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EP-4741492-A2 - NECROSIS INHIBITOR

EP4741492A2EP 4741492 A2EP4741492 A2EP 4741492A2EP-4741492-A2

Abstract

Provided herein are compositions comprising an endoplasmic/sarcoplasmic reticulum calcium channel inhibitor and a gap junction inhibitor for use in a variety of methods, such as methods for treating or preventing necrosis, methods for treating or preventing cell death, methods for treating or preventing tissue damage, or methods for treating or preventing organ damage. The compositions may also comprise a plasma membrane calcium channel inhibitor and/or a calcium chelator. Also provided are compositions comprising a calpain inhibitor and a cathepsin inhibitor for use in a variety of methods. Also provided are compositions comprising calcium chelators, preferably in relatively high doses, for use in a variety of methods.

Inventors

  • KERN, Carina

Assignees

  • Linkgevity Limited

Dates

Publication Date
20260513
Application Date
20240109

Claims (15)

  1. A combination comprising dantrolene, or a pharmaceutically acceptable salt or a solvate thereof, and quinine, or a pharmaceutically acceptable salt or a solvate thereof.
  2. The combination of claim 1, further comprising one or more additional endoplasmic/sarcoplasmic reticulum calcium channel inhibitors.
  3. The combination of claim 2, wherein the additional endoplasmic/sarcoplasmic reticulum calcium channel inhibitor is a ryanodine receptor antagonist; optionally wherein the additional ryanodine receptor antagonist is selected from one or more of DHBP dibromide, cis-Ned 19, trans-Ned 19, ryanodine, SKF 86365 hydrochloride, ruthenium red, procaine, and tetracaine; optionally wherein the additional ryanodine receptor antagonist is ryanodine.
  4. The combination of any one of claims 1-3, further comprising one or more additional gap junction inhibitors.
  5. The combination of claim 4, wherein the additional gap junction inhibitor is selected from (i) one or more of a fatty acid, a polyamine and a cyclodextrin, optionally wherein the fatty acid contains 13-21 carbons, or (ii) a connexin inhibitor and/or a pannexin inhibitor, preferably a connexin inhibitor, or (iii) one or more of 18α-glycyrrhetinic acid, 18β-glycyrrhetinic acid, carbenoxolone disodium, heptanol, octanol, halothane, oleic acid, oleamide, linoleic acid, arachidonic acid, palmitoleic acid, flufenamic acid, myristic acid, lauric acid, quinidine, dihydroquinidine, mefloquine, meclofenamic acid, probenecid, niflumic acid, flufenamic acid, astaxanthin, and retinoic acid.
  6. The combination of any one of claims 1-5, further comprising one or more plasma membrane calcium channel inhibitors.
  7. The combination of claim 6, wherein the plasma membrane calcium channel inhibitor is selected from one or more of amlodipine, aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine, efonidipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, pranidipine, fendiline, gallopamil, verapamil, diltiazem, mibefradil, bepridil, flunarizine, fluspirilene, fendiline, gabapentin and pregabalin; preferably wherein the plasma membrane calcium channel inhibitor is selected from one or more of arandipine, clevidipine, efonidipine, felodipine, isradipine, lercanidipine, manidipine, nifedipine, nimodipine, nitrendipine, gallopamil, verapamil, diltiazem, mibefradil, fluspirilene, gabapentin or pregabalin.
  8. The combination of any one of claims 1-7, further comprising one or more calcium chelators.
  9. The combination of claim 8, wherein the calcium chelator is selected from one or more of EDTA (Ethylenedioxy-diethylene-dinitrilo-tetraacetic acid); EGTA (Ethylene glycol-bis-(2-aminoethyl)-N,N,N',N'-tetraacetic acid); DTPA (diethylenetriaminepentaacetic acid); HEDTA (N-(2-Hydroxyethyl)ethylenediamine-N, N',N'-triacetic acid Trisodium salt); NTA (Nitrilotriacetic acid); BAPTA ((1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid)); BAPTA AM (2-[N-[2-(acetyloxymethoxy)-2-oxoethyl]-2-[2-[2-[bis[2-(acetyloxymethoxy)-2-oxoethyl]amino]phenoxy]ethoxy]anilino]acetic acid acetyloxymethyl ester); citric acid; TPEN (N,N,N',N'-Tetrakis(2-pyridylmethyl)ethylenediamine); sodium citrate; and DMSA (dimercapto succinic acid); preferably wherein the calcium chelator is one or more of DTPA, BAPTA AM, sodium citrate, and citric acid.
  10. The combination of dantrolene, or a pharmaceutically acceptable salt or a solvate thereof, and quinine, or a pharmaceutically acceptable salt or a solvate thereof, for use in therapy.
  11. Dantrolene, or a pharmaceutically acceptable salt or a solvate thereof, for use in therapy, wherein the dantrolene, or pharmaceutically acceptable salt or solvate thereof, is administered in a combination with quinine, or a pharmaceutically acceptable salt or a solvate thereof.
  12. Quinine, or a pharmaceutically acceptable salt or a solvate thereof, for use in therapy, wherein the quinine, or pharmaceutically acceptable salt or solvate thereof, is administered in a combination with dantrolene, or a pharmaceutically acceptable salt or a solvate thereof.
  13. The combination for use according to any one of claims 10-12, wherein the combination is as defined in any one of claims 2-9.
  14. The dantrolene and/or the quinine, for use according to any one of claims 10-13, wherein the dantrolene, or pharmaceutically acceptable salt or solvate thereof, and quinine, or pharmaceutically acceptable salt or solvate thereof, are administered simultaneously, separately or sequentially.
  15. The combination of any one of claims 1-9, or the dantrolene and/or the quinine for use according to any one of claims 10-14, for use in a method of treating or preventing (i) necrosis, (ii) tissue damage, (iii) organ damage, or (iv) cell death, in a subject.

Description

Field of the Invention The present invention relates to methods of treating or preventing necrosis, cell death, tissue damage, or organ damage. The invention relates to medical use of calcium activity inhibitors, calpain inhibitors, cathepsin inhibitors and/or gap junction inhibitors, particularly in treating or preventing necrosis, cell death, tissue damage, or organ damage. The invention also extends to cosmetic compositions, food products and food preservatives comprising calcium activity inhibitors, calpain inhibitors, cathepsin inhibitors and/or gap junction inhibitors, and methods of using the same to store food, cells, tissues, and organs, and methods of using the same to culture cells, tissues or organs. For example, the invention may relate to calpain inhibitors in combination with cathepsin inhibitors. For example, the invention may relate to calcium chelators, particularly where the calcium chelators are used at relatively high doses. The invention also relates to the advantageous combination of one or more endoplasmic/sarcoplasmic reticulum calcium channel inhibitors (such as one or more ryanodine receptor antagonists) and one or more gap junction inhibitors. Thus, the invention also relates to medical use of one or more endoplasmic/sarcoplasmic reticulum calcium channel inhibitors (such as one or more ryanodine receptor antagonists) in combination with one or more gap junction inhibitors, particularly in treating or preventing necrosis, cell death, tissue damage, or organ damage. The invention also extends to cosmetic compositions, food products and food preservatives comprising one or more endoplasmic/sarcoplasmic reticulum calcium channel inhibitors (such as one or more ryanodine receptor antagonists) in combination with one or more gap junction inhibitors, and methods of using the same to store food, cells, tissues, and organs, and methods of using the same to culture cells, tissues or organs. The combination of the one or more endoplasmic/sarcoplasmic reticulum calcium channel inhibitors (such as one or more ryanodine receptor antagonists) and the one or more gap junction inhibitors may be further combined with (i) one or more plasma membrane calcium channel inhibitors, and/or (ii) one or more calcium chelators. Background Necrosis is one of two main types of cell death that occur in living organisms, the other being programmed cell death (also known as apoptosis). One aspect of the invention herein relates to treating or preventing cell death, which encompasses treating or preventing necrosis and/or apoptosis. Necrosis has been characterized as passive, accidental cell death resulting from environmental perturbations (i.e., a stressful trigger) with uncontrolled release of cellular contents. It is believed to be mediated by random intracellular events. If necrotic cells in a tissue are left untreated, the necrosis will spread to neighbouring cells and tissues. This, in turn, can lead to irreversible organ damage (e.g., organ failure), and even death. Apoptosis, on the other hand, is described as an active, programmed process of autonomous cellular dismantling. Unlike necrosis, apoptosis does not typically spread to neighbouring cells or tissues. Current treatments for necrosis target the triggers of necrosis, rather than trying to directly stop/prevent the cellular changes associated with necrosis; this is because necrosis is traditionally believed to be mediated by random intracellular events. As these work by only attempting to block triggers, their effectiveness is limited to the extent that the trigger is the sole cause of necrosis, treatment must be given early enough to supress the trigger, and the treatment may be associated with an unwanted trade off. One such class of drugs is immunosuppressants. They work by supressing secondary inflammation that can trigger necrosis, e.g., TNF-α inhibition. A trade-off associated with immunosuppressants is the increased risk of infection. There is therefore a need for an improved therapy for directly treating cell death, necrosis and other medical conditions that occur downstream of necrosis. Statements of the Invention According to a first aspect of the invention, there is provided a calcium activity inhibitor, a calpain inhibitor, a cathepsin inhibitor and/or a gap junction inhibitor for use in treating or preventing (i) necrosis, (ii) tissue damage, (iii) organ damage, or (iv) cell death in a subject. For example, one or more cathepsin inhibitors in combination with one or more calpain inhibitors may be used. As another example, one or more calcium chelators may be used. According to a preferred aspect of the invention, there is provided a composition comprising one or more endoplasmic/sarcoplasmic reticulum calcium channel inhibitors (such as one or more ryanodine receptor antagonists) and one or more gap junction inhibitors for use in a method of treating or preventing (i) necrosis, (ii) tissue damage, (iii) organ damage, or (iv) cell death