WO2016130385A2 - Ablation tissulaire par modification rapide et prolongée du potentiel de membrane - Google Patents

Ablation tissulaire par modification rapide et prolongée du potentiel de membrane Download PDF

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WO2016130385A2
WO2016130385A2 PCT/US2016/016464 US2016016464W WO2016130385A2 WO 2016130385 A2 WO2016130385 A2 WO 2016130385A2 US 2016016464 W US2016016464 W US 2016016464W WO 2016130385 A2 WO2016130385 A2 WO 2016130385A2
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blocker
tissue
channels
cells
combination
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WO2016130385A3 (fr
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George Mbella Ekema
Marjet Danteel HEITZER
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B2018/00315—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body for treatment of particular body parts
    • A61B2018/00333—Breast
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B2018/00571—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body for achieving a particular surgical effect
    • A61B2018/00577—Ablation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N7/00—Ultrasound therapy

Definitions

  • the present invention relates to tissue ablation devices and methods, particularly the ablation of undesirable tissue, such as a cancerous or non-cancerous tumor, infected tissue, adipose tissue, wound, etc.
  • Each cell in the human body has a potential difference with its extracellular milieu owing to a difference in the concentrations of the main physiological ions (Na + , K + , Ca 2+ , and CI " ) between the cell and the extracellular milieu.
  • the potential difference can be measured across the plasma membrane and represents the membrane potential (V m ) of the cell.
  • V m changes in response to a change in conductance (or permeability) of one or more of the major ion types, and also depends on the concentrations of the major ions inside the cell and in the extracellular milieu, as shown in the Goldman-Hodgkin-Katz equation below (Goldman, 1 43; Hodgkin and Katz, 1949):
  • V m RT/F In ((RNa+ [Na + ] 0 + P K+ [K + ] 0 + P a - [Cf] 0 ) / ( Na+ [Na + ] ; + P K+ [K + ] ; + P a - [CI " ],)) where R is the ideal gas constant, Tis the temperature, and F is the Faraday constant.
  • R is the ideal gas constant
  • F is the Faraday constant.
  • the role of V m is different in excitable and non-excitable cells.
  • Excitable cells such as neurons and muscle fibers, function primarily by rapid changes in V m that are followed by an immediate return to the resting V m .
  • the role of V m in non-excitable cells is not as clear. There is, however, an increasing body of knowledge that suggests that V m may have important regulatory roles in non-excitable cells.
  • V m adipose tissue
  • V m adipose tissue
  • V m of cells in proliferating breast cancer is more depolarized than cells in normal breast tissue (Marino et al., 1994);
  • V m of proliferating hepatocellular carcinoma cells is more depolarized than normal hepatocytes (Binggeli and Cameron, 1980; Stevenson et al., 1989);
  • V m of cells in proliferating skin cancer is more depolarized than benign skin cells (Melczer and Kiss, 1957; Woodrough et al., 1975);
  • V m of adipocytes is significantly more depolarized than other cells in
  • Clarence D. Cone Jr. was a pioneer in elucidating the role of V m in cancer pathophysiology. His finding that sarcoma cells attained hyperpolarized V m prior to entering the M phase of mitosis was published in 1969 (Cone, 1969). Shortly after, he showed that mitosis was inhibited by hyperpolarized R values (Cone, 1970). He later theorized that proliferation of cancer cells is dependent on V m (Cone, 1971), a theory that was also supported by earlier findings correlating V m and malignant transformation of cells (Tokuoka and Mori oka, 1957; Johnstone, 1959). Such early findings suggested important regulatory roles of V m in non-excitable cells.
  • V m changes in non-excitable cells are slow (Lobikin et al., 2012), but appear to be vital in regulating important cell functions, such as differentiation, proliferation, and metastasis (Binggeli and Weinstein, 1986; Schwab et al., 2007; Blackiston et al., 2009; Sundelacruz et al., 2009). Indeed, we have determined that a rapid and sustained change in V m results in the death of non-excitable cells by apoptosis.
  • V m is involved in the etiology and pathophysiology of cancer (Kunzelmann, 2005; Fiske et al., 2006; Stuhmer et al., 2006; Prevarskaya et al., 2010; Becchetti, 2011; Brackenbury, 2012), and it is, therefore, not surprising that a lot of effort is directed to ion channels, pumps, and transporters for more effective cancer treatments.
  • hERG Human Ether a go-go K + channels are expressed in many cancers (Ouadid-Ahidouch et al., 2001; Farias et al., 2004; Pardo et al., 2005; Hemmerlein et al., 2006; Ousingsawat et al., 2007; Ortiz et al., 2011; Rodriguez-Rasgado et al., 2012). Inhibition of hERG reduces proliferation of the cancer cell lines in which it is expressed, whereas
  • the hyperpolarization activates Ca 2+ -activated K + (K Ca ) channels (Ouadid-Ahidouch et al., 2001), due to elevated intracellular Ca 2+ (Nilius and Wohlrab, 1992; Ouadid-Ahidouch and Ahidouch, 2008).
  • K Ca K +
  • Several ion channel blockers have, therefore, been advanced as potential cancer treatments. Using ion channel blockers to treat cancer is, however, complicated by various factors, which is why there are no channel-blocking cancer cures six decades after knowing that ion channels regulate cancer cells.
  • the confounding factors include the following:
  • Ion channel blockers do not synchronize the V m values of the cells in a tumor.
  • cancerous tumor consists of stem cells, proliferating cells, and malignant (or potentially malignant) cells.
  • Proliferating cells typically have depolarized V m values and are the target of ion channel modulators.
  • the modulators do not target the cancer stem cells and the malignant (or potentially malignant) cells because these cells have relatively hyperpolarized V m values. Additionally, the non-proliferating cancer cells may not express the targeted ion channel at their particular stage in the cell cycle.
  • Ion channel blockers cannot affect cells in the V m range of normal tissue without causing massive adverse effects.
  • ion channel blockers The action of ion channel blockers is not specific to the undesirable tissue and would, therefore, cause significant undesirable effects. Ions channels and pumps are highly conserved, and most tissues in the human body share the same core ion channels and pumps. Where different ion channels are expressed, they are hardly ever unique to a particular tissue. For example, the relatively rare ion channel, hERG, expressed by some cancers, is also expressed in the heart, and blocking it would result in ventricular arrhythmia.
  • Ion channel blockers have been known to inhibit proliferation of cancer cells for at least 45 years (Cone, 1970), but due to the limitations outline above, and others, they have not successfully been used as treatments for cancer.
  • the current invention allows for the use of ion channel modulators to rapidly kill cancer cells and cells in other undesirable tissues, such as adipose tissue and wound. Unlike electrical ablation methods in the prior art that use high-voltage electricity to ablate undesirable tissue, the current invention accomplishes ablation of undesirable tissue by rapidly altering the V m values of the targeted tissue by means of a low-voltage electrical current (alternatively, a mechinal vibration or osmotic force) and at least one ion channel blocker, or pump blocker, to sustain the change in V m .
  • a low-voltage electrical current alternatively, a mechinal vibration or osmotic force
  • Davalos and Rubinsky disclose a new method for the ablation of undesirable tissue, such as cells of a cancerous or non-cancerous tumor, that involves the placement of electrodes into or near the vicinity of the undesirable tissue and the application of high -voltage electrical pulses, causing irreversible electroporation of the cells throughout the entire area of the undesirable tissue.
  • the electric pulses irreversibly permeate the cell membranes, thereby invoking cell death.
  • the method disclosed by Davalos and Rubinsky is similar to other methods that use electrical pulses, with a few differences in the amplitude, duration, shape, and number of repeats of the electrical pulses. The method is similar with the others in that they all use high voltages.
  • Electroporation pulses are defined as those electrical pulses that through a specific combination of amplitude, shape, time, length, and number of repeats produce no other substantial effect on biological cells than the permeabilization of the cell membrane.
  • the range of electrical parameters that produce electroporation is bounded by: a) parameters that have no substantial effect on the cell and the cell membrane, b) parameters that cause substantial thermal effects (Joule heating) and c) parameters that affect the interior of the cell, e.g. the nucleus, without affecting the cell membrane.
  • Joule heating the thermal effect that electrical currents produce when applied to biological materials has been known for centuries. It was noted in the previous paragraph that electrical thermal effects which elevate temperatures to values that damage cells are commonly used to ablate undesirable tissues.
  • the pulse parameters that produce thermal effects are longer and/or have higher amplitudes than the electroporation pulses whose only substantial effect is to permeabilize the cell membrane.
  • RF radiofrequency
  • electrode heating electrode heating
  • induction heating electrical pulses that produce thermal effects are distinctly different from the pulses which produce
  • electroporation The distinction can be recognized through their effect on cells and their utility.
  • the effect of the thermal electrical pulses is primarily on the temperature of the biological material, and their utility is in raising the temperature to induce tissue ablation through thermal effects.
  • the effect of the electroporation parameters is primarily on the cell membrane, and their utility is in permeabilizing the cell membrane for various applications. Electrical parameters that only affect the interior of the cell, without affecting the cell membrane, were also identified recently. They are normally referred to as "nanosecond pulses". It has been shown that high amplitude, and short (substantially shorter than electroporation pulses - nanoseconds versus milliseconds) length pulses can affect the interior of the cell and in particular the nucleus without affecting the membrane.
  • nanosecond pulses Studies on nanosecond pulses show that they are "distinctly different than electroporation pulses" (Beebe, Fox, Rec, Somers, Stark, and Schoenbach, 2001).
  • Several applications have been identified for nanosecond pulses. One of them is for tissue ablation through an effect on the nucleus (Schoenbach, Beebe, and Buescher, 2002). Another is to regulate genes in the cell interior (Gunderson et al., 2003).
  • Electrical pulses that produce intracellular effects are distinctly different from the pulses which produce electroporation. The distinction can be recognized through their effect on cells and their utility. The effect of the intracellular electrical pulses is primarily on the intracellular contents of the cell, and their utility is in manipulating the intracellular contents for various uses - including ablation.
  • Irreversible electroporation uses very high voltage pulses, in the order of 680 V/cm or higher, whereas the current invention uses low voltage pulses, in the order of 0.1 to 10 V in the immediate vicinity of the undesirable tissue;
  • Irreversible electroporation uses electric pulses to create holes in the plasma membrane for random substances to flow into cells and kill them, whereas the current invention uses ion channel blockers or pump inhibitors to prevent ions from flowing into and/or out of cells in response to the applied low- voltage electrical pulse;
  • Irreversible el ectrop oration relies on leakiness to kill cells of an undesirable tissue, whereas the current invention relies on a rapid and sustained change in the V m of the cell, e.g.
  • Irreversible electroporation can be used to treat mainly cancerous tumors and very limited amounts of other undesirable tissues, whereas the current invention can be used to ablate any type of undesirable tissue, e.g., cells of a cancerous or non-cancerous tumor, infected tissue, adipose tissue, wound, etc.;
  • Cell death from irreversible electroporation is by leakiness, whereas cell death by the current invention is by apoptosis;
  • cell death, with the current invention is by apoptosis, it allows the immune system to recognize and destroy cells of the undesirable tissue, and this is not true for irreversible electroporation;
  • For irreversible electroporation to completely ablate a tumor all the cells of the tumor must be targeted and successfully pulsed with high voltage, whereas with the current invention an undesirable tissue can be completely ablated by targeting only a portion of the tissue
  • the second category of electrical tissue ablation, electrochemotherapy has been used for the ablation of cancerous tumors in combination with a chemotherapeutic agent. It is essentially a reversible electroporation that uses high voltage to create holes in the plasma membrane, so that chemotherapeutic agents can be delivered into the cell cytoplasm (Heller, Gilbert, and Jaroszeski, 1999). See also US5468223 A to Mir. It is a drug delivery method, rather than a primary electrical ablation. Tissue electroporation is now becoming an increasingly popular minimally invasive surgical technique for introducing small drugs and macromolecules into cells in specific areas of the body.
  • This technique is accomplished by injecting drugs or macromolecules into the affected area and placing electrodes into or around the targeted tissue to generate reversible permeabilizing electric field in the tissue, thereby introducing the drugs or macromolecules into the cells of the affected area (Mir, 2001).
  • electroporation to ablate undesirable tissue was notably used by Okino and Mohri in 1987 and Mir et al. in 1991, but delivery of substances into cells by electroporation has been known for more than a century. They recognized that some drugs for treatment of cancer, such as bleomycin and cisplatin, are effective in killing cancer cells but have difficulties penetrating the cell membrane.
  • EGT electrogenetherapy
  • ECT and EGT studies have been summarized in several publications (Jaroszeski et al., 1999; Heller, Gilbert, and Jaroszeski, 1999; Mir, L. M., 2001; Davalos, R. V., 2002).
  • Electrochemotherapy uses very high voltage pulses, in the order of 189 V/cm or higher, whereas the current invention uses low voltage pulses, in the order of 0.1 to 10 V in the immediate vicinity of the undesirable tissue;
  • Electrochemotherapy uses electric pulses to deliver cytotoxic drugs into a cell, whereas the current invention uses ion channel blockers and/or ion pump inhibitors to prevent ions from moving across the cell membrane in response to the applied low-voltage electrical pulse;
  • Electrochemotherapy relies on cytotoxic drugs to kill cancer cells, whereas the current invention relies on a rapid and sustained change in the V m of the cell, e.g. from 20 mV to -180 mV to kill the cells of any undesirable tissue;
  • Electrochemotherapy is used to treat only cancerous tumors, cutaneous and subcutaneous tumors in particular, whereas the current invention can be used to ablate any type of undesirable tissue, e.g., cells of a cancerous or non-cancerous tumor, infected tissue, adipose tissue, wound, etc.;
  • Cell death from electrochemotherapy is by cytotoxicity, whereas cell death by the current invention is by apoptosis;
  • cell death, with the current invention is by apoptosis, it allows the immune system to recognize and destroy cells of the undesirable tissue, and this is not true for electrochemotherapy;
  • For electrochemotherapy to completely ablate a tumor all the cells of the tumor must be targeted and successfully
  • Young et al. disclosed a tissue ablation probe comprising an elongated probe shaft, at least one electrode carried by the distal end of the probe shaft, and a pharmaceutical agent carried by the probe shaft.
  • the device disclosed by Young et al. is vastly different from the current invention in several important ways, including the following:
  • the pharmaceutical agent in Young et al. is a chemotherapeutic drug; hence, the device is essentially an electrochemotherapeutic device. As such, all of the differences outlined above between the current invention and electrochemotherapy apply.
  • the current invention discloses a low-voltage ablation means that is not disclosed by Young et al.
  • the current invention can be used to ablate any type of undesirable tissue
  • the device in Young et al. is primarily a cancer ablation device.
  • Werneth et al. disclosed a low-power tissue ablation system.
  • the low-power tissue ablation system disclosed by Werneth et al. is drastically different from the current invention.
  • the low-power ablation system is a thermal ablation system, whereas the current invention uses a low-voltage electrical field and ion channel blocker(s) to ablate undesirable tissue.
  • the current invention does not use heat to ablate tissue and does not generate heat in the ablation process.
  • the current invention ablates undesirable tissue regardless of histological type. For example, it is unnecessary to determine the histological type of a cancerous tumor in order to ablate said cancerous tumor.
  • the cancer cells in the targeted area of said cancerous tumor release an apoptotic signal and die.
  • the apoptotic signal is propagated among like tissue, causing cancer cells beyond the targeted area to die.
  • the dead cancer cells are acted upon by the immune system, which now has an easier time to recognize said cancer cells as foreign.
  • the immune system therefore, would attack and kill said cancer cells that may be present in the blood stream, lymphatic system, or in a metastasized site that may be close or far from the original cancerous tumor.
  • the cells in the targeted area of said non-cancerous tumor release an apoptotic signal and die.
  • the apoptotic signal is propagated among like tissue, causing like cells beyond the targeted area to die also. Additionally, the dead cells are acted upon by the immune system, which removes them.
  • the cells of the infected tissue release an apoptotic signal and die.
  • the apoptotic signal is propagated among like tissue, causing the infected cells beyond the targeted area to die.
  • HPV human papilloma virus
  • the infection included several dozens of warts in the pubis, perineum, and peri-anal regions. Only a couple of warts in the pubis were targeted for treatment, but it was sufficient to completely eliminate all of the warts in the pubis, perineum, and peri-anal regions.
  • a low-voltage electrical current alternatively, a mechanical vibration or osmotic force.
  • the voltage administered in the undesirable tissue is lower than that required for electroporation.
  • the current inventions employs a low-voltage current that merely alters the V m of the targeted cells in the undesirable tissue.
  • the ion channel blocker(s) could be highly nonspecific and, therefore contraindicated as systemic drugs.
  • the current invention uses therapeutic doses of highly nonspecific ion channel blocker(s) within the undesirable tissue.
  • the ion channel blocker is directly injected into the undesirable tissue or is placed in a biodegradable capsule, which is then placed in the undesirable tissue.
  • the ion channel blocker is introduced in a gel-like matrix, such as collagen, containing a vasoconstrictor, such as endothelin, or is delivered in a biodegradable capsule. Additionally, the collagen is designed to facilitate the immune response following treatment.
  • Figures 1 and 4 relate to the introduction of ion channel blocker(s) and/or ion pump inhibitor(s) into an undesirable tissue
  • Figures 2 and 5 relate to the application of low-voltage electrical current to said undesirable tissue
  • Figure 3 shows the anatomical relationship of a distant undesirable tissue that may be ablated by treating and ablating a primary undesirable tissue, and in which:
  • Figure 1 shows the introduction of an ion channel blocker(s) and/or ion pump inhibitor(s) into an exemplary undesirable tissue (cancerous tumor) by means of an injection-type device.
  • Figure 2 shows the application of a low-voltage current into said exemplary undesirable tissue by means of two exemplary electrodes introduced into said undesirable tissue.
  • Figure 3 shows the anatomical relationship between two exemplary undesirable tissues
  • Figure 4 shows the introduction of an ion channel blocker(s) and/or pump inhibitor(s) into an exemplary undesirable tissue (cancerous tumor) by means of a capsule-type device.
  • Figure 5 shows the application of a low-voltage current into said exemplary undesirable tissue by means of two exemplary electrodes introduced into said undesirable tissue following release of ion channel blocker(s) or pump inhibitor(s) by means of said capsule-type device.
  • the ion channel blocker is an ion channel blocker(s) and/or pump inhibitor(s) (9).
  • the ion channel blocker is a non-specific blocker of potassium channels, such as tetraethylammonium chloride, or a non-specific blocker of voltage- gated potassium (Kv) channels, such as 4-aminopyridine (4-AP) and kaliotoxin.
  • Kv voltage- gated potassium
  • the ion channel blockers comprise Kv xy channel blockers, such as terfenadine, psora 4, margatoxin, linopirdine dihydrochloride, dofetilide, bapta am, astemizole, or in combination with shaker potassium (Ks) channel blockers, such as agitoxin 2, and/or in combination with blockers of KCNQ X; MinK, HVA(L), LVA(T), CFTR, CICas, SK X , CLC-x, CLC-K X , Kir xy , MaxiK, ROMK, IRK, BIR, RACTK, K(ATP), and AD AC.
  • Ks shaker potassium
  • the ion channel blocker is a non-specific blocker of sodium channels, such as neosaxitoxin, tetrodotoxin, and saxitoxin.
  • the ion channel blockers comprise epithelial sodium (ENaC) channel blockers, such as amiloride, and/or combination of specific sodium channel blockers, as above with the potassium channel blockers, to ensure complete blockage of sodium into the cells of the undesirable tissue, e.g., a class lx agent or combination of class lx agents.
  • the ion channel blocker is a non-specific blocker of calcium channels, such as bepridil hydrochloride.
  • the ion channel blocker(s) comprises a combination of L-, T-, N-, P-, Q-, and R-type calcium channel blocker(s), such as co- agatoxin, amlodipine besylate, benidipine hydrochloride, cilnidipine, co-conotoxin, diltiazem hydrochloride, efonidipine hydrochloride monoethanolate, felodipine, flunarizine
  • Said embodiment comprising a combination of specific calcium channel blockers such as to totally block calcium current in the undesirable tissue.
  • the ion channel blocker(s) is a non-specific blocker of chloride channels, such as DIDS.
  • the ion channel blocker(s) comprises a combination of selective (specific) chloride channel blockers, such as CaCCinh-Aoi, CFTRin -m, chromanol 293B, DCPIB, GaTx2, glibenclamide, lonidamine, NPPB, and talniflumate.
  • Said embodiment comprising a combination of specific chloride channel blockers such as to totally block chloride current in the undesirable tissue.
  • the ion channel blocker(s) is a non-specific blocker of transient receptor potential (TRP) channels, such as 2-APB.
  • TRP transient receptor potential
  • the ion channel blocker(s) comprises a combination of specific blocker(s) of TRPA1, TRPC, TRPM, TRPML, TRPP, and TRPV, such as A967079, AP18, HC030031, GsMTx4, ML204, Pyr3, SKF 96365 hydrochloride, AMTB hydrochloride, ononetin, 9-phenanthrol, TC-1 2000, gadolinium chloride, amiloride hydrochloride, benzamil, EIPA, and phenamil.
  • Said embodiment comprising a combination of specific TRP channel blockers such as to totally block TRP current, in response to alteration of the membrane potential, of cells in the undesirable tissue.
  • the ion channel blocker(s) is a combination of a non-specific blocker of potassium channels with at least one non-specific blocker of calcium, chloride, sodium, or TRP channels in a therapeutic dose.
  • the ion channel blocker(s) is a combination of a nonspecific blocker of calcium channels with at least one non-specific blocker of potassium, chloride, sodium, or TRP channels in a therapeutic dose.
  • the ion channel blocker(s) is a combination of a nonspecific blocker of chloride channels with at least one non-specific blocker of potassium, calcium, sodium, or TRP channels in a therapeutic dose.
  • the ion channel blocker(s) is a combination of a nonspecific blocker of sodium channels with at least one non-specific blocker of potassium, chloride, calcium, or TRP channels in a therapeutic dose.
  • the ion channel blocker(s) is a combination of a nonspecific blocker of TRP channels with at least one non-specific blocker of potassium, chloride, sodium, or calcium channels in a therapeutic dose.
  • the ion channel blocker(s) is a combination of a specific blocker(s) of calcium channels with at least one specific blocker of potassium, chloride, sodium, or TRP channels subtypes in a therapeutic dose.
  • the ion channel blocker(s) is a combination of a specific blocker(s) of potassium channels with at least one specific blocker of calcium, chloride, sodium, or TRP channels subtypes in a therapeutic dose.
  • the ion channel blocker(s) is a combination of a specific blocker(s) of chloride channels with at least one specific blocker of calcium, potassium, sodium, or TRP channels subtypes in a therapeutic dose.
  • the ion channel blocker(s) is a combination of a specific blocker(s) of sodium channels with at least one specific blocker of calcium, chloride, potassium, or TRP channels subtypes in a therapeutic dose. In yet another embodiment, the ion channel blocker(s) is a combination of a specific blocker(s) of TRP channels with at least one specific blocker of calcium, chloride, sodium, or potassium channels subtypes in a therapeutic dose.
  • the therapeutic dosage of ion channel blocker(s) is combined with an adjuvant such as iodine in a therapeutic dose.
  • the therapeutic dosage of ion channel blocker(s) is combined with a vasoconstrictor, such as endothelin.
  • the ion channel blocker is introduced into the undesirable tissue, prior to application of, or during application of, a low-voltage electrical current, by means of an injection-type device (1).
  • the injection-type device (1) is an
  • the injection-type device (1) is an electrochemical apparatus as described by Mir et al. (US 005674267A) and herein incorporated by reference in its entirety.
  • the injection-type device (1) is adapted to deliver blockers using the equipment in minimally invasive and robotic surgery.
  • the channel blocker(s) is introduced into the undesirable tissue by means of a catheter.
  • an electrical field is applied to cells of the undesirable tissue.
  • the electric field is applied by means of needle electrodes.
  • At least two needle electrodes (4 & 5) are introduced into the undesirable tissue, and a low-voltage pulse generator is used to apply an electrical field between them, such that the V m of the cells in said electrical field is changed from a resting value to a relatively depolarized or hyperpolarized value.
  • the pulse applicator is intended to apply a variable electric field to cells located between a pair of needles 1, 2 . . . n. To achieve this, it comprises a pulse generator, a selector switch and a control unit.
  • the pulse generator comprises a low-voltage power supply, which is connected to the mains supply by a mains cord, and to the selector switch via a switch connected to the generator's positive output, and a capacitor connected in parallel across its positive output and negative output. Because the pulse generator is low-voltage, the power supply could be a battery source, e.g. lithium ion and nickel/cadmium, allowing for a small, compact device.
  • the power supply could be a battery source, e.g. lithium ion and nickel/cadmium, allowing for a small, compact device.
  • Each electrode 1, 2, . . . n can be connected either to the positive pole of the low-voltage power supply, or to its negative pole by means of two relays belonging to selector switch.
  • a control unit controls the power supply switch and changeover switch according to the instructions it receives from an operator or via a program.
  • the electric pulse applicator is, thus, able to apply previously determined pulse cycles between needles 1, 2 . . . n in twos and in all possible combinations. These cycles can be determined by any means, particularly experimental, in order to provide the best possible results.
  • the relays are formed by a bar relay or REED bulb relay, the excitation for which is produced either by physical displacement of a small magnet whose position is slaved, or by a conventional command using a coil. This displacement is produced by a conventional position slaving system ensured by a coil. Due to this arrangement, the selector switch can be made very compact. So, by closing relay X 1 and relay Y n , it is possible, when the switch is closed, to send a pulse between electrodes 1 and n, electrode 1 being the positive electrode and electrode n the negative electrode.
  • the electric contact is established with the tissue via the electrodes over all their non-insulated length, the produced field thus extending into the depth of the tissue. It is, therefore, possible to subject cells to electric fields, which would not be accessible, at least not easily, from electrodes simply placed on the surface of the tissue.
  • the pulses applied to each pair of needles are rectangular pulses having an amplitude of 0.1 to 150 V and a pulse length of 10 to 10 8 ⁇ . Where more than a single pulse is applied, these pulses are spaced, for each pair of needles, by an adjustable interval in the range 0.2 to 2 s.
  • each pair of needles it is possible, for example, to apply multiple successive pulses of the same polarity, or several pulses of a first polarity followed later in the cycle by several pulses of the opposite polarity.
  • the pulse sequences between the different pairs of needles can be interleaved.
  • the electric fields thus produced can be approximately uniformly distributed, including depth, since the needles penetrate into the tissue and define a set of volume of tissue, each of these volumes being included between a pair of electrodes.
  • each needle 1, 2 . . . n comprises a base, a head, a connector comprising a flat surface and a base.
  • the base comprises a stem, which is terminated by a point.
  • One or more parts of the stem preferably comprises an insulating sleeve, made from polytetrafluoroethylene (PTFE), for example, which provides, when inserted into tissue, a means of preventing the application of electric pulses to areas other than the target area in the undesirable tissue.
  • PTFE polytetrafluoroethylene
  • the insulating sheath in the base of the needle is removable and can function as a catheter or miniature trocar.
  • a mechanical stimulus such as vibration from massage, vortex, sound, etc
  • the mechanical stimulus is applied externally, e.g. to stimulate subcutaneous adipose tissue that is being ablated.
  • the mechanical stimulus such as vibration from massage, vortex, sound, etc, is applied by means of devices used in minimally invasive and robotic surgery.
  • an ion flux is applied to cells of the undesirable tissue.
  • the ion flux is applied by means of an injection-type device.
  • the ion flux is applied by means of a catheter.
  • the ion flux is applied by means of devices used in minimally invasive and robotic surgery.
  • 'Blocker' is used interchangeably with 'modulator' in this patent application, and the use of one refers to the full scope and definition of both.
  • Bioelectric controls of cell proliferation ion channels, membrane voltage and the cell cycle. Cell Cycle 8, 3519-3528.
  • IGF-1 activates hEAG K(+) channels through an Akt-dependent signaling pathway in breast cancer cells: role in cell proliferation. J. Cell. Physiol. 212, 690-701. Brackenbury W. J. (2012). Voltage-gated sodium channels and metastatic disease. Channels (Austin) 6, 352-361.
  • Pardo L. A. Contreras-Jurado C, Zientkowska M., Alves F., Stuhmer W. (2005). Role of voltage-gated potassium channels in cancer. J. Membr. Biol. 205, 115-124. Pardo L. A., Del Camino D., Sanchez A., Alves F., Bruggemann A., Beckh S., et al. (1999). Oncogenic potential of EAG K(+) channels. EMBO J. 18, 5540-5547.

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Abstract

L'invention concerne un procédé pour l'ablation d'un tissu indésirable, tel que des cellules d'une tumeur cancéreuse ou non cancéreuse, d'un tissu infecté, d'un tissu adipeux, d'une plaie, etc., comprenant l'injection d'au moins un bloqueur de canal ionique ou de pompe ionique dans ledit tissu indésirable puis l'application d'un courant électrique basse tension dans ledit tissu indésirable pour déclencher un changement rapide et prolongé du potentiel de membrane (Vm) des cellules ciblées, ce qui entraîne la mort dudit tissu indésirable grâce à un processus de mort cellulaire programmée (apoptose) suivi par l'action du système immunitaire sur toute cellule ayant survécu dans le tissu indésirable. En variante, selon le type de tissu, une vibration mécanique ou une force osmotique peut être utilisée à la place d'un courant électrique basse tension.
PCT/US2016/016464 2015-02-10 2016-02-03 Ablation tissulaire par modification rapide et prolongée du potentiel de membrane Ceased WO2016130385A2 (fr)

Applications Claiming Priority (4)

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US201562114280P 2015-02-10 2015-02-10
US62/114,280 2015-02-10
US201562134680P 2015-03-18 2015-03-18
US62/134,680 2015-03-18

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3579838A1 (fr) * 2017-02-09 2019-12-18 University of Leeds Inhibiteurs des canaux ioniques trpc destinés à être utilisés en thérapie

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5468223A (en) * 1992-11-30 1995-11-21 C.N.R.S. Paris Electrochemotherapy
EP1278471B1 (fr) * 2000-04-27 2005-06-15 Medtronic, Inc. Appareil d'ablation sensible aux vibrations
EP1696812B1 (fr) * 2003-12-24 2015-07-22 The Regents of The University of California Ablation de tissu avec electroporation irreversible
CA2615267A1 (fr) * 2005-07-11 2007-01-18 Ablation Frontiers, Inc. Systeme d'ablation de tissu a faible consommation d'energie
US10245098B2 (en) * 2008-04-29 2019-04-02 Virginia Tech Intellectual Properties, Inc. Acute blood-brain barrier disruption using electrical energy based therapy
EP3030185B1 (fr) * 2013-08-06 2023-05-10 Memorial Sloan Kettering Cancer Center Système et milieu à accessibilité numérique pour l'ablation et/ou le dommage tissulaire in vivo

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3579838A1 (fr) * 2017-02-09 2019-12-18 University of Leeds Inhibiteurs des canaux ioniques trpc destinés à être utilisés en thérapie
US12053475B2 (en) 2017-02-09 2024-08-06 University Of Leeds TRPC ion channel inhibitors for use in therapy
EP3579838B1 (fr) * 2017-02-09 2026-04-15 University of Leeds Inhibiteurs des canaux ioniques trpc4 destinés à être utilisés en thérapie

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