Combination preparation comprising varespladib and a dimercapto chelating agent for treatment and / or prophylaxis of snakebites

Abstract

The invention relates to a combination preparation for use in a method of treatment and / or prophylaxis of snakebites, wherein the combination preparation comprises one or more compositions that contain varespladib, methylvarespladib, hydroxy-varespladib, hydroxy-methylvarespladib, methoxy-varespladib, methoxy-methylvarespladib and / or corresponding salts, esters, amides or solvates, and a dimercapto chelating agent. The ingredients of the combination preparation are advantageously mutually complementary for effective combating or prophylaxis of snakebites and at the same time keep the level of side effects low.

Description

[0001] Combination drug comprising varespladib and a dimercapto-chelating agent for the treatment and / or prophylaxis of snakebites

[0002] The invention relates to a combination preparation for use in a method for the treatment and / or prophylaxis of snakebites.

[0003] Snakebites pose a frequently underestimated threat to the health of humans and animals. It is estimated that approximately 5 million individuals are affected by snakebites each year. The death rate is around 138,000 annually, and the number of people suffering serious health consequences is estimated at between 400,000 and 500,000. Sub-Saharan Africa and South Asia are particularly affected. This is due not only to the increased prevalence of venomous snakes but also to the fact that the majority of people in these regions work in agriculture and are therefore more exposed to the risk of snakebites. Furthermore, the remoteness of the affected regions makes medical care difficult. It is estimated that approximately 75% of all deaths attributable to snakebites are due to delayed medical treatment.

[0004] Snakebites pose a danger not only in tropical regions but also in Europe. Particularly in the Alps, but also in the Pyrenees, various parts of France and Italy, the Balkans, and Greece, several viper species are found, such as the asp viper (Vipera aspis), the common European adder (Vipera berus), and the European horned viper (Vipera ammodytes). While the snakes usually flee from humans and only bite when they feel directly threatened, animals, especially dogs, are at high risk in these regions. This is due to the behavior of dogs. They explore their surroundings close to the ground with their noses and paws, which increases the likelihood of encountering snakes hidden in the grass, bushes, or under stones. In such cases, the dog may attack the snake, which then defends itself with a bite.Furthermore, many dogs have a strong play instinct and mistakenly see the snake as a toy.

[0005] Snake venoms (venoms) can have different modes of action. In particular, a distinction is made between neurotoxic venoms, hemotoxic venoms, and cytotoxic venoms.

[0006] Neurotoxic venoms affect the nervous system by blocking signal transmission between nerve cells. Most often, the venoms interact with the acetylcholine receptors of nerve cells, thus preventing the transmission of nerve impulses. The lack of signals to the muscles leads to paralysis and can, for example, cause respiratory arrest or cardiac arrest. Examples of snakes with neurotoxic venoms include the cobra and various sea snakes.

[0007] Hemotoxic venomas impair blood circulation by inhibiting blood coagulation. This occurs through an effect on the coagulation factor fibrinogen. These venomas can also have a hemorrhagic effect and damage blood vessels. This damage is mediated by metalloproteases or serine proteases. Thrombin-like enzymes (TLEs) can mimic thrombin activity, converting fibrinogen to fibrin and thus inducing coagulation. Fibrinolytic enzymes break down fibrin clots. Kallikrein-like enzymes activate kallikrein, leading to the production of bradykinin, which increases vascular permeability and induces pain.

[0008] Hemotoxic venomas often lead to internal bleeding. They can also damage tissue and cause necrosis around the bite site. Pit vipers, rattlesnakes, copperheads, and water moccasins, among others, produce hemotoxic venomas.

[0009] Cytotoxic venoms attack tissue and cells at the bite site, which can lead to necrosis. They can attack cell membranes, resulting in cell lysis and apoptosis.

[0010] Many venomous snakes produce venoms that fall into several of the aforementioned categories and consequently cause a wide range of symptoms. This complicates treatment. The European viper species mentioned are among these snakes.

[0011] WO 2016 / 081826 A2 describes the use of varespladib and methylvarespladib for the treatment of snakebites. These are 1H-indole-3-glyoxylamides that act as inhibitors of phospholipase A2, specifically secretory phospholipase A2 (SPLA2). Vipers can release phospholipase A2 from their venom glands. Phospholipase A2 (phosphatidylcholine-2-acylhydrase) is an enzyme that hydrolytically cleaves phospholipids. Since the lipid bilayer of a cell membrane is composed, among other things, of phospholipids, their cleavage leads to the destruction of the cell membrane and thus ultimately to cell destruction and inflammation. Phospholipase A2 is also responsible for the distribution of snake venom throughout the body. Varespladib and related compounds inhibit the action of phospholipase A2 and are therefore particularly effective against cytotoxic venomas.Methylvarespladib is an orally available prodrug of varespladib, which undergoes ester hydrolysis upon entering the gastrointestinal tract, forming the actually active varespladib.

[0012] The chemical structures of varespladib (2-[[3-(2-Amino-2-oxoacetyl)-2-ethyl- 1 -(phenylmethyl)-1 H-indol-4-yl]oxy]-acetic acid, C21H20N2O5) and methylvarespladib (methyl-2-[[3-(2-amino-2-oxoacetyl)-2-ethyl-1 -(phenylmethyl- 1 H-indol-4-yl]oxy]acetate, C22H22N2O5) are shown below:

[0013]

[0014] Varespladib Methylvarespladib

[0015] In principle, the use of varespladib or methylvarespladib against snakebites is effective; however, according to WO 2016 / 081826 A2, relatively high doses of up to 500 mg per kg body weight per day must sometimes be administered. In this context, it should be noted that phospholipases also occur naturally in various tissues and in blood plasma.

[0016] In particular, they act as digestive enzymes for the breakdown of glycerophospholipids. The use of varespladib can therefore impair enzymatic processes in the body. Even though side effects must be accepted when treating potentially life-threatening snakebites, it would be desirable to be able to reduce the dosage. This could also allow its use as a prophylactic.

[0017] The objective is therefore to provide compositions for the treatment or prophylaxis of snakebites that have fewer side effects or allow the administration of varespladib at a lower dose. This objective is achieved according to the invention by a combination preparation for use in a method for the treatment and / or prophylaxis of snakebites, wherein the combination preparation comprises one or more compositions which

[0018] - Varespladib, Methylvarespladib, Hydroxy-Varespladib, Hydroxy-Methylvarespladib, Methoxy-Varespladib, Methoxy-Methylvarespladib and / or corresponding salts, esters, amides or solvates and

[0019] - contain a dimercapto chelating agent.

[0020] The dimercapto chelating agent is advantageously dimercaprol, dimercaptopropanesulfonic acid, dimercaptosuccinic acid, and / or corresponding salts, esters, amides, or solvates. A single dimercapto chelating agent or a combination of two or more dimercapto chelating agents can be used.

[0021] It has surprisingly been found that a combination preparation of varespladib or methylvarespladib and dimercaprol is particularly advantageous. Dimercaprol, or 2,3-dimercapto-1-propanol (C3H8OS2), has the structural formula shown below:

[0022] Dimercaprol was originally developed as an antidote for the chemical warfare agent lewisite, hence the name British Anti-Lewisite (BAL). Its action is based on its ability to form chelate complexes with heavy metal ions. Accordingly, it is also known as an antidote for mercury, arsenic, or lead poisoning. As an antidote for snake venom, the effect of the dimercapto chelating agent is due to the fact that some components of snake venom require metal ions such as calcium or zinc to exert their toxic effects. This applies particularly to hemotoxic venoms that affect the coagulation cascade. This can involve both procoagulant and anticoagulant effects. One advantage of dimercapto chelating agents is that their effect is not limited to a single snake venom but is broadly effective against snake venoms that rely on metal ions.Especially in combination with (methyl)varespladib, the combination preparation according to the invention allows for the treatment of snake venom across a wide range, regardless of the exact species of snake. This is of particular importance because victims of a snakebite are often unaware of the specific snake involved, as most people have only limited knowledge of snakes. Furthermore, the snake usually disappears after the bite. Identifying the snake venom is time-consuming, which hinders rapid treatment, yet such treatment is essential for a successful outcome.

[0023] Instead of or in combination with dimercaprol, dimercaptopropanesulfonic acid (DMPS) and / or dimercaptosuccinic acid (DMSA) can also be used. Like dimercaprol, these compounds are complexing agents whose effect is due to two thiol groups; the advantages of using dimercaprol described above therefore apply essentially analogously to dimercaptopropanesulfonic acid (C3H8O3S3) and dimercaptosuccinic acid (C4H6O4S2). DMPS and DMSA are generally better tolerated than dimercaprol itself. Furthermore, DMPS and DMSA are more water-soluble than dimercaprol, which is why these compounds are also easier to administer orally. The structures of dimercaptopropanesulfonic acid and dimercaptosuccinic acid are shown below:

[0024] Dimercaptopropanesulfonic acid Dimercaptosuccinic acid

[0025] The compounds can also exist in the form of the corresponding salts, esters, amides, or solvates. DMPS, for example, can be used in the form of the corresponding sodium salt, which is also known as unithiol. Dimercaptopropanesulfonic acid is usually 2,3-dimercapto-1-propanesulfonic acid, and dimercaptosuccinic acid is 2,3-dimercaptosuccinic acid. Wherever this application refers to dimercaprol, DMPS, or DMSA, this also includes the corresponding salts, esters, amides, and solvates.

[0026] The combination of varespladib or methylvarespladib on the one hand and a dimercapto chelating agent on the other for the treatment of snakebites offers the possibility of combating different aspects of snake venoms simultaneously, thereby increasing the overall effectiveness of the antivenom. This synergistic effect also allows for a low dosage of each individual component. On the one hand, (methyl)varespladib inhibits phospholipase A2, thus protecting cells from cell membrane damage and associated inflammatory processes. On the other hand, the dimercapto chelating agent chelates metal ions, which are essential cofactors for some snake venoms, and prevents disruption of the coagulation cascade.Due to the fact that different mechanisms of snake venom are targeted, the combination preparation according to the invention has a broad spectrum of application for various snake venoms. The synergistic effect increases effectiveness, while keeping the dosage of the individual components low reduces side effects of the active ingredients. Dimercaprol and dimercaptopropanesulfonic acid can exist in any chirality, as the (R)- or (S)-isomer, as a racemate, or as a mixture of the two enantiomers in any ratio. Dimercaptosuccinic acid has two chiral centers, so it can exist as the (2R,3R)-, (2S,3S)-isomer, and in the meso-form. In principle, the aforementioned enantiomers and diastereomers can exist in any ratio; however, meso-dimercaptosuccinic acid is preferred as a complexing agent.

[0027] In addition to or instead of the dimercapto chelating agent, other compounds exhibiting an inhibitory effect on metalloproteinases may also be present in the combination preparation according to the invention. Inhibitors of matrix metalloproteinases are particularly relevant. These may include doxycycline, marimastat, batimastat, prinostat, deferoxamine, compounds from the tetracycline group, llomastat (galardin), TIMP-1 (tissue inhibitor of metalloproteinase), TIMP-2, TIMP-3 and / or TIMP-4, or corresponding salts, esters, amides, or solvates.

[0028] Instead of or in combination with varespladib or methylvarespladib, a corresponding compound can also be used in which the phenyl group of (methyl)varespladib bears an additional hydroxy or methoxy group. These compounds are subsequently referred to as hydroxy-varespladib, hydroxy-methylvarespladib, methoxy-varespladib, and methoxy-methylvarespladib. The structural formulas are shown below:

[0029]

[0030] R = OH or OCHs

[0031] The additional hydroxy or methoxy group can be located at any position on the phenyl ring, preferably at the 3- or 4-position, i.e., in the meta or para position. Accordingly, these are in particular 3-hydroxyvarespladib or 3-methoxyvarespladib, or 4-hydroxyvarespladib or 4-methoxyvarespladib, or the corresponding derivatives of methylvarespladib. Where varespladib or methylvarespladib is mentioned within the scope of this invention, the corresponding compounds having an additional hydroxy or methoxy group on the phenyl ring are also covered.

[0032] In addition to or instead of (methyl)varespladib or corresponding derivatives, other compounds may also be present in the combination preparation according to the invention which have an inhibitory effect on the phospholipases, in particular on the secretory phospholipase A2 (SPLA2). Examples include A-84543, lipoic acid, Aristocholia alkaloids, bromoenol lactone, boswellic acids and other extracts of Boswellia serrata, crotapotin, darapladib, elemolic acid, ellagic acid, flavonoids, extracts of Tragia involucrata, indomethacin and other NSAIDs (nonsteroidal anti-inflammatory drugs), manoalide, methylarachidonyl fluorophosphonate (MAFP), phosphoric acid mono[1-[(hexadecyloxy)methyl]-2-(2,2,2-trifluoroethoxy)ethyl]monomethyl ester (MJ33), neoflavonoids, flavonoids, quercetin, scalaradial and / or tetracycline or corresponding salts, esters, amides or solvates.

[0033] The combination preparation according to the invention can contain varespladib or methylvarespladib on the one hand and the dimercapto chelating agent on the other hand in a single composition. However, a combination preparation consisting of two or more compositions is also possible, one of which contains (methyl)varespladib and another of which contains the dimercapto chelating agent. The essential feature of the invention is that both active ingredients are intended for simultaneous or closely spaced administration.

[0034] According to a preferred embodiment, varespladib or methylvarespladib, or their derivatives, are present as an inclusion compound with cyclodextrin. Cyclodextrins are cyclic oligosaccharides consisting of α-1,4-glycosidically linked glucose units. They are characterized by an internal cavity in which they can enclose foreign molecules to form an inclusion compound. Since the internal cavity is hydrophobic and the outer surface is polar, nonpolar organic compounds can be introduced into an aqueous environment and dissolved there. This increases the bioavailability of (methyl)varespladib. Furthermore, the enclosed (methyl)varespladib is protected from reaction with other compounds. In particular, the bioavailability following oral administration is significantly improved.

[0035] The cyclodextrin used is generally an α-, β-, γ-, or β-cyclodextrin, wherein an α-cyclodextrin 6, a β-cyclodextrin 7, a γ-cyclodextrin 8, and an β-cyclodextrin 9 have glucose units. A β-cyclodextrin is particularly preferred with regard to the cavity size. According to the invention, cyclodextrins also include derivatives of cyclodextrin, i.e., cyclodextrins that bear additional residues or in which hydroxyl groups of the cyclodextrin are functionalized to other groups. Examples are sulfobutyl β-cyclodextrin, 2-hydroxypropyl β-cyclodextrin, or methyl β-cyclodextrin. Furthermore, the combination preparation according to the invention advantageously comprises, in addition to (methyl)varespladib as a phospholipase A2 inhibitor and a dimercapto chelating agent, a serine protease inhibitor. As already mentioned in the introduction, a number of snake venoms are based on the action of serine proteases.Accordingly, combining it with a serine protease inhibitor can further increase the effectiveness of the combination drug, especially since this attacks a third mechanism of action of snake venom.

[0036] The serine proteases used can include, among others, SVSP1 and / or SVSP2 inhibitors. Specifically, examples include aprotinin, phenylmethylsulfonyl fluoride, 4-(2-aminoethyl)benzenesulfonyl fluoride, leupeptin, antithrombin III, α1-antitrypsin, α2-macroglobulin, soybean trypsin inhibitor, Bowman-Birk inhibitor, gabexate, nafamostat, camostat, ulinastatin, ecotin, and / or hesperetin, or corresponding salts, esters, amides, or solvates.

[0037] The main aspect of the present invention is a combination preparation comprising, on the one hand, varespladib or a corresponding derivative of varespladib and, on the other hand, a dimercapto chelating agent. Alternatively, the invention also relates to a combination preparation comprising at least one of the phospholipase inhibitors mentioned herein, at least one of the metalloprotease inhibitors mentioned herein, and / or at least one of the serine protease inhibitors mentioned herein, wherein any inhibitors may be combined. A combination preparation comprising at least one phospholipase inhibitor, at least one metalloprotease inhibitor, and at least one serine protease inhibitor is particularly advantageous.

[0038] The combination preparation according to the invention is used in particular for the treatment or prophylaxis of bites from European vipers. These include, in particular, the common European adder (Vipera berus), the asp viper (Vipera aspis), and the European horned viper (Vipera ammodytes). These are found in various regions of Europe, including the Alps. The venoms of European vipers are characterized by a complex mixture of toxins with varying effects. The composition of the venoms can also vary within a species, depending, for example, on the region, as well as on the age and diet of the animal.

[0039] The venom of the asp viper contains components that disrupt the blood coagulation process, which can lead to uncontrolled (internal) bleeding. Furthermore, the venom also contains neurotoxins, although to a lesser extent than in other viper species. These neurotoxins can disrupt signal transmission between nerve cells, leading to muscle weakness, paralysis, and, in severe cases, even respiratory arrest. Finally, cytotoxins can damage cells and cause swelling, inflammation, pain, and necrosis. The venom of the common European adder exhibits fundamentally similar properties.

[0040] In addition to viper bites, other snake bites can also be treated, such as those from rattlesnakes. Examples include the western diamondback rattlesnake, also known as the Texas rattlesnake (Crotalus atrox), and the diamondback rattlesnake (Crotalus adamanteus). Rattlesnake venom attacks blood cells and destroys tissue at the bite site. By inhibiting the action of phospholipases and complexing metal ions, the consequences of a rattlesnake bite can be significantly reduced.

[0041] The combination preparation according to the invention is particularly advantageous for use in animals, especially dogs. The number of snakebites in humans in Europe is relatively low because the European vipers in question are mostly shy and retreat when humans approach. Furthermore, the amount of venom injected is, in most cases, such that a fatal outcome in humans is unlikely.

[0042] Dogs, however, are at considerable risk in the affected regions. Firstly, dogs almost always have a significantly lower body weight than humans, meaning the amount of venom injected per kilogram of body weight per bite is usually three to four times higher. A dog's faster metabolism also leads to a quicker spread of the venom throughout its body. Secondly, unlike humans, dogs walk on all fours, making it much easier for a snake to attack. In particular, a bite can strike a dog's face, which is especially dangerous because the bite can damage vital structures or cause swelling that obstructs the airways. Finally, a dog's natural hunting and play instincts mean that the likelihood of coming into contact with a snake is considerably higher than for a human.Nevertheless, the combination preparation according to the invention can of course also be used in humans, for example in children, who, due to their lower body weight and their playful nature, are also at greater risk than adults. In America, approximately 150,000 dogs are killed by snakes every year, especially by the western diamondback rattlesnake (Crotalus atrox), which is primarily found in the southwestern United States and in Mexico.

[0043] Preferably, the combination preparation is intended and formulated for oral administration. It is also possible to formulate one of the active ingredients for oral administration, while the other is administered via a different route, i.e., parenterally. In particular, intramuscular or intravenous administration by injection is suitable in this context. Oral administration is preferred due to its simplicity and ease of use, even for laypersons, especially with regard to administration to animals such as dogs. Accordingly, the combination preparation may be in the form of tablets, capsules, or liquid. The formulation should be such that the bioavailability of the active ingredients is maximized. Therefore, in addition to the actual active ingredients, the combination preparation typically contains further excipients.Oral administration also makes the prophylactic use of the combination preparation possible. For example, a dog can be given a sufficient amount as a prophylactic measure before a walk or hunting trip in a high-risk area. For oral administration, the application of varespladib or its derivatives as an inclusion compound with cyclodextrin, as described above, is particularly advantageous because the cyclodextrin significantly increases water solubility and thus bioavailability. The combination preparation according to the invention is a medical device in the sense that no pharmacological effect is achieved, since the active ingredients (methyl)varespladib and the dimercapto chelating agent are not metabolized. The inhibition of phospholipase A2 and the complexation of the metal ions occur via non-covalent bonds; no new covalent bonds are formed.Accordingly, the process is reversible and (methyl)varespladib and the dimercapto chelating agent are not converted into other substances.

[0044] Preferably, the active ingredients are dosed so that, when administered orally, a single dose per kg of body weight of the treated human or animal is required.

[0045] - 0.5 to 4 mg varespladib, methylvarespladib, hydroxy-varespladib, hydroxy-methylvarespladib, methoxy-varespladib, methoxy-methylvarespladib and / or a corresponding salt, ester, amide or solvate and

[0046] - contains 4 to 10 mg of a dimercapto chelating agent.

[0047] Single doses per kg of body weight are particularly preferred.

[0048] - 1 to 3 mg, preferably approx. 2 mg varespladib, methylvarespladib, hydroxy-varespladib, hydroxy-methylvarespladib, methoxy-varespladib, methoxy-methylvarespladib and / or a corresponding salt, ester, amide or solvate and

[0049] - 5 to 8 mg, preferably approx. 6.5 mg of a dimercapto chelating agent.

[0050] It has surprisingly been found that the combination of (methyl)varespladib and dimercapto chelating agents allows for correspondingly low concentrations in the formulations. The low dosage of the individual components also reduces the risk of side effects.

[0051] In a preferred application, varespladib, methylvarespladib, hydroxy-varespladib, hydroxy-methylvarespladib, methoxy-varespladib, methoxy-methylvarespladib, or a corresponding salt, ester, or amide is administered at intervals of 6 to 10, preferably approximately 8 hours, while the composition containing the dimercapto chelating agent is administered at intervals of 10 to 14, preferably approximately 12 hours. In this way, even an acute snakebite can be effectively treated. The aforementioned intervals have proven advantageous in ensuring effective treatment with minimal side effects.

[0052] The combination drug may contain pharmaceutically acceptable additional components. In this context, pharmaceutically acceptable means that the components are suitable for administration to humans or animals without exhibiting disproportionate side effects relative to the main effect.

[0053] The formulations may contain, for example, additional PLA2 inhibitors. Examples include N-acetylcysteine ​​or ochnaflavone. They may also contain other antivenoms that exert the same, similar, or different effects as varespladib or methylvarespladib and dimercaprol or DMPS or DMSA. For example, acetylcholinesterase inhibitors or mAChR antagonists (muscarinic acetylcholine receptor antagonists) may be used against neurotoxic venoms. Other optional components of the formulations include NMDA receptor antagonists, antibiotics, or substances that improve the distribution of the active ingredients in the body. Examples of the latter are lidocaine and bupivacaine.

[0054] The formulations can have a physiological pH of 7.4 to 8.5. Common buffers can be used in this context. For capsules or tablets, common components such as gelatin, talc, lactose, mannitol, starch, cellulose, glucose, sucrose, methylcellulose, and magnesium stearate can be used. Injectable formulations can be in the form of physiological saline solution.

Claims

Patent claims 1. Combination preparation for use in a procedure for the treatment and / or prophylaxis of snakebites, wherein the combination preparation comprises one or more compositions which - Varespladib, methylvarespladib, hydroxy-varespladib, hydroxy-methylvarespladib, methoxy-varespladib, methoxy-methylvarespladib and / or corresponding salts, esters, amides or solvates and - contain a dimercapto chelating agent.

2. Combination preparation for use according to claim 1, characterized in that the dimercapto chelating agent is selected from the group consisting of dimercaprol, dimercaptopropanesulfonic acid, dimercaptosuccinic acid and corresponding salts, esters, amides and solvates.

3. Combination preparation for use according to claim 1 or 2, characterized in that varespladib, methylvarespladib, hydroxy-varespladib, hydroxy-methylvarespladib, methoxy-varespladib, methoxy-methylvarespladib and / or the corresponding salt, ester or amide is present at least partially in the form of an inclusion compound with a cyclodextrin.

4. Combination preparation for use according to claim 3, characterized in that the cyclodextrin is an α-, β-, γ- or β-cyclodextrin.

5. Combination preparation for use according to one of claims 1 to 4, characterized in that the combination preparation comprises a further metalloprotease inhibitor, in particular a matrix metalloprotease inhibitor.

6. Combination preparation for use according to claim 5, characterized in that the metalloproteinase inhibitor is selected from the group consisting of: doxycycline, marimastat, batimastat, prinomastat, deferoxamine, compounds from the group of tetracyclines, llomastat (galardin), TIMP-1 (tissue inhibitor of metalloproteinase), TIMP-2, TIMP-3, TIMP-4 and / or corresponding salts, esters, amides or solvates.

7. Combination preparation for use according to any one of claims 1 to 6, characterized in that the combination preparation comprises at least one serine protease inhibitor.

8. Combination preparation for use according to claim 7, characterized in that the serine protease inhibitor is selected from the group consisting of: aprotinin, phenylmethylsulfonyl fluoride, 4-(2- Aminoethyl)benzenesulfonyl fluoride, leupeptin, antithrombin III, α1-antitrypsin, α2-macroglobulin, soybean trypsin inhibitor, Bowman-Birk inhibitor, gabexate, nafamostat, camostat, ulinastatin, ecotin, hesperetin and / or corresponding salts, esters, amides or solvates.

9. Combination preparation for use according to any one of claims 1 to 8, characterized in that the combination preparation comprises a further phospholipase inhibitor.

10. Combination preparation for use according to claim 9, characterized in that the phospholipase inhibitor is selected from the group consisting of: A-84543, lipoic acid, aristocholia alkaloids, bromoenol lactone, Boswellic acids and other extracts of Boswellia serrata, crotapotin, darapladib, elemolic acid, ellagic acid, flavonoids, extracts of Tragia involucrata, indomethacin and other NSAIDs (nonsteroidal anti-inflammatory drugs), manoalide, methylarachidonyl fluorophosphonate (MAFP), phosphoric acid mono[1- [(hexadecyloxy)methyl]-2-(2,2,2-trifluoroethoxy)ethyl]monomethyl ester (MJ33), neoflavonoids, flavonoids, quercetin, scalaradial, tetracycline and / or corresponding salts, esters, amides or solvates.

11. Combination preparation for use according to one of claims 1 to 10, characterized in that the composition serves for the treatment and / or prophylaxis of bites of European vipers.

12. Combination preparation for use according to claim 11, characterized in that the viper is a common European adder, asp viper or European horned viper.

13. Combination preparation for use in animals according to any one of claims 1 to 12.

14. Combination preparation for use in dogs according to claim 13.

15. Combination preparation for use according to any one of claims 1 to 14, characterized in that the use is in the form of oral administration.

16. Combination preparation for use according to claim 15, characterized in that a single dose per kg body weight - 0.5 to 4 mg varespladib, methylvarespladib, hydroxy-varespladib, hydroxy-methylvarespladib, methoxy-varespladib, methoxy-methylvarespladib and / or a corresponding salt, ester, amide or solvate and - 4 to 10 mg of the dimercapto chelating agent exhibits.

17. Combination preparation for use according to claim 16, characterized in that a single dose per kg body weight - 1 to 3 mg, preferably approx. 2 mg varespladib, methylvarespladib, hydroxy-varespladib, hydroxy-methylvarespladib, methoxy-varespladib, methoxy-methylvarespladib and / or a corresponding salt, ester, amide or solvate and - contains 5 to 8 mg, preferably approximately 6.5 mg of the dimercapto chelating agent.

18. Combination preparation for use according to any one of claims 1 to 17, characterized in that - Varespladib, methylvarespladib, hydroxy-varespladib, hydroxy-methylvarespladib, methoxy-varespladib, methoxy-methylvarespladib and / or a corresponding salt, ester, amide or solvate at intervals of 6 to 10, preferably approximately 8 hours and - the dimercapto chelating agent is administered at intervals of 10 to 14, preferably approximately 12 hours.

19. Combination preparation for use according to any one of claims 1 to 17, characterized in that varespladib, methylvarespladib, hydroxy-varespladib, hydroxy-methylvarespladib, methoxy-varespladib, methoxy-methylvarespladib and / or a corresponding salt, ester, amide or solvate as well as the dimercapto chelating agent are present in a single composition.

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