform, volumetric dispersion of said molecule, relative to said electrode.
  • said at least one electrode is connected by wire to said controller.
  • said at least one electrode is a wireless electrode.
  • at least one electrode is implantable.
  • said at least one electrode is mounted on a catheter.
  • said at least one electrode is an external electrode.
  • said apparatus is implantable.
  • said apparatus is comprises in a cylindrical body adapted for implantation inside a blood vessel.
  • said apparatus is wholly external to the patient.
  • said transport effect comprises iontophoresis.
  • said transport effect comprises electroporation.
  • said non-cardiac excitable tissue comprises uterine tissue.
  • said non-cardiac excitable tissue comprises bladder tissue.
  • said non-cardiac excitable tissue comprises digestive tissue.
  • said transport effect comprises releasing a molecule from a circulating reservoir.
  • said circulating reservoir comprises liposomes in a blood stream.
  • said controller coordinates the interaction of a systemic molecule and locally available molecule, to have a synergistic effect.
  • said local molecule blocks an effect of said systemic molecule.
  • said local molecule enhances an effect of said systemic molecule.
  • said systemic molecule blocks an effect of said local molecule away from said a locality where said local molecule is provided.
  • said systemic molecule enhances an effect of said local molecule.
  • electrical treatment apparatus for use with an associated molecule source, comprising: at least one electrode; a sensor for sensing a functional state of a non-cardiac tissue; a power source for electrifying said at least one electrode; and a controller, which is programmed to activate the power source to selectively electrify said at least one electrode to apply at least one electric field including a transport effect for transporting a molecule in a desired manner, synchronized to said sensed functional state.
  • FIG. 1 is a schematic illustration of an excitable tissue connected to a non-excitatory signal providing device, in accordance with an exemplary embodiment of the invention
  • Fig. 2 is a schematic box diagram of internal sub-components of the device of Fig. 1, in accordance with an exemplary embodiment of the invention
  • Figs. 3A-3E illustrate various practices of electrode configuration and placement, in accordance with exemplary embodiments of the invention
  • Fig. 4 is a schematic illustration of a molecule provision apparatus, in accordance with an exemplary embodiment of the invention.
  • Fig. 5 is a schematic showing of a catheter-based molecule provision configuration, in accordance with an exemplary embodiment of the invention.
  • Fig. 6 illustrates a vascular treatment device, in accordance with an exemplary embodiment of the invention.
  • Fig. 1 is a schematic illustration of an excitable tissue (e.g., a heart) 102 connected to a non-excitatory signal providing device 100 and showing various optional features of such a connection, in accordance with an exemplary embodiment of the invention.
  • excitable tissue e.g., a heart
  • non-excitatory signal providing device 100 showing various optional features of such a connection, in accordance with an exemplary embodiment of the invention.
  • the method sand devices can also be applied to non-cardiac excitable tissues, such as the uterus, the GI tract (e.g. stomach, large and small intestines) or the bladder.
  • specific cardiac structures are described, such as coronary vessels and the S A node, corresponding structures in the excitable structures may replace them.
  • Some structures may have an inexact correspondence, for example, a pacemaker location in the uterus or other excitable tissue may move.
  • device 100 is operative to provide non- excitatory signals to the heart and/or otherwise control the heart, as a whole or in portions thereof, an exemplary embodiment of the invention, some or all of the non-excitatory signals generated by device 100 are used to transport a molecule into the heart tissue or surrounding tissues, in which tissues application of an electrical field might adversely affect the heart.
  • One or more electrode leads 104 provide electricity from device 100 to one or more electrodes 106.
  • a pacer signal electrode 110 may be used to pace the heart, possibly every beat, but optionally not at the same beats as the application of non-excitatory signals.
  • a sensor 108 may be used to provide feedback .to device 100 on the effect of the signal and/or the transported molecule.
  • non-excitatory signal rather than a standard pacing signal (a signal whose task is to generate a dependable initiation of a cardiac cycle) results in a much wider range of relevant molecules (e.g. heavy, large or less polarized molecules) and treatment possibilities.
  • relevant molecules e.g. heavy, large or less polarized molecules
  • higher energies and/or longer transport pulses are used.
  • the following table compares a typical pacemaker and a non- excitatory signal providing device in accordance with exemplary embodiments of the invention:
  • various types of transport effects can be achieved, for example voltage based effects, current density based effects and/or charge based effects.
  • the available current and voltage amplitudes make it easier to transport large molecules, provide deep tissue iontophoresis or even electroporation.
  • the available durations complement the available amplitudes levels by allowing a much longer transport time.
  • the use of large electrodes and mesh electrodes, for example as described below, allows the local treatment of many locations in the heart and/or the treatment or large areas of the heart, which is not possible using a standard pacing lead. Also, this can lower the impedance of the electrode.
  • an exemplary range for iontophoresis is between 200 Hz and 10 MHz, for example between 2 and 15 kHz.
  • DC waveforms are used. Wave from generators are described in US patent applications 08/110,109 and 07/957,209, both abandoned, the disclosures of which are incorporated herein by reference. With regard to electroporation, frequencies between 0.017 and 10 Hz are suggested. Voltages between 100 and 10,000 volts are suggested, with electrodes between 0.5 and 10 cm apart. Pulse durations are suggested between 1 microsecond and 1 second, more typically 100 msec. It is noted, however, that by providing a non-excitatory field to counteract adverse affects, a wider range of fields and field parameters is available, so the above should be taken as only exemplary field parameters.
  • exemplary pulses and/or apparatus which may be useful can be found in US patent application 08/129,252, now abandoned, US patent 5,634,899, US patent 5,286,254, US patent 5,087,243, US patent 5,458,568, US patent 5,282,785 and US patent 5,236,413, the disclosures of which are incorporated herein by reference.
  • the applied transport pulses may have a net zero charge flow or they may have a non-zero net charge flow, which may need to be compensated by an after-transport charge zeroing current, that balances out the charge emitted by the electrode.
  • the non-excitatory field is combined with an excitatory, portion, for example for pacing.
  • (f) ability to self transport into cells. Some molecules, such as viruses and liposomes can more readily insert themselves into cells than raw DNA.
  • ion channels (provided directly or genes for ion channels provided) can modulate electrical activity and/or cause metabolic changes. This can result in death for some cells and in a cure for other cells. Specifically, increased population of membrane potassium channels can shorten action potential, lower membrane potential and/or change the refractory periods of a cell.
  • Drug combinations are examples of drugs.
  • Drug vs. non-drugs Although many of the suitable molecules are drugs, other molecules may also find use, for example signaling molecules, such as hormones, cytokines and/or paracrinic signals/hormones, both natural and synthetic. Additionally or alternatively, various types of genetic-related molecules may be used. Alternatively or additionally, membrane proteins, such as voltage gated channels may be used. Alternatively or additionally, structural proteins, such as actin, may be used. Alternatively or additionally, housekeeping proteins, such as Ubiquitin, may be used. Alternatively or additionally, solutes, such as glucose, cAMP, AMP, ADP, ATP and metal salts maybe used.
  • the molecules may be associated with other materials, to assist in transport or in the entry into cells and/or nucleus of cells, h one example, a drug may be adsorbed to a pellet, which pellet is more easily transported by the fields. In another example, the molecule is incorporated in a virus.
  • a particular desirable class of molecules is gene-related molecules, such as DNA, RNA, mRNA, etc., anti-sense molecules and proteins that affect transcription.
  • Microorganisms In some cases, it may be desirable to insert complete or semi- complete microorganisms or cell components into living cells, for example mitochondria, viruses or plasmids.
  • the molecule may interact in a beneficial, neutral or adverse manner with one or more of the transport method, the provision method, the cardiac sensitivity (e.g., to electrical fields and certain molecules) and or the instantaneous activity of the heart. These effects (if negative) may be overcome or enhanced, in some embodiments of the invention, by suitable varying of the transport method and of the molecule properties, for example as classified above.
  • electroporation techniques are used to provide gene therapy to the heart, hi gene therapy, genetic material or a carrier thereof, such as plasmids, artificial chromosomes or viruses particles are provided into a cell.
  • suitable genetic material include, anti-sense DNA, RNA and poly-peptides to block the expression of genes which have an undesirable effect.
  • tagging material is inserted to the cell, to serve as a trigger for more complex activity, hi one example, regeneration of particular cells is achieved by tagging cells using a genetic marker. A second therapy is applied systemically but is only taken up or only triggers the tagged cells.
  • the provided genetic material may be used for various purposes, including, for example modifying the cell genotype, curing a genetic defect or a viral disease, causing a cell to differentiate in a desired manner or changing the function of a cell, such as changing the conduction velocity, action potential profile and/or leakage current characteristics of the cell.
  • Mulligan RC et al. describe a mechanism for targeting stem cells to where they are required in the body. It is believed such stem cells are targeted by a localized inflammation process, which process may be artificially and locally induced using a suitable molecule in accordance with an exemplary embodiment of the invention.
  • a particular aspect of some types of genetic therapy is that the cell's behavior is modified.
  • the cell may affect other, neighboring, cells, for example by creating copies of the genetic material (e.g., virus) or by extruding hormones and other cellular-communication chemicals.
  • tissues near clogged arteries are genetically modified, for example with a plasmid, to generate an anti-coagulant, a clot dissolver or a vascular dilator. These materials are optionally provided locally in a therapeutic concentration, so that they are diluted in the general blood stream. Alternatively or additionally, these materials only reach active concentrations and/or required activity times if the blood volume flow is reduced relative to normal blood vessels.
  • the heart as a whole is affected by the treatment of a small set of cells.
  • cells can be treated to include more calcium or sodium channels, thereby causing the treated cells to form a pacing loci.
  • the effect may vary in duration, thereby allowing different pacing locations to be chosen.
  • Fig. 2 is a box diagram of exemplary sub-components of an exemplary device 100, in accordance with an exemplary embodiment of the invention. Although many possible sub- components are shown, some embodiments do not require all of the sub components, for example, some embodiments do not include watchdogs or programming input. For clarity, connecting lines between the sub-components are not shown.
  • the non-excitatory signals are generated by a signal generator 132 and outputted to the electrodes via an output coupler 140.
  • the power for driving the output signals may be provided directly from a power sources 120, or, more typically, using a capacitor bank 126 to accumulate power, hi a device that includes a pacing feature, some or all of these elements may be optionally shared between the pacemaker and the non-excitatory signal pathways.
  • a CPU 122 is optionally provided to control device 100.
  • a clock source 128 may be used to maintain an internal clock.
  • CPU 122 uses a state-machine model of the heart to assess if the heart is operating as expected and/or to determine the possible timing of non-excitatory pulses, especially for drug transport.
  • state-machine models may be used.
  • non-state machine model is used.
  • Various types of models are described in "Design of Cardiac Pacemakers,", ed. John G. Webster, 1995, by the Institute of Electrical and Electronics Engineers, h e, New York, NY, the disclosure of which is incorporated herein by reference.
  • CPU 122 utilizes sensor data from a sensor input 130, in determine application parameters. Although only a single sensor is shown, in some devices, more than one sensor is used.
  • device 100 includes a memory 134 for storing programming instructions, applied sequences and/or statistics and/or full data of the response of the heart at various times.
  • a programming input 136 preferably wireless, but optionally wired, is provided to allow programming the device, for example using RF, ultrasound or magnets.
  • a feedback output 138 is provided for presenting information from device 100 to an external programmer or user.
  • a particular use of the programming features is to assist in setting and modifying treatment regimes and/or adjusting existing regimes to take into account observations by a treating physician. Another use is allowing a patient to be treated at home and report by remote means, such as a telephone, the actual treatment and/or its effect. The setting of treatment parameters may also be by remote means.
  • Another possible use of output 138 (and programming input 136) is for receiving feedback from the patient.
  • the user of the device can activate device 100, using a handheld remote controller, which may optionally also beam energy, for example using RF radiation.
  • the remote control may include activation logic for the device.
  • a single remote controller can activate multiple devices, for example one or more of, a non-excitatory signal controller, a pacemaker, a drug targeting electric field(e.g., device 100) and a drug reservoir, to achieve a desired treatment effect.
  • the user activates device 100 in response to pain, for example, to release blood vessel dilating molecules in response to angina pectoris or to inhibit premature uterine contractions.
  • device 100 includes one or more watchdogs 124.
  • a first type of watchdog watches over the device itself to assure that it is working within the operational parameters defined for it. For example, two processors run concurrently, and if one is not responding, the other one generates an alert.
  • a second type of watchdog watches over the heart to assure that the heart does not, as a result of the treatment, exceed operational and/or functional parameters defined for the heart's activity, hi one example, the watchdog checks to see if the heart is acting differently after the transport pulse. Alternatively or additionally, the watchdog searches for particular tattletale signals of damage more likely to be caused by the treatment, for example, a certain type of arrhythmia in an pro-arrhythmic drug treatment or VT caused by the transport pulse.
  • the damage and/or danger may be immediate, for example the detection of an injury current or of VT.
  • the damage or danger detected may be longer term, for example, if the treatment causes a forced relaxation of part of the heart, which relaxation may cause hypertrophy or an aneurysm.
  • a separate feedback loop may be provided to detect if the treatment is having a desired effect, for example a desired remodeling of cardiac tissue.
  • the watchdog is implemented as a separate processor and/or sensor.
  • the watchdog comprises separate software.
  • the output of the watchdogs may include, for example, output to the patient, to a remote service center and/or may include a changing in the device parameters, for example to stop or modify the treatment or to provide symptom countering treatment, such as blocking of undesirable action potentials of transport of a different molecule.
  • device 100 is implantable.
  • device 100 is optionally encased in a small capsule, to be implanted in the chest or the stomach of the patient.
  • Device 100 may be integrated with a pacemaker or it may be a separate entity.
  • device 100 is external.
  • the electrodes are optionally internal, optionally reaching the heart either via a catheter inserted in the blood stream or via a hole in the skin, for example to effect a near-by vessel or part of the heart.
  • the molecules may be provided using the same catheter or in a tube alongside the electrodes. Alternatively, other molecule provision methods, for example as described below, may be used.
  • the electrodes may be external to the body, for example as used in some external pacemakers.
  • Various electrode schemes may be used, including, two large, two small, one large and many small, an array, electrode(s) in lungs and/or electrode(s) in esophagus.
  • the electrification of the electrodes matches the heart's position and/or global or local refractory state.
  • an external device is used for a short- term treatment, such as for gene therapy, for recovery from surgery or for recovery from a serious arrhythmia or acute ischemic event.
  • an implanted device may be used for medium term treatment.
  • a previously implanted device may be reprogrammed to apply a non-excitatory pulse as described herein, h some embodiments of the invention, only the electrodes are implanted and wireless. The rest of the device is external and is used to power and drive the electrodes, for example using RF radiation.
  • a stent applies non- excitatory pulses to transport an anti-re-occlusion drug into the blood vessel walls.
  • the drug may be provided in many ways, including, for example, from the blood stream, from a reservoir of the stent or from a catheter.
  • the device is a dedicated device.
  • some or all of the functionality may be achieved using a modified pacemaker, in which substantially only the programming and/or electrodes are modified.
  • the suitability of existing pacemaker circuitry and/or power supplies may depend, for example, on the effect desired (e.g., electroporation or iontophoresis) and on the molecule size, polarity and/or other properties, such as protective enclosure.
  • device 100 comprises a kit of two devices, one for providing the electrical fields and one for providing the molecule. Either or both of the devices may be implantable, external, partially implanted or transvascular.
  • a drug source controller 142 is optionally provided in device 100 to control the provision of molecules.
  • a third device such as an external or implanted controller (not shown), synchronizes the operation of the two devices.
  • one device is used for transporting the molecule and another device is used for pacing or non-excitatory control (molecule provision can be by either of the devices or using a separate device).
  • the other device can be used to counteract adverse effects of the transport and/or the applied molecules, h an exemplary embodiment of the invention, the two devices can communicate, for example using a wireless link, such as an ultrasonic link or a wired link, such as a fiber optic cable.
  • a wireless link such as an ultrasonic link or a wired link, such as a fiber optic cable.
  • Figs. 3A-3E illustrate various practices of electrode configuration and placement, in accordance with exemplary embodiments of the invention.
  • the type of electrode can be an important factor in determining the strength and distribution of the electric field. By changing the type and shape of the electrode, different types of transport may be effected. In addition, the depth of penetration and spatial distribution of the molecule into the cardiac tissue is affected, not only by the electrification of the electrode but also by the shape of the electrode.
  • the placement of the electrodes determines which part of the heart is affected and, together with a suitable selection of electrode type and shape, allows localized treatment of specific portions of the heart, such as the SA node.
  • certain multi-electrode types such as mesh electrodes or electrode arrays, provide a greater temporal and spatial control of the electric field.
  • the electrodes may be placed anywhere on the heart (e.g., inside the muscle, inside blood vessels or inside the heart), in some embodiments of the invention, the electrodes are placed at an arterial entrance, an area of infraction, at an ectopy site, near a block or an AV node, inside or at a border of a scar and/or at the nervous plexus.
  • Fig. 3 A illustrates the placement of a point electrode 160 on a cardiac segment 150. i a point electrode the strongest part of the electric field is in a close proximity to the electrode, indicated by a dotted line 162.
  • a bi-polar electrode is used, the localization of the field is even greater, being mainly between the two electrodes.
  • a common return electrode may be used, for example a casing of device 100 or a second electrode attached to a substantially remote portion of the heart.
  • Various tip shapes may be provided, for example, solid or meshwork balls, multi-fingered tips, spirals and/or a barb.
  • Fig. 3B illustrates the placement of a line electrode 164 on cardiac segment 150.
  • a simplest type of line electrode has contacts along its length, as shown.
  • a line electrode may comprise a plurality of spaced apart point electrodes which may be electrified in parallel or possibly in various orders, as a linear array.
  • a region 166 affected by electrode 166 is substantially larger than that of a point electrode. This can be used to apply a molecule to a larger portion of the heart or even to create a "fence" by applying a desensitizing drug along the electrode, i some embodiments of the invention, such a line electrode is curved.
  • Fig. 3C illustrates the deployment of a pair of line electrodes 168 and 170.
  • the affected area (in which there is a significant electric field) is marked by a dotted line as 172.
  • the two electrodes may be electrified with a same polarity or with opposing polarities. Additionally, if one or both lines comprises a linear array of point electrodes, these point electrodes may be scanned in synchrony or not.
  • the size and shape of affected area 172 is dependent on the type of electrification. For example , if the two electrodes are electrified with different voltages, there will typically be very small field outside of the electrodes, which may, in some embodiments, prevent the molecules from being transported outside of the electrified area.
  • Fig. 3D illustrates a mesh electrode 174 having a plurality of vertexes 176.
  • the entire mesh is electrified as a single element, i another embodiment, only the vertexes (or other segregated section of the mesh) are electrified (e.g., an array), hi another embodiment, at least some of the vertexes can be selectively electrified.
  • One advantage of selectively electrifying mesh (or line) vertexes in an electrode array is that there is finer control over the shape, location and intensity of the field and this control can be exerted in real-time, without requiring movement of the electrodes.
  • control is for modifying the transport field to effect a certain transport effect, for example as defined below, for adapting a pre-conceived electrification protocol to a particular heart and/or situation and/or to match the actual or expected propagation of the molecule in the heart.
  • control may be used to match the propagation of electrical waves in the heart or to match changes in the contractile state of cardiac muscle.
  • these states are estimated using a model.
  • these states may be measured using suitable sensors.
  • the molecule is provided at a mesh electrode.
  • the mesh electrode is electrified in a manner which distributes the molecules in a desired manner, for example electrifying pairs of vertexes in the mesh such that each such pair defines a different transport vector, for example all the electrification pairs sharing a common electrode.
  • the timing, amplitude and/or other electrification parameters are different for each electrode pair, taking into account, for example the different average activation times of the heart and/or the instantaneous different activation time.
  • Such an instantaneous activation time may be detected, for example, using the mesh electrodes as sensors or by providing dedicated sensors.
  • Fig. 3E illustrates the use of a plate electrode 178.
  • a plate electrode 178 may have apertures (not shown) formed in it, so it is not completely solid, hi an exemplary embodiment of the invention, electrode 178 may serve as a reservoir, for example including a suitable matrix encapsulating the molecule, or having an inner volume, for example enclosed by an electrically permeable membrane.
  • the electrode configurations of Figs. 3A-3E maybe applied outside of the heart muscle, inside the heart muscle or on the inside of the heart. Additionally, when using electrode pairs, one may be inside the heart tissue and one outside the heart tissue. Alternatively or additionally, at least one of the electrodes may be floating inside the heart, hi some embodiments, the electrodes are coated with a layer of material to retard clotting.
  • the molecules may be provided in various manners; for example as described below.
  • Two main types of provision should be differentiated, localized provision and systemic provision.
  • localized provision methods the concentration of the supplied molecule is significant only at or about the treatment area.
  • concentration of the supplied molecule is significant only at or about the treatment area.
  • One possible advantage of this type of provision is that effects on other body portions are reduced.
  • Another possible advantage is that a smaller amount of molecule may be used.
  • Another possible advantage is that a higher concentration of molecule can be realized at the treatment zone.
  • hi systemic provision methods one possible advantage is that there is no need to provide a molecule at precise temporal and/or spatial coordinates. Rather, the electrical transport effect is used to locally increase the effectiveness of the molecule, by transporting it to the tissue to be affected, for example from the blood stream.
  • FIG. 4 is a schematic illustration of a molecule provision apparatus, in accordance with an exemplary embodiment of the invention.
  • a lead 180 has at its end an electrode 182, for applying a non-excitatory electric field to a heart segment 150 and a drug- eluting portion 184.
  • lead 180 is a hollow tube which caries the molecule from a reservoir inside device 100 (not shown). Such a reservoir is amenable to replenishment, for example as known in the art of replenishing implanted medication pumps.
  • lead 180 itself may serve as a reservoir.
  • lead 180 is a hollow tube which caries the molecule from a reservoir inside device 100 (not shown).
  • Such a reservoir is more amenable for replenishment, for example as known in the art of replenishing implanted medication pumps.
  • lead 180 itself may serve as a reservoir.
  • lead 180 is hollow and filled with a liquid medicament.
  • the medicament is solid and is dissolved by body fluids only at the distal end thereof, hi another example, a molecule is constrained in a gel matrix inserted inside lead 180.
  • an electric field is used to advance the molecules along the lead, for example as described in US patent 5,865,787.
  • a reservoir may be useful where local provision of a molecule is desirable.
  • tip 184 may be porous, allowing the molecules to slowly diffuse out.
  • an electric field applied by electrode 182 is used to elute the molecule from tip 184.
  • Tip 184 maybe, for example, between electrode 182 and the heart, on an opposite side of the heart from the electrode or side by side with it. Additionally, one or both of electrode 182 and tip 184 maybe inserted into the cardiac tissue. A same field may be used for eluting and for transport or a different field may be used. Alternatively or additionally, one or more additional electrodes 184 may be used to assist in the eluting.
  • PCT publication WO 98/15317 describes a limited range of possibilities for selectively eluting molecules from a drug-eluting tip.
  • the freedom of electrode shape, charge polarity, charge amplitude, charge duration, charge location and waveform allow a much wider range of methods to be practiced.
  • the polarity of the field determines the polarity of molecule eluted.
  • the field amplitude determines what size molecule is transported and/or opens pores in a barrier material between the molecule reservoir and the outside of the tip.
  • molecules with dipole charges may be selected by applying a suitable elution frequency.
  • non-electrical transport methods are used to free the molecules, for example, operating pumps or openings in a reservoir.
  • Fig. 5 is a schematic showing of a catheter-based molecule provision configuration, in accordance with an exemplary embodiment of the invention.
  • a catheter 188 is used to provide the desired molecule from outside of the body, to its tip in a vicinity of electrode 192.
  • the catheter may be drug eluting over a portion of its length.
  • the molecules may be provided at a location from which they are advanced away from the electrode. Alternatively, the molecules may be attracted towards the electrode. Alternatively or additionally, the electrodes may be electrified to prevent the advance of the molecules in an undesired direction.
  • the molecules may be provided into a vascular bed of the area adjacent electrode 192, for example into a main coronary artery, h an exemplary embodiment of the invention, the application of the electrical field is timed to match the arrival of the molecule bolus. Alternatively or additionally, the provision of the molecule is over an extended period. In an exemplary embodiment of the invention, the application of the electrical field
  • tip 190 may block the flow of blood, optionally temporarily, for example using an inflatable balloon collar.
  • a double collar catheter having two spaced apart collars and a hollow lumen, may be used to block flow to only a portion of a vessel, while providing a molecule to the blocked off area and allowing the flow of blood to by-pass through the lumen of the catheter.
  • tip 190 may be pressed against the tissue to be treated, optionally in the direction of the field, so that the molecule can only advance through the tissue and not into the blood flow.
  • a local electric field may be applied to reduce or increase blood flow, for example by relaxing or contracting the blood vessel muscles. Such relaxation may also assist in the penetration of the molecule through or into the vessel walls.
  • the timing of the application of the electric field may take into account a model of propagating of blood in a heart in general and/or in the particular treated heart.
  • a model maybe derived, for example, from radiological studies of the propagation of radio-opaque dyes in the coronary vessels.
  • tip 190 injects the molecule directly into tissue.
  • Such injection may be achieved by providing a sharp tip at tip 190 or by the catheter exiting the blood flow or being provided not through the vascular system, for example through tissue or along body lumens such as the lungs or the GI tract.
  • Electrode 192 may be implanted by a catheter that may also be provided from outside the body, h one exemplary embodiment of the invention, the catheter and electrode are combine in a single invasive device. This device may be inserted into the body and brought to a desired treatment location, for example the apex of the heart. Then, a molecule is eluted (optionally at the electrode) and an electric field applied to treat the region.
  • a bipolar electrode may be used or the second electrode may be provided outside the body, or inside, for example using a second catheter, between which catheters a transport electric field andor a heart control electric field are applied.
  • the tip of the catheter inside the body includes a grasping device for attaching to a portion of a tissue adjacent the treatment area.
  • Such a catheter optionally includes a sensor for sensing local activity of the heart or is controlled (e.g., field application and/or molecule provision) using an external sensor, such as a 12-lead EKG sensor. Possibly, the catheter elutes a molecule along a portion of its length, allowing, for example, a length of a coronary vessel to be treated. Different molecules or concentrations of molecules may be eluted at different points along the catheter.
  • the combined catheter-electrode may be provided via the vascular system.
  • an endoscopic or throactoscopic approach may be used.
  • Such a device may be used for relatively chronic treatment, for example one treatment a week after a coronary event.
  • the device may be used for acute treatment, for example to provide a drug to a portion of the heart during cardiac surgery.
  • Another method of localized provision of a molecule is by injecting it into the heart using a syringe (from outside the body).
  • a syringe from outside the body.
  • the entry and retraction of the syringe are controlled using a spring-loaded device, so that contact with the heart is during a non-excitable portion of the cardiac cycle, to prevent arrhythmia.
  • Many systemic molecule application methods are known and may be used with various embodiments of the invention, including drip-feeding into a vein, catheterization into the right atrium, ingestion, inhalation and intra- vascular or intra-muscular injection.
  • device 100 includes a data input port for indicating when a drug is injected or otherwise provided into the user, so that the application of the non-excitatory signal can be timed to when the drug (or other molecule) is available at the electrodes.
  • a data input port for indicating when a drug is injected or otherwise provided into the user, so that the application of the non-excitatory signal can be timed to when the drug (or other molecule) is available at the electrodes.
  • Such an input may be provided for example using a magnet or an RF field.
  • the non-excitatory pulse used for transporting the molecule may be a separate pulse from that used for a non-excitatory based treatment, it may be a combined transport-treatment pulse or it may be a same pulse which has both a treatment effect and a transport effect. Possibly, a molecule may be selected or adapted for treatment by it matching available pulse forms or pulses which have a known therapeutic effect.
  • the transport mechanism may be that of removing the molecule from a reservoir using an electric field. Thereafter, the molecule can diffuse into the adjacent tissue (or wherever the blood caries it) or an active transport (e.g., an electric field) into adjacent tissue may be used.
  • an active transport e.g., an electric field
  • Transport into tissue can be, for example, iontophoresis.
  • uncharged molecules for example those with a dipole charge may be used.
  • the application of the electric field may make the tissue more porous to the diffusion of the molecule.
  • two or more of the above transport mechanisms are used together.
  • electroporation into the cardiac cells themselves maybe used .instead of or in addition to iontophoresis, for example, iontophoresis to advance a drug into the cardiac tissue and then electroporation to insert the drug into the cells.
  • the two mechanisms may optionally be applied in separate cardiac cycles.
  • selectivity may be achieved, besides selectivity of the transported molecule, described above, hi one example, the iontophoresis of a molecule is affected by the tissue through which the molecule travels.
  • the field strength used for electroporation is selected to affect only certain types of tissue, for example based on their taxonomy (muscle vs. nerve cells) or based on their health.
  • the molecules may be transported during any part of the cardiac cycle, to take advantage of (or avoid) particular electrochemical and/or physiological conditions.
  • a molecule may be selectively provided and/or transported so that it is available at the cells when their channels in the cell membrane open as part of the cardiac cycle. Such a molecule may be transported through the channel or it may be used to block the channel or to maintain it open for longer periods.
  • a transport pulse may be provided to maintain the channels open for longer periods (or close them), for example to provide a desirable biochemical state in the cell with which the molecule can interact or to allow the molecule to enter through the open channel.
  • the exact electrification parameters may need to be determined for a particular patient, tissue type and/or tissue health state.
  • diffusion of drugs and other molecules in the heart may be enhanced by diffusion between cardiac muscle cell groups, in which groups, the cell-ends are fused together.
  • the transport may be affected by the fiber direction and/or other macro-cellular structures. These effects can be used to selectively diffuse molecules along a direction.
  • these variation in tissue characteristics may affect a desired electric field to be used for transport between and/or into cells, hi an exemplary application, an electric field is used to transport a molecule into endocardial trabecula, while they are being filled. Then when they contract and force blood into the surrounding cardiac tissue, the transport is enhanced.
  • a second electric field is timed to the contraction.
  • the transport of molecules may take into account the variations in muscle tone over the cardiac cycle. Thus, an increased field may be required while the muscle is tense. Alternatively, the transport is selectively applied while the muscle is relaxed, to increase the depth of penetration of the molecule. Alternatively, the transport is applied when the muscle is tense, to assure a shallower penetration,
  • a multi-beat transport scheme in which a molecule is transported to an area to be treated by a transport process which is longer than one beat, hi one example, a molecule may be transported 1mm each heart beat, for a total of five beats, to achieve a penetration depth of 5mm.
  • the control exerted on the heart using the molecules and/or a non-excitatory electric field can be of various types. Three particular types of control which may be desirously achieved are global control, local control and global control using local interactions. In an example of global control, a gene may be provided to the entire heart, to correct a disease causing mutation in a particular patient.
  • a drug may be provided to an infracted area to promote healing or prevent further damage.
  • control of the SA node, of the AV node or of a particular conduction pathway may be used to affect the activation of the heart as a whole.
  • the type of interaction of the molecule with the heart may depend on cellular or on cardiac processes, for example, a drug maybe provided to coincide with the high levels of availability of free calcium.
  • a molecule may be provided so that it is available over a longer period of time, such as an entire beat or several heart beats. Exemplary periods of time for a molecule to be available are 0.1, 1, 10, 100 or 1000 seconds, e.g., in some cases substantially permanently.
  • the duration of the molecule effect, which may be divorced for the duration of availability may be, for example, 1, 10, 100 or 100 seconds, e.g., in some cases substantially permanent.
  • Some types of long cardiac-related cycles include the circadian rhythm exercise-rest cycles and the application of molecules to the heart to permanently change the shape and/or activation of the heart, hi an exemplary application, electric fields are used to stimulate angiogenesis and a stimulating molecule, such as VEGF is also provided to enhance the angiogenesis effect.
  • the molecule (and transport field) may be applied every beat or only every few beats.
  • a single transport event continues over several beats or has the duration of several beats, for example with the local tissue being desensitized so it does not contract.
  • selective molecule providing is used to control the heart locally and/or for temporally short periods, such as seconds or tens of seconds.
  • This effect is achieved by selectively transporting fast acting drugs to target tissues, in short times and without substantially providing the drugs to nearby tissues.
  • this affect is achieved by electrically (or using suitable eluted pharmaceuticals) desensitizing neighboring tissue from responding to the drugs.
  • INTERACTION BETWEEN DEVICE AND EXCITABLE TISSUE, OTHER THAN TRANSPORT The interaction between device 100 and the molecule may extend beyond transport. For example, one or more of the following effects can be achieved instead of or in addition to transport:
  • Device 100 applies fields that counteract or avoid negative effects of the molecule. As a result, molecules with a higher toxicity may be used, used at a higher dosage and/or used in a less rigidly monitored situation.
  • device 100 applies fencing or tissue desensitizing fields, as described in some of the above applications, to prevent propagation of undesirable activation potentials in the heart.
  • device 100 applied fields which reduce conduction velocity in tissue whose conduction velocity is undesirably increased by the provision of a drug.
  • the molecule may serve to prevent or counteract an adverse effect of the non-excitatory control pulse.
  • the molecule may be provided to avoid or counter act negative effects of the applied fields.
  • the fields in question may be excitatory or non-excitatory.
  • a molecule is provided to prevent or counteract edge effects at the fringes of applied non- excitatory fields.
  • Device 100 applies fields that synergistically interact with the molecule.
  • each of the molecule and the field work to increase cardiac contractility, and the combination is synergetic.
  • One such exemplary molecule is caffeine.
  • Another example of synergistic interaction is provided by Dobutamine (an example of an adrenergic agonist).
  • Device 100 applies fields which prepare a portion of the heart for an applied molecule. Such preparation may include, for example, relaxation to allow better transport by an electric field, or without one. Another example is prevention or provision of blood flow to a portion of the heart, by manipulation the cardiac activation profile, Thus, a transport-related electric field may be applied before any molecule is provided.
  • preparation is keeping a segment of the heart from contracting so that it has more available energy to respond to a drug.
  • the electric fields may be applied to extend the duration of a cardiac cycle, to allow more time for transport of a molecule between beats or to allow more time for the molecule to take effect.
  • a blood vessel wall is stimulated or relaxed to assist or otherwise modulate the transport through the vessel wall. Such control is especially useful for preventing the transport of a molecule in an undesired vector.
  • the transport related field may be applied near the location of the transport filed or at a remote location. For example, a field that dilates or contracts blood vessels may be applied to control the flow of blood through the area being treated or the molecule provision area, hi some embodiments of the invention, vascular control is provided independent of transport pulses and/or molecule provision.
  • Device 100 applies fields, which by themselves do not interact with the molecules, but, as part of a complete control scheme, both these fields and the molecule act together to effect a desired control of the heart.
  • a drug may be used to reduce overall conduction velocity in a ventricle, while an electric field is applied to increase the velocity at a certain location in the ventricle, h another example, a locally provided molecule is used to stimulate angiogenesis, while an electric field is used to reduce the work performed by the treated tissue, to allow it to receive and/or have available energy for the angiogenesis.
  • the size of the area and/or volume to which a non-excitatory electric field is applied may coincide with the molecule-affected area.
  • CALIBRATION Device 100 may be programmed and/or have parameters selected to match a particular patient (described below).
  • one or more of a set of programs may be selected to be applied by device 100.
  • the patient state is evaluated, to determine a desirable treatment.
  • this evaluation is performed using device 100, in a purely sensory mode, or, optionally, with device 100 applying test treatments and determining their effects.
  • various external stimuli may be provided, for example pharmaceuticals and their effects and/or interactions with device 100 monitored by device 100 and/or other apparatus.
  • one or more of the following regional pathologies may be identified:
  • the identification may use various imaging methods, for example ECHO for hypo/dis/a-kinesis of ventricular walls.
  • Various method may be used to evaluate perfusion, for example Technetium based imaging.
  • Position sensing based methods may be used to evaluate regional function, for example systems provided by the Biosense h e. corporation and/or ECG systems. These methods could be used to design and focus the treatment to the regions of interest.
  • DEVICE PROGRAMMING hi an exemplary embodiment of the invention device 100 is programmed or otherwise controlled to provide a desired spatial and/or temporal regimen to the heart. Such a regimen can define which part of the heart is treated with which molecule and/or electrical field for what duration and under what circumstances.
  • Such programming may be done in advance of implantation and/or therapy or it may be provided into device 100 just before or during therapy.
  • device 100 is used for experimental use, for example to determine which electric fields and/or molecules and/or combinations thereof have desirable therapeutic effects. Such a detennination may be applied during product design or even when planning a therapeutic plan for a patient, as described herein.
  • Programming input 136 may be used for providing input from an external programmer.
  • Device 100 may be non-autonomous, in that all programming comes from outside.
  • a semi-autonomous device may be provided, in which external programming is required only on occasion, possibly at the instigation of device 100.
  • cardiac parameters taken into account may be local parameters, such as conduction velocity or global parameters, such as heart rate.
  • the cardiac parameters may be rapidly changing parameters, such as heart rate or they may be slowly changing parameters such as tissue performance, Perfusion and/or viability, or maximum diastolic extension over a period of time.
  • the programming responds to non-cardiac parameters, such as time of day or day of the week, for example to match the therapy to an expected or current activity level.
  • Various device parameters may be programmable, including, for example, pulse parameters such as temporal, spatial, amplitude, polarity, envelope and/or frequency of the applied transport, transport related, excitatory (e.g., pacing) and/or non-excitatory fields.
  • various molecule provision parameters may be controllable, for example the molecule type, timing of provision, amount provided and duration.
  • a complete script e.g. a short program
  • script parameters may be selected.
  • a particular example of a script parameter is which sensor to use for monitoring and its associated threshold levels or other value-response function.
  • the programming may be enhanced by providing feedback about the operation and effects of device 100.
  • the information may be sensed and/or stored by device 100 for later readout by the programmer. Alternatively, the information may be gleaned using other physical examination techniques, for example medical imaging.
  • Exemplary types of feedback include one or more of: feedback on molecule provision and penetration, various actually realized fields, the effect of such fields for transport or on cardiac tissue and/or the effect of the provided molecule, on the local tissue, the heart and/or the circulatory system as a whole. Alternatively or additionally, feedback on the quality and degree of synchronization between the heart, molecule provision and/or the various electrical fields, may be desirable. Exemplary sensors are described below.
  • feedback is provided with regard to the penetration of the molecules.
  • the arrival of the molecules at the desired tissue depth can be monitored by detecting the effect of the molecules.
  • by transporting radioactive or other marker drugs it is possible to image or otherwise view the tissue and determine which cells were affected.
  • a marker drug may be the same as the one used for therapy or it may be a different one, specifically selected for ease of detection.
  • the provision and/or effect of molecules may be detected by applying an electric field to the treated area and based on the response of the tissue estimate the molecule effect and/or arrival. h some cases, real-time feedback is desired, either to control device 100 in operation or to adjust programming parameters based on their effect.
  • sensors may be used in conjunction with and/or as part of device 100. Such sensors may measure various cardiac parameters, including, for example, pCO2, p ⁇ 2 pH, SO2, wall motion, local or global electrical activity, endocardial acceleration, regional impedance, regional APD, HR variability, LVP or aortic pressures (peak, max dP/dt), respiration rate, cardiac output and/or thoracic impedance (for estimating changes in stroke volume). Many such suitable sensors are known in the art. Alternatively or additionally, the sensors may measure systemic parameters, such as blood pressure. Alternatively or additionally, the sensors may measure local molecule concentrations and or metabolic products.
  • the sensors may be implanted in the body. Alternatively, in some embodiments, the sensors may be outside the body, even if device 100 is inside the body.
  • the patient himself serves as a sensor, for example indicating to device 100 or its external programmer, body feelings, such as pain, shortness of breath, dizziness and/or lack or abundance or energy.
  • SAFETY In some exemplary embodiments of the invention, device 100 may include one or more of the following safety features:
  • Toxicology watchdog This type of watchdog monitors one or more cardiac parameters and/or the response of the heart to various stimuli, to determine if the supplied molecules have an adverse effect on the heart. As a result, protective measures, such as fencing, may be applied, or the dosage or other parameters of drug delivery may be modified.
  • Defibrillation circuit Upon detection of defibrillation and/or VT, this circuit can apply a defibrillation current to the heart.
  • a defibrillator may have charged capacitors continuously available in a standby mode. When not required for fibrillation, some of the charge may be used for applying large non-excitatory fields, for example for molecule transport.
  • (c) Molecule flow monitor This monitor checks that the supply rate of the molecule matches the programmed supply rate. Thus, blockages and/or leaks may be detected.
  • the monitor may directly monitor the flow and/or the molecule reservoir state. Alternatively, the monitor may determine the supply rate indirectly by analyzing cardiac and/or other patient physiological parameters.
  • Non-excitatory electric fields may be used to create fences in the heart which prevent the propagation of undesirable (expected or not) activation potentials.
  • Such field may act, for example, by desensitizing cardiac tissue using a DC field or by extending a refractory period of the cells by applying an electric pulse during an end of the refractory period.
  • a heart is remodeled, by providing genetic material or other molecules which cause certain parts of the heart to atrophy or enlarge, h another example, the activation of the heart is modeled, for example by causing a cell type, such as an AV node cell, to increase its conduction velocity, for example by suitable over-expression or under-expression of certain ion pumps or channels.
  • cell parameters which may be changed using this method include sensitivity (to hormones electrical signals and/or other feedback loops in the heart), plateau duration, excitation window duration and self-pacing rate (SA node).
  • At least certain types of long QT syndrome patients are treated by causing the expression of suitable ion channels or pumps to those cells that require it.
  • This expression can be caused by providing the gene that creates the channels or creates a protein that transports the channels to the cell membrane, as well as by blocking a gene which stops the production of the channel.
  • drugs for maintaining the dilation of blood vessels or drugs for reducing oxygen requirements may be applied.
  • molecules damaged or destroyed by the ischemic event may be provided by electrical transport techniques.
  • hormones and/or other angiogenesis factors are electrically transported to ischemic tissue and/or other tissue in the heart to cause increased blood vessel generation.
  • repeated transport pulses possibly from different electrodes are used to maintain a particular volume distribution of the provided molecule(s).
  • these molecules define a gradient along which blood vessels or other tissue grow, or various cells, such as lymphocytes, travel, h another example, this distribution defines an area into which new growth will not enter.
  • VEGF and/or other growth factors are locally provided, to prevent their adverse effects on other parts of the heart and/or body.
  • a locally provided molecule is Adriamycin or other chemotherapy anti-cancer molecules.
  • a drug which suspend activity of a heart cell is applied to points of a mesh electrode. After detecting the effects of suspension on the electrical activity of the heart, an electrode having a desired effect is used to provide a killing dose of the same drug or of a different drug.
  • selective ablation is possible even without first determining the effect of a "suspending" drug.
  • Fig. 6 illustrates a vascular treatment device 800, in accordance with an exemplary embodiment of the invention, hi a coronary vessel application, iontophoresis and electroporation become possible in blood vessels which are near the heart.
  • Example treatments include anti-clotting drugs, drugs to prevent re-stenosis, drugs to prevent stenosis and gene therapy to convert the blood vessel cells to those having a desired function, such as excretion of a desired anti-clotting factor.
  • Such an the electric field may be applied using a dedicated suitable stent or to augment the behavior of a stent which needs to be implanted.
  • Exemplary device 800 is stent-like, having a cylindrical body 802.
  • a plurality of electrodes 804 and 806 are provided, which are electrified by a power supply 810.
  • the power supply is a battery.
  • the power supply comprises an antenna 812 for receiving RF radiation and a converter for converting the received radiation in suitable voltages.
  • power supply 810 include control logic and/or one or more sensors, for example for sensing a cardiac activity, for example for synchronization purposes or a sensor for sensing the blood vessel state.
  • electrodes 804 and 806 can serve as antenna 812.
  • a wired external power source is provided and connected to device 800.
  • device 800 is used with blood vessels not adjacent to the heart, hi some embodiments of the invention, antenna 812 also serves to apply a voltage across the vessel in which device 800 is situated.
  • a molecule reservoir 808 is provided between two adjacent electrodes, for example on an outside surface of body 802. When a voltage potential is formed between electrode 804 and electrode 806, the molecule is transported from reservoir 808.
  • the molecule may then diffuse into a surrounding wall of a blood vessel.
  • the voltage field between the electrodes has a sufficient component to transport the molecule perpendicular to device 800.
  • the voltage field opens pores in the vessel wall to enhance the diffusion of the molecule.
  • device 800 comprises two or more layers, with one polarity electrode in one layer and a second polarity electrode in the other layer.
  • device 800 is mounted outside the blood vessel, hi such a case, a cylindrical body shaped like body 802 in the figure may not be required, so wireless patch-shaped electrodes may be provided instead.
  • a work increasing excitatory (e.g., over pacing) or non-excitatory (e.g., contractility enhancing) pulse is applied to provide oxygen stress, while, at a same time, angiogenesis enhancing molecules are provided, locally or systemically.
  • the salvage of ischemia-damaged tissue is enhanced by both reducing its oxygen requirements using a desensitizing electric field (or fences) and by locally providing work-reducing molecules, such as calcium blockers.
  • the calcium blockers are systemically provided in a form that has difficulty crossing blood vessel walls. By application of a local field, the calcium blockers affect substantially only the treated area.
  • the molecule and the electric field are applied simultaneously, h other cases, they are alternated, for example to allow the tissue to recuperate from adverse effects of one or the other. Once the tissue has sufficiently recuperated, it may be trained back to shape and/or have angiogenesis enhancing methods applied to it.
  • hypertrophy of a part of the heart is treated by applying a suitable electrical control sequence to reduce the cardiac activity of the part and applying a molecule to reduce the hypertrophy.
  • the device is used to release a molecule from a circulating reservoir.
  • the device is stent- like, for example as shown in Fig. 6.
  • the device may comprise electrodes inside or outside the blood vessel.
  • the reservoir comprises a plurality of liposomes that encapsulate a molecule.
  • device 800 may include electrodes for applying a field across the blood vessel, to release molecules from a circulating reservoir, alternatively or additionally, to applying an iontophoresis field, an electrophoresis field and/or a field for releasing a molecule from reservoirs 808.
  • the electrification of the electrodes and/or their layout may be different for the different effects, for example for liposome release or migration, different polarity electrode elements may be provided on opposite sides of device 800, so that the field is applied across the blood vessel.
  • electrodes 804 and/or 806 For extraction from reservoir 808, a voltage between two nearby electrodes may be applied, h an exemplary embodiment of the invention, electrodes 804 and/or 806 comprise multiple parts, which can be selectively electrified to achieve various field directions and/or strengths under the control of controller 810.
  • a sensor in device 800 maybe used to synchronize the application of the release and/or transport fields to local and/or global activity of the excitable tissue.
  • other effects can be achieved by the fields, as described above.
  • the transport field, the release filed and the control filed may be the same or different fields and/or two effects may be combined in a single field.
  • device 800 is used to release molecules in the vascular bed of an organ to be treated, for example in a coronary artery of the heart or a renal artery.
  • the molecules are released into a vessel that passes near the tissue to be treated.
  • the molecules are released in the vessel, to be transported, (e.g., electrically) through the vessel walls into nearby tissue.
  • Reservoir 808, or multiple reservoirs may include a same molecule or different as in the circulating reservoir. Alternatively or additionally, multiple reservoirs with different materials may be provided.
  • non-electrical release from reservoir 808 is used. At least one or the reservoirs in device 800 may be pointed inwards, to release its contents into the blood stream. Alternatively or additionally, it may be pointed outwards, to release its contents into the vessel wall. Alternatively or additionally, the release direction may be controlled by the particular transport electric field applied. In a non-stent device, the reservoir may be provided and/or activated separately from the electrodes.
  • the locally released molecule may interact with a systemically available molecule, h one example, the locally available molecule is an antagonist for the systemic molecule, so that the systemic molecule has a different or no effect locally (e.g., Heparin and its antagonist Protamine).
  • the systemic molecule prevents the local molecule from having an effect away from where it is released, for example, due to the lower concentration of the local molecule.
  • an enhancement effect may be provided, with the local molecule enhancing or activating the systemic molecule, or vice versa.
  • the systemic molecule may be provided as a circulating reservoir or by injection or other means.
  • the systemic molecule is released locally, together with another locally released molecule from device 800.
  • device 800 is used to genetically modify (e.g., by eluting viruses or direct electrophoresis of DNA) the vascular tissues. These modified tissues may elut a chemical that interacts with the systemic drugs (or otherwise provided molecule).
  • the modified cells may include fewer or a greater number of receptors (or other reason for sensitivity) for the systemic drug.
  • the modified cells may exhibit a higher or lower uptake or transport rate for the drug.
  • two sensors are provided, one at the entrance to the targeted tissue and one at a different location, for example elsewhere in the vascular system or at the vascular exit from the targeted tissue.
  • the second sensor which may also be mounted on a stent, possibly a molecule releasing stent, may measure the amount of the released molecule in the blood stream. The measurement may be direct, or a easily detectable tag may be released with the molecule.
  • Such measurement may be applied during testing of dosage or during calibration or regular use of device 800.
  • the second device may indicate to the user that the level of circulating molecule is too high (or too low).
  • the second device may automatically elute an antagonist to the molecule secreted by the first device.
  • such automatic secretion is performed without a sensor, for example, based on calibration of the device or by external activation.
  • NON-CARDIAC APPLICATIONS The above application has focused on cardiac applications. It should be noted that similar devices may be used for non-cardiac applications, in whole organs or in portions of excitable or non-excitable tissues.
  • the heart typically has two properties not found in other excitable tissue: synchronous operation and significant and immediate health risk due to adverse effects.
  • the brain for example, as a whole, does not exhibit unitary synchronized behavior as does the heart.
  • the stomach on the other hand, while it is synchronous, does not pose immediate life-threatening danger as a result of adverse effects.
  • many non-cardiac tissue may cause discomfort (sort or long term) and/or pain, if incorrectly activated.
  • an excitatory transport or release pulse may be used.
  • the electric fields applied are synchronized to the activation in the excitable tissue.
  • a propagation stopping field (fencing) may be used to prevent propagation of the effects of the transport pulse.
  • excitable tissues may be relaxed by application of a suitable non-excitatory or excitatory pulse, thus possibly assisting transport.
  • the pulse may target excitable components of the tissue, for example blood vessels.
  • the electric field may be applied to stiffen excitable tissue, thus preventing molecule uptake.
  • the application of electrical field and/or molecules ignores the excitatory (or excitation disruption) effect of the electric field, but uses other features described herein, for example multiple vectored molecule distribution using electrode arrays, reduction of blood flow or implantable wireless electrodes having associated therewith molecule reservoirs.
  • non-pain causing effects such as muscle contractions, or even pain causing effects, such as muscle spasms may be ignored or taken into account when applying the fields.
  • cardiac applications can allow the transport field to be excitatory.
  • One exemplary application is treatment of irritable bowel syndrome using locally transported anti-inflammatory drugs, such as steroids.
  • the drugs and/or a transport-related signal possibly timed to the normal bowel electrical activity so as not to interfere with it.
  • the electrical signal also controls the bowels.
  • a device similar to that of Fig. 6 may be used.
  • the drugs are released in the upper or lower mesenteric arteries, to better target them to the bowels.
  • a systemic inhibitor is provided, to reduce the effect of the drugs on tissues outside of the bowels.
  • COPD and asthma are treated, for example, using adrenergic agonists, phosphodiesterase inhibitors, steroids and/or cholinergic antagonists.
  • the electric fields may be selectively applied to prevent inadvertently affecting the heart.
  • muscle relaxants to bladder are locally provided, for example at night, to treat overflow incontinence caused by an over excited bladder.
  • a suitable implantable device may be, for example, a stent implanted inside the urethra. Local provision may prevent possibly systemic and/or organ specific side effects of smooth muscle relaxants, for example, hypotension, digestive problems and/or cardiac effects.
  • VEGF vascular endothelial growth factor
  • uterine contractions are suppressed during labor, or during an early labor, using targeted tocolytic drugs and/or suitable electrical pulses.
  • contractions are enhanced and/or controlled while and/or shortly after providing a drug.
  • the uterus is relaxed when the drug is provided, to assist in tissue penetration.
  • the uterus may be contacted after the provision, to enhance delivery.
  • muscle relaxants may be supplied, locally to a muscle limb and/or a part thereof.
  • TARGETED PROTECTION h an exemplary embodiment of the invention, protection of an organ from a system effect is supplied by providing, at a vascular entrance to organ, a device that releases antagonist molecules.
  • the release may be synchronized to the availability of systemic molecules, for example, both being controlled by a same controller. Any type of release mechanism may be used, including electrical and non-electrical mechanisms, hi a particular example, the kidney is protected from cyclosporine, an anti-rejection drug, which may provided for preventing rejection of an implanted heart. Alternatively or additionally, the system may be protected from a molecule targeted to a particular tissue, for example, by releasing the antagonist at the vascular exit from the tissue. For example, an antagonist for a cardiac stimulator, at the exit from the coronary vessels. Alternatively or additionally to chemical antagonists, antibodies may be used for tagging and/or activity prevention. Tagging may be used for collecting information about dosages and its effects and/or for stimulating removal by the pagocytic system.
  • a suitable antagonist is used to counteract toxic effects of a molecule used to release a drug from a liposome.
  • a systemic, less active molecule is provided, with an activator being released at a vascular entrance to an organ and/ a deactivator being released at the vascular exit from the organ.
  • the device e.g., device 800
  • the device is provided as a kit that may be used with a variety of molecules, organs, treatment protocols and/or systemic provision protocols.
  • the kit may include, for example, a stent and an external controller, for providing programming of the stent and/or real-time control of the stent.
  • such a kit includes multiple stents, for example for providing an activator/deactivator pair of molecules.
  • a multi-catheter system is used to provide multiple types of molecules and/or multiple electrode locations.

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Abstract

La présente invention concerne un appareil de traitement électrique (100) devant être utilisé avec une source de molécules associée, comprenant au moins une électrode (106); une alimentation (120) pour électrifier ladite électrode; et une commande programmée pour activer l'alimentation (120) et électrifier de manière sélective l'électrode (106) afin d'appliquer au moins un champ électrique à effet de transport pour transporter une molécule donnée de façon ciblée et à effet de régulation non excitateur pour réguler l'activité d'au moins une partie d'un tissu excitable non cardiaque; la programmation étant sélectionnée pour fournir une quantité ciblée de ladite molécule à la partie de tissu excitable ou aux vaisseaux associés, en combinant au moins l'interaction entre l'effet de transport et l'effet de régulation.
PCT/IL2000/000832 1999-06-04 2000-12-13 Dispositif d'administration de medicaments WO2001093951A1 (fr)

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AU18815/01A AU1881501A (en) 2000-06-04 2000-12-13 Drug delivery device
US10/048,803 US7171263B2 (en) 1999-06-04 2000-12-13 Drug delivery device
AU18820/01A AU1882001A (en) 2000-06-04 2000-12-14 Drug delivery device
US10/048,802 US7092753B2 (en) 1999-06-04 2000-12-14 Drug delivery device
PCT/IL2001/000056 WO2001052931A1 (fr) 2000-01-21 2001-01-21 Regulateur d'ecoulement sanguin
AU27023/01A AU2702301A (en) 2000-01-21 2001-01-21 Blood flow controller

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US13755399P 1999-06-04 1999-06-04
ILPCT/IL00/00319 2000-06-04

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006119467A2 (fr) 2005-05-04 2006-11-09 Impulse Dynamics Nv Modification d'activite de proteine
US7840264B1 (en) 1996-08-19 2010-11-23 Mr3 Medical, Llc System and method for breaking reentry circuits by cooling cardiac tissue
US7908003B1 (en) 1996-08-19 2011-03-15 Mr3 Medical Llc System and method for treating ischemia by improving cardiac efficiency
US8934975B2 (en) 2010-02-01 2015-01-13 Metacure Limited Gastrointestinal electrical therapy
US8958872B2 (en) 1996-01-08 2015-02-17 Impulse Dynamics, N.V. Electrical muscle controller
US9101765B2 (en) 1999-03-05 2015-08-11 Metacure Limited Non-immediate effects of therapy
US9265930B2 (en) 1997-07-16 2016-02-23 Metacure Limited Methods and devices for modifying vascular parameters
US9289618B1 (en) 1996-01-08 2016-03-22 Impulse Dynamics Nv Electrical muscle controller
US9713723B2 (en) 1996-01-11 2017-07-25 Impulse Dynamics Nv Signal delivery through the right ventricular septum
US9931503B2 (en) 2003-03-10 2018-04-03 Impulse Dynamics Nv Protein activity modification
US11439815B2 (en) 2003-03-10 2022-09-13 Impulse Dynamics Nv Protein activity modification
US11779768B2 (en) 2004-03-10 2023-10-10 Impulse Dynamics Nv Protein activity modification
WO2024018361A1 (fr) * 2022-07-18 2024-01-25 Impulse Dynamics Nv Thérapie pour insuffisance cardiaque électrique non excitatrice aiguë

Families Citing this family (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6713291B2 (en) * 1999-01-28 2004-03-30 Alan D. King Electrodes coated with treating agent and uses thereof
AU4947100A (en) * 1999-06-04 2000-12-28 Impulse Dynamics N.V. Drug delivery device
US7171263B2 (en) 1999-06-04 2007-01-30 Impulse Dynamics Nv Drug delivery device
WO2002070065A2 (fr) * 2001-03-05 2002-09-12 Medtronic, Inc. Stimulation en vue de l'administration d'un traitement moleculaire
US7400931B2 (en) * 2002-09-18 2008-07-15 Cardiac Pacemakers, Inc. Devices and methods to stimulate therapeutic angiogenesis for ischemia and heart failure
US20040122422A1 (en) * 2002-12-24 2004-06-24 Moshe Ein-Gal Medical device on helical support
US8500713B2 (en) 2003-10-29 2013-08-06 Medtronic, Inc. Implantable electroporation therapy device and method for using same
JP2007530124A (ja) * 2004-03-25 2007-11-01 コーニンクレッカ フィリップス エレクトロニクス エヌ ヴィ 薬物送達能力を有する除細動電極
US7729761B2 (en) * 2004-07-14 2010-06-01 Cardiac Pacemakers, Inc. Method and apparatus for controlled gene or protein delivery
AU2005289828A1 (en) 2004-09-24 2006-04-06 The Board Of Trustees Of The Leland Stanford Junior University Methods and devices for the non-thermal, electrically-induced closure of blood vessels
US8010191B2 (en) 2004-12-20 2011-08-30 Cardiac Pacemakers, Inc. Systems, devices and methods for monitoring efficiency of pacing
US8005544B2 (en) 2004-12-20 2011-08-23 Cardiac Pacemakers, Inc. Endocardial pacing devices and methods useful for resynchronization and defibrillation
US8010192B2 (en) 2004-12-20 2011-08-30 Cardiac Pacemakers, Inc. Endocardial pacing relating to conduction abnormalities
AR047851A1 (es) 2004-12-20 2006-03-01 Giniger Alberto German Un nuevo marcapasos que restablece o preserva la conduccion electrica fisiologica del corazon y un metodo de aplicacion
US8290586B2 (en) 2004-12-20 2012-10-16 Cardiac Pacemakers, Inc. Methods, devices and systems for single-chamber pacing using a dual-chamber pacing device
US8423139B2 (en) 2004-12-20 2013-04-16 Cardiac Pacemakers, Inc. Methods, devices and systems for cardiac rhythm management using an electrode arrangement
US20140081155A1 (en) * 2012-09-14 2014-03-20 Scott R. Coggins Methods And Apparatus for Wireless Electrode Having Power Conservation

Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5087243A (en) 1990-06-18 1992-02-11 Boaz Avitall Myocardial iontophoresis
US5286254A (en) 1990-06-15 1994-02-15 Cortrak Medical, Inc. Drug delivery apparatus and method
US5387419A (en) 1988-03-31 1995-02-07 The University Of Michigan System for controlled release of antiarrhythmic agents
US5415629A (en) * 1993-09-15 1995-05-16 Henley; Julian L. Programmable apparatus for the transdermal delivery of drugs and method
US5458568A (en) 1991-05-24 1995-10-17 Cortrak Medical, Inc. Porous balloon for selective dilatation and drug delivery
US5501662A (en) 1992-05-22 1996-03-26 Genetronics, Inc. Implantable electroporation method and apparatus for drug and gene delivery
US5634899A (en) 1993-08-20 1997-06-03 Cortrak Medical, Inc. Simultaneous cardiac pacing and local drug delivery method
WO1998015317A1 (fr) 1996-10-07 1998-04-16 Sulzer Intermedics Inc. Electrode a injection de medicament regulable
US5779661A (en) * 1995-12-11 1998-07-14 Physion, S.R.L. Method of treating dysfunctional bladder syndromes by electromotive drug administration
WO1999024110A1 (fr) * 1997-11-06 1999-05-20 A?+¿ Science Invest Ab Procede d'electropermeabilisation de structures cellulaires et d'organites individuels et leur utilisation
WO2000074773A1 (fr) * 1999-06-04 2000-12-14 Impulse Dynamics N.V. Dispositif d'administration de medicaments

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5236413B1 (en) * 1990-05-07 1996-06-18 Andrew J Feiring Method and apparatus for inducing the permeation of medication into internal tissue
WO2000016741A1 (fr) * 1998-09-21 2000-03-30 Elan Corporation, Plc Procede et systeme permettant d'ameliorer l'administration d'un agent

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5387419A (en) 1988-03-31 1995-02-07 The University Of Michigan System for controlled release of antiarrhythmic agents
US5286254A (en) 1990-06-15 1994-02-15 Cortrak Medical, Inc. Drug delivery apparatus and method
US5087243A (en) 1990-06-18 1992-02-11 Boaz Avitall Myocardial iontophoresis
US5458568A (en) 1991-05-24 1995-10-17 Cortrak Medical, Inc. Porous balloon for selective dilatation and drug delivery
US5501662A (en) 1992-05-22 1996-03-26 Genetronics, Inc. Implantable electroporation method and apparatus for drug and gene delivery
US5865787A (en) 1992-10-06 1999-02-02 Cortrak Medical, Inc. Simultaneous cardiac pacing and local drug delivery
US5634899A (en) 1993-08-20 1997-06-03 Cortrak Medical, Inc. Simultaneous cardiac pacing and local drug delivery method
US5415629A (en) * 1993-09-15 1995-05-16 Henley; Julian L. Programmable apparatus for the transdermal delivery of drugs and method
US5779661A (en) * 1995-12-11 1998-07-14 Physion, S.R.L. Method of treating dysfunctional bladder syndromes by electromotive drug administration
WO1998015317A1 (fr) 1996-10-07 1998-04-16 Sulzer Intermedics Inc. Electrode a injection de medicament regulable
WO1999024110A1 (fr) * 1997-11-06 1999-05-20 A?+¿ Science Invest Ab Procede d'electropermeabilisation de structures cellulaires et d'organites individuels et leur utilisation
WO2000074773A1 (fr) * 1999-06-04 2000-12-14 Impulse Dynamics N.V. Dispositif d'administration de medicaments

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9186514B2 (en) 1996-01-08 2015-11-17 Impulse Dynamics Nv Electrical muscle controller
US8958872B2 (en) 1996-01-08 2015-02-17 Impulse Dynamics, N.V. Electrical muscle controller
US9289618B1 (en) 1996-01-08 2016-03-22 Impulse Dynamics Nv Electrical muscle controller
US9713723B2 (en) 1996-01-11 2017-07-25 Impulse Dynamics Nv Signal delivery through the right ventricular septum
US7840264B1 (en) 1996-08-19 2010-11-23 Mr3 Medical, Llc System and method for breaking reentry circuits by cooling cardiac tissue
US7908003B1 (en) 1996-08-19 2011-03-15 Mr3 Medical Llc System and method for treating ischemia by improving cardiac efficiency
US9265930B2 (en) 1997-07-16 2016-02-23 Metacure Limited Methods and devices for modifying vascular parameters
US9101765B2 (en) 1999-03-05 2015-08-11 Metacure Limited Non-immediate effects of therapy
US9931503B2 (en) 2003-03-10 2018-04-03 Impulse Dynamics Nv Protein activity modification
US11439815B2 (en) 2003-03-10 2022-09-13 Impulse Dynamics Nv Protein activity modification
US8977353B2 (en) 2004-03-10 2015-03-10 Impulse Dynamics Nv Protein activity modification
US9440080B2 (en) 2004-03-10 2016-09-13 Impulse Dynamics Nv Protein activity modification
US10352948B2 (en) 2004-03-10 2019-07-16 Impulse Dynamics Nv Protein activity modification
US11779768B2 (en) 2004-03-10 2023-10-10 Impulse Dynamics Nv Protein activity modification
WO2006119467A2 (fr) 2005-05-04 2006-11-09 Impulse Dynamics Nv Modification d'activite de proteine
US8934975B2 (en) 2010-02-01 2015-01-13 Metacure Limited Gastrointestinal electrical therapy
WO2024018361A1 (fr) * 2022-07-18 2024-01-25 Impulse Dynamics Nv Thérapie pour insuffisance cardiaque électrique non excitatrice aiguë

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