Combination therapy for envenomation

Abstract

Tyrosine kinase inhibitor (TKI) for use in a method of prevention, treatment, inhibition, delay, and / or amelioration of the effects of envenomation in a subject. Said TKI wherein the method further co

Description

Field of the Invention The present invention relates to the prevention, treatment, inhibition, delay and / or amelioration of the effects of envenomation, especially by snake venom. The present invention employs a phospholipase A2 (PLA2) inhibitor, a matrix metalloprotease inhibitor, and a tyrosine kinase inhibitor. Background of the Invention Envenomation, especially from snakebites, remains the deadliest of the neglected tropical diseases, with its burden overwhelmingly on rural communities in low- and middle-income countries. Morbidity (i.e. permanent disabilities) from snakebite envenomation affects approximately 400,000 people annually worldwide. Envenomation, especially from snakebites, can cause significant muscle damage and fibrosis. Tissue damage at the bite site often leaves victims with catastrophic life-long injuries and is largely untreatable by current antivenoms. While phospholipase A2S (PLA2S) and some three-finger toxins (3FTXs) present in venoms cause direct myotoxicity by affecting the membrane, metalloproteases present in venoms degrade various components (primarily collagen) of the extracellular matrix (ECM) around the skeletal muscle and blood capillaries. As the ECM acts as a robust scaffold to promote innate muscle regeneration, its extensive damage detrimentally affects regeneration and often results in unwarranted fibrosis and muscle loss, leading to permanent disabilities. PLA2S are present in elapid and viper venoms, metalloproteases are predominantly present in viper venoms, and 3FTXs are predominantly present in elapid snake venoms. Most medically important viper venoms cause extensive muscle damage, which conventionally requires prompt clinical attention to save limbs. Current antivenoms are largely ineffective against severe local envenoming, which involves painful progressive swelling, blistering and / or tissue necrosis / muscle damage around the bite site. This can lead to loss of limb function, amputation and lifelong disability. Developing safe, affordable, and easy-to-administer treatments will be critical in achieving the World Health Organization's (WHO) goal to halve snakebite-related deaths and disabilities by 2030. Surgical treatments, such as debridement, fasciotomy and amputations, are used to manage the effects of local envenomation. These are expensive, challenging to perform, and often result in the removal of significant amounts of tissue and / or limbs, leading to permanent disabilities. Publications have described that the use of 2,3-dimercapto-l-propanesulfonic acid (DMPS), marimastat, and varespladib, alone or in combinations, inhibit the cytotoxicity of a range of snake venoms; and that dual therapeutic combination of DMPS or marimastat with varespladib significantly inhibit the dermonecrotic activity of snake venoms (e.g. US2023054792A1, Albulescu, LO., et al., Nat Commun 11, 6094 (2020). doi: 10.1038 / s41467-020-19981-6; Hall et al., Nat Commun. 2023; 14:7812, doi: 10.1038 / s41467-023-43510-w). Due to the functional similarities between matrix metalloproteases in humans and venom metalloproteases from snakes, it would be expected that matrix metalloprotease inhibitors would prevent venom-induced damage to the ECM and promote muscle regeneration without fibrosis. Surprisingly, trials performed by the present inventors have shown that matrix metalloprotease inhibitors such as marimastat worsen muscle fibrosis in a subject suffering from snake envenomation. Summary of the Invention According to a first aspect, the claimed invention provides a tyrosine kinase inhibitor (e.g. nilotinib) for use in a method of prevention, treatment, inhibition, delay and / or amelioration of the effects of envenomation in a subject. It has been found that tyrosine kinase inhibitors such as nilotinib provide significant and surprising effects in relation to the prevention, treatment, inhibition, delay and / or amelioration of the effects of envenomation in a subject. Specifically, tyrosine kinase inhibitors such as nilotinib have surprisingly been found to be able to provide a dramatic reduction in venom-induced fibrosis. In some instances, tyrosine kinase inhibitors such as nilotinib have been found to completely prevent fibrosis following venom-induced damage. Muscle tissues treated with compositions comprising nilotinib following envenomation have exhibited substantially reduced amounts of damage and up to full regeneration of the tissue. Increased levels of the structural molecules laminin and dystrophin have been detected in envenomated muscle tissue treated with compositions including nilotinib. The presence of higher levels of these structural molecules indicates the increased health of the muscle tissues following treatment with compositions including nilotinib. Furthermore, decreased levels of markers associated with cellular and tissue repair, immunoglobulin G (IgG), cluster of differentiation 31 (CD31) and platelet-derived growth factor receptor a (PDGFRa) were detected in envenomated muscle tissue treated with compositions including nilotinib. The lower levels of these markers further indicate the reduced damage in tissues following envenomation following treatment with compositions including nilotinib. Some previous studies have examined the effects of nilotinib in the treatment of the effects of a single component of snake venom, such as a 3FTX. However, snake venom is a combination of several different toxins. As such, the prevention, treatment, inhibition, delay and / or amelioration of the effects of envenomation present a significantly more difficult challenge compared to the treatment of the effects of a single component of snake venom, and the results presented herein are particularly surprising. Particularly beneficial results have been obtained where the tyrosine kinase inhibitor is administered with a PLA2 inhibitor (e.g. varespladib) and / or administered with a matrix metalloprotease inhibitor (e.g. marimastat). As such, the method of the compound for use of the first aspect may further comprise administering a phospholipase A2 (PLA2) inhibitor (e.g. varespladib) and / or administering a matrix metalloprotease inhibitor (e.g. marimastat). According to a second aspect, the claimed invention provides a kit comprising a tyrosine kinase inhibitor (e.g. nilotinib), and either or both of a phospholipase A2 (PLA2) inhibitor (e.g. varespladib) and a matrix metalloprotease inhibitor (e.g. marimastat). The PLA2 inhibitor, the tyrosine kinase inhibitor and the matrix metalloprotease inhibitor may each be referred to as a component of the invention. The claimed invention has been found to provide significant and surprising results in relation to the prevention, treatment, inhibition, delay and / or amelioration of the effects of an envenomation. As shown by the Examples, in an in vivo study, a combination of PLA2 inhibitor (varespladib), tyrosine kinase inhibitor (nilotinib) and matrix metalloprotease inhibitor (marimastat) completely prevented fibrosis and promoted tissue regeneration following venom-induced damage, and the muscle looked very similar to the undamaged control muscles. This is particularly surprising because, as shown by the Examples, long-term use of marimastat, either alone or in combination with varespladib, can detrimentally affect muscle regeneration, leading to smaller fibres and fibrosis. However, in the claimed invention, the administration of marimastat with varespladib and nilotinib provides better results than the combination of varespladib and nilotinib alone. As shown in the Examples, in vivo studies have shown that the claimed components prevent venom-induced muscle damage. As shown in the Examples, in vivo studies have shown that the claimed components prevent venom-induced muscle fibrosis Furthermore, as shown in the Examples, in vivo studies have shown that the claimed components can promote complete muscle regeneration following venom-induced damage. It has been found that the components of the claimed kit can surprisingly provide synergistic effects compared to the components themselves. Preferably the venom is viper snake venom (e.g. from the Russell’s viper). Viper snakes cause around 60% of overall snakebite incidents globally and cause significant muscle damage due to the venom’s effect in affecting the blood supply to the tissue, destroying the ECM and damaging the muscle fibres. For the subject, the present invention enables limbs and other significant portions of the body to be saved from the effects of a snakebite. For example, the invention can prevent venom-induced systemic envenomation effects such as neurotoxicity, haemotoxicity, nephrotoxicity and cytotoxicity as well as other effects of envenomation that are induced by PLA2 and metalloproteases. For the wider population, there are significant socioeconomic benefits from reduced long-term healthcare requirements and enhanced activity of the population in regions that are significantly afflicted by envenomation from snakebites. It is thought that, following envenomation by a snakebite, phospholipase A2, metalloproteases and 3FTXs in venom cause myotoxicity, weakening the ECM and thereby causing fibrosis. Nilotinib, a tyrosine kinase inhibitor, has been reported to reduce fibrosis following notexin (a 3FTX)-induced acute muscle damage by promoting the apoptosis of fibro-adipogenic progenitor cells (FAPs) through blocking the tumour necrosis factor pi (TGF-pi)-induced p38 kinase activation in these cells. Tyrosine kinase inhibitors such as nilotinib have previously found application in the treatment of chronic myeloid leukaemia (Lemos, D., et al., Nat Med 21, 786-794 (2015). doi: 10.1038 / nm.3869). Notexin is found in the venom of snakes of the family Elapidae (elapids, such as cobras). However, notexin differs significantly from the whole venom, which is a mixture of various toxins including other components, such as metalloproteases, that affect muscle and induce fibrosis. 3FTX causes a small amount of necrosis; however, snake venom typically destroys muscle ECM, causing a massive inflammatory response and far more significant amounts of necrosis. Alternative anti-fibrotic drugs, such as soluble activin receptor type IIB, have been previously investigated for use in the treatment of envenomation (Sonavane, M. et al., Toxins 2025, 17, 59; https: / / doi.org / 10.3390 / toxinsl7020059). Soluble activin receptor type IIB is a large protein that counteracts the actions of myostatin and activin to promote muscle regeneration. However, this large molecule possesses numerous disadvantages, such as the inability to be used in oral formulations, high production costs and unknown side effects. It can only be taken via parenteral routes. Therefore, the use of “small molecule” compounds, such as nilotinib, to tackle muscle damage and fibrosis provides more benefits in tackling this issue. In addition, owing to the different mechanism of action of soluble activin receptor type IIB compared to tyrosine kinase inhibitors such as nilotinib, the results of the present invention remain surprising. Furthermore, the effects of such previous studies have not been as significant as those reported herein. US 2021 / 0260029 Al describes the use of a PLA2 inhibitor selected from the group consisting of varespladib, methylvarespladib, or a pharmaceutically acceptable salt thereof and at least one additional agent selected from the group consisting of a metalloproteinase inhibitor, a snake antivenom or a mixture thereof for inhibiting, delaying and / or ameliorating the effects of snake envenomation. The disclosure of US 2021 / 0260029 Al focusses on the simple neutralisation of PUA2, and may not have a significant effect on preventing the effects of local envenomation. However, the claimed invention can prevent, treat, inhibit, delay and / or ameliorate the effects of local envenomation. This can be achieved by simultaneously inhibiting toxins present in venom and promoting tissue regeneration. As discussed above, the claimed invention provides significant and surprising results. The components of the present invention can be used to prevent, treat, inhibit, delay and / or ameliorate the effects of an envenomation, especially by snake venom. According to a third aspect, the claimed invention provides a PUA2 inhibitor (e.g. varespladib) for use in a method of prevention, treatment, inhibition, delay and / or amelioration of the effects of envenomation in a subject, wherein the method comprises administering a tyrosine kinase inhibitor (e.g. nilotinib), and optionally administering a matrix metalloprotease inhibitor (e.g. marimastat). According to a fourth aspect the claimed invention provides a matrix metalloprotease inhibitor (e.g. marimastat) for use in a method of prevention, treatment, inhibition, delay and / or amelioration of the effects of envenomation in a subject, wherein the method comprises administering a tyrosine kinase inhibitor (e.g. nilotinib), and optionally administering a PUA2 inhibitor (e.g. varespladib). According to a fifth aspect the claimed invention provides a method of prevention, treatment, inhibition, delay and / or amelioration of the effects of envenomation in a subject, the method comprising administering to the subject a tyrosine kinase inhibitor (e.g. nilotinib). The method may further comprise administering to the subject a PLA2 inhibitor (e.g. varespladib) and / or administering to the subject a matrix metalloprotease inhibitor (e.g. marimastat). According to a sixth aspect the claimed invention provides a PLA2 inhibitor (e.g. varespladib) for use in the manufacture of a medicament for the prevention, treatment, inhibition, delay and / or amelioration of the effects of envenomation in a subject, wherein the prevention, treatment, inhibition, delay and / or amelioration comprises the administration of a tyrosine kinase inhibitor (e.g. nilotinib), and optionally wherein the prevention, treatment, inhibition, delay and / or amelioration comprises the administration of a matrix metalloprotease inhibitor (e.g. marimastat). According to a seventh aspect the claimed invention provides a matrix metalloprotease inhibitor (e.g. marimastat) for use in the manufacture of a medicament for the prevention, treatment, inhibition, delay and / or amelioration of the effects of envenomation in a subject, wherein the prevention, treatment, inhibition, delay and / or amelioration comprises the administration of a tyrosine kinase inhibitor (e.g. nilotinib), and optionally wherein the prevention, treatment, inhibition, delay and / or amelioration comprises the administration of a PLA2 inhibitor (e.g. varespladib). According to an eighth aspect the claimed invention provides a tyrosine kinase inhibitor (e.g. nilotinib) for use in the manufacture of a medicament for the prevention, treatment, inhibition, delay and / or amelioration of the effects of envenomation in a subject. The prevention, treatment, inhibition, delay and / or amelioration may further comprise the administration of a matrix metalloprotease inhibitor (e.g. marimastat) and / or the administration of a PLA2 inhibitor (e.g. varespladib). According to a ninth aspect the claimed invention comprises a pharmaceutical composition comprising a tyrosine kinase inhibitor (e.g. nilotinib) and either or both of a PLA2 inhibitor (e.g. varespladib) and a matrix metalloprotease inhibitor (e.g. marimastat). Brief Description of the Drawings Embodiments of the present invention will now be described by way of example with reference to the accompanying drawings, in which: Figure 1 shows the percentage weight loss of the TA muscle of mice in the treated groups: Russell’s viper venom (DR); DR and varespladib (V); DR and marimastat (M); DR+V+M; DR and antivenom (AV); DR, AV and V; DR, AV and M; DR+AV+V+M; and negative control; Figure 2 shows the percentage picrosirius red positive area of mouse muscle treated with: Russell’s viper venom (DR); DR and varespladib (V); DR and marimastat (M); DR+V+M; DR and antivenom (AV); DR, AV and V; DR, AV and M; DR+AV+V+M; and negative control; Figure 3 shows the percentage weight loss of the TA muscle of mice (A), the percentage picrosirius red positive area of mouse muscle (B), and the percentage collagen deposition (C) in the muscle of mice treated by cardiotoxin (CTX); and CTX and marimastat (M); Figure 4 shows the percentage weight loss of the TA muscle of mice (A), the percentage picrosirius red positive area (B) of mouse muscle, and the percentage damaged area (C) in muscle of mice treated by: Russell’s viper venom (DR); DR and nilotinib (N); DR, N and varespladib (V); and DR+N+V+M; Figure 5 shows the percentage laminin-positive area (A) and the percentage dystrophin-positive area (B) of muscle tissue treated by: Russell’s viper venom (DR); DR and nilotinib (N); DR, N and varespladib (V); and DR+N+V+M; and Figure 6 shows the percentage immunoglobulin G positive area (A), the level of cluster of differentiation 31 (B), and the percentage platelet-derived growth factor receptor a area (C) for muscle tissue treated by: Russell’s viper venom (DR); DR and nilotinib (N); DR, N and varespladib (V); and DR+N+V+M. Detailed Description of the Invention The effects of envenomation in a subject may include muscle fibrosis; tissue (e.g. muscle) necrosis, damage and / or loss; increased levels of markers associated with cellular and tissue repair (e.g. IgG, CD31 and / or PDGFRa); neurotoxicity; haemotoxicity; nephrotoxicity; and / or cytotoxicity. The envenomation may be caused by contact with a venom or poison. In particular, envenomation may be caused by the injection of venom including from an animal (invertebrate or vertebrate). Most frequently, envenomation is the result of a snakebite. The venom may be from any venomous animal (e.g. snake). Venomous snakes may be of a family selected from Atractaspididae (atractaspidids), Colubridae (colubrids) Elapidae (elapids), Hydrophidae (sea snakes) and Viperidae (viperids), all of which include venomous snakes. Preferably the venom is from a snake of the Viperidae (viperids) family, i.e. a viper. The venom may be from a snake selected from purple-glossed snake, centipede eater, burrowing asp, Revoil's short snake, Chilorhinophis, Hypoptophis, Homoroselaps, Macrelaps, Micrelaps, boomslang, spitting cobras, green mamba, black mamba, Keelback snake, sea snake, taipan, brown snake, coral snake, krait, death adder, tiger snake, mamba, king cobra, cobra, any true vipers (e.g. Russell's viper), saw-scaled viper, puff adder, carpet viper, horned viper, and any pit vipers (including rattlesnake, lancehead, copperhead, hump-nosed pit viper, Malabar pit viper and cottonmouth). Preferably the venom is from a snake selected from Indian cobra, common krait, Russell's viper, and saw-scaled viper. Most preferably the venom is from a Russell’s viper. The PLA2 inhibitor, the tyrosine kinase inhibitor and the matrix metalloprotease inhibitor may each be referred to as a component of the invention. The phospholipase A2 (PLA2) inhibitor may be selected from the list consisting of varespladib, methyl varespladib, darapladib, manoalide, U-73122 (CAS registry number (RTM) 112648-68-7), Quinacrine, Quercetin, Chlorpromazine, Aristolochic Acid, Cinnamycin, MJ33 (CAS registry number (RTM) 1135306-36-3), ETYA (CAS registry number (RTM) 1191-85-1), N-(p-Amylcinnamoyl) anthranilic acid, ML349 (CAS registry number (RTM) 890819-86-0) and arachidonyl trifluoromethyl ketone. Preferably the PLA2 inhibitor is selected from the list consisting of varespladib, methyl varespladib, and darapladib. Most preferably the PLA2 inhibitor is varespladib. The matrix metalloprotease inhibitor may be selected from the list consisting of marimastat, batimastat (BB-94), prinomastat (AG3340), tanomastat (BAY 12-9566), CGS-27023 (CAS registry number (RTM) 169799-04-6), ilomastat, doxycycline hyclate, TAPI-1 (CAS registry number (RTM) 163847-77-6), actinonin, NNGH (CAS registry number (RTM) 161314-17-6), tissue inhibitors of metalloproteinases (TIMPs, e.g. TIMP-1, TIMP-2, TIMP-3, TIMP-4), squalamine, genistein, nobiletin, myricetin, curcumin, xanthorhizzol, theaflavin, resveratrol, actinonin, matlystatin B, nicotinamide, betulinic acid, glycyrrhetinic acid, catechin, bryostatins (e.g. bryostatin-1), tetracyclines (e.g. Doxycycline and minocycline) and metal chelators (e.g. unithiol, ethylenediaminetetraacetic acid (EDTA), diethylene triamine pentaacetic acid (DTPA), N,N'-bis(2-aminoethyl)ethylenediamine-N,N'-diacetic acid (TPEN), l,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), IDHA (imidodisuccinic acid), ethylenediamine-N,N'-disuccinic acid (EDDS), ethylenediamine-N(o-hydroxyphenylacetic)-N’(p-hydroxyphenylacetic) acid (o,p-EDDHA), ethylenediamine-N,N’bis(o-hydroxyphenyl)acetic acid (o,o-EDDHA), and ethylene glycol-bis(2-aminoethylether)-N,N,N',N'-tetraacetic acid (EGTA)). Unithiol is a preferred metal chelator. Metal chelators such as those disclosed above chelate Zn ions that are necessary for metalloprotease activity, thereby indirectly inhibiting the function of matrix metalloproteases. Preferably the matrix metalloprotease inhibitor is selected from marimastat and prinomastat. Most preferably the matrix metalloprotease inhibitor is marimastat. The tyrosine kinase inhibitor may be selected from the list consisting of nilotinib, Acalabrutinib, Adavosertib, Afatinib, Alectinib, Anlotinib, Apatinib, Aumolertinib, Avapritinib, Axitinib, Bosutinib, Cabozantinib, Canertinib, cetuximab, Crenolanib, Dacomitinib, Damnacanthal, Dasatinib, Entospletinib, Entrectinib, Erlotinib, Foretinib, Fostamatinib, Fruquintinib, Futibatinib, Gefitinib, Gilteritinib, Glesatinib, HS-10365, Ibrutinib, Icotinib, Idelalisib, IDRX-42, Imatinib, Infigratinib, Ivosidenib, Lapatinib, Larotrectinib, Lazertinib, Lenvatinib, Linifanib, Lorlatinib, Masitinib, Midostaurin, Mirdametinib, Mobocertinib, Motesanib, Mubritinib, Nemtabrutinib, Nilotinib, Neratinib, Netarsudil, Nimotuzumab, Nintedanib, Olverembatinib, panitumumab, Pazopanib, Pirtobrutinib, Ponatinib, Radotinib, Regorafenib, Remibrutinib, Repotrectinib, Ropsacitinib, Savolitinib, Selpercatinib, Sorafenib, Sitravatinib, Sunitinib, Sunvozertinib, T790M, Tesevatinib, Tolebrutinib, V600E, Vatalanib, vandetanib and Zasocitinib. Most preferably the tyrosine kinase inhibitor is nilotinib. Compositions A pharmaceutical composition (e.g. formulation) may comprise one or more of the components of the invention together with a pharmaceutically acceptable carrier, adjuvant, excipient, diluent, filler, buffer, stabiliser, preservative, lubricant or any other related materials. To prepare the pharmaceutical compositions of this invention, an effective amount of the or each component of the invention, as the active ingredient(s), can be combined in intimate admixture with a pharmaceutically acceptable carrier. The carrier may take a wide variety of forms depending on the form of preparation desired for administration. The pharmaceutical compositions can be in any form suitable for administration by inhalation or gastric tube, or oral, parenteral (including intravenous, intramuscular and intraperitoneal), topical, intranasal, ophthalmic, otic, rectal, intra-vaginal, subcutaneous or transdermal (e.g. using a patch, cream, or autoinjector (such as an EpiPen®-like auto injector)) administration. The components of the invention may be administered by oral administration (e.g. by tablet or capsule), inhalation (e.g. using an inhaler), gastric tube (nasogastric tube or orogastric tube), transdermal administration (e.g. using an autoinjector or transdermal patch), or injection. Preferably the components of the invention are for oral administration. Preferably the components of the invention are provided as three separate tablets (one for each component). The carrier may be water (e.g. water for injection), saline or a pH buffer (e.g. citrate, phosphate, acetate and / or sodium bicarbonate). Preferably the pH of the composition is from 5.5 to 9.0, or 6.0 to 8.0 (e.g. phosphate buffer), more preferably from 6.5 to 8.0. Solid dosage forms for oral administration include capsules, tablets (including dispersable tablets), chews, lozenges, pills, powders, and multi-particulate preparations (granules). In such solid dosage forms, one or more of the components of the invention, can be admixed with at least one inert excipient, diluent, or carrier. Suitable excipients, diluents or carriers include materials such as sodium citrate or dicalcium phosphate and / or (a) one or more fillers or extenders (e.g., microcrystalline cellulose) starches, lactose, sucrose, mannitol, silicic acid, xylitol, sorbitol, dextrose, calcium hydrogen phosphate, dextrin, alpha-cyclodextrin, beta-cyclodextrin, polyethylene glycol, medium chain fatty acids, titanium oxide, magnesium oxide, aluminium oxide); (b) one or more binders (e.g., carboxymethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, gelatine, gum Arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, alginates, polyvinylpyrrolidone, sucrose, acacia); (c) one or more humectants (e.g., glycerol); (d) one or more disintegrating agents (e.g., agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, sodium carbonate, sodium lauryl sulphate, sodium starch glycolate, cross-linked polyvinyl pyrrolidone, croscarmellose sodium A-type, polyacrilin potassium (an ion exchange resin)); (e) one or more solution retarders (e.g., paraffin); (f) one or more absorption accelerators (e.g., quaternary ammonium compounds); (g) one or more wetting agents (e.g., cetyl alcohol, glycerol monostearate,); (h) one or more adsorbents (e.g., kaolin, bentonite); and / or (i) one or more lubricants (e.g., talc, calcium stearate, magnesium stearate, stearic acid, polyoxyl stearate, cetanol, talc, hydrogenated castor oil, sucrose esters of fatty acid, dimethylpolysiloxane, microcrystalline wax, yellow beeswax, white beeswax, solid polyethylene glycols, sodium lauryl sulfate). In the case of capsules and tablets, the dosage forms may also comprise buffering agents. Solid compositions may also be used as fillers in soft or hard filled gelatine capsules using such excipients as lactose, as well as high molecular weight polyethylene glycols. Solid dosage forms such as tablets, dragees, capsules, and granules may be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may also contain opacifying agents, and can also be of such composition that they release the compound of the present disclosure and / or the additional pharmaceutical agent in a delayed manner. Examples of embedding compositions that can be used are polymeric substances and waxes. The component or components may also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the compound of the present disclosure or the combination, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifiers, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, sesame seed oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, and fatty acid esters of sorbitan, or mixtures of these substances. Besides such inert diluents, the composition may also include excipients, such as wetting agents, emulsifying and suspending agents, sweetening, flavouring, and perfuming agents. Oral liquid forms of the compounds of the disclosure or combinations include solutions, wherein the active compound is fully dissolved. Examples of solvents include all pharmaceutically precedented solvents suitable for oral administration, particularly those in which the compounds of the disclosure show good solubility, e.g., polyethylene glycol, polypropylene glycol, edible oils, and glyceryl- and glyceride-based systems. Glyceryl- and glyceride-based systems may include glyceryl tricaprylate / caprate, medium chain triglyceride, glyceryl triacetate i.e. triacetin, medium chain mono- and diglycerides, caprylic / capric triglyceride, caprylic / capric / succinic triglyceride, propylene glycol dicaprylate / dicaprate, oleoyl macrogol-6 glycerides, glyceryl monooleate, glyceryl monooleate. Suspensions, in addition to the compound of the present disclosure or the combination, may further comprise carriers such as suspending agents, e.g., ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, or mixtures of these substances. Where the composition is intended for parenteral administration, it can be formulated for intravenous, intramuscular, intraperitoneal, subcutaneous administration or for direct delivery into a target organ or tissue by injection, infusion or other means of delivery. Preferably the composition is for intravenous administration, for example via cannula. The delivery can be by bolus injection, short-term infusion or longer term infusion and can be via passive delivery or through the utilisation of a suitable infusion pump. Pharmaceutical compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacterio stats, co-solvents, organic solvent mixtures, cyclodextrin complexation agents, emulsifying agents (for forming and stabilizing emulsion formulations), liposome components for forming liposomes, gellable polymers for forming polymeric gels, lyophilisation protectants and combinations of agents for, inter alia, stabilising the active ingredient in a soluble form and rendering the formulation isotonic with the blood of the intended recipient. Pharmaceutical formulations for parenteral administration may also take the form of aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents (R. G. Strickly (2004), Solubilizing Excipients in oral and injectable formulations, Pharmaceutical Research, Vol 21(2), p 201 -230). Liposomes are closed spherical vesicles composed of outer lipid bilayer membranes and an inner aqueous core and with an overall diameter of <100 pm. Depending on the level of hydrophobicity, moderately hydrophobic drugs can be solubilized by liposomes if the drug becomes encapsulated or intercalated within the liposome. Hydrophobic drugs can also be solubilized by liposomes if the drug molecule becomes an integral part of the lipid bilayer membrane, and in this case, the hydrophobic drug is dissolved in the lipid portion of the lipid bilayer. The composition may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use. The pharmaceutical composition can be prepared by lyophilising a ligand and / or complex of the invention. Lyophilisation refers to the procedure of freeze- drying a composition. Freeze-drying and lyophilisation are therefore used herein as synonyms. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets. Pharmaceutical compositions of the present invention for parenteral injection can also comprise pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. The compositions of the present invention may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminium monostearate and gelatine. The pharmaceutical composition may be in a form suitable for intravenous administration, for example by injection or infusion. For intravenous administration, the solution can be dosed as is or can be injected into an infusion bag (containing a pharmaceutically acceptable excipient, such as 0.9% saline or 5% dextrose), before administration. The present invention may employ a dosage, or dosage form, of the PLA2 inhibitor (e.g. varespladib) of Img or higher, such as 50mg or higher, preferably lOOmg or higher, or 200mg or higher, such as 300mg or higher, or 400mg or higher, for example, 450mg or higher, or 500mg. The dosage, or dosage form, of the PLA2 inhibitor, may be 2.0g or lower, such as 1.5g or lower, preferably 1.0g or lower, such as 800mg or lower, or 600mg or lower, or 550mg or lower. The dosage, or dosage form, of the PLA2 inhibitor may be from Img to 2.0g, preferably from lOOmg to 1,0g, such as from 300mg to 800mg. The present invention may employ a dosage, or dosage form, of the matrix metalloprotease inhibitor (e.g. marimastat) of Img or higher, such as 50mg or higher, preferably lOOmg or higher, or 200mg or higher, such as 300mg or higher, or 400mg or higher, for example, 450mg or higher, or 500mg. The dosage, or dosage form, of the matrix metalloprotease inhibitor, may be 2.0g or lower, such as 1.5g or lower, preferably 1.0g or lower, such as 800mg or lower, or 600mg or lower, or 550mg or lower. The dosage, or dosage form, of the matrix metalloprotease inhibitor may be from Img to 2.0g, preferably from lOOmg to 1.0g, such as from 300mg to 800mg. The present invention may employ a dosage, or dosage form, of the tyrosine kinase inhibitor (e.g. nilotinib) of Img or higher, such as 50mg or higher, preferably lOOmg or higher, or 200mg or higher, such as 300mg or higher, or 400mg. The dosage, or dosage form, of the tyrosine kinase inhibitor, may be 2.0g or lower, such as 1.5g or lower, preferably 1.0g or lower, such as 800mg or lower, or 600mg or lower, or 500mg or lower, such as 550mg or lower. The dosage, or dosage form, of the tyrosine kinase inhibitor may be from Img to 2.0g, preferably from lOOmg to 1.0g, such as from 200mg to 600mg. The present invention may relate to additionally administering another therapeutic and / or inhibitor of venom toxins, such as an antivenom. For example, methods and uses of the invention may comprise administering the other therapeutic and / or inhibitor of venom toxins; and kits and compositions of the invention may comprise the therapeutic and / or inhibitor of venom toxins. The antivenom may comprise antibodies, such as polyclonal, monoclonal and / or recombinant antibodies, and / or their derivatives (especially fragment antigen-binding (Fab), F(ab’)2 fragment and / or single-domain antibody (sdAb) thereof). Exemplary antivenoms include polyvalent antivenoms produced against multiple venoms (equine or ovine), such as Crotalidae polyvalent immune Fab (ovine). Administration regimen The compounds and compositions of the invention may be administered to a human or animal subject, for example, a subject that is a mammal, preferably a human. The mammal may be non-human. Suitable non-human animals include, but are not limited to, primates (such as marmosets and monkeys), commercially farmed animals (such as birds, horses, cows, sheep and pigs) and domestic animals (such as dogs, cats, mice, rats, guinea pigs, ferrets, gerbils and hamsters). The compounds and compositions of the invention can be in any form suitable for oral, parenteral, topical, intranasal, ophthalmic, otic, rectal, intra-vaginal, or transdermal administration. Preferably the compounds and compositions of the invention of the invention are for oral administration. The PLA2 inhibitor, the matrix metalloprotease inhibitor, and the tyrosine kinase inhibitor may be administered simultaneously, sequentially or separately. The claimed invention may comprise the administration of a composition comprising the PLA2 inhibitor, the matrix metalloprotease inhibitor, and the tyrosine kinase inhibitor. The claimed invention may comprise the administration of a composition comprising the PLA2 inhibitor and the tyrosine kinase inhibitor; the PLA2 inhibitor and the matrix metalloprotease inhibitor; and / or the matrix metalloprotease inhibitor, and the tyrosine kinase inhibitor. It is preferable for the matrix metalloprotease inhibitor to be administered for the first few days; as such, preferably, the PLA2 inhibitor and the tyrosine kinase inhibitor are administered as a composition, and simultaneously, sequentially or separately to the matrix metalloprotease inhibitor. Administration may begin 1 minute or more following envenomation, such as 30 minutes or more, or 2 hours or more, for example 6 hours following envenomation. Administration may begin 2 months or less following envenomation, such as 1 month or less following envenomation, preferably 2 weeks or less following envenomation, or 1 week or less following envenomation, for instance 5 days or less, or 2 days or less following envenomation. Administration may begin from 1 minute to 2 months following envenomation, such as from 30 minutes to 2 weeks following envenomation. The tyrosine kinase inhibitor may be administered at a frequency of from four times per day to once per week, or three times per day to once per week, such as from two times per day to once per week, or from once per day to once per week. The tyrosine kinase inhibitor may be administered at a frequency of from four times per day to once every three days, such as from four times per day to once every two days, or from four times per day to once daily. Preferably the tyrosine kinase inhibitor is administered at a frequency of three times per day to once every two days, more preferably twice daily (i.e. two times per day). The duration of administration of the tyrosine kinase inhibitor (or its combinations) may be 2 days or more, such as 5 days or more, preferably 7 days or more, for example 10 days or more, or 12 days or more, especially 13 or 14 days or more. The duration of administration of the tyrosine kinase inhibitor may be 6 months or less, such as 2 months or less, preferably 1 month or less, such as 21 days or less, or 18 days or less, for example, 15 or 14 days or less. The duration of administration of the tyrosine kinase inhibitor may be from 2 days to 6 months, preferably from 7 days to 1 month, such as from 10 to 21 days. For the tyrosine kinase inhibitor, the administration frequency may be from four times per day to once per week, and the duration of administration may be 2 days or more, such as 7 days or more, for example from 7 days to 1 month. The tyrosine kinase inhibitor may be administered in a dose of Img or higher (e.g. from Img to 2.0g, preferably from lOOmg to 1.0g) at a frequency of four times per day to once per week (preferably from three times daily to once every two days, more preferably twice daily), and optionally for a duration of 2 days or more (e.g. 7 days or more, for example from 7 days to 1 month). The PLA2 inhibitor may be administered at a frequency of from four times per day to once per week, or three times per day to once per week, such as from two times per day to once per week, or from once per day to once per week. The PLA2 inhibitor may be administered at a frequency of from four times per day to once every three days, such as from four times per day to once every two days. Preferably the PLA2 inhibitor is administered at a frequency of three times per day to once every two days, more preferably twice daily. The duration of administration of the PLA2 inhibitor (or its combinations) may be 2 days or more, such as 5 days or more, preferably 7 days or more, for example 10 days or more, or 12 days or more, especially 13 or 14 days or more. The duration of administration of the PLA2 inhibitor may be 6 months or less, such as 2 months or less, preferably 1 month or less, such as 21 days or less, or 18 days or less, for example 15 or 14 days or less. The duration of administration of the PLA2 inhibitor may be from 2 days to 6 months, preferably from 7 days to 1 month, such as from 10 to 21 days. For the PLA2 inhibitor, the administration frequency may be from three times per day to once per week, and the duration of administration may be 2 days or more, such as 7 days or more, for example from 7 days to 1 month. The PLA2 inhibitor may be administered in a dose of Img or higher (e.g. from Img to 2.0g, preferably from lOOmg to 1.0g) at a frequency of four times per day to once per week (preferably from three times daily to once every two days, more preferably twice daily), and optionally for a duration of 2 days or more (e.g. 7 days or more, for example from 7 days to 1 month). The matrix metalloprotease inhibitor may be administered as a one-off or multiple doses. The matrix metalloprotease inhibitor may be administered at a frequency of from four times per day to once per week, or three times per day to once per week, such as from two times per day to once per week, or from once per day to once per week. The matrix metalloprotease inhibitor may be administered at a frequency of from four times per day to once every three days, such as from four times per day to once every two days. Preferably the matrix metalloprotease inhibitor is administered at a frequency of three times per day to once every two days, more preferably twice daily. The duration of administration of the matrix metalloprotease inhibitor (or its combinations) may be 1 day or more, preferably 2 days or more, or 3 days or more. The duration of administration of the matrix metalloprotease inhibitor may be 1 month or less, preferably 14 days or less, such as 10 days or less, more preferably 7 days or less, such as 5 days or less, or 4 days or less, for example 3 days or less. The duration of administration of the matrix metalloprotease inhibitor may be from 1 days to 1 month, preferably from 2 days to 7 days, such as from 2 to 5 days. For the matrix metalloprotease inhibitor, the administration frequency may be from three times per day to once per week (e.g. from three times per day to once every three days), and the duration of administration may be 1 day or more, such as from 1 day to 1 month, preferably from 2 days to 7 days. The matrix metalloprotease inhibitor may be administered in a dose of Img or higher (e.g. from Img to 2.0g, preferably from lOOmg to 1.0g) at a frequency of four times per day to once per week (preferably from three times daily to once every two days, more preferably twice daily), and optionally for a duration of 1 day or more (e.g. from 1 day to 1 month, preferably from 2 days to 7 days). The method may comprise administering the tyrosine kinase inhibitor at a frequency of from three times per day to once per week (e.g. twice daily to once every two days), administering the PLA2 inhibitor at a frequency of from three times per day to once per week (e.g. twice daily to once every two days), and administering the matrix metalloprotease inhibitor as a one-off dose or at a frequency of from three times per day to once per week (e.g. twice daily to once every two days). The method may comprise: administering the tyrosine kinase inhibitor at a frequency of from three times per day to once per week, and for a duration of 2 days or more (for example from 7 days to 1 month); and administering the PLA2 inhibitor at a frequency of from three times per day to once per week, and for a duration of 2 days or more (for example from 7 days to 1 month); and administering the matrix metalloprotease inhibitor as a single dose, or administering the matrix metalloprotease inhibitor at a frequency of from three times per day to once per week (e.g. from three times per day to once every three days) and for a duration of 1 day or more (preferably from 2 days to 7 days). Examples Example 1: Russell’s viper venom damages the cultured myoblasts and myotubes Russell’s viper venom caused significant damage to cultured human myoblast (ABI 190) and embryonic kidney (HEK293T) cell lines at concentrations of 6.25 pg / mL and above. In line with these data, Russell’s viper venom substantially affected the area of cultured myotubes and compromised the differentiation capacity of human (AB 1167 GFP-expressing) myoblasts. Biochemical characterisation revealed that Russell’s viper venom has high metalloprotease activity. SDS-PAGE and reverse-phase high-performance liquid chromatography analyses confirmed the protein profile for venom with a prominent protein at ~65kDa, which was confirmed as a PHI metalloprotease by mass spectrometry analysis. Notably, the currently used polyvalent antivenom (comprising antibodies produced against venom proteins in hyperimmunised animals such as horses) produced against the Indian ‘Big Four’ snakes (Russell’s viper, cobra, krait and saw-scaled viper) failed to prevent the venom-induced damage in human myoblasts and embryonic kidney cells although it partially reversed the damage. These data demonstrate that the venom contains higher levels of metalloproteases, which are likely to cause extensive muscle damage. Example 2: Varespladib and marimastat only partially reverse venom-induced muscle damage in mice (comparative) To determine the effect of Russell’s viper venom (DR) in inducing muscle damage and the ability of varespladib (V) and marimastat (M) to prevent such damage, an in vivo experiment in mice was performed. Animals were divided into different groups (6 in each), and they received drugs or antivenom (AV) alone or different combinations of these therapeutics. The venom (10 pg) was administered intramuscularly (i.m.) into the TA muscle of mice. Then varespladib (120 pg) and marimastat (120 pg) were administered intraperitoneally (i.p.) after a one-hour injection of venom, and then they [varespladib (60 pg) and marimastat (60 pg)] were injected at every 24 hours until the muscle was collected at days 1, 3, 7 and 14. NC=negative control. The percentage of muscle loss following venom injection with / without drugs on day 14 was calculated by comparing the venom-damaged TA muscle with the control TA muscles (considered as 100%). These data demonstrate that varespladib and its combination with AV showed some protection from muscle loss, although muscle loss was not completely averted. Figure 1 of the accompanying drawings shows the results of this study. * represents the comparison of all bars with DR (Russell’s viper venom alone) and # represents the comparison with the negative control. The venom administration resulted in -20% muscle weight loss by day 14. However, the administration of varespladib largely prevented this muscle loss, although marimastat did not display a significant effect. Haematoxylin and eosin (H&E)-stained sections revealed that on day 1, the venom-induced excessive necrosis of muscle fibres, oedema and immune response, which are more evident on day 3. By day 7. venom-treated muscles showed early signs of muscle regeneration (as evidenced through centrally located nuclei) yet with significant necrotic areas. Incomplete regeneration, atrophic muscle fibres and fibrous tissues are evident on day 14. In line with these data, venom increased IgG infiltration and reduced the levels of dystrophin, laminin and collagen IV at different time points. The presence of embryonic myosin heavy chain (eMHC) at the later stages indicates ongoing damage. The angiogenesis was also affected in venom-treated muscle in the early stages, as evidenced by reduced expression of CD31. These data demonstrate that Russell’s viper venom induces extensive damage to the ECM, blood capillaries and muscle fibres via necrosis. Varespladib and its combination with marimastat reduced the level of muscle damage and promoted regeneration by day 14. However, marimastat alone did not promote muscle regeneration to the same extent as varespladib or its combination with varespladib or antivenom. Notably, varespladib and its combination with antivenom slightly increased the muscle fibre size, but marimastat did not exert this effect. Varespladib and its combinations retained the architecture of laminin, but marimastat did not prevent damage to laminin. Moreover, varespladib reduced the IgG infiltration and increased the dystrophin and eMHC levels at different time points. Antivenom alone, or its combination with marimastat, did not offer significant benefits to the damaged muscle. These data suggest that varespladib and its combinations are capable of preventing venom-induced muscle damage to an extent. The antivenom alone did not offer any benefits in preventing venom-induced muscle damage. The drugs or antivenom alone did not cause any adverse damage to the muscles or systemically in the animals. Example 3: Venom-induced fibrosis is not fully prevented by varespladib and marimastat (comparative) Figure 2 of the accompanying drawings shows the impact of drugs and antivenom in controlling fibrosis following venom-induced damage, specifically showing the collagen contents in venom (with / without drugs and antivenom)-treated mice, by picrosirius red positive area. *represents the comparison of all bars with DR; # represents comparison with the negative control; and &represents the comparison between varespladib and marimastat alone following venom-induced damage. Russell’s viper venom-induced an excessive development of fibrosis in the damaged muscle. While varespladib reduced the fibrosis slightly more than marimastat, it was unable to fully prevent this condition. Marimastat and antivenom, as well as their combinations, displayed only a limited benefit in reducing fibrosis. The drugs and antivenom alone did not cause any alterations to the ECM or induce fibrosis. The results obtained from marimastat-treated mice are surprising as it was expected that the inhibition of venom metalloproteases would prevent damage to the ECM and promote muscle regeneration without fibrosis. Based on these data, it was hypothesised that the long-term administration of marimastat affects the activity of newly expressed matrix metalloproteases that are critical for the remodelling of the ECM, which in turn promotes muscle regeneration. To establish if marimastat disrupts muscle regeneration and promotes fibrosis in the absence of venom metalloproteases, marimastat was tested in a cardiotoxin (CTX, a non-enzymatic 3FTX, similar to notexin mentioned above) -induced muscle damage model in mice. Tissue samples were analysed to determine the TA muscle weight loss, the picrosirius red positive area, and the percentage collagen deposition. The results of this study are shown by Figure 3A-C of the accompanying drawings. As expected, CTX-damaged muscle had fully regenerated by day 14 without any significant weight loss (Figure 3A). The regenerated fibres with centrally located nuclei are evident throughout the CTX-damaged muscle. However, CTX+marimastat-treated mice showed significant muscle weight loss and poor regeneration, as demonstrated through smaller regenerating fibres and significant infiltration of leukocytes. The percentage TA muscle weight loss, picrosirius red positive area and percentage collagen deposition were all increased in tissues of subjects treated with CTX and marimastat, compared to CTX alone (Figures 3A-C). Notably, the fibrotic area was not observed in CTX-treated muscles, although marimastat treatment resulted in a higher amount of fibrosis and laminin (data not shown in Figures). There were no differences observed in the expression of CD31 and dystrophin and IgG levels (data not shown in Figures). Overall, these data confirm that the long-term use of marimastat can detrimentally affect muscle regeneration, leading to smaller fibres and fibrosis. Example 4: Treatment with varespladib, marimastat and nilotinib tackles fibrosis and promotes perfect muscle regeneration following venom-induced damage (invention) The ability of varespladib, marimastat and nilotinib to promote regeneration and control fibrosis in Russell’s viper venom-damaged muscle was analysed. Figure 4A-C shows the results of this study into the impact of nilotinib, and combination therapies comprising nilotinib, on the promotion of muscle regeneration and the control of fibrosis. The p values (*p<0.1, **p<0.01, ***p<0.001 and ****p<0.0001) shown are as calculated using one-way ANOVA followed by Dunnett’s post-hoc test. Asterisks (*) represent the comparison of all bars with the venom-alone group and hashes (#) denote the comparison of combination therapy with nilotinib alone or nilotinib + varespladib groups. As shown by Figure 4A, nilotinib alone did not offer any protective effects in TA muscle in mice that were treated with venom, as there was no muscle weight loss. However, the combination of nilotinib and varespladib, and the combination also including marimastat each significantly reduced the amount of muscle weight loss. *represents the comparison of all bars with DR. # represents the comparison of nilotinib alone with the full combination therapy. To develop a substantial level of fibrosis to study the impact of nilotinib under in vivo settings, the dose of venom was increased to 17.5 pg / 20 g mouse, which indeed resulted in extensive fibrosis. As shown in Figure 4B, the daily administration of nilotinib dramatically reduced venom-induced fibrosis by day 14 compared to the venom-alone group (DR) as determined by picrosirius red staining. *represents the comparison of all bars with DR. #when comparing nilotinib alone with the full combination therapy. Furthermore, a combination of varespladib and nilotinib showed better anti-fibrotic effects. Despite positive outcomes, fibrosis and necrotic areas were still observed in this combination treatment involving varespladib and nilotinib. However, a combination of varespladib (daily), nilotinib (daily) and marimastat (only for the first three days after venom administration) completely prevented the fibrosis following venom-induced damage, and the muscle looked very similar to the undamaged control muscles. The remaining picrosirius red positive area shown in combination therapy is the same as in the undamaged muscle, confirming there is no fibrosis. Further H&E staining of muscle sections was performed to determine the percentage of damaged tissue area. Figure 4C of the accompanying drawings shows the results of this study. The analysis revealed a large amount of damage with infiltration of leukocytes and very few regenerating fibres in venom-treated muscles. However, the combination of three drugs (including nilotinib) substantially reduced such effects and fully promoted regeneration of the muscle tissue. The combination therapy provides much better results than nilotinib alone or nilotinib with varespladib. Figure 5 of the accompanying drawings shows the effects of nilotinib; nilotinib and varespladib; and varespladib, nilotinib and marimastat on laminin (Figure 5A) and dystrophin (Figure 5B) levels in envenomated muscle tissue, compared to venom-alone group. *represents the comparison of all bars with DR. # represents the comparison of nilotinib alone and nilotinib + varespladib with full combination therapy. Higher levels of laminin and dystrophin were detected in muscles when treated with either nilotinib alone or the combinations. Levels of dystrophin were particularly enhanced by the combination of nilotinib and varespladib, and particularly significant increases in the levels of dystrophin were observed following treatment with the combination of varespladib, nilotinib and marimastat. Figure 6 of the accompanying drawings shows the effects of nilotinib; nilotinib and varespladib; and varespladib, nilotinib and marimastat on markers of cellular and tissue repair, compared to venom-alone group. *represents the comparison of all bars with DR. Specifically, the level of immunoglobulin G (IgG) infiltration was substantially decreased by nilotinib alone; the combination of nilotinib with varespladib provided a further decrease; and a complete decrease was attained with the combinational therapy also including marimastat (Figure 6A). Furthermore, the level of cluster of differentiation 31 (CD31, also known as platelet endothelial cell adhesion molecule 1) was also reduced by each of nilotinib alone, the combination of nilotinib with varespladib, and the combinational therapy also including marimastat (Figure 6B). In addition, the level of fibro / adipogenic progenitor (FAP) marker, platelet-derived growth factor receptor a (PDGFRa) was significantly reduced by each of nilotinib alone, the combination of nilotinib with varespladib, and the combinational therapy also including marimastat (Figure 6C). These data suggest that a treatment regimen comprising nilotinib can significantly prevent and treat Russell’s viper venom-induced muscle damage and fibrosis. Further enhanced effects have been observed in relation to the combination of nilotinib and varespladib; and yet further enhanced effects were observed for the combination of varespladib, nilotinib and marimastat. Surprisingly, following the administration of the combination therapy including varespladib, nilotinib and marimastat, fibrosis was completely reversed and muscle tissue appeared completely healthy.

Claims

1. A tyrosine kinase inhibitor for use in a method of prevention, treatment, inhibition, delay and / or amelioration of the effects of envenomation in a subject, and 5 wherein the method further comprises administering:(a) a phospholipase A2 (PLA2) inhibitor, and / or(b) a matrix metalloprotease inhibitor.

2. The tyrosine kinase inhibitor for use of claim 1, wherein the tyrosine kinase 10 inhibitor is selected from the list consisting of Acalabrutinib, Adavosertib, Afatinib, Alectinib, Anlotinib, Apatinib, Aumolertinib, Avapritinib, Axitinib, Bosutinib, Cabozantinib, Canertinib, cetuximab, Crenolanib, Dacomitinib, Damnacanthal, Dasatinib, Entospletinib, Entrectinib, Erlotinib, Foretinib, Fostamatinib, Fruquintinib, Futibatinib, Gefitinib, Gilteritinib, Glesatinib, HS-10365, Ibrutinib, Icotinib, Idelalisib, 15 IDRX-42, Imatinib, Infigratinib, Ivosidenib, Lapatinib, Larotrectinib, Lazertinib, Lenvatinib, Linifanib, Lorlatinib, Masitinib, Midostaurin, Mirdametinib, Mobocertinib, Motesanib, Mubritinib, Nemtabrutinib, Nilotinib, Neratinib, Netarsudil, Nimotuzumab, Nintedanib, Olverembatinib, panitumumab, Pazopanib, Pirtobrutinib, Ponatinib, Radotinib, Regorafenib, Remibrutinib, Repotrectinib, Ropsacitinib, Savolitinib, 20 Selpercatinib, Sorafenib, Sitravatinib, Sunitinib, Sunvozertinib, Tesevatinib, Tolebrutinib, Vatalanib, vandetanib and Zasocitinib.

3. The tyrosine kinase inhibitor for use of claim 2, wherein the tyrosine kinase inhibitor is nilotinib.

254. The tyrosine kinase inhibitor for use of any preceding claim, wherein option (a) of claim 1 applies, and wherein the PLA2 inhibitor is selected from the list consisting of varespladib, methyl varespladib, darapladib, manoalide, U-73122, Quinacrine, Quercetin, Chlorpromazine, Aristolochic Acid, Cinnamycin, MJ33, ETYA, N-(p-30 Amylcinnamoyl) anthranilic acid, ML349 and arachidonyl trifluoromethyl ketone.

5. The tyrosine kinase inhibitor for use of claim 4, wherein the PLA2 inhibitor is selected from the list consisting of varespladib, methyl varespladib, and darapladib.10 09 256. The tyrosine kinase inhibitor for use of claim 5, wherein the PLA2 inhibitor is varespladib.

7. The tyrosine kinase inhibitor for use of any preceding claim, wherein option (b) 5 of claim 1 applies, and wherein the matrix metalloprotease inhibitor is selected from the list consisting of marimastat, batimastat (BB-94), prinomastat (AG3340), tanomastat (BAY 12-9566), CGS-27023 (CAS 169799-04-6), ilomastat, doxycycline hyclate, TAPI-1 (CAS 163847-77-6), actinonin, NNGH (CAS 161314-17-6), tissue inhibitors of metalloproteinases, squalamine, genistein, nobiletin, myricetin, curcumin, 10 xanthorhizzol, theaflavin, resveratrol, actinonin, matlystatin B, nicotinamide, betulinic acid, glycyrrhetinic acid, catechin, bryostatins, and tetracyclines.

8. The tyrosine kinase inhibitor for use of claim 7, wherein the matrix metalloprotease inhibitor is marimastat or prinomastat.

159. The tyrosine kinase inhibitor for use of claim 8, wherein the matrix metalloprotease inhibitor is marimastat.

10. The tyrosine kinase inhibitor for use of any preceding claim, wherein option (b) 20 of claim 1 applies, and wherein the matrix metalloprotease inhibitor is administered for a duration of from 2 to 7 days.

11. The tyrosine kinase inhibitor for use of any preceding claim, wherein the venom was snake venom.2512. The tyrosine kinase inhibitor for use of claim 11, wherein the snake is of the Viperidae family.

13. The tyrosine kinase inhibitor for use of any preceding claim, wherein the method30 further comprises administering an antivenom.

14. A PLA2 inhibitor for use in a method of prevention, treatment, inhibition, delay and / or amelioration of the effects of envenomation in a subject, wherein the method comprises administering a tyrosine kinase inhibitor.3515. The PLA2 inhibitor for use of claim 14, wherein the method further comprises administering a matrix metalloprotease inhibitor.

16. A matrix metalloprotease inhibitor for use in a method of prevention, treatment, 5 inhibition, delay and / or amelioration of the effects of envenomation in a subject, wherein the method comprises administering a tyrosine kinase inhibitor.

17. The matrix metalloprotease inhibitor for use of claim 16, wherein the method further comprises administering a PLA2 inhibitor.1010 09 25IntellectualPropertyOfficeApplication GB2505478.4Search report under Section 17 of the Patents Act 1977Date search completed: 11 July 2025Claims searched: 1-25International classificationSubclass and subgroup Valid from A61K31 / 164 01 / 01 / 2006 A61K31 / 405 01 / 01 / 2006 A61K31 / 506 01 / 01 / 2006 A61P39 / 02 01 / 01 / 2006Field of searchWorldwide search of patent documents classified in the following areas of the IPC:A61KDatabases used in the preparation of this search report:SEARCH-NPL; SEARCH-PATENTDocuments considered to be relevantPatent literatureCategory Relevant Document of relevanceclaimsX 18, 25 CN 118416071 A (AFFILIATED TONGJI HOSPITAL OF TONGJI MEDICAL COLLEGE OF HUAZHONG UNIV SCI &TECH), Paragraph 47, claim 1Non-patent literatureCategory Relevant claims Document of relevance X 1-3, 15-17, 21,24 Toxicon, 55, 01 / 02 / 2010, N. G. Nascimento et al., "Contribution of mast cells to the oedema induced by Bothrops moojeni snake venom and a pharmacological assessment of the inflammatory mediators involved”, 343-352, https: / / doi.org / 10.1016 / j.toxicon.2009.08.009, Abstract, section 3.2, section 4 page 347 X 1-3, 17, 21, 24 Inflammation, 45, 2, 01 / 04 / 2022, N. Zerakra-Chabane et al., “Mast Cells Modulate the Immune Response and Redox Status of the Gastrointestinal Tract in Induced Venom Pathogenesis”, 509-527, https: / / 10.1007 / s10753-021-01562-4, Column 2 page 523 - column 1 page 524 X 18, 25 Nutrition Research, 78, 19 / 05 / 2020, A. R. Saxena et al., “Lower concentrations of curcumin inhibit Her2-Akt pathway components in human breast cancer cells, and other dietary botanicals potentiate this and lapatinib inhibition”, 93-104, https: / / doi.org / 10.1016Zj.nutres.2020.05.007, Section 2.1,3.7 X 18, 25 Indian Journal of Clinical Biochemistry, 40, 01 / 01 / 2025, H. Effat et al., “The Combined Impact of Curcumin: Piperine and Sorafenib on microRNAs and Different Pathways in Breast Cancer Cells.”, 32-45, https: / / doi.org / 10.1007 / s12291-024-01212-0, page 35 column 2 X 1-3, 17, 21, 24 Journal of Neurophysiology, 85, 3, 01 / 03 / 2001, G. M. de Plater et al., “Venom from the platypus, Ornithorhynchus anatinus, induces a calcium-dependent current in cultured dorsal root ganglion cells”, 1340-1345, https: / / doi.org / 10.1152 / jn.2001.85.3.1340,, page 1342 column 2, page 1343 column 1-2Categories Letter or symbol Description X Document indicating lack of novelty or inventive step. Y Document indicating lack of inventive step, if combined with another document of the same category. & Member of the same patent family. A Document indicating technological background. P Document published on or after the priority date but before the fling date of the present application. E Earlier application published on or after the filing date of the present application.

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