MX2008002641A - Therapeutically activeî±-msh analogues - Google Patents

Abstract

The invention describes peptide analogues of a-melanocyte-stimulating hormone (a-MSH), which posses an increased efficay compared to the nativeα-MSH peptide. Theα-MSH analogues exhibit increased anti-inflammatory effects and increased capability to prevent ischemic conditions compared toα-MSH. The invention further discloses use of the peptides for the manufacture of pharmaceutical compositions for the treatment or prophylaxis of a condition in the tissue of one or more organs of a mammal, and moreover pharmaceutical compositions.

Description

ANALOGUES OF a-MSH THERAPEUTICALLY ACTIVE Field of the Invention The invention relates to peptide analogues of an α-melanocyte stimulating hormone (α-MSH), which possess an increased efficacy compared to the native α-MSH peptide. The a-MSH analogues exhibit increased anti-inflammatory effects and increased ability to treat or prevent damage to the whole body, organs or cells associated with ischemia or ischemia followed by vascular reperfusion compared to a-MSH.

BACKGROUND OF THE INVENTION The native peptide a-melanocyte stimulating hormone (a-MSH) is known as the native agonist for the melanocortin (MC) type 1, type 3, type 4 and type 5 receptor. MC receptors belong to the class of receptors coupled to the G protein. All the receptor subtypes are coupled to a G stimulator protein, which means that the stimulation of receptors involves the increased production of cAMP. ACTH is the native ligand for the type 2 receptor (MC2). A series of studies has been developed on MC receptors in a variety of tissues. It's known that the type 1 receptor (MCI), to which a-MSH binds with high affinity, is expressed in various tissues and cells such as the brain, including astrocytes, testes, ovaries, macrophages and neutrophils. However, it is likely that MCI is expressed in an even wider range of tissues although this remains to be established. The selectivity for MC receptors to bind to different MSH peptides varies. MCI binds with high affinity to a-MSH and with a lower affinity also to β-MSH, β-MSH and ACTH. It has been reported that MC2 binds only to ACTH, but to none of the MSH peptides. The highest affinity for the ligands of the other receptors include α-MSH (receptor-MC3) and β-MSH (receptor-MC4). In contrast, MC5 binds with much lower affinity to MSH peptides with the same pattern as MCI (ie the highest affinity for a-MSH). MSH peptides that act through the stimulation of MC receptors have a variety of functions including immunomodulation, anti-inflammation, regulation of body temperature, pain perception, aldosterone synthesis, blood pressure regulation , heart rate, vascular tone, blood flow to the brain, nerve growth, placental development, synthesis / release of a variety of hormones such as aldosterone, thyroxine, prolactin, FSH. ACTH has a greater effect on the stimulation of steroidogenesis. Also, a-MSH induces the formation of pigment in the skin. It is important to emphasize that a variety of actions of the MSH Peptides, especially a-MSH, are not completely established with respect to which receptors are involved. It has been speculated that the anti-inflammatory action of a-MSH involves a variety of processes that include interference with NO production, the action of endothelin-1, the formation of interleukin 10, which is again linked to the receptors MCI expressed in macrophages and monocytes. It has been shown that stimulation of MC receptors with a-MSH is important in a variety of inflammatory processes (Lipton and Catania 1997): 1) Inhibit the chemotactic migration of neutrophils (Catania 1996). 2) Analogs that include a-MSH inhibit the release of cytokines (IL-1, TNF-a) in response to treatment with LPS (Goninard 1996). 3) Inhibit TNF-a in response to a bacterial endotoxin (Wong, K.Y. et al., 1997). 4) The administration of ICV or IP of a-MSH inhibits the production of central TNF-α by locally administered LPS. 5) It has been shown that a-MSH reduces inflammation in experimental inflammatory bowel disease (Rajora, N. et al., 1997), Acute renal failure induced by ischemia (Star, R. A. et al., 1995). 6) a-MSH also has some protective effect by inhibiting the induction and acquisition of contact hypersensitivity and induces hapten tolerance and it is speculated that a-MSH can mediate the important negative regulation of cutaneous inflammation and hyperproliferative diseases of the skin (Luger, T.A. , 1997). To this end, a-MSH causes an increased release of IL-8 from dermal microvasculature endothelial cells (Hartmeyer, M., 1997). Both hypoxia (ischemia) and reperfusion injury are important factors in human pathophysiology. Examples of tissue hypoxia predisposing to injury during reperfusion include circulatory shock, myocardial ischemia, stroke, temporary renal ischemia, major surgery, and organ transplantation. Because diseases as a consequence of ischemia are extremely common causes of morbidity and mortality and because organ transplantation is becoming more frequent, treatment strategies with the potential to limit reperfusion injuries are very necessary in order to to improve public health. The fundamental pathophysiology of reperfusion injury from ischemia is complex and involves not only a classic inflammatory reperfusion response with neutrophil infiltration, but also the expression of cytokine genes that include tumor necrosis factor-a (TNF-a), interleukin (IL) -lß, IL-6, IL-8, interferon-? and intercellular adhesion molecule-1 (ICAM-1) within the tissue / organ with reperfusion. In addition, it has been suggested that locally produced TNF-α contributes to postischemic organ dysfunction as in the heart after infarction by direct depression of contractability and induction of apoptosis. Due to the complex nature of the ischemia and / or reperfusion injuries, the simple concepts of anti-inflammatory treatment have been shown to be inefficient: therefore, most experimental studies address the fact that the concomitant interaction with more than one of the pathways activated is necessary in order to protect against reperfusion injury. It has been shown that a-MSH has both anti-inflammatory, anti-oxidant and anti-apoptotic capabilities, which gives a good explanation for the effectiveness of this compound in order to protect against reperfusion injury. It is known that certain modifications of amino acid residues in the amino acid sequence of α-MSH result in increased affinity for receptors (for example the MC4 receptor), a prolonged biological activity or a binding profile of the polypeptide plus specific for receptors (Schióth et al. 1998, Hruby et al. 1995, Sawyer et al. 1980, Hiltz et al. 1991, Scardenings et al. 2000). However, when aspiring towards the generation of peptide drugs, these peptides still have problems with a low stability towards enzymatic degradation. As stated above, the problem in the development of therapeutically active peptide drugs is that the peptides are degraded rapidly and very effectively by enzymes, generally with half-lives in the range of minutes. Proteases and other proteolytic enzymes are ubiquitous, particularly in the gastrointestinal tract, and therefore peptides are usually susceptible to degradation, at multiple sites with oral administration and to some extent in the blood, liver, kidney and vascular endothelium. In addition, a given peptide is usually susceptible to degradation at more than one junction within the main structure; Each hydrolysis site is mediated by a certain protease. Even if these obstacles are overcome, for neuropeptides in particular, it has been difficult to transport them through the blood-brain barrier. In order to increase the metabolic stability of peptides, a technology called SIP (Structured Induced Probe) has been developed by Larsen and collaborators 1999 (WO 99/46283). The SIP technology is based on the use of inducing probes of structures, which are represented by short sequences of peptides, that is (Lys) 6 added to the C terminal or the N terminal or to both C and N terminations of the precursor peptide . The structural inducing probe limits the precursor peptide in a more ordered conformation based on intramolecular hydrogen bonds, whereby the peptide chimera (peptide linked to the probe) is less susceptible to proteases in contrast to peptides in the configuration of random spiral. As a result of the structuring, the peptide chimera is much more difficult to degrade by a protease. The addition of a SIP to a biologically active peptide generally results in an increase in the enzymatic stability of the peptide while the biological activity is maintained at the same time (Rizzi et al. 2002).

Brief Description of the Invention The present invention has surprisingly shown that SIP modification of a-MSH and a-MSH analogs at the N-terminus of the peptides increases the maximum efficiency of the peptides compared to the native peptide at -MSH. The peptides of the invention exhibit increased anti-inflammatory effects and increased capacity to prevent ischemic conditions compared to native a-MSH. Thus, the present invention relates to "specific peptides comprising a modification with SIP in the N-terminal part of the peptide and an amino acid sequence of a-MSH or a variant of a-MSH in the C-terminal part of the In a first aspect, the invention provides a peptide totaling from 12 to 19 amino acid residues comprising the amino acid sequence: X-Aa? -Aa2-Aa3-Aa4-Aa5-Y-Aa6-Aa7-Z wherein X comprises six amino acid residues R1-R2-R3-R4-R5-R6, wherein R1, R2, R3, R4, R5 and R6 can independently be Lys or Glu and wherein Y comprises an amino acid sequence selected from His-Phe-Arg, His- (D-Phe) -Arg, His-Nal-Arg and His- (D-Nal) -Arg and wherein Z comprises an amino acid sequence selected from Lys-Pro-Val and Lys-Pro- (D-Val), and wherein ai, Aa2, Aa3, Aa4, Aa5, Aa6 and Aa7 can independently be any natural or unnatural amino acid residue or they may be absent and wherein the carboxy terminus of the peptide is -C (= 0) -B1, wherein Bl is selected from OH, NH2, NHB2, N (B2 ) (B3), OB2 and B2, where B2 and B3 are independently selected from C 1-6 optionally substituted alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 6 to C aryl, optionally substituted 7 to 16 carbon aralkyl and alkylaryl of 7 to 16 atoms carbon optionally substituted; and wherein the amino terminus of the peptide is (B4) HN-, (B4) (B5) N- or (B6) HN-, wherein B4 and B5 are independently selected from H, alkyl of 1 to 6 carbon atoms optionally substituted, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 6 -C 10 aryl, optionally substituted 7 to 16 carbon aralkyl and optionally substituted C 7 -C 16 alkylaryl; B6 is B4-C (= 0) -. The invention also relates to the use of peptides for the manufacture of pharmaceutical compositions for the treatment or prophylaxis of a condition in the tissue of one or more organs of a mammal. In addition, the present invention relates to a composition,. for example a pharmaceutical composition, comprising one or more peptides according to the invention and a pharmaceutically acceptable carrier, to peptides according to the invention for use in medicine and to methods for treating a condition in the tissue of one or more organs from a mammal comprising administering an effective dose of a peptide according to the invention. Specifically, the invention is directed to a method for treating conditions caused by ischemia, inflammation and / or toxic effects of poisoning or drug treatment.

Description of the Invention The present invention relates to therapeutically active peptides having the effects of improving or preventing organ dysfunction induced by ischemia, inflammation and / or toxic effects of poisoning or drug treatment. As defined herein, a peptide sequence is "therapeutically active" if it can be used for the treatment, remission or attenuation of a disease state, physiological condition, symptoms or etiological indication (s) or evaluation or diagnosis thereof . A peptide sequence is "prophylactically active" if it can be used to prevent a disease state, physiological condition, symptoms or etiological indications. A pharmacologically active agent is also physiologically and / or biologically active. The pharmacological activity measures the effect of a substance (peptide) on physiological and / or biological systems in vitro, in vivo or ex vivo and can be tested using standard in vitro, in vivo or ex vivo assays known in the art for a particular peptide or a peptide with a similar physiological function.

The peptides of the invention The present invention relates to peptides comprising the amino acid sequence of a-MSH or a variant of a-MSH in the C-terminal part of the peptide and a structural inducing probe (SIP) in the N-part peptide terminal. The peptides of the invention are referred to as α-MSH analogues. In the present specification and the claims, these terms are used as synonyms. The variant of a-MSH is defined as an amino acid sequence that is modified in comparison to the a-MSH of natural origin (Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys- Pro-Val, SEQ ID NO: 101) by having at least one deletion, substitution, addition or modification of amino acid residues within the sequence. The a-MSH variant preferably has the structure: Aa! -Aa2-Aa3-Aa4-Aa5-Y- Aa6-Aa7-Z, wherein Y comprises an amino acid sequence selected from His-Phe-Arg, His- (D -Phe) -Arg, His-Nal-Arg and His- (D-Nal) -Arg and wherein Z comprises an amino acid sequence selected from Lys-Pro-Val and Lys-Pro- (D-Val), and in where i, Aa2, Aa3, Aa4, Aa5, Aa6 and Aa7 can be independently any natural or unnatural amino acid residue or may be absent. In the present context, the term "amino acid residue" means any amino acid residue of natural origin (natural amino acid residue) or amino acid residue that is not of natural origin (unnatural amino acid residue). A natural amino acid residue is defined as an amino acid residue that exists in nature, such as Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Lie, Leu, Lys, Met, Phe, Pro, Ser, Tyr, Thr, Trp, Val. Examples of preferred natural amino acid residues with respect to the structure of the variant of a-MSH are Ser, Tyr, Met, Glu, Lie, Trp and Gly. An unnatural amino acid residue is defined as an amino acid residue that does not exist in nature, but is created experimentally. The non-natural amino acid residues include amino acid residues a, β or β? synthetics (either in the L configuration or the D configuration) as well as amino acids modified in the side chain such as modified tyrosines wherein the aromatic ring is further substituted with for example one or more halogen atoms, sulfone groups, nitro groups, etcetera and / or the phenol group becomes an ester group, etcetera, including amino acids protected in the side chain, wherein the side chains of amino acids are protected according to methods known to the person skilled in peptide chemistry, as described in for example Bodanszky et al. 1994 and J. Jones and Jones 1991 Examples of preferred non-natural amino acid residues are Norleucine (Nle), Nal (beta-2-naphthyl-alanine), D-Nal (beta-2-naphthyl-d-alanine), D-phenylalanine (D-Phe). and D-valine (D-Val). In the broadest aspect, the present invention relates to a peptide totaling from 12 to 19 amino acid residues comprising the amino acid sequence: X-Aa? -Aa2-Aa3-Aa4-Aa5-Y-Aa6-Aa7 -Z wherein X comprises six amino acid residues R1-R2-R3-R4-R5-R6, wherein R1, R2, R3, R4, R5 and R6 can independently be Lys or Glu and wherein Y comprises an amino acid sequence selected from His-Phe-Arg, His- (D-Phe) -Arg, His-Nal-Arg and His- (D-Nal) -Arg and wherein Z comprises an amino acid sequence selected from Lys-Pro-Val and Lys-Pro- (D-Val) and wherein Aai, Aa2, Aa3, Aa4, Aa5, Aa6 and Aa7 can independently be any natural or unnatural amino acid residue or they can be absent and wherein the carboxy terminus of the peptide is -C (= 0) -B1, wherein Bl is selected from OH, NH2, NHB2, N (B2) (B3), 0B2 and B2, wherein B2 and B3 are independently selected from C 1-6 optionally substituted alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 6 to C aryl, optionally substituted aralkyl of 7 to 16 carbon atoms and alkylaryl of 7 to 16 atoms carbon optionally substituted; and wherein the amino terminus of the peptide is (B4) HN-, (B4) (B5) N- or (B6) HN-, wherein B4 and B5 are independently selected from H, alkyl of 1 to 6 carbon atoms optionally substituted, optionally substituted C2-C6 alkenyl, optionally substituted C6-C10 aryl, optionally substituted aralkyl of 7 to 16 carbon atoms, and optionally substituted C7-6 alkylaryl; B6 is B4-C (= 0) -. In the context of the present invention, the term "optionally substituted" is intended to mean that the group in question can be substituted one or more times, such as 1 to 5 times, preferably 1 to 3 times, much more preferably one to two times, for one or more groups selected from alkyl of 1 to 8 carbon atoms, alkoxy of 1 to 18 atoms carbon, oxo (which can be represented in the tautomeric form of enol), carboxyl, amino, hydroxy (which when present in an enol system can be represented in the tautomeric form of keto), nitro, cyano, dihalogen -alkyl of 1 to 8 carbon atoms, trihalogen-alkyl of 1 to 8 carbon atoms, halogen. In general, the above substituents may be susceptible to additional optional substitution. In the present context, the term "alkyl of 1 to 6 carbon atoms" is intended to refer to a straight or branched saturated hydrocarbon chain wherein the longer chains have from one to six carbon atoms, such as methyl, ethyl , n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tere-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl and octyl. A branched hydrocarbon chain is proposed to refer to an alkyl group of 1 to 6 carbon atoms substituted at any carbon atom by a hydrocarbon chain. In the present context, the term "alkenyl of 2 to 6 carbon atoms" is intended to refer to a linear or branched hydrocarbon group having from two to six carbon atoms and containing one or more double bonds. Illustrative examples of alkenyl groups of 2 to 6 carbon atoms include allyl, homoalloy, vinyl, crotyl, butenyl, pentenyl and hexenyl. The examples Illustrative of alkenyl groups of 2 to 6 carbon atoms with more than one double bond include the butadienyl, pentadienyl, hexadienyl and hexatrienyl groups as well as the branched forms thereof. The position of the unsaturation (the double bond) can be at any position along the carbon chain. In the present context, the term "cycloalkyl of 3 to 8 carbon atoms" is intended to cover rings of three, four, five, six, seven and eight members comprising carbon atoms only while the term "heterocyclyl" is proposes to refer to rings of three, four, five, six, seven and eight members where the carbon atoms together with from 1 to 3 heteroatoms constitute the ring. The heteroatoms are independently selected from oxygen, sulfur and nitrogen. However, cycloalkyl rings of 3 to 8 carbon atoms and heterocyclyl may optionally contain one or more unsaturated bonds located in such a way that an aromatic p-electron system does not arise. Illustrative examples of preferred "cycloalkyl of 3 to 8 carbon atoms" are carbocycles cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclopentadiene, cyclohexane, cyclohexene, 1,3-cyclohexadiene, 1,4-cyclohexadiene, cycloheptane, cycloheptene, 1,2-cycloheptadiene, 1,3-cycloheptadiene, 1,4-cycloheptadiene and 1, 3, 5-cycloheptatriene. Illustrative examples of "heterocyclyls" are heterocycles 2H-tipirane, 3H-tipirane, 4H-tipirane, tetrahydrothiopyran, 2H-pyran, 4-pyran, tetrahydropyran, piperidine, 1,2-dithiine, 1,2-dithiane, 1,3 -dithin, 1,3-dithiane, 1,4-dithiine, 1,4-dithiane, 1,2-dioxin, 1,2-dioxane, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin , 1,4-dioxane, piperazine, 1,2-oxathiane, 1,2-oxathiane, 4H-1, 3-oxathiane, 1,3-oxatiane, 1,4-oxathiane, 1,4-oxatiane, 2H-1 , 2-thiazine, tetrahydro-1,2-thiazine, 2H-1,3-thiazine, 4H-1,3-thiazine, 5,6-dihydro-4H-thiazine, 4H-1,4-thiazine, tetrahydro-1 , 4-thiazine, 2H-1, 2-oxazine, 4H-1,2-oxazine, 6H-1, 2-oxazine, 2H-1, 3-Oxazine, 4H-1, 3-oxazine, 4H-1, 4 -oxazine, maleimide, succinimide, imidazole, pyrazole, pyrrole, oxazole, furazan, barbituric acid, thiobarbituric acid, dioxopiperazine, isoxazole, hydantoin, dihydrouracil, morpholine, trioxane, 4H-1, 2, 3-trithin, 1, 2, 3 -tritian, 1, 3, 5-trityl, hexahydro-1, 3, 5-triazine, tetrahydrothiophene, tetrahydrofuran, pyrr olin, pyrrolidine, pyrrolidone, pyrrolidione, pyrazoline, pyrazolidine, imidazoline, imidazolidine, 1,2-dioxole, 1,2-dioxolane, 1,3-dioxole, 1,3-dioxolane, 3H-1,2-dithiol, 1, 2-dithiolane, 1,3-dithiol, 1,3-dithiolane, isoxazoline, isoxazolidine, oxazoline, oxazolidine, thiazoline, thiozolidine, 3H-1, 2-oxathiol, 1,2-oxathiolane, 5H-1,2-oxathiol, 1,3-oxathiol, 1,3-oxathiolane, 1,2,3-trithiol, 1,2,3- trithiolane, 1,2,4-trithiolane, 1,2,3-trioxol, 1,2,3-trioxolane, 1,2,4-trioxolane, 1,2,3-triazoline and 1,2,3-triazolidine. The linkage to the heterocycle may be at the heteroatom position or via a carbon atom of the heterocycle. In the present context, the term "aryl" is proposed to refer to a carbocyclic aromatic ring or ring system. In addition, the term "aryl" includes fused ring systems wherein at least two aryl rings or at least one aryl group and at least one cycloalkyl group of 3 to 8 carbon atoms or at least one aryl group and at least one heterocyclyl group, share at least one chemical bond. strative examples of "aryl" rings include optionally substituted phenyl, naphthalenyl, phenanthrenyl, anthracenyl, acenaphthylenyl, tetralinyl, fluorenyl, indenyl, indolyl, coumaranyl, coumarinyl, chromanyl, isochromanyl and azulenyl. A preferred aryl group is phenyl. In the present context, "aralkyl of 7 to 16 carbon atoms" is proposed to refer to an aryl group of 6 to 10 carbon atoms substituted by alkyl of 1 to 6 carbon atoms.

In the present context, "alkylaryl of 7 to 16 carbon atoms" is proposed to refer to an alkyl group of 1 to 6 carbon atoms substituted by aryl of 6 to 10 carbon atoms. In one embodiment, the invention relates to a peptide totaling from 12 to 19 amino acid residues comprising an amino acid sequence selected from the group consisting of X-Y-Z, X -Aa? -Aa2-YZ, X -Aax-Aa2-Aa3-YZ, X -Aa? -Aa2-Aa3-Aa4-YZ, X -Aa1-Aa2-Aa3-Aa4-Aa5-YZ, X -Aa? -Y-Aa6-Z, X -Aa? -Aa2-Y-Aa6-Z, X -Aa? -Aa2-Aa3-Y-Aa6-Z, X -Aa? -Aa2-Aa3-Aa4-Y-Aa6- Z, X -Aa? -Aa2-Aa3-Aa4-Aa5-Y-Aa6-Z, X -Aa? -Y-Aae-Aa7-Z, X -Aa? -Aa2-Y-Aa6-Aa7-Z, X -Aa? -Aa2-Aa3-Y-Aae-Aa7-Z, X -Aa? -Aa2-Aa3-Aa4-Y-Aa6-Aa7-Z and X -Aax-Aa2 -Aa3 -Aa4 -Aa5-Y-Aa6 -Aa7- Z where X comprises six amino acid residues R1-R2-R3- R4-R5-R6, wherein R1, R2, R3, R4, R5 and R6 can independently be Lys or Glu and wherein Y comprises an amino acid sequence selected from His-Phe-Arg, His- (D-Phe) - Arg, His-Nal-Arg and His- (D-Nal) -Arg and wherein Z comprises an amino acid sequence selected from Lys-Pro-Val and Lys-Pro- (D-Val) and wherein ai, Aa2, Aa3, Aa4, Aa5, Aa6 and Aa7 may independently be any natural or unnatural amino acid residue or may be absent and wherein the carboxy terminus of the peptide is -C (= 0) -B1, wherein Bl is selected from OH, NH2, NHB2, N (B2) (B3), OB2 and B2, wherein B2 and B3 are independently selected from alkyl of 1 to 6 carbon atoms optionally substituted, alkenyl of 2 to 6 carbon atoms optionally substituted, aryl of 6 optionally substituted at 10 carbon atoms, aralkyl of 7 to 16 carbon atoms optionally substituted and alkylaryl of 7 to 16 carbon atoms optionally substituted; and wherein the amino terminus of the peptide is (B4) HN-, (B4) (B5) N- or (B6) HN-, wherein B4 and B5 are independently selected from H, alkyl of 1 to 6 carbon atoms optionally substituted, alkenyl of 2 to 6 carbon atoms optionally substituted, aryl of 6 to 10 carbon atoms optionally substituted, aralkyl of 7 to 16 optionally substituted carbon atoms and alkylaryl of 7 to 16 carbon atoms optionally substituted; B6 is B4-C (= 0) -. In a preferred embodiment, the invention relates to a peptide, wherein the peptide comprises the amino acid sequence: X -Aa? -Aa2-Aa3-Aa4-Aa5-Y-Aa6-Aa7-Z. wherein Aax, Aa2, Aa3, Aa4, Aa5, Aa6 and Aa7 can independently be any natural or non-natural amino acid. In this manner, Aalf Aa2, Aa3, Aa4, Aa5, Aa6 and Aa7 are all present in the peptide of the invention. In one embodiment, the invention relates to peptides according to the invention, where the amino terminus is (B4) HN-, where B4 = H. In a further embodiment, the invention relates to peptides according to the invention, wherein the carboxy terminus of the peptide is -C (= 0) -B1, where Bl = OH. Various methods can be used to stabilize the peptides against degradation and to decrease the ability of the peptides to react with other compounds, agents and / or peptides / proteins, for example in the plasma. The invention also relates to peptides according to the invention modified by means of methods of this type known in the art. In a preferred embodiment, the invention relates to peptides of according to the invention, wherein the amino terminus of the peptide is modified by means of acetylation. Thus, in a preferred embodiment, the invention relates to peptides according to the invention, wherein the amino terminus is (B6) HN-, wherein B6 = B4-C (= 0) - and B4 = CH3. In another preferred embodiment, the invention relates to peptides according to the invention, wherein the carboxy terminus of the peptide is modified by means of amidation. In this manner, the invention relates to peptides according to the invention, wherein the carboxy terminus of the peptide is -C (= 0) -B1, where Bl = NH2. In the broader aspect of the invention, X is selected from Lys-Lys-Lys-Lys-Lys-Lys (SEQ ID NO: 37), Glu-Lys-Lys-Lys-Lys-Lys (SEQ ID NO: 38) , Lys-Glu-Lys-Lys-Lys-Lys (SEQ ID NO: 39), Lys-Lys-Glu-Lys-Lys-Lys (SEQ ID NO: 40), Lys-Lys-Lys-Glu-Lys-Lys (SEQ ID NO: 41), Lys-Lys-Lys-Lys-Glu-Lys (SEQ ID NO: 42), Lys-Lys-Lys-Lys-Lys-Glu (SEQ ID NO: 43), Glu-Glu- Lys-Lys-Lys-Lys (SEQ ID NO: 44), Glu-Lys-Glu-Lys-Lys-Lys (SEQ ID NO: 45), Glu-Lys-Lys-Glu-Lys-Lys (SEQ ID NO: 46), Glu-Lys-Lys-Lys-Glu-Lys (SEQ ID NO: 47), Glu-Lys-Lys-Lys-Lys-Glu (SEQ ID NO: 48), Lys-Glu-Glu-Lys-Lys -Lys (SEQ ID NO: 49), Lys-Glu-Lys-Glu-Lys-Lys (SEQ ID NO: 50), Lys-Glu-Lys-Lys-Glu-Lys (SEQ ID NO: 51), Lys- Glu-Lys-Lys-Lys-Glu (SEQ ID NO: 52), Lys-Lys-Glu-Glu-Lys-Lys (SEQ ID NO: 53), Lys-Lys-Glu-Lys-Glu-Lys (SEQ ID DO NOT: 54), Lys-Lys-Glu-Lys-Lys-Glu (SEQ ID NO: 55), Lys-Lys-Lys-Glu-Glu-Lys (SEQ ID NO: 56), Lys-Lys-Lys-Glu-Lys -Glu (SEQ ID NO: 57), Lys-Lys-Lys-Lys-Glu-Glu (SEQ ID NO: 58), Glu-Glu-Glu-Lys-Lys-Lys (SEQ ID NO: 59), Glu- Glu-Lys-Glu-Lys-Lys (SEQ ID NO: 60), Glu-Glu-Lys-Lys-Glu-Lys (SEQ ID NO: 61), Glu-Glu-Lys-Lys-Lys-Glu (SEQ ID NO: 62), Glu-Lys-Glu-Glu-Lys-Lys (SEQ ID NO: 63), Glu-Lys-Glu-Lys-Glu-Lys (SEQ ID NO: 64), Glu-Lys-Glu-Lys -Lys-Glu (SEQ ID NO: 65), Glu-Lys-Lys-Glu-Glu-Lys (SEQ ID NO: 66), Glu-Lys-Lys-Glu-Lys-Glu (SEQ ID NO: 67), Glu-Lys-Lys-Lys-Glu-Glu (SEQ ID NO: 68), Lys-Lys-Lys-Glu-Glu-Glu (SEQ ID NO: 69), Lys-Lys-Glu-Lys-Glu-Glu ( SEQ ID NO: 70), Lys-Lys-Glu-Glu-Lys-Glu (SEQ ID NO: 71), Lys-Lys-Glu-Glu-Glu-Lys (SEQ ID NO: 72), Lys-Glu-Lys -Lys-Glu-Glu (SEQ ID NO: 73), Lys-Glu-Lys-Glu-Lys-Glu (SEQ ID NO: 74), Lys-Glu-Lys-Glu-Glu-Lys (SEQ ID NO: 75) ), Lys-Glu-Glu-Lys-Lys-Glu (SEQ ID NO: 76), Lys-Glu-Glu-Lys-Glu-Lys (SEQ ID NO: 77), Lys-Glu-Glu-Glu-Lys- Lys (SEQ ID NO: 78), Lys-Ly s-Glu-Glu-Glu-Glu (SEQ ID NO: 79), Lys-Glu-Lys-Glu-Glu-Glu (SEQ ID NO: 80), Lys-Glu-Glu-Lys-Glu-Glu (SEQ ID NO: 81), Lys-Glu-Glu-Glu-Lys-Glu (SEQ ID NO: 82), Lys-Glu-Glu-Glu-Glu-Lys (SEQ ID NO: 83), Glu-Lys-Lys-Glu -Glu-Glu (SEQ ID NO: 84), Glu-Lys-Glu-Lys-Glu-Glu (SEQ ID NO: 85), Glu-Lys-Glu-Glu-Lys-Glu (SEQ ID NO: 86), Glu-Lys-Glu-Glu-Glu-Lys (SEQ ID NO: 87), Glu-Glu-Lys-Lys-Glu-Glu (SEQ ID NO: 88), Glu-Glu-Lys-Glu-Lys-Glu ( SEQ ID NO: 89), Glu-Glu-Lys-Glu-Glu-Lys (SEQ ID NO: 90), Glu-Glu-Glu-Lys-Lys-Glu (SEQ ID NO: 91), Glu-Glu-Glu-Lys-Glu -Lys (SEQ ID NO: 92), Glu-Glu-Glu-Glu-Lys-Lys (SEQ ID NO: 93), Lys-Glu-Glu-Glu-Glu-Glu (SEQ ID NO: 94), Glu-Lys-Glu- Glu-Glu-Glu (SEQ ID NO: 95), Glu-Glu-Lys-Glu-Glu-Glu (SEQ ID NO: 96), Glu-Glu-Glu-Lys-Glu-Glu (SEQ ID NO: 97), Glu-Glu-Glu-Glu-Lys-Glu (SEQ ID NO: 98), Glu-Glu-Glu-Glu-Glu -Lys (SEQ ID NO: 99), Glu-Glu-Glu-Glu-Glu-Glu (SEQ ID NO: 100) The presently preferred peptides of the invention are established compounds of the following peptide sequences: Lys-Lys-Lys-Lys-Lys -Lys-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val (SEQ ID NO: 1) Glu-Glu-Glu-Glu-Glu-Glu-Ser-Tyr -Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val (SEQ ID NO: 2) Lys-Lys-Lys-Lys-Lys-Lys-Ser-Tyr-Ser-Met-Glu -His-Phe-Arg- Trp-Gly-Lys-Pro- (D-Val) (SEQ ID NO: 3) Glu-Glu-Glu-Glu-Glu-Glu-Ser-Tyr-Ser-Met-Glu-His -Phe-Arg- Trp-Gly-Lys-Pro- (D-Val) (SEQ ID NO: 4) Lys-Lys-Lys-Lys-Lys-Lys-Ser-Tyr-Ser-Nle-Glu-His- ( D-Phe) - Arg-Trp-Gly-Lys-Pro-Val (SEQ ID NO: 5) Glu-Glu-Glu-Glu-Glu-Glu-Ser-Tyr-Ser-Nle-Glu-His- (D- Phe) - Arg-Trp-Gly-Lys-Pro-Val (SEQ ID NO: 6) Lys-Lys-Lys-Lys-Lys-Lys-Ser-Tyr-Ser-Nle-Glu-His- (D-Phe) -Arg-Tr -Gly-Lys-Pro- (D-Val) (SEQ ID NO: 7) Glu-Glu-Glu-Glu-Glu-Glu-Ser-Tyr-Ser-Nle-Glu-His- (D-Phe) -Arg-Trp-Gly-Lys-Pro- (D-Val) (SEQ ID NO: 8) Lys-Lys-Lys-Lys-Lys-Lys-Ser-Tyr-Ser-Nle-Glu-His-D-Nal-Arg-Trp-Gly-Lys-Pro-Val (SEQ ID NO: 9) Glu- Glu-Glu-Glu-Glu-Glu-Ser-Tyr-Ser-Nle-Glu-His-D-Nal-Arg-Trp-Gly-Lys-Pro-Val (SEQ ID NO: 10) Lys-Lys-Lys- Lys-Lys-Lys-Ser-Tyr-Ser-Nle-Glu-His-D-Nal-Arg-Trp-Gly-Lys-Pro- (D-Val) (SEQ ID NO: 11) Glu-Glu-Glu- Glu-Glu-Glu-Ser-Tyr-Ser-Nle-Glu-His-D-Nal-Arg-Trp-Gly-Lys-Pro- (D-Val) (SEQ ID NO: 12) Lys-Lys-Lys- Lys-Lys-Lys-Ser-Ser-lie-lie-Ser-His-Phe-Arg-Trp-Gly-Lys-Pro-Val (SEQ ID NO: 13) Glu-Glu-Glu-Glu-Glu-Glu- Ser-Ser-lie-lie-Ser-His-Phe-Arg-Trp-Gly-Lys-Pro-V (SEQ ID NO: 14) Lys-Lys-Lys-Lys-Lys-Lys-Ser-Ser-Ile -lie-Ser-His-Phe-Arg-Trp-Gly-Lys-Pro- (D-Val) (SEQ ID NO: 15) Glu-Glu-Glu-Glu-Glu-Glu-Ser-Serie-lie -Ser-His-Phe-Arg-Trp-Gly-Lys-Pro- (D-Val) (SEQ ID NO: 16) Lys-Lys-Lys-Lys-Lys-Lys-Ser-Ser-Ile-Ile-Ser -His- (D-Phe) -Arg-Trp-Gly-Lys-Pro-Val (SEQ ID NO: 17) Glu-Glu-Glu-Glu-Glu-Glu-Ser-S er-Ile-Ile-Ser-His- (D-Phe) -Arg-Trp-Gly-Lys-Pro-Val (SEQ ID NO: 18) Lys-Lys-Lys-Lys-Lys-Lys-Ser-Ser- Ile-Ile-Ser-His- (D-Phe) -Arg-Trp-Gly-Lys-Pro- (D-Val) (SEQ ID NO: 19) Glu-Glu-Glu-Glu-Glu-Glu-Ser- Ser-Ile-Ile-Ser-His- (D-Phe) - Arg-Trp-Gly-Lys-Pro- (D-Val) (SEQ ID NO: 20) Lys-Lys-Lys-Lys-Lys-Lys-Ser-Ser-Ile-lie-Ser-His-D-Nal- Arg-Trp-Gly-Lys-Pro-Val (SEQ ID NO: 21) Glu-Glu-Glu-Glu-Glu-Glu-Ser-Ser-lie-lie-Ser-His-D-Nal-Arg-Trp- Gly-Lys-Pro-Val (SEQ ID NO: 22) Lys-Lys-Lys-Lys-Lys-Lys-Ser-Ser-lie-Ile-Ser-His-D-Nal-Arg-Trp-Gly-Lys- Pro- (D-Val) (SEQ ID NO: 23) Glu-Glu-Glu-Glu-Glu-Glu-Ser-Ser-lie-lie-Ser-His-D-Nal-Arg-Trp-Gly-Lys- Pro- (D-Val) (SEQ ID NO: 24) Lys-Lys-Lys-Lys-Lys-Lys-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val (SEQ ID NO: 25) Glu-Glu-Glu-Glu-Glu-Glu-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val (SEQ ID NO: 26) Lys-Lys-Lys-Lys-Lys- Lys-Met-Glu-His-Phe-Arg-Tr-Gly-Lys-Pro- (D-Val) (SEQ ID NO: 27) Glu-Glu-Glu-Glu-Glu-Glu-Met-Glu-His- Phe-Arg-Trp-Gly-Lys-Pro- (D-Val) (SEQ ID NO: 28) Lys-Lys-Lys-Lys-Lys-Lys-Nle-Glu-His- (D-Phe) -Arg- Trp-Gly-Lys-Pro-Val (SEQ ID NO: 29) Glu-Glu-Glu-Glu-Glu-Glu-Nle-Glu-His- (D-Phe) -Arg-Trp-Gly-Lys-Pro- Val (SEQ ID NO: 30) Lys-Lys-Lys-Lys-Lys-Lys-Nle-Glu-His- (D-Phe) -Arg-Trp-Gly-Ly s-Pro- (D-Val) (SEQ ID NO: 31) Glu-Glu-Glu-Glu-Glu-Glu-Nle-Glu-His- (D-Phe) -Arg-Trp-Gly-Lys-Pro- (D-Val) (SEQ ID NO: 32) Lys-Lys-Lys-Lys-Lys-Lys-Nle-Glu-His-D-Nal-Arg-Trp-Gly-Lys-Pro-Val (SEQ ID NO: 33) Glu-Glu-Glu-Glu-Glu- Gl? -Nle-Glu-His-D-Nal-Arg-Trp-Gly-Lys-Pro-Val (SEQ ID NO: 34) Lys-Lys-Lys-Lys-Lys-Lys-Nle-Glu-His-D -Nal-Arg-Trp-Gly-Lys-Pro- (D-Val) (SEQ ID NO: 35) and Glu-Glu-Glu-Glu-Glu-Glu-Nle-Glu-His-D-Nal-Arg- Trp-Gly-Lys-Pro- (D-Val) (SEQ ID NO: 36). Stabilization can be performed by modifying the N and / or C terminal of the peptide as described above, such as for example to acetylate the N-terminus of the peptide of the invention and / or to amidate the C-terminus of the peptide of the invention. The amino acid sequences are provided by means of the three letter code known for natural amino acids. Modifications and substitutions of natural amino acid residues are abbreviated as follows: Nle is the abbreviation for Norleucine. D-Nal is the abbreviation for beta-2-naphthyl-d-alanine. D-Val (D-valine) is the abbreviation for Valina's D configuration. D-Phe (D-phenylalanine) is the abbreviation for the P-configuration of phenylalanine. In a preferred embodiment, the invention relates to a peptide, which is an acetylated compound at the N-terminus and amidated at the C-terminus of: Lys-Lys-Lys-Lys-Lys-Lys-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val (SEQ ID NO: 1). In still another preferred embodiment, the invention relates to a peptide according to the invention, which is an acetylated compound at the N-terminus and amidated at the C-terminus of: Glu-Glu-Glu-Glu-Glu-Glu-Ser -Tyr-Ser- Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val (SEQ ID NO: 2) In yet another preferred embodiment, the invention relates to a peptide according to the invention, which is an acetylated compound at the N-terminus and amidated at the C-terminus of: Lys-Lys-Lys-Lys-Lys-Lys-Ser-Tyr-Ser Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro- (D-Val) (SEQ ID NO: 3). In yet a preferred embodiment, the invention relates to a peptide according to the invention, which is an acetylated compound at the N-terminus and amidated at the C-terminus of: Lys-Lys-Lys-Lys-Lys-Lys-Ser -Tyr-Ser- Nle-Glu-His- (D-Phe) -Arg-Trp-Gly-Lys-Pro-Val (SEQ ID NO: 5). In yet another preferred embodiment, the invention relates to a peptide according to the invention, which is an acetylated compound at the N-terminus and amidated at the C-terminus of: Lys-Lys-Lys-Lys-Lys-Lys-Ser -Tyr-Ser- Nle-Glu-His- (D-Nal) -Arg-Trp-Gly-Lys-Pro-Val (SEQ ID NO: 9). In a further preferred embodiment, the invention relates to a peptide according to the invention, which is an acetylated compound in the terminalN and amidated at terminal C of: Lys-Lys-Lys-Lys-Lys-Lys-Ser-Ser-Ile-Ile-Ser-His-Phe-Arg-Trp-Gly-Lys-Pro-Val (SEQ ID NO : 13). In another preferred embodiment, the invention relates to a peptide according to the invention, which is an acetylated compound at the N-terminus and amidated at the C-terminus of: Lys-Lys-Lys-Lys-Lys-Lys-Ser Ser-Ile-Ile-Ser-His- (D-Phe) -Arg-Trp-Gly-Lys-Pro-Val (SEQ ID NO: 17). As described above, the peptides of the invention possess an increased therapeutic effect and / or an increased maximum response and / or an increased maximum efficacy as compared to the naturally occurring peptide a-MSH. The inventor has examined the biological effects of some of the peptides of the invention: Ac- (Lys) 6-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2 (SEQ ID NO: 1 * acetylated at terminal N and amidated at terminal C), Ac- (Glu) 6-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro -Val-NH2 (SEQ ID NO: 2 * acetylated at the N-terminus and amidated at the C-terminus), Ac- (Lys) 6-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly -Lys-Pro- (D-Val) -NH2 (SEQ ID NO: 3 * acetylated at the N-terminus and amidated at the C-terminus), Ac- (Lys) 6-Ser-Tyr-Ser-Nle-Glu-His - (D-Phe) -Arg-Trp-Gly-Lys- Pro-Val-NH2 (SEQ ID NO: 5 * acetylated at the N-terminus and amidated at the C-terminus), Ac- (Lys) g-Ser-Tyr-Ser-Nle-Glu-His- (D-Nal) - Arg-Trp-Gly-Lys-Pro-Val-NH2 (SEQ ID NO: 9 * acetylated at the N-terminus and amidated at the C-terminus), Ac- (Lys) 6-Ser-Ser-Ile-Ile-Ser- His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2 (SEQ ID NO: 13 * acetylated at the N-terminus and amidated at the C-terminus), Ac- (Lys) 6-Ser-Ser-Ile- Ile-Ser-His- (D-Phe) -Arg-Trp-Gly-Lys-Pro-Val-NH2 (SEQ ID NO: 17 * acetylated at the N-terminus and amidated at the C-terminus). In general, "Ac-" indicates that the peptide of the invention is acetylated at the N-terminus and "-NH2" indicates that the peptide of the invention is amidated at the C-terminus. In a suspension of human leukocytes (experimental configuration 1), the seven peptides inhibited in a dose-dependent manner the accumulation of TNF-α induced by LPS (Examples 1-7). Surprisingly, it was found that all seven peptides were more effective, defined as the maximum inhibitory effect on TNF-α production, as well as more potent, defined as the concentration of the compound necessary to provide maximum inhibition of TNF- accumulation. a, that the native melanocyte stimulating hormone, a-MSH (Examples 1-7).

The inventor has also investigated the effect of the seven peptides listed above (SEQ ID NO: 1 *, SEQ ID NO: 2 *, SEQ ID NO: 3 *, SEQ ID NO: 5 *, SEQ ID NO: 9 *, SEQ ID NO: 13 * and SEQ ID NO: 17 *, all acetylated at terminal N and amidated at terminal C) in a configuration where systemic inflammation was induced by intravenous infusion of LPS in rats (experimental configuration 2 ). It was shown that the peptides significantly inhibit the accumulation of TNF-α induced by LPS in the circulating blood. Surprisingly, the Seven Peptides (SEQ ID NO: 1 *, SEQ ID NO: 2 *, SEQ ID NO: 3 *, SEQ ID NO: 5 *, SEQ ID NO: 9 *, SEQ ID NO: 13 * and SEQ ID NO: 17 *, all acetylated at terminal N and amidated at terminal C) were able to inhibit the concentration of TNF-a in circulating blood to a higher degree than the native melanocyte stimulating hormone a-MSH (examples 1-7). The inventor has also investigated the effect of the peptides: Ac- (Lys) s-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2 (SEQ ID NO: 1 * acetylated at N-terminal and amidated at terminal C) and Ac- (Lys) 6-Ser-Tyr-Ser-Nle-Glu-His-D-Phe-Arg-Trp-Gly-Lys-Pro-Val- NH2 (SEQ ID NO: 5 * acetylated at the N-terminus and amidated at the C-terminus). In a configuration in which inflammation was induced by inhalation of LPS in rats (experimental setup 3) and it was shown that the two peptides (SEQ ID NO: 1 * and 5 *) significantly inhibit the accumulation of eosinophils induced by LPS within of the lungs (examples 1 and 2). Surprisingly, the peptide (SEQ ID NO: 5 *) in addition to this effect on eosinophils also markedly inhibited the infiltration of neutrophils to a much higher degree than that found in rats treated with the native melanocyte stimulating hormone, a-MSH (example 2). Temporal ischemia of the kidney is frequently observed as a consequence of reduced blood pressure, hypovolemia, surgical interventions that involve reduction in renal and / or aortic blood flow or associated with septicemia. This results in acute renal failure induced by ischemia, which for a large fraction deteriorates in chronic renal failure. Currently there is no efficient treatment to prevent the development of kidney failure. A common finding in the subsequent ischemic phase is the development of urinary concentration defects with the formation of an increased production of solute-free urine. Experimental acute renal failure induced ischemia (ARF) induced by ischemia and reperfusion in rats is known to cause characteristic structural alterations in renal duct epithelia in association with a deterioration of urinary concentration mechanisms. This model of ARF induced by ischemia provides an appropriate environment to evaluate the effect of an MSH analog on an ischemia-induced injury. The present inventor has investigated the effect of the peptide Ac- (Lys) 6-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2 (SEQ ID NO: 1 * acetylated at terminal N and amidated at terminal C) and compared the effect of the peptide with the effect of the native peptide α-MSH on temporary bilateral obstruction of the renal arteries induced by severe acute renal failure (experimental setting 6). When evaluated five days after the temporary blockage of the renal arteries, the rats treated with a vehicle developed polyuria defined by a diuresis 101% higher than the control rats, which had been subjected to a feigned obstruction of the renal arteries. Surprisingly, the compound (SEQ ID NO: 1 * acetylated at the N-terminus and amidated at the C-terminus) administered in the same molar amount as the native a-MSH peptide completely normalized the diuresis indicating that the peptide had the ability to protect against the ARF, induced ischemia, while treatment with the native peptide in this environment was unable to normalize urine production. Acute myocardial infarction (AMI) is one of the most common causes of death in developed countries. AMI almost always occurs in patients with coronary atheroma due to sudden coronary thrombosis. Today, fibrinolytic therapy or coronary, transluminal, percutaneous, primary (PTCA) angioplasty are standard treatments and can achieve early reperfusion in 50-70% of patients (the rate of spontaneous reperfusion is less than 30%). The goal of reperfusion is to reduce the size of the infarct, thereby reducing the development of impaired myocardial function. The total effect of fibrinolysis / PTCA is a 20% reduction in short and long-term mortality. However, AMI is associated with an inflammatory reaction, which is a precondition for healing and scarring. Coronary artery blockage critically reduces the flow of blood to the myocardial portion, which markedly impairs energy metabolism. A significant duration of ischemia (> 20 minutes) induces a heart attack and results in an inflammatory response, which is both accelerated and increased when reperfusion of ischemic myocardium is performed. Myocardial ischemia / reperfusion (MIR) not only activates a classical inflammatory reperfusion response with neutrophil infiltration, but also the expression of myocardial cytokine genes that include tumor necrosis factor-a (TNF-a), interleukin ( IL) -lß, IL-6, IL-8, interferon-β and intercellular adhesion molecule-1 (ICAM-1). This local myocardial overexpression of cytokines may play a critical role not only in the modulation of infarct size, but also in the progress of myocardial dysfunction, including remodeling of the vascular wall, heart failure and cardiac hypertrophy. In addition, it has been suggested that locally produced TNF-α contributes to post-ischemic myocardial dysfunction via a direct depression of contractility and induction of apoptosis. A growing number of experimental studies have shown that anti-inflammatory / anti-oxidant / anti-apoptotic strategies have the ability to reduce infarct size in animal models of MIR. However, clinical studies have not shown significant effects in humans. In a myocardial ischemia / reperfusion model in rats in which the left anterior coronary artery was obstructed for 60 minutes, treatment with a peptide according to the invention was administered just before the removal of the coronary artery obstruction and the rats were then followed for another three hours . Then, the ability of the peptides to reduce infarct size was evaluated and compared to the effect of the native peptide α-MSH (experimental configuration 5). Surprisingly the three peptides: Ac- (Lys) 6-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2 (SEQ ID NO: 1 * Acetylated in the terminal N and amidated at terminal C) Ac- (Lys) 6-Ser-Tyr-Ser-Nle-Glu-His-D-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2 (SEQ ID NO: 5 * acetylated at terminal N and amidated at terminal C) and Ac- (Lys) e-Ser-Tyr-Ser-Nle-Glu-His-D-Nal-Arg-Trp-Gly-Lys-Pro-Val-NH2 (SEQ ID NO: 9 * acetylated at the N-terminus and amidated at the C-terminus) reduced the infarct size to a higher degree than the native a-MSH peptide (Examples 1, 3-4). In view of the functional properties of the peptides described above and in the examples, the invention relates to peptides having at least one of the following properties: a) inhibit LPS-induced TNF-a production by human leukocytes b) inhibit eosinophil infiltration induced by inflammation within the lungs c) inhibit neutrophil infiltration induced by inflammation within the lungs d) inhibit the accumulation of TNF -induced inflammation in circulating blood e) reduce acute renal failure induced by ischemia f) reduce the size of myocardial infarction g) reduce the degree of heart failure after myocardial infarction h) reduce pulmonary vascular hypertension i) reduce Kidney failure induced by cisplatin The peptide may have more than one of these properties, such as, for example 2, 3, 4, 5, 6, 7, 8 or all of the above properties. These properties can be tested as summarized in the examples. As described above, the a-MSH analogs of the invention are characterized as having an increased efficacy compared to the native a-MSH. In this specification and the claims, the term "efficacy" is defined as a maximum response that can be obtained by a compound. The a-MSH analogs of The invention is capable of producing a higher maximum response compared to native a-MSH in the various experiments described in the examples. Preferably, an α-MSH analogue of the invention inhibits the production of TNF-α induced by LPS by human leukocytes by a minimum of 10%, more preferably by 25% and much more preferably by 40% in comparison with a-MSH . In addition, an α-MSH analog of the invention can inhibit eosinophil infiltration induced by inflammation within the lungs as measured by the ability to reduce the number of eosinophils within the fluid collected by a bronchoalveolar lavage or a comparable method. The minimum expected effect which is a reduction of 10%, more preferably 25% and much more preferably 50% in eosinophils is found when compared to a-MSH. In addition, an a-MSH analog of the invention can inhibit neutrophil infiltration induced by inflammation within the lungs as measured by the ability to reduce the number of neutrophils within the fluid collected by a bronchoalveolar lavage or a comparable method. The minimum expected effect which is a reduction of 10%, more preferably 20% and much more preferably 40% in neutrophils is found when it is compared to the a-MSH. An a-MSH analog of the invention can also inhibit the accumulation of TNF-a induced by inflammation in circulating blood by a minimum of 10%, more preferably 25% and much or more preferably 40% compared to a-MSH. In addition, an α-MSH analogue of the invention can reduce acute renal failure induced by ischemia as measured by the ability to reduce the degree of pos-ischemic polyuria. The minimum expected effect that is a 10% reduction, more preferably 30% and much more preferably 50% in polyuria is found when compared to a-MSH. In addition, an α-MSH analogue of the invention can reduce the size of the myocardial infarction as evidenced by the ability to reduce the size of the necrotic area within the ischemic myocardium. The minimum expected effect which is a reduction of 10%, more preferably 20% and much more preferably 30% in infarct size is found when compared to a-MSH. In a further aspect, an α-MSH analogue of the invention can reduce the degree of heart failure after myocardial infarction as evidenced by the cardiac performance evaluated through direct measurement of the diastolic pressure of the left ventricular end or a similar quantitative measurement. The minimum expected effect which is a reduction of 10%, more preferably 20% and much more preferably 25% in the degree of heart failure is found when compared to a-MSH. In a still further aspect, an α-MSH analog of the invention can reduce pulmonary vascular hypertension. The minimum expected effect which is a reduction of 10%, more preferably 20% and much more preferably 30% in pulmonary artery pressure is found when compared to a-MSH. In another aspect, an α-MSH analog of the invention can reduce renal insufficiency induced by cisplatin. The minimum expected effect which is a reduction of 10%, more preferably 20% and in the much more preferable 30% environment in the hypomagnesia and / or glomerular filtration rate is found when compared to the a-MSH. As described at the beginning, the native peptide a-melanocyte-stimulating hormone (a-MSH) is known as the native agonist for the melanocortin (MC) type 1, type 3, type 4 and type 5 receptor, while ACTH is the native ligand for the Type 2 receptor (MC2). As the peptides comprise the sequence of amino acids of a-MSH or an analogue thereof, the peptides of the invention have the ability to stimulate one or more melanocortin receptors, ie the melanocortin receptor type 1, 3, 4 or 5.

Methods of Preparation of the Peptides of the Invention The peptides of the invention can be prepared by methods known per se in the art. Thus, α-MSH, a-MSH variants, α-MSH analogs and X-configuration can be prepared by standard peptide preparation techniques such as solution synthesis or solid phase synthesis Merrifield type. In a possible synthesis strategy, the peptides of the invention can be prepared by means of solid phase synthesis by first constructing the pharmacologically active peptide sequence (a-MSH, a-MSH variant or a-MSH analog) using well-known standard protection, coupling and deprotection procedures, then sequentially coupling the amino acid sequence of the X-configuration into the active peptide in a manner similar to the construction of the active peptide and finally cleaving the complete peptide from the carrier. This strategy produces a peptide, where the X sequence of the peptide is covalently bound to the pharmacologically active peptide in the N-terminal nitrogen atom of the peptide. Another possible strategy is to prepare the peptide / analog sequence of a-MSH and the X-configuration (or parts thereof) separately by means of solution synthesis, solid phase synthesis, recombinant techniques or enzymatic synthesis, followed by the coupling of the two sequences by means of condensation procedures of well-known segments, either in solution or using solid phase techniques or a combination thereof. In one embodiment, the a-MSH peptide / analog can be prepared by recombinant DNA methods and the X-configuration can be prepared by solid phase synthesis. The conjugation of the a-MSH peptide / analog and the X-configuration can be carried out through the use of the chemical ligation. This technique allows the assembly of totally deprotected peptide segments in a highly specific manner (Liu et al., 1996). The conjugation can also be performed by means of peptide bond formation catalyzed by protease, which offers a highly specific technique for combining segments of totally deprotected peptides via a peptide bond (Kullmann, 1987). Examples of suitable solid support materials (SSMs) are for example functionalized resins such as polystyrene, polyacrylamide, polydimethylacrylamide, polyethylene glycol, cellulose, polyethylene, polyethylene glycol grafted in polystyrene, latex, Dynabeads ™, and so on. It should be understood that it may be necessary or desirable that the C-terminal amino acid of the peptide sequence of the X-configuration or the C-terminal amino acid of the α-MSH, variant of α-MSH or analog of α-MSH bind to solid support material by means of a common connector such as 2,4-dimethoxy-4'-hydroxy-benzophenone, 4- (4-hydroxy-methyl-3-methoxyphenoxy) -butyric acid, 4-hydroxy-methylbenzoic acid, acid 4-hydroxymethyl-phenoxyacetic acid, 3- (4-hydroxymethylphenoxy) propionic acid and p- [(R, S) -a [1- (9H-fluoren-9-yl) methoxyformamido] -2,4-dimethoxybenzyl] -phenoxy acid -acetic. The peptides of the invention can be excised from the solid support material by means of an acid such as trifluoroacetic acid, trifluoromethanesulfonic acid, hydrogen bromide, hydrogen chloride, hydrogen fluoride, etc. optionally in combination with one or more suitable "cleansers". for the purpose, for example, ethanedithiol, triisopropylsilane, phenol, thioanisole, etc. or the peptide conjugate of the invention can be excised from the solid support by means of a base such as ammonia, hydrazine, an alkoxide such as sodium ethoxide, a hydroxide such as sodium hydroxide, and so on. The peptides of the invention can also be prepared by means of recombinant DNA technology using general methand principles known to the person skilled in the art. A nucleic acid sequence encoding the peptide of the invention can be prepared synthetically by standard established meth for example the phosphoamidite method. According to the phosphoamidite method, the oligonucleotides are synthesized for example in an automatic DNA synthesizer, purified, hybridized, ligated and cloned into suitable vectors. The nucleic acid sequence encoding the peptide of the invention is then inserted into a recombinant expression vector, which can be any vector which can be conveniently attached to recombinant DNA meth The selection of the vector will often depend on the host cell into which it is to be introduced. In this way, the vector can be a vector of autonomous replication, ie a vector which exists as an extrachromosomal entity, the replication of which is dependent on chromosomal replication, for example a plasmid. Alternatively, the vector may be one which, when introduced into a host cell, is 4 integrates into the genome of the host cell and replicates together with the chromosome (s) in which (s) it has been integrated. In the vector, the nucleic acid sequence encoding the peptide of the present invention must be operably linked to a suitable promoter sequence. The promoter can be any nucleic acid sequence, which shows transcription activity in the preferred host cell and can be derived from genes encoding proteins either homologous or heterologous to the host cell. Examples of suitable promoters for directing the transcription of the nucleic acid sequence encoding the peptide in mammalian cells are the SV 40 promoter, the MT-1 promoter (metallothionein gene) or the adenovirus 2 major late promoter, a promoter of the Rous sarcoma virus (RSV), cytomegalovirus promoter (CMV) and a bovine papilloma virus (BPV) promoter. A promoter suitable for use in insect cells is the polyhedrin promoter. Examples of suitable promoters for directing the transcription of the nucleic acid sequence encoding the peptide of the invention, especially in a bacterial host cell, are promoters obtained from the lac operon of E. coli, the agarase gene from Streptomyces coelicolor ( dagA), the levansucrase gene from Bacillus subtilis (sacB), the alpha-amylase gene of Bacillus licheniformis (amyL), the maltogenic amylase gene of Bacillus stearothermophilus (amyM), the alpha-amylase gene of Bacillus amyloliquefaciens (amyQ), the Bacillus penicillinase gene licheniformis (penP), the xylA and xylB genes of Bacillus subtilis and the prokaryotic beta-lactamase gene, as well as the tac promoter. Additional promoters are described in "Useful proteins from recombinant bacteria" in Scientific American, 1980, 242: 74-94; and in Sambrook et al., 1989, supra. Examples of suitable promoters for directing the transcription of the nucleic acid sequence encoding the peptide of the invention in a fungal filamentous host cell are the promoters obtained from the genes encoding the TAKA amylase from Aspergillus oryzae, Rhizomucor miehei aspartic proteinase, neutral alpha-amylase of Aspergillus niger, acid-stable alpha-amylase of Aspergillus niger, glucoamylase of Aspergillus niger or Aspergillus awamori (glaA), lipase of Rhizomucor miehei, alkaline protease of Aspergillus oryzae, triosa phosphate isomerase of Aspergillus oryzae, acetamidase of Aspergillus nidulans, trypsin-like protease from Fusarium oxysporum (as described in U.S. Patent No. 4,288,627, which is incorporated herein by reference) and hybrids thereof. The Particularly preferred promoters for use in filamentous fungal host cells are the promoters of TAKA amylase, NA2-tpi (a hybrid of the promoters of the genes encoding the neutral amylase of Aspergillus niger and the triose phosphate isomerase of Aspergillus oryzae) and gla . In a yeast host, the useful promoters are obtained from the enolase gene of Saccharomyces cerevisiae (ENO-1), the galactokinase gene of Saccharomyces cerevisiae (GAL1), the alcohol dehydrogenase / glyceraldehyde-3-phosphate dehydrogenase genes of Saccharomyces cerevisiae (ADH2 / GAP) and the 3-phosphoglycerate kinase gene of Saccharomyces cerevisiae. Other useful promoters for yeast host cells are described by Romanos et al., 1992, Yeast 8: 423-488. The nucleic acid sequence encoding the peptide of the invention can also be operably linked to a suitable terminator, such as the human growth hormone terminator. Preferred terminators for filamentous fungal host cells are obtained from the genes encoding Aspergillus oryzae TAKA amylase, Aspergillus niger glucoamylase, Aspergillus nidulans anthranilate synthase, Aspergillus niger alpha-glucosidase and trypsin-like protease of Fusarium oxysporum. Preferred terminators for yeast host cells are obtained from genes encoding Saccharomyces cerevisiae enolase, Saccharomyces cerevisiae cytochrome C (CYC1) or Saccharomyces cerevisiae glyceraldehyde-3-phosphate dehydrogenase. Other terminators useful for yeast host cells are described by Romanos et al., 1992, supra. The vector may further comprise elements such as polyadenylation signals (e.g., from SV 40 or the Elb region of adenovirus 5), transcriptional enhancer sequences (e.g., the SV 40 enhancer) and translation enhancer sequences (e.g. the sequences encoding the VA adenovirus RNAs). In addition, the preferred polyadenylation sequences for the filamentous fungal host cells are obtained from the genes encoding Aspergillus oryzae TAKA amylase, Aspergillus niger glucoamylase, Aspergillus nidulans anthranilate synthase and Aspergillus niger alpha-glucosidase. Polyadenylation sequences useful for yeast host cells are described by Guo and Sherman, 1995, Molecular Cellular Biology 15: 5983-5990. The recombinant expression vector can further comprising a DNA sequence that makes it possible for the vector to replicate in the host cell in question. Examples of this sequence (when the host cell is a mammalian cell) is SV 40 or the origin of replication polyoma. Examples of bacterial origins of replication are the origins of replication of the plasmids pBR322, pUC19, pACYC177, pACYC184, pUBUO, pE194, pTA1060 and pAMßl. Examples of the origin of replication for use in a yeast host cell are the origin of replication of 2 microns, the combination of CEN6 and ARS4 and the combination of CEN3 and ARS1. The origin of replication can be one that has a mutation to make its function sensitive to temperature in the host cell (see for example, Ehrlich, 1978, Proc Nati Acad Sci USA 75: 1433). The vector may also comprise a selectable marker, e.g., a gene the product of which complements a defect in the host cell, such as the gene encoding dihydrofolate reductase (DHFR) or one which confers resistance to a drug, e.g. neomycin, geneticin, ampicillin or hygromycin. Suitable markers for yeast host cells are ADE2, HIS3, LEU2, LYS2, MET3, TRP1 and URA3. A selectable marker for use in a fungal filamentous host cell can be selected from the group that includes, but is not limited to, amdS (acetamidase), argB (ornithine carbamoyltransferase), bar (phosphinotricin acetyltransferase), hygB (hygromycin phosphotransferase), niaD (nitrate reductase), pyrG (orotidine-5'-phosphate decarboxylase), sC (sulfate adenyltransferase), trpC (anthranilate synthase) and glufosinate resistance markers, as well as equivalents of other species. For use in an Aspergillus cell, the amdS and pyrG markers of Aspergillus nidulans or Aspergillus oryzae and the bar marker of Streptomyces hygroscopicus are preferred. In addition, the selection can be made by cotransformation, for example, as described in WO 91/17243, where the selectable marker is in a separate vector. The methods used to ligate the nucleic acid sequences encoding the peptide of the invention, the promoter and the terminator, respectively, and to insert them into suitable vectors containing the information necessary for replication, are well known to those skilled in the art. field (see for example Sambrook et al., op.cit.). The host cell into which the expression vector is introduced can be any cell that is capable of producing the peptide of the invention and can be a eukaryotic cell, such as invertebrate cells. (insects) or vertebrate cells, for example Xenopus laevis oocytes or mammalian cells, in particular insect and mammalian cells. Examples of suitable mammalian cell lines are COS cell lines (e.g., ATCC CRL 1650), BHK (e.g., ATCC CRL 1632, ATCC CCL 10) or CHO (e.g., ATCC CCL 61). Methods for transfecting mammalian cells and for expressing DNA sequences introduced into cells can be any method known in the field (eg MANIATIS, T., EF FRITSCH and J. SAMBROOK, 1982 Molecular Cloning: A Laboratory Manual. Harbor Laboratory Press, Cold Spring Harbor, NY). The host cell can also be a unicellular pathogen, for example a prokaryotic cell, or a non-unicellular pathogen, for example a eukaryotic cell. Useful unicellular cells are bacterial cells such as gram-positive bacteria including, but not limited to, a Bacillus cell, eg, Bacillus alkalophilus, Bacillus amyloliquefaciens, Bacillus brevis, Bacillus circulans, Bacillus coagulans, Bacillus lautus, Bacillus lentus , Bacillus licheniformis, Bacillus megaterium, Bacillus stearothermophilus, Bacillus subtilis and Bacillus thuringiensis; or a Streptomyces cell, for example, Streptomyces lividans or Streptomyces murinus or bacteria Gram-negative such as E. coli and Pseudomonas sp. The transformation of a bacterial host cell can be effected, for example, by the transformation of protoplasts, by the use of competent cells, by means of electroporation or by means of conjugation. The host cell can be a fungal cell. "Fungi" as used in this document includes the phylum Ascomycota, Basidiomycota, Chytridiomycota and Zygomycota as well as Oomycota and all the mitosporic fungi. Representative groups of Ascomycota include, for example, Neurospora, Eupenicillium (= Penicillium), Emericella (= Aspergillus), Eurotium (= Aspergillus) and the true yeasts listed above. The fungal host cell can also be a yeast cell. "Yeast" as used herein includes ascosporogenous yeast (Endomycetales), basidiosporogenous yeast and yeast belonging to the Imperfecti fungi (Blastomycetes). The medium used to grow the cells can be any conventional means suitable for developing mammalian cells, such as a serum-containing or serum-free medium containing appropriate supplements or a suitable medium for developing insect, yeast or fungal cells. Suitable means are available from commercial suppliers or can be prepared according to recipes published (for example in the catalogs of the American Type Culture Collection). The peptide of the invention produced by the cells can then be recovered from the culture medium by means of conventional procedures which include the separation of the host cells from the medium by centrifugation or filtration., the precipitation of the proteinaceous components of the supernatant or filtrate by means of a salt, for example ammonium sulfate, the purification by means of a variety of chromatographic procedures, for example ion exchange chromatography, affinity chromatography or the like. In this manner, the present invention relates to methods for the preparation of the peptides according to the invention, by means of recombinant DNA technology comprising the steps consisting of (a) introducing a nucleic acid sequence encoding the peptide in a host cell and (b) culturing the host cell and (c) isolating the culture peptide or (a) culturing a recombinant host cell comprising a nucleic acid sequence encoding the peptide under conditions that allow the production of the peptide and (b) isolating the peptide from the culture. Use The invention also relates to peptides according to the invention for use in medicine, in particular for use in connection with one or more of the conditions, disorders or diseases mentioned above or below. In one embodiment, the invention relates to the use of one or more peptides according to the invention for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of a condition in the tissue of one or more organs of a mammal. The organ is not limited to, but can be selected from the group consisting of kidney, liver, brain, heart, muscles, bone marrow, skin, skeleton, lungs, respiratory tract, spleen, exocrine glands, bladder, endocrine glands, organs of reproduction including the fallopian tubes, eyes, ears, vascular system, the gastrointestinal tract including the small intestine, colon, rectum and anal canal and prostate gland. As described above, the peptides of the invention exhibit increased anti-inflammatory effects and increased capacity to prevent ischemic conditions compared to a-MSH. In this manner, the present invention relates to the use of one or more peptides according to the invention for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of a condition in the tissue of one or more organs of a mammal, wherein the condition is an ischemic or inflammatory condition. The condition may also be due to insufficient cells, tissues or organs induced by toxins or drugs. In the present specification and the claims, the term "treatment" will generally include the treatment of an existing condition as well as the prevention of this condition (prophylactic treatment) unless the text specifically excludes this interpretation. In its broadest concept, the invention refers to any condition wherein the normal function of the organ (s) or tissue (s) is altered due to ischemia or inflammation. The injury can include an acute and / or chronic injury. Chronic injury includes situations of repetitive injuries that alternate with periods of complete or partial recovery of the function of the organ (s) or tissue (s).

Ischemia In the present specification and the claims, ischemia is defined as a reduced blood flow to one or more organs resulting in a reduced supply and / or utilization of oxygen by the tissues. Ischemia can occur in one or more organs that include (list without cataloging): brain, heart, extremities, kidney, spleen, liver, intestine, stomach, lungs, eyes, skin, muscles, pancreas, endocrine organs and others. Ischemia induces multiple reduced tissue reactions including neutrophil accumulation, other inflammatory responses, and cell death by reduced / complete arrest in the arterial blood supply. Ischemia is implicated in multiple diseases, associated with major surgery and as a result of other serious diseases. The identification of compounds that can inhibit or prevent (either completely or partially) many of the cell / tissue / organ damage or destructions that occur as a result of ischemia is very useful. The condition to be treated may be due to or caused by tissue ischemia such as in arterial stenosis or any other complete or partial restriction in the blood supply. Ischemia can be acute or chronic depending on the severity of the disease and, in addition, the condition can be reversible or irreversible. An example of a reversible condition may be due to a decrease in blood pressure during surgery or another intervention, which affects the blood perfusion of the organ. Accordingly, the condition to be treated can be any decrease in systemic blood flow such as hypotension, which can affect systemic blood flow to the intestine., heart, kidney or any other organ. In one embodiment, the invention relates to the use of a peptide according to the invention for the manufacture of a pharmaceutical composition for the treatment of ischemia, wherein the condition is caused by acute, subacute or chronic ischemia. Acute, subacute or chronic ischemia of an organ or limb or tissue can be caused by a wide variety of diseases. These include (non-limiting list) atheromatous disease with thrombosis, embolism of the heart or blood vessel of any organ, vascular spasm, aortic aneurysm or aneurysms in other organs, thoracic or abdominal or dissecting aortic aneurysm, hypotension due to heart disease, hypotension due to a systemic disease that includes infection or allergic reactions, hypotension due to one or more toxic compounds or poison (s) or drug (s). In a second embodiment, the invention relates to the use of a peptide according to the invention for the manufacture of a pharmaceutical composition for the treatment of ischemia, wherein the condition is caused for secondary ischemia. Ischemia secondary to a disease or condition can be observed in one or more of the selected diseases and conditions of: diabetes mellitus, hyperlipidemia, thromboangitis obliterans (Buerger's disease), Takayasu's syndrome, temporal arteritis, mucocutaneous lymph node syndrome (disease) Ka Asaki), cardiovascular syphilis, connective tissue disorders such as Raynaud's disease, phegmasia coerulae dolens, blood vessel trauma including iatrogenic trauma such as cannulation or surgery or organ transplantation. In addition, the list includes ischemia caused by surgery of one or more organs, transplantation of one or more organs, surgical insertion transplants, devices, grafts, prostheses or other biomedical compounds or devices. In a third embodiment, the invention relates to the use of a peptide according to the invention, wherein the condition is caused by ischemia due to septic shock or conditions associated with systemic hypotension.

Inflammatory Condition By the term "an inflammatory condition" is meant in the present context a condition in which Mechanisms such as a reaction of specific T lymphocytes or an antibody with antigen cause the recruitment of inflammatory cells and chemical, mediating, endogenous chemicals. In some cases, the normal function of the organ or tissue will be altered by an increase in vascular permeability and / or by contraction of the viceral smooth muscle. These inflammatory conditions can give rise to inflammatory diseases. In one embodiment, the invention relates to the use of one or more peptides according to the invention for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of a condition in the tissue of one or more organs of a mammal, wherein the Condition is an inflammatory condition. An inflammatory condition can be caused by inflammatory diseases that include (non-limiting list): arthritis (which includes diseases associated with arthritis), osteoarthritis, rheumatoid arthritis; spondyloarthropathies (for example, ankylosing spondylitis), reactive arthritis (which includes arthritis following rheumatic fever), Henoch-Schonlein purpura, and Reiter's disease. In addition, inflammatory diseases include connective tissue disorders such as systemic lupus erythematosus, polymyositis / dermatomyositis, systemic sclerosis, mixed connective tissue disease, sarcoidosis and primary Sjogrens syndrome including dry keratoconjunctivitis, polymyalgia rheumatica and other types of vasculitis, crystal deposition diseases (including gout), pyrophosphate arthropathy, acute calcified periarthritis . In addition, inflammatory diseases include juvenile arthritis (Still's disease), psoriasis, osteoarthritis, osteoarthritis secondary to permeability, congenital dysplasias, displaced femoral epiphysis, Perthes disease, intra-articular fractures, meniscectomy, obesity, recurrent dislocation, repetitive actions, stools of crystals and diseases and cartilage metabolic abnormalities that include pyrophosphate arthropathy, ochronosis, hemochromatosis, avascular necrosis that includes Falsiform Cell disease-, therapy with corticosteroids or other drugs, Caisson disease, septic or infectious arthritis (including tuberculous arthritis, meningococcal arthritis, gonococcal arthritis, salmonella arthritis), infective endocarditis (including endocarditis induced by the species Streptococcus viridans, Enterococcus Faecalis, Staphylococcus aureus, Staphylocossus epidermidis, Histoplasma, Brucella, Candida and Aspergellus and Coxiella Burnet ii), viral arthritis (which includes infection with rubella, mumps, hepatitis B, HIV or Parvovirus) or recurrent hemarthrosis. In addition, inflammatory diseases include vasculitis such as infectious vasculitis due to infections with bacterial species that include spirochetic diseases such as Lyme disease., syphilis, rickets and mycobacterial infections, fungal, viral or protozoal infections. In addition, inflammatory diseases include noninfectious vasculitis including Takayasu arteritis, Giant Cell Arteritis (Temporal arteritis and polymyalgia rheumatica), Buerger's disease, polyarteritis nodosa, microscopic polyarteritis, Wegener's granulomatosis, Churg-Strauss syndrome, vasculitis as a consequence of connective tissue diseases including Systemic Lupus Erythematosus, Polymyositis / Dermatomyositis, Systemic Sclerosis, Mixed Connective Tissue Disease, sarcoidosis and Primary Sjogrens Syndrome. In addition, inflammatory diseases include vasculitis as a result of rheumatoid arthritis. In addition, inflammatory diseases include noninfectious vasculitis as a result of hypersensitivity and leukocitoplastic vasculitis including Serum Disease, Henoch-Schonlein purpura, drug-induced vasculitis, mixed cryoglobulinemia essential, hypocomplementemia, Vasculitis associated with other types of malignancies, inflammatory bowel disease and primary biliary cirrhosis, Goodpasture syndrome. In addition, inflammatory diseases include all kinds of arthritis in children such as Juvenile Chronic arthritis that includes Still's disease, juvenile rheumatoid arthritis, juvenile ankylosing spondylitis. In addition, inflammatory diseases include diseases of the upper and lower airways such as chronic obstructive pulmonary diseases (COPD), allergic and non-allergic asthma, allergic rhinitis, allergic and nonallergic conjunctivitis. In addition, inflammatory diseases also include allergic and non-allergic dermatitis. In addition, inflammatory diseases include all kinds of depositional diseases such as Gout, pyrophosphate arthropathy and acute calcified periarthritis. In addition, inflammatory diseases include all kinds of inflammatory conditions that cause back pain that include infections, septic discitis, tuberculosis, malignancies (such as metastasis, myeloma, and others), spinal tumors, ankylosing spondylitis, acute disc prolapse, chronic discs / osteoarthritis, osteoporosis and osteomalacia. It also includes Pagets disease, hyperparathyroidism, renal osteodystrophy, spondylolisthesis, congenital abnormalities due to spinal stenosis and fibromyalgia. In addition, inflammatory diseases include all kinds of soft tissue rheumatism including bursitis, tenosynovitis or peritendinitis, enthesitis, nerve compression, periarthritis or capsulitis, muscle tension and muscle dysfunction. In addition, inflammatory diseases include inflammatory diseases of the gastrointestinal system (which include stomatitis of all kinds, pemphigus, bullous pemphigoid and benign pemphigoid of mucous membranes), salivary gland diseases (such as sarcoidosis, salivary duct obstruction and Sjogrens syndrome), inflammation of the esophagus (for example due to gastro-intestinal reflux). esophageal or infections with candida species, herpes simplex and cytomegalovirus), inflammatory diseases of the stomach (including acute and chronic gastritis, helicobacter pylori infection and Mentriers disease), inflammation of the small intestine (including celiac disease, enteropathy due to sensitivity to gluten, dermatitis herpetiformis, tropical sprue, Whipple's disease, radiation enteritis, systemic amyloidosis, connective tissue disorders - including lupus systemic erythematosus, polymyositis / dermatomyositis, systemic sclerosis, mixed connective tissue disease and sarcoidosis), eosinophilic gastroenteritis, intestinal lymphangiectasia, inflammatory bowel disease (which includes Chrohn's disease and ulcerative colitis), diverticular disease of the colon and irritable bowel syndrome. In a preferred embodiment, the invention relates to the use of one or more peptides according to the invention for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of a condition in the tissue of one or more organs of a mammal, wherein The condition is an inflammatory condition selected from lung inflammation, arthritis, dermatitis, pancreatitis and inflammatory bowel diseases.

Insufficiency of cells, tissues and organs induced by drugs In one embodiment, the present invention relates to the use of one or more peptides according to the invention for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of cell, tissue or cell failure. Organs induced by toxins or drugs.

In the present specification and claims, "drug-induced insufficiency of cells, tissues and organs" is defined as changes in the function and / or morphology of a cell, a tissue or an organ induced by a pharmacological compound. The pharmacological compound includes but is not restricted to chemotherapeutic agents for cancer that include cisplatin, carboplatin, dacarbezine, procarbazine, altretamine, semustine, lomustine, carmustine, busulfan, thiotepa, melphalan, cyclophosphamide, chlorambucil, mechlorethamine, azacitidine, cladribine, cytarabine, fludarabine, fluorouracil, mercaptopurine, metrotrexate, thioguanine, allopurinol, bleomycin, dactinomycin, daunorubicin , docetaxel, doxorubicin (adriamycin), etoposide, idarubicin, irinotecan, mitomycin, paclitaxel, plicamycin, topotecan, vinblastine, vincristine, vinorelbine, amasacrine, asparaginase, hydroxyurea, mititan, mitoxantrone; Antibiotics such as aminoglycosides including streptomycin, neomycin, kanamycin, amikacin, gentamicin, tobramycin, sisomycin and nitilmycin; immunosuppressive compounds such as cyclosporin, tricyclic antidepressants, lithium salts, prenylamine and phenothizine derivatives. Conditions where the normal function of the cell, tissue or organ is altered include conditions associated with ischemia, acute and / or chronic inflammation, allergy, rheumatic diseases, infection including viral, fungal, bacterial, prion and other microbes and infectious agents known in the field, all forms of toxic reactions including drug-induced toxicity and acute and chronic injury. Chronic injury includes situations of repetitive injuries that alternate with periods of complete or partial recovery of the function of the organ (s) or tissue (s). Conditions where the normal function of the cell, tissue or organ is altered may also include injury, which is associated with the implantation of one or more organs or other devices for transplantation and it is contemplated that the peptides of the invention will also be useful. in the treatment or prevention of conditions. The organ can be of the individual himself, the animal itself or of other individuals or animals. This includes organ transplants, bone transplants, soft tissue implants (silicone implants), metal and plastic implants or other implantable medical devices. An individual represents humans as well as other mammals. The condition to be treated can also be caused by a cancer or by a premalignant disorder that has an impact on the organ, for example on the respiratory system which includes lungs, bronchioles, airways above and / or over the heart and / or over the kidneys and / or over the gastrointestinal system, including acute leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia, Hodgkin's disease, lymphosarcoma, myeloma, metastatic carcinoma of any origin. It is contemplated that the peptides of the invention will also be useful in the treatment or prevention of conditions. In addition, the condition to be treated may be caused by any disease selected from diabetes mellitus, conditions with increased levels in fasting LDL-cholesterol, conditions with increased levels, combined in fasting LDL-cholesterol and triglycerides, conditions with increased fasting levels of triglycerides, conditions with increased levels of fasting HDL-cholesterol, retroperitoneal fibrosis, lupus erythematosus, polyarteritis nodosa, scleroderma, polymyositis, dermatomyositis, rheumatoid arthritis, anaphylaxis, serum sickness, hemolytic anemia and allergic agranulocytosis. It is contemplated that the peptides of the invention will also be useful in the treatment or prevention of conditions. Many infections can have an influence on the tissue and alter normal function resulting in decreased performance, which can be improved by administering an effective dose of a peptide. the invention. These infections include infections by protozoa, viruses, bacteria and fungi and include conditions such as AIDS, bacterial septicemia, systemic fungal infections, rickets diseases, toxic shock syndrome, infectious mononucleosis, chlamydia thrachomatis, chlamydia psittaci, cytomegalovirus infection, campylobacteria, salmonella, influenza, poliomyelitis, toxoplasmosis, Lassa fever, yellow fever, bilarciasis, bacteria of the genus coli, enterococci, proteus, klebsiella, pseudomonas, staphylococcus aureus, staphylococcus epidermidis, candida albicans, tuberculosis, mumps, infectious mononucleosis, hepatitis and Coxackie virus . The condition to be treated may be associated with a chemical trauma that involves one or more toxic substances and / or drugs. These drugs include tricyclic antidepressants, lithium salts, prenylamine, phenothizine derivatives, cancer chemotherapeutic agents including cisplatin, carboplatin, dacarbezine, procarbazine, altretamine, semustine, lomustine, carmustine, busulfan, thiotepa, melphalan, cyclophosphamide, chlorambucil, mechlorethamine , azacitidine, cladribine, cytorabine, fludarabine, fluorouracil, mercaptopurine, metrotrexate, thioguanine, allopurinol, bleomycin, dactinomycin, daunorubicin, docetaxel, doxorubicin (adriamycin), etoposide, idarubicin, irinotecan, mitomycin, paclitaxel, plicamycin, topotecan, vinblastine, vincristine, vinorelbine, amasacrine, asparaginase, hydroxyurea, mititan, mitoxantrone; Antibiotics such as aminoglycosides including streptomycin, neomycin, kanamycin, amikacin, gentamicin, tobramycin, sisomycin and nitilmycin; and immunosuppressive compounds such as cyclosporin. Physical trauma including electromagnetic radiation can also cause damage, which can be alleviated by administering an effective dose of an α-MSH analogue according to the present invention. The condition to be treated according to the present invention may further include a connective tissue disease such as scleroderma, systemic lupus erythematosus or by neuromyopathic disorders such as Duchenne-type progressive muscular dystrophy, Friedreich's ataxia and myotonic dystrophy. The condition can be related, for example, to the tissue of the intestine of the mammal. The invention also relates to the use of a peptide according to the invention, wherein the condition is selected from the group consisting of myocardial ischemia, angina, pericarditis, myocardial infarction, Myocardial ischemia, myocarditis, myxoedema and endocarditis. In one embodiment, the invention relates to the use of a peptide according to the invention, wherein the condition is associated with cardiac arrhythmia.

Methods of treatment The invention also relates to methods for the treatment or prevention of a condition in the tissue of one or more organs of an individual mammal in need thereof, the method comprising administering an effective dose of one or more peptides according to the invention. invention. The condition may be an ischemic or inflammatory condition and / or may result from toxic effects of poisoning or drug treatment. The method of treatment of the invention may be of special utility in relation to conditions caused by or associated with the transplantation of any organ or blood vessel, including the prevention of the graft-versus-host reaction. Under these conditions, the whole organ is extremely sensitive to all alterations with respect to nutrition, metabolism, perfusion, etc. and it is believed that the treatment according to the present invention stabilizes the condition and makes the tissue more resistant to any situation that causes tension in the function of the organ. The method according to the present invention also includes the administration of an effective dose of a peptide of the invention to organ transplantation during transport to the recipient, which includes the addition of an effective dose of a peptide of the invention to the transport medium. . In addition, the present application provides evidence that treatment with an α-MSH analog according to the invention in serious diseases such as myocardial ischemia dramatically prevents death and organ dysfunction. One of the most common cardiac conditions is intermittent angina or angina pectoris where the treatment according to the invention may be of special interest. Conditions that are related to angina include unstable angina, stable angina, and Prinzmetal variant angina. In an additional aspect, prevention and treatment can be used in situations caused by pericarditis, myocardial infarction, myocardial ischemia, myocarditis, myxoedema and endocarditis. The condition to be treated may be associated with cardiac arrhythmia. Either as the primary disease or as a result of another condition of the individual. Examples of miscellaneous causes of arrhythmia include acute infections particularly those that affect the lungs, pulmonary embolism, hypotension, shock, anoxaemia or anemia which can precipitate myocardial ischemia and thus cause arrhythmia. The arrhythmia will aggravate the circulatory disturbance and thus establish a vicious circle that is self-perpetuating. It is believed that the treatment according to the present invention will increase the threshold for the development of the arrhythmia thus preventing the development of the arrhythmia. The effect can be directly on the conduction system or indirectly when acting on a condition that deceives or that is the cause of the arrhythmia. A syndrome or arrhythmia that can be alleviated according to the present method can be either primary or secondary and can be selected from ventricular or supra-ventricular tachyarrhythmias, atrioventricular block, sick sinus disease, Wolff-Parkinson-White syndrome, Lenégres disease, Lev's disease, any syndrome that involves an abnormal myocardial connection between the atrium and the ventricle. The antiarrhythmic therapy performed with the aim of suppressing an arrhythmia is always associated with the risk of creating new arrhythmias. Arrhythmias can occur as a toxic reaction due to an overdose of the drug However, particularly during treatment with the group of drugs known as class IA drugs, arrhythmias can occur as a side effect not dependent on the dosage - an idiosyncratic reaction - which develops very well at drug concentrations within the therapeutic range. According to a further embodiment, the condition can be caused by one or more antiarrhythmic drugs including digitalis, quinidine, disopyramide, adenosine, aprindin, flecainide, amiodarone, sotalol, meciletine, beta-blockers and verapamil. It is contemplated that treatment with an α-MSH analogue according to the invention will decrease the risk of developing arrhythmias due to concomitant treatment with other antiarrhythmic drug (s). In a further aspect of the invention, the condition can be characterized by one or more abnormalities measured by an electrocardiogram (ECG). The abnormality in the ECG can be related to a selected alteration of one or more changes in the selected configuration of the P wave, the ST segment, the T wave, the QRS complex, the Q wave, the delta wave and the U wave. Other conditions which can be alleviated by the administration of an effective dose of a peptide according to the invention are the effect of the disturbance of electrolytes in the organ (for example the heart) as well as the disturbance itself, which includes abnormalities in the relative concentrations of individual ions with each other. This condition includes an abnormal concentration in the serum of one or more of the electrolytes selected from the group consisting of potassium, calcium, sodium and magnesium. According to the present invention, the tissue that can be affected includes one or more types of cells present in the organ and can be selected from epithelial cells, macrophages, the monocytes of the reticulo-endothelial system, neutrophil granulocytes, eosinophil granulocytes, basophil granulocytes. , T cells, B cells, mast cells and dendritic cells. Especially, T cells, B cells and mast cells may be of some interest in this regard. A preferred aspect of the invention relates to prevention or treatment wherein a dose of an α-MSH analog according to the invention is administered prophylactically to prevent the progress of the condition or any symptoms of the condition. A preventive or prophylactic treatment can be a constant treatment during for example surgery or for the prevention of heart attacks in a patient suffering from coronary stenosis. The preventive treatment It can also be for a limited period. The expert will be able to evaluate the specific treatment program based on the actual situation. In a preferred embodiment, the treatment or prevention is capable of reducing the size of the infarction with ischemia of the coronary arteries. This infarct size can be reduced by 20%, such as at least 30%, preferably at least 50% compared to the untreated individual. Accordingly, the dose of an α-MSH analogue according to the invention is administered prophylactically for the prevention of establishment of the condition or any symptom of the condition. The dose of an α-MSH analogue according to the invention can be administered as an individual dosage, as a regular or continuous administration or as a sequential administration. Administration can be a systemic administration, local administration including the use of drug target systems, catheters and implants, oral administration, parenteral administration, such as subcutaneous, intramuscular, intravenous administration, intraperitoneal administration, intrathecal administration, pulmonary administration, example by means of inhalation, topical administration, transmucosal administration, transdermal administration.

Accordingly, administration includes systemic administration; injection into the tissue or into a body cavity that includes the joints; the implant in the tissue or in a body cavity; Topical application to the skin or to any gastrointestinal surface or to a mucosal surface that includes the covering of the body cavities. As is evident from the foregoing, the present invention relates to the use of a peptide according to the invention for the preparation of a medicament for the treatment or prevention of any of the conditions disclosed herein by any route of relevant administration.

Formulations and pharmaceutical compositions The invention also relates to pharmaceutical compositions comprising one or more peptides according to the invention. The pharmaceutical compositions may further comprise one or more pharmaceutical carriers. In addition, the pharmaceutical compositions may further comprise one or more pharmaceutically acceptable excipients. The pharmaceutical compositions according to the invention can be, but are not limited to, a parenteral, oral, topical, trans-mucosal or trans-dermal composition.

In the following examples, suitable compositions containing one or more peptides according to the invention are administered. For administration to an individual (an animal or a human) the substance (s) is preferably formulated in a pharmaceutical composition containing the substance (s) and, optionally, one or more excipients pharmaceutically acceptable The compositions may be in the form of, for example, solid, semi-solid or fluid compositions such as, for example, but not limited to bioabsorbable patches, affusions, dressings, hydrogel dressings, hydrocolloid dressings, films, foams, foils, bandages. , plasters, delivery devices, implants, powders, granules, granules, capsules, agarose or chitosan beads, tablets, pills, tablets, microcapsules, microspheres, nanoparticles, sprays, aerosols, inhalation devices, gels, hydrogels, pastes, ointments , creams, soaps, suppositories, vaginal suppositories, dentifrices, solutions, dispersions, suspensions, emulsions, mixtures, lotions, mouth rinses, shampoos, enemas, equipment containing for example two separate containers, wherein the first of the containers contains a peptide according to the invention and the second container contains a suitable medium proposed to be added to the first rec before use in order to obtain a composition ready for use; and in other suitable forms such as, for example implants or the coating of implants or in a form suitable for use in connection with the implant or transplant. The compositions can be formulated in accordance with conventional pharmaceutical practice, see for example "Remington: The science and practice of pharmacy" 20th edition Mack Publishing, Easton PA, 2000 ISBN 0-912734-04-3 and "Encyclopedia of Pharmaceutical Technology" , edited by Swarbrick, J. & J.C. Boylan, Marcel Dekker, Inc., New York, 1988 ISBN 0-8247-2800-9. A pharmaceutical composition comprising an active substance serves as a drug delivery system. In the present context, the term "drug delivery system" denotes a pharmaceutical composition (a pharmaceutical formulation or a dosage form), which upon administration presents the active substance to the body of a human or animal. Thus, the term "drug delivery system" includes simple pharmaceutical compositions such as, for example, creams, ointments, liquids, powders, tablets, etc. as well as more sophisticated formulations such as sprays, plasters, bandages, dressings , devices, et cetera. As mentioned above, a composition Pharmaceutical for use according to the invention may comprise pharmaceutically or cosmetically acceptable excipients. The selection of pharmaceutically acceptable excipients in a composition for use according to the invention and the optimum concentration thereof can not be generally predicted and must be determined on the basis of an experimental determination thereof. As well, if a pharmaceutically acceptable excipient is suitable for use in a pharmaceutical composition it is generally dependent on what kind of dosage form is selected. However, a person skilled in the field of pharmaceutical formulation can find guidance for example "Remington: The science and practice of pharmacy" 20th edition Mack Publishing, Easton PA, 2000 ISBN 0-912734-04-3. A pharmaceutically acceptable excipient is a substance, which is substantially harmless to the individual to whom the composition will be administered. This excipient normally satisfies the requirements provided by the national drug agencies. Official Pharmacopoeias such as the British Pharmacopoeia, the Pharmacopoeia of the United States of America and the European Pharmacopoeia establish standards for well-known pharmaceutically acceptable excipients.

A review of the pharmaceutical compositions relevant for use according to the invention is provided below. This review is based on the particular administration route. However, it is appreciated that in those cases where a pharmaceutically acceptable excipient can be employed in different dosage forms or compositions, the application. of a particular pharmaceutically acceptable excipient is not limited to a particular dosage form or a particular function of the excipient.

Parenteral compositions For systemic application, the compositions according to the invention may contain conventionally non-toxic pharmaceutically acceptable carriers and excipients including microspheres and liposomes. The compositions for use according to the invention include all kinds of solid, semi-solid and fluid compositions. Compositions of particular relevance are, for example, solutions, suspensions, emulsions, gels, implant tablets and implants. The pharmaceutically acceptable excipients may include solvents, buffering agents, preservatives, humectants, chelating agents, antioxidants, stabilizers, emulsifying agents, suspending agents, gel forming agents, diluents, disintegrating agents, binding agents, lubricants and wetting agents. For examples of the different agents see below.

Topical, trans-mucous and trans-dermal compositions For application to the mucosa or skin, the compositions for use according to the invention may contain pharmaceutically acceptable, conventionally non-toxic carriers and excipients including microspheres and liposomes. The compositions for use according to the invention include all kinds of solid, semi-solid and fluid compositions. Compositions of particular relevance are, for example, pastes, ointments, hydrophilic ointments, creams, gels, hydrogels, solutions, emulsions, suspensions, lotions, liniments, sublingual tablets, suppositories, enema, pessaries, molded pessaries, vaginal capsules, vaginal tablets, shampoos. , gels, soaps, bars, sprays, powders, films, foams, pads, sponges (for example collagen sponges), pads, dressings (such as, for example, absorbent wound dressings), affusions, bandages, plasters and transdermal supply. Pharmaceutically acceptable excipients may include solvents, buffering agents, preservatives, humectants, chelating agents, antioxidants, stabilizers, emulsifying agents, suspending agents, gel-forming agents, ointment bases, suppository bases, penetration enhancers, perfumes, protective agents of the skin, diluents, disintegrating agents, bonding agents, lubricants and wetting agents. For examples of the different agents see below.

Oral compositions For application to the mucosa or skin, the compositions for use according to the invention may contain pharmaceutically acceptable, conventionally non-toxic carriers and excipients including microspheres and liposomes. The composition for use according to the invention includes all kinds of solid, semi-solid and fluid compositions. Compositions of particular relevance are for example solutions, suspensions, emulsions, uncoated tablets, modified release tablets, gastro-resistant tablets, orodispersible tablets, effervescent tablets, chewable tablets, soft capsules, hard capsules, modified release capsules, gastro capsules -resistant, uncoated granules, effervescent granules, granules for the preparation of liquids for oral use, coated granules, gastro-resistant granules, modified release granules, powders for oral administration and powders for the preparation of liquids for oral use. Pharmaceutically acceptable excipients may include solvents, buffering agents, preservatives, humectants, chelating agents, antioxidants, stabilizers, emulsifying agents, suspending agents, gel forming agents, diluents, disintegrating agents, bonding agents, lubricants, coating agents and wetting agents . For examples of the different agents see below.

Examples of various agents Examples of solvents are, but are not limited to, water, alcohols, vegetable or marine oils (for example edible oils such as almond oil, castor oil, cocoa butter, coconut oil, corn oil, cottonseed oil, flaxseed oil, olive oil, palm oil, peanut oil, poppyseed oil, rapeseed oil, sesame oil, soybean oil, sunflower oil and seed oil tea), mineral oils, oils fatty acids, liquid paraffin, polyethylene glycols, propylene glycols, glycerol, liquid polyalkylsiloxanes and mixtures thereof. Examples of buffering agents are, but are not limited to, citric acid, acetic acid, tartaric acid, lactic acid, hydrogen phosphoric acid, diethylamine, and the like. Examples of preservatives for use in compositions are, but are not limited to, parabens, such as methyl p-hydroxybenzoate, ethyl, propyl, butylparaben, isobutylparaben, isopropylparaben, potassium sorbate, sorbic acid, benzoic acid, methyl benzoate. , phenoxyethanol, Bronopol®, Bronidox®, MDM-hydantoin, iodopropynyl butylcarbamate, EDTA, benzalkonium chloride and benzyl alcohol or mixtures of preservatives. Examples of humectants are, but are not limited to, glycerin, propylene glycol, sorbitol, lactic acid, urea and mixtures thereof. Examples of chelating agents are, but are not limited to, sodium EDTA and citric acid. Examples of antioxidants are, but are not limited to, butylated hydroxy-anisole (BHA), ascorbic acid and derivatives thereof, tocopherol and derivatives thereof, cysteine and mixtures thereof. The examples of emulsification agents are, but are not limited to, gums of natural origin, for example gum acacia or gum tragacanth; phosphatides of natural origin, for example soybean lecithin; sorbitan monooleate derivatives; lanolins; wool alcohols; esters of sorbitan; monoglycerides; fatty alcohols; esters of fatty acids (for example triglycerides of fatty acids); and mixtures thereof. Examples of suspending agents are, but are not limited to, celluloses and cellulose derivatives such as, for example, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carrageenan, gum acacia, gum arabic, gum tragacanth and mixtures thereof. . Examples of gel bases which increase viscosity are, but are not limited to, liquid paraffin, polyethylene, fatty oils, colloidal silica or aluminum, zinc soaps, glycerol, propylene glycol, tragacanth gum, carboxyvinyl polymers, silicates magnesium aluminum, Carbopol®, hydrophilic polymers such as, for example, starch or cellulose derivatives such as, for example, carboxymethylcellulose, hydroxyethylcellulose and other cellulose derivatives, water-swellable hydrocolloids, carrageenans, hyaluronate (for example hyaluronate gel optionally containing sodium chloride) and alginates that include propylene glycol alginate. Examples of ointment bases are, but are not limited to, beeswax, paraffin, cetanol, cetyl palmitate, vegetable oils, sorbitan esters of fatty acids (SpanMR), polyethylene glycols and condensation products between sorbitan esters of acids fatty acids and ethylene oxide, for example polyoxyethylene sorbitan monooleate (Tween ™). Examples of hydrophobic ointment bases are, but are not limited to, paraffins, vegetable oils, animal fats, synthetic glycerides, waxes, lanolin and liquid polyalkylsiloxanes. Examples of hydrophilic ointment bases are, but are not limited to, solid macrogols (polyethylene glycols). Examples of powdered components are, but are not limited to, alginate, collagen, lactose, powder which is capable of forming a gel when applied to a wound (absorbs fluid / wound exudation). Examples of diluents and disintegrating agents are, but are not limited to, lactose, sucrose, Emdex ™, calcium phosphates, calcium carbonate, calcium sulfate, mannitol, starches and microcrystalline cellulose. The examples of linking agents are, but not are limited to, sucrose, sorbitol, acacia gum, sodium alginate, gelatin, starches, cellulose, carboxymethylcellulose, sodium, methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone and polyethylene glycol. Examples of wetting agents are, but are not limited to, sodium lauryl sulfate and Polysorbate 80MR. Examples of lubricants are, but are not limited to, talc, magnesium stearate, calcium stearate, silicon oxide, Precirol ™ and polyethylene glycol. Examples of coating agents are, but are not limited to, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpropylidone, ethylcellulose and polymethylacrylates. Examples of suppository bases are, but are not limited to, cocoa butter, adeps solidus and polyethylene glycols. The a-MSH analog may be present in the medicament in an amount of 0.001-99%, typically 0.01-75%, more typically 0.1-20%, especially 1-15% such as 1-10% by weight of the medication. The dose depends on the condition being treated.

The individual drugs can be used in doses known in the art. It is contemplated that the dose of one or more peptides according to the invention will be in the range of 1 ng to 100 mg per kg of body weight, typically from 1 μg to 10 mg per kg of body weight, more typically from 10 μg to 1 mg per kg of body weight, such as 50-500 μg per kg of body weight. In a still further aspect, the present invention relates to a pharmaceutical composition as described above, comprising one or more peptides according to the invention optionally with a pharmaceutically acceptable carrier. The pharmaceutical compositions according to the present invention can be prepared by the use of conventional techniques known in the art and with conventional pharmaceutical carriers. In addition, the pharmaceutical composition may be in any form suitable for any of the uses described herein. The invention described and claimed in this document is not limited in scope by the specific embodiments disclosed in this document, since these modalities are proposed as illustrations of various aspects of the invention. It is proposed that any equivalent embodiment be within the scope of this invention. Actually, several modifications of the invention in addition to those shown and described in this document will become apparent to those experts in the field from the above description. It is also proposed that these modifications are within the scope of the appended claims. Several references are cited in this document, the description of which is incorporated by reference in its entirety. Throughout this specification, the word "comprise" or variations such as "comprises" or "comprising" shall be understood to imply the inclusion of an element, integer or set step or a group of elements, integers or steps, but not the exclusion of some other element, integer or step or group of elements, integers or steps. With respect to the above description of the various aspects of the present invention and the specific modalities of these aspects it should be understood that any peculiarity and characteristic described or mentioned above in connection with an aspect and / or an embodiment of an aspect of the invention it also applies by analogy to any or all of the other aspects and / or embodiments of the described invention. Next, the invention will be described by means of the following non-limiting Figures and Examples.

EXAMPLES Next, the methods for testing the peptides of the invention are described in general. The results for the peptides tested are given in Examples 1-7. The objective of the methods is to test the peptides of the invention for the anti-inflammatory effects and the ability to inhibit or prevent the deterioration or destruction of cells / tissue / organs that occurs as a result of ischemia., inflammation or toxic effects of a drug. An inflammatory response or an exacerbation in chronic inflammation is characterized by the production of mediators derived from cells such as tumor necrosis factor a (TNF) -a, interleukins (IL-Iß, IL-8), nitric oxide (NO) and oxygen-free radicals, which will eventually induce widespread endothelial damage with loss of arteriolar tone in systemic vessels, increased capillary permeability, sustained hypotension and organ dysfunction, which in the lungs is associated with the accumulation of leukocytes including neutrophils and eosinophils within the alveolar space. A lipopolysaccharide (LPS), released from infectious agents, plays a central role in the inflammatory response to infection by inducing a variety of inflammatory mediators including TNF-α. Therefore, it is believed that Treatments with the ability to inhibit the production of TNF-a have marked anti-inflammatory effects. The inventor is using stimulation with LPS to produce an inflammatory response in a variety of configurations (see experimental configurations 1-3) and the primary marker for an anti-inflammatory effect of the peptides according to the invention is the ability to inhibit the production of TNF-a. Ischemia induced by reduced / complete arrest in the arterial blood supply induces multiple tissue reactions that include neutrophil accumulation, other inflammatory responses and cell death. The identification of compounds that could inhibit or prevent (either completely or partially) many of the cell / tissue / organ impairments or destruction that occur as a result of ischemia / inflammation is very useful. The inventor is using two models of temporal ischemia: 1) the reperfusion model of myocardial ischemia in rats, which mimics the development of acute myocardial infarction followed by restoration of blood supply as achieved by either therapy fibrinolytic or coronary angioplasty (experimental configuration 4); 2) bilateral obstruction of renal arteries, which induces acute renal failure (ARF) comparable to AFR induced by the temporary reduction in renal blood supply as seen in patients undergoing major surgical interventions (an example could be surgical intervention due to an abdominal aortic aneurysm) (experimental configuration 5). Nephrotoxicity is a well-known side effect for treatment with cisplatin. Although not necessarily, dose-limiting renal toxicity still affects most patients and a significant decrease in glomerular filtration rate is observed during treatment. The renal toxicity of cisplatin is observed as a direct cytotoxic damage to the nephrons in the outer medulla especially in the S-3 segment of the proximal ducts and in the thin ascending limb of the loop of Henle. Therefore, treatment with cisplatin frequently results in tubular reabsorption defects including a deteriorated ability to dilute the urine. Hypomagnesemia is observed in approximately 50% of patients treated with cisplatin and is probably due to a defect in the reabsorption of renal magnesium (Mg). A recent study has suggested that Mg supplementation is a crucial factor in the protection against the nephrotoxic actions of Cyclosporin A and has recently suggested a possible relationship between Mg loss and cisplatin-induced nephrotoxicity. Therefore, the treatment aimed at preventing hypomagnesemia would have beneficial effects in order not only to reduce the need for Mg supplementation, but also in order to reduce the renal toxicity of cisplatin. The effect of the peptides according to the invention on the nephrotoxicity induced by cisplatin is examined in the experimental configuration.

Methods and Materials The peptides of the present invention are the test compounds in the methods described below.

Experimental setup 1 Inhibition of LPS-induced TNF-α production by human leukocytes in vitro 20 ml of human blood are collected in vacutainer tubes containing EDTA. PBMCs are isolated using Ficoll-Paque Plus ™ as in the Amersham Instruction 71-7167-00 AD, 2002-06. The PBMCs are counted using a Blue Solution of Tryphan BlueMR (Sigma) and incubated in RPMI 1640, (Applichem), supplemented with 10 mM Hepes (Sigma), 2 mM L-glutamine (Sigma), 0.1% BSA (Sigma) ) and 50U / 50 μg / mL of Penicillin / Streptomycin (Sigma) in the concentration of 5 x 105 cells / mL. Isolated PBMC are incubated in a humidified atmosphere of 5% CO 2, 95% air, at 37 ° C, in 24-well flat bottom plates (Corning Incorporated) with a medium, 10 ng LPS / mL (Sigma) and test compound. After 18 hours, the samples are centrifuged and the TNF-α in the supernatants is measured using the Alpha Tumor Necrosis Factor [(h) TNF-a] of Human Biotrak ELISA System ™ (Amersham). Samples are incubated as follows by donor: PBMC's in RPMI (Time Control) PBMC's with 10 ng of LPS / mL (Vehicle) PBMCs, 10 ng of LPS / mL, a-MSH or a-MSH analog 10" 17M PBMC's, 10 ng LPS / mL, a-MSH or a-MSH analogue 10"1SM PBMC's, 10 ng LPS / mL, a-MSH or a-MSH analogue 10" 13M PBMC's, 10 ng LPS / mL , α-MSH or α-MSH analog 10"1: LM PBMC's, 10 ng LPS / mL, a-MSH or a-MSH analogue 10" 9M PBMC's, 10 ng LPS / mL, a-MSH or analogous a-MSH 10"7M All samples are diluted from an initial stock solution between 1.4x10" M and 1.8x10"3M All solutions are handled in flasks coated with BSA to protect them against binding of the compound to the surface of the vials The data are presented as mean ± SE The effect of the test compounds on the release of TNF-α induced by LPS is expressed as the percentage accumulation of TNF-a in the LPS-vehicle group. All comparisons are analyzed with Student's unpaired t-test. The differences are considered significant at probability levels (p) of 0.05.

Experimental Configuration 2 Inhibition of TNF-α production induced by LPS in rats in vivo Experimental animals. Female Wistar rats (220-240 g) are obtained from Charles River, Sulzfeld, Germany and are housed in a temperature room (22-24 ° C) and humidity (40-70%) controlled with a light-dark cycle 12 hours (the lights come on from 6:00 AM to 6:00 PM). The rats are maintained on a standard diet for rodents with 140 mmol / kg of sodium, 275 mmol / kg of potassium and 23% of protein (Altromin International, Lage, Germany) and have free access to water. Preparation of the animals. Under anesthesia of isoflurane-nitrous oxide, the animals are implanted with permanent Tygon ™ medical grade catheters in the abdominal aorta and the inferior vena cava, respectively, via a femoral artery and a vein. After the instrumentation, the animals are housed individually for 7-10 days until the day of the experiment.

Experimental protocol Prior to the experiments, all rats adapt to the retention cage used for the experiments by training them for two periods of two hours each. On the day of the experiment, the animal is transferred to a retention cage and an intravenous infusion of vehicle solution containing 150 mM glucose is initiated. The infusion rate is 0.5 ml / h throughout the experiment. After a short period of adaptation, the infusion of lipopolysaccharide (LPS) begins. The LPS (E. coli serotype 0127 B8, L 3129, Sigma, St. Louis, USA) is administered at a dose of 4 mg / kg of body weight transferred as an i.v. for 1 hour. Arterial blood samples of 0.3 ml are taken 60, 90 and 120 minutes after the start of the LPS infusion and it is>. they immediately replace heparinized blood from a normal donor rat. Experimental groups: In addition to the infusion of LPS, all rats are treated with a bolus injection of: Vehicle (0.5 mL of isotonic saline); a-MSH in one of the following doses: 50 μg / kg pe; 200 μg / kg / pc or 1000 μg / kg pe; Test compound in one of the following doses: 50 μg / kg pe; 200 μg / kg / pc or 1000 μg / kg pe. Measurement of TNF-a in plasma: Blood samples are collect in a test tube previously cooled with 0.5 mM EDTA, pH 7.4 and 20 x 106 IU / ml aprotinin. After centrifugation at 4 ° C, the plasma samples are transferred to the pre-cooled test tubes and stored at -20 ° C for subsequent measurements of TNF-α. TNF-α in the plasma is determined by means of an ELISA assay (Biotrak, Amersham, UK). Statistical analysis. The results are presented as means ± SE. A two-way ANOVA analysis for repeated measurements is used to test the differences between the groups. In the case of P < 0.05, the differences between corresponding periods are evaluated by unpaired t-tests with the Bonferroni correction of the level of statistical significance.

Experimental Configuration 3 Inhibition of neutrophil and eosinophil infiltration after inhalation of LPS in rats Male Sprague-Dawley rats (weight ~ 200 g) of M & BA / S, DK-8680 Ry, Denmark, are used for all experiments . The rats are caged in standard type 3 cages and are housed in a room at temperature (22-24 ° C) and humidity (40-70%) controlled with a light-dark cycle of 12 hours (the light is turned on 6). : 00 AM to 6:00 PM). The diet is a special formulation sterilized in Autoclave Altromin 1324MR, Produced by Altromin Denmark, Chr. Pedersen A / S, 4100 Ringsted, Denmark. Diet and water are administered ad libitum. After acclimatization, the rats are randomly distributed to the experimental groups and dosed i.v. with the test compound at the start of the LPS induction and once again 8 hours after the induction of LPS. The rats in groups of 3 were anesthetized with 0.1 ml of Hypnorm ™ / Dormicum ™ per 100 g and dosed i.v with the test compound. Immediately after dosing, they are placed in the inhalation chamber where they are attached to a nebulized solution of LPS. The concentration of LPS is 1 mg / ml. The dosing time is 15 minutes. The rats are euthanized 24 hours after dosing with the test substance. At the end, the rats are euthanized with C02 / 02. Then, the bronchoalveolar lavage is performed when installing and removing 6 x 2.5 ml of PBS to the right lung. The washing is done with the lungs remaining in the chest after the removal of the sternum and the ribs. The connection to the right lung is tied during this procedure. The bronchoalveolar fluid (BALF) is centrifuged at 1000 rpm at 4 ° C for 10 minutes. After removal of the supernatant, the cell pellet is resuspended in 0.5 ml of PBS and performs the total cell count. Two BALF slides dyed with May-Grüwald Giemsa tincture are made from each rat. The BALF of each rat is subjected to a total cell count and a differential leukocyte count. Experimental groups: In addition to the infusion of LPS, all rats were treated with bolus injections of either: Vehicle (0.5 mL of isotonic saline); a-MSH: 200 μg / kg / pc a-MSH analogue: 200 μg / kg / pc Finally, a non-inhaled time control group of LPS is treated with a vehicle. Statistics The data are presented as means ± S.E. Between groups, comparisons are made by means of an analysis of variance followed by the Less Differences test Significant of Fishers. The differences are considered significant at the 0.05 level.

Experimental Configuration 4 Inhibition of cytokine release induced by LPS and pulmonary hypertension in pigs in vivo Landrace sows (~ 30 kg) are fasted overnight but are allowed free access to water. Then, the sows are previously medicated with intramuscular ketamine (10 mg / kg) and midazolam (0.25 mg / kg). Anesthesia is induced with intravenous ketamine (5 mg / kg). The sows are intubated orally and the anesthesia is maintained with a continuous intravenous infusion of fentanyl (60 μg / kg / h and midazolam (6 mg / kg / h) .The animals are ventilated with a volume controlled ventilator (Servo 900MR ventilator; Elema, Solna, Sweden) with a positive end expiratory pressure of 5 cm H20.The volume of pulmonary ventilation is maintained at 10-15 ml / kg and the respiratory rate is adjusted (20-25 breaths / minute) to maintain a normocapnia (arterial carbon dioxide tension [PaC02] in the range of 34-45 mmHg) The ventilation is carried out with oxygen in air in order to reach an arterial oxygen tension (Pa02) higher than 105 mmHg. and 2 venous coats are placed in the carotid artery and the corresponding veins for infusion, for blood pressure measurements through the fluid-filled catheter, for blood sampling and for catheter insertion. n-GanzMR (Edwards Lifescience Corp., Irvine, CA) is inserted into the pulmonary artery via the right superior vena cava. The location of the balloon tip catheter is determined by observing the characteristic pressure trace on the screen as it is done advance through the right side of the heart into the pulmonary artery as well as through X-rays. Another catheter (5 French, St. Jude Medical Company, St. Paul, MN) is inserted into the left carotid artery for continuous monitoring of blood pressure and blood sampling. A urine catheter is inserted for urine collection. A temporary placement catheter is inserted through the venous sheath to the right atrium (guided by x-rays) to standardize the heart rate, when evaluating cardiac performance. Hemodynamic supervision. Continuous observations are made of arterial blood pressure, heart rate (from the electrocardiogram) and pulmonary artery pressure (PAP). Infusion of lipopolysaccharide. The lipopolysaccharide endotoxin of Escherichia coli, (E. coli 026: _6, Bacto Lipopolysaccharides; Difco Laboratories, Detroit, MI) is dissolved in saline 120 minutes before each experiment to dissolve any precipitated product. After a period of stabilization, the lipopolysaccharide infusion is initiated at the reference line at a rate of 2.5 μg / kg / h and gradually increased to 15 μg / kg / minute for 30 minutes. After this, the infusion was maintained at a rate of 2.5 μg / h kg / h for 150 minutes and then discontinued.

Intervention groups: The control group is given a vehicle in a volume equal to the intervention group immediately before the LPS infusion is started. The intervention group is administered a dose of a-MSH analog, 200 μg / kg, as an individual intravenous bolus injection. Cytokines Fresh frozen plasma samples (-80 ° C) obtained from blood stabilized with EDTA are used for measurements of TNF-a by the use of enzyme-linked immunosorbent assays commercially available according to the manufacturer's instructions. Statistics The data are presented as means + S.E.

Among the group, comparisons are made by means of an analysis of variance followed by the Differences test Less Significant of Fishers. The differences are considered significant at the 0.05 level.

Experimental setup 5 Inhibition of myocardial infarct size, induced by a 60-minute obstruction of the left anterior descending coronary artery in rats Wistar female rats reared barrier-free and free of specific pathogens (250 g) are obtained from Charles River, Hannover, Germany. The animals are they are housed in a temperature room (22-24 ° C) and humidity (40-70%) controlled with a 12-hour light-dark cycle (the light is switched on from 6:00 a.m. to 6:00 p.m.). All animals are given free access to the tap water and a granulated rat diet containing approximately 140 mmol / kg of sodium, 275 mmol / kg of potassium and 23% protein (Altromin ™ Catalog No. 1310, Altromin International, Lage, Germany). The rats are instrumented with permanent Tygon ™ medical grade catheters in the inferior vena cava and the abdominal aorta via the femoral vein and an artery. One week later, the rats were anesthetized in an inhalation chamber with 4% isoflurane in 02. After the insertion of an endotracheal tube, the animal was artificially ventilated with 1.0% isoflurane in 02 using a rodent fan from Hugo Basile . The volume of pulmonary ventilation is 8-10 ml / kg of p.c. and the breathing rate is 75 min "1, which maintains the arterial pH between 7.35 and 7.45 During the surgery, the animal is placed on a heated table that maintains the rectal temperature at 37-38 ° C. The standard ECG ( second contact) is measured using a Hugo Sachs ECG Coupler and is collected online at 4,000 Hz in PowerLab After the parental thoracotomy and the pericardial opening, the left anterior descending coronary artery (LAD) is localized visually. An atraumatic 6-0 silk suture with an obstruder that allows reopening of the ligature is placed around the LAD between the pulmonary trunk and the lower right end of the left atrium. After 10 minutes, the left anterior descending coronary artery (LAD) becomes obstructed. Successful obstruction is confirmed by alterations in the ECG (elevation of the ST segment and increase in the amplitude of the R wave) and by a decrease in MAP. Reperfusion is done after 60 minutes when the obstruction is opened. The control rats are operated in a feigned manner. The rats are subjected to one of the following i.v. treatments: Vehicle: 0.5 ml of 150 mM NaCl. a-MSH: 200 μg or 1000 μg of α-melanocyte stimulating hormone / kg of p.c. in 0.5 ml of 150 mM NaCl. Test Compound 200 μg or 1000 μg test compound / kg p.c. in 0.5 ml of 150 mM NaCl. The treatment is administered 5 minutes before reperfusion. Determination of ischemic and necrotic myocardium size Rats remain anesthetized after ischemia / reperfusion and re-obstruction is performed.

LAD after a three-hour reperfusion. During this period, the ECG and the MAP are measured continuously. Then, the Evans Blue dye (1 ml, 2% w / v) is administered i.v. to determine the size of the ischemic area. The heart is removed and cut into horizontal slices to determine the size of the ischemic area and to separate the ischemic myocardium from non-ischemic myocardium. The ischemic area is isolated and incubated in 0.5% triphenyltetrazolium chloride solution for 10 minutes at 37 ° C. The size of the necrotic tissue is then measured by the use of a program of computerized images. An additional configuration of animals is treated with postoperative buprenorphine and returned to their cages for the measurement of left ventricular end diastolic pressure (LVEDP) two weeks later in order to assess the effect of pharmacological treatment on the development of the insufficiency. congestive heart LVEDP is measured using Microtip 2FR catheters inserted into the left ventricle via the right carotid artery. The concentration of isoflurane is adjusted to stabilize the mean arterial pressure (MAP) at 85-90 mmHg. Statistics The data are presented as means ± S.E. Within the group, the comparisons are analyzed with Student's paired t-test. Among the group, comparisons are made by means of an analysis of variance followed by the Less Significant Differences of Fishers test. The differences are considered significant when 0.05 level.

Experimental setup 6 Inhibition of renal failure induced by a bilateral 40-minute obstruction of the renal arteries in rats Wistar female rats reared barrier-free and free of specific pathogens (250 g) is obtained from Charles River, Hannover, Germany. The animals are housed in a room temperature (22-24 ° C) and humidity (40-70%) controlled with a light-dark cycle of 12 hours (the light is turned on from 6:00 AM to 6:00 PM ). All animals are given free access to the tap water and a granulated rat diet containing approximately 140 mmol / kg of sodium, 275 mmol / kg of potassium and 23% protein (Altromin ™ Catalog No. 1310, Altromin International, Lage, Germany). The rats, which have been previously instrumented with a chronic venous catheter, are placed in metabolic cages and after a period of acclimation of two days to the metabolic cages, the experimental ARF is induced by the obstruction of both renal arteries during 60 minutes. . During surgery, the rats are anesthetized with isoflurane-nitrous oxide and placed on a heated table to maintain the temperature rectal at 37 ° C. Both kidneys are exposed through incisions on the sides, immobilized when dissected free of perirenal fat, then a small portion of the renal artery is dissected gently from the vein. The renal arteries are obstructed with a small vascular surface clamp (pressure 60 g, World Precision Instruments, UK) for 40 minutes. Total ischemia is confirmed by observing discoloration of the entire surface of the kidneys. During the period of ischemia, the wounds are temporarily closed to maintain body temperature. After the small forceps are removed, the kidneys are observed for an additional 2-5 minutes to ensure the color change, indicating a reflux of blood. Then, the wounds are closed with 3-0 silk ligatures. The rats are returned to lce metabolic cages and the urine output and water uptake is measured daily in 24 hours for five days. As a control group, the rats are subjected to simulated operations identical to those used for rats with RFA without obstruction of the renal arteries. The mock-operated rats are monitored in parallel to the rats with RFA. The rats are subjected to one of the following i.v. treatments: Vehicle: 0.5 ml of 150 mM NaCl. α-MSH: 200 μg of α-melanocyte stimulating hormone / kg of p.c. in 0.5 ml of 150 mM NaCl. Test compound: 200 μg test compound / kg p.c. in 0.5 ml of 150 mM NaCl. The treatment is administered 5 minutes before reperfusion of the kidney and subsequently 6 and 24 hours later. Statistics The data are presented as means ± S.E. Within the group, the comparisons are analyzed with the Student's paired t-test. Between the group, comparisons are made by means of an analysis of variance followed by the Less Significant Differences test of Fishers. The differences are considered significant at the 0.05 level.

Experimental setup 7 Inhibition of renal insufficiency induced by Cisplatin Rats, which have been previously instrumented with a chronic venous catheter, are placed in metabolic cages and after a period of acclimation to the metabolic cages, the rats are treated with an intraperitoneal injection of cisplatin 5.0 mg / kg pc in 0. 5 ml of 150 mM NaCl or vehicle (0.5 ml of 150 mM NaCl).

Five days later, the rats are then returned to the metabolic cages and the urine output is measured daily and water collection in 24 hours and it is collected during the following five days. All rats are then anesthetized in halothane / N20 and an arterial blood sample is collected in pre-cooled EDTA-coated flasks. Blood samples are collected in a test tube previously cooled with 0.5 mM EDTA, pH 7.4 and 20 x 106 IU / ml of aprotinin. After centrifugation at 4 ° C, the plasma samples are transferred to pre-cooled test tubes and stored at -20 ° C for subsequent measurements of creatinine and Magnesium (Mg). In addition to this, creatinine is also measured in the urine collected in the period of the last 24 hours before blood collection. The creatinine clearance (Ccr), used as an index of the glomerular filtration rate (GFR), can then be calculated as Ccr = Vu x Ucr / Pcr, where Vu is the production of urine in 24 hours; UCR is the concentration of creatinine in the urine and Pcr is the concentration of creatinine in the plasma. The measurement of creatinine in urine and plasma is made through the use of VITROS 950MR clinical clinical systems (Ortho-Clinical Diagnostics Inc., Johnson &Johnson, NJ) and Roche Hitachi Modular ™ (Roche Diagnostics, Mannheim, Germany). The rats are subjected to one of the following i.v. treatments: Vehicle: 0.5 ml of 150 mM NaCl. α-MSH: 200 μg of α-melanocyte stimulating hormone / kg of p.c. in 0.5 ml of 150 mM NaCl. Test compound: 200 μg test compound / kg p.c. in 0.5 ml of 150 mM NaCl. The treatment is administered minutes before reperfusion of the kidney and subsequently 6 and 24 hours later. Statistics The data are presented as means ± S.E. Within the group, the comparisons are analyzed with the Student's paired t-test. Within the group, comparisons are made by means of an analysis of variance followed by the Less Significant Differences test of Fishers. The differences are considered significant at the 0.05 level.

Results Example 1 The test compound is the analog of α-MSH # 1: Ac-Lys-Lys-Lys-Lys-Lys-Lys-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly -Lys-Pro-Val-NH2 (SEQ ID No. 1 * acetylated at the N-terminus and amidated at the C-terminus) The compound is tested in experimental configurations 1-7.

Inhibition of LPS-induced TNF-α production by human leukocytes iii vitro Both a-MSH and the a-MSH # 1 analogue (SEQ ID NO: 1 *) reduce TNF-a accumulation in a dose-dependent manner induced by LPS in the suspension of human leukocytes. Surprisingly, the inhibitory effect of the a-MSH # 1 analog (SEQ ID NO.l *) is markedly more pronounced than the anti-inflammatory effect of the native a-MSH peptide. Α-MSH inhibits the accumulation of TNF-α at 73 ± 9% of the maximum response (LPS-Vehicle). In contrast to this, the analogue of a-MSH # 1 (SEQ ID NO.l *) is capable of reducing the accumulation of TNF-a at 47 ± 2% of the vehicle (P <0.01 vs a-MSH) (see Figure 1).

Inhibition of LPS-induced TNF-α production in rats in vivo Both a-MSH and the a-MSH # 1 analogue (SEQ ID NO.l *) reduce the accumulation of TNF-a in rats during i.v. of LPS. The maximum inhibitory effect of a-MSH as well as the a-MSH # 1 analogue (SEQ ID NO.l *) is achieved at a dose of 200 μg / kg body weight and the maximum inhibitory effect on TNF production -a is displayed 120 minutes after the start of the LPS infusion. Surprisingly, the inhibitory effect of the a-MSH # 1 analogue (SEQ ID NO.l *) is markedly more pronounced than the anti-inflammatory effect of the native peptide a-MSH. While a-MSH inhibits the concentration of TNF-α in the plasma of rats at 17 ± 3% of the maximal response (LPS-Vehicle), the analogue of a-MSH # 1 (SEQ ID NO.l *) is able to reduce the accumulation of TNF-a to 9 ± 1% of the vehicle (P = 0.05 vs a-MSH) (see Figure 2).

Inhibition of neutrophil and eosinophil infiltration after inhalation of LPS in rats Both the a-MSH and the a-MSH # 1 analog (SEQ ID NO.l *) reduce the inflammatory response to inhalation of LPS within the alveolar space as shown by a marked reduction of eosinophils in the BALF collected 24 hours after inhalation of LPS. Treatment with a-MSH reduces the number of eosinophils within the BALF to 26.7 + 4.3 x 10 5 cells (P vs Vehicle <0.05) and the analog of a-MSH # 1 (SEQ ID NO.l *) reduces the number of eosinophils at 49.0 ± 10.5 x 10 5 cells (P vs Vehicle <0.05) compared to vehicle-treated rats where the number of eosinophils within the BALF is 164.6 ± 42.2 x 10 5 cells (see Figure 3). According to the foregoing, the effect of the number of neutrophils within BALF is similar for a-MSH and the analog of a-MSH # 1 (SEQ ID NO.l *). Inhibition of cytokine release and pulmonary hypertension induced by LPS in pigs in vivo The a-MSH # 1 analogue (SEQ ID NO.l *) has marked anti-inflammatory effects shown by marked reduction in plasma concentrations of TNF-a after infusion of LPS in pigs treated with the analogue of -MSH # 1 (SEQ ID NO.l *). In addition to this anti-inflammatory effect, the a-MSH # 1 analogue (SEQ ID NO.l *) also surprisingly has the ability to protect against the development of pulmonary hypertension as evidenced by marked attenuation in the LPS-induced increases. in the PAP found in rats treated with the analogue of a-MSH # 1 (SEQ ID NO.l *) (maximum increase in PAP: Vehicle: 22 ± 4 mmHg vs analog of a-MSH # 1 (SEQ ID NO.l *): 8 ± 2 mmHg; p = 0.05) (See Figure 4).

Inhibition of the size of myocardial infarction, induced by a 60 minute obstruction of the left anterior descending coronary artery in rats In contrast to a-MSH, the a-MSH analogue # 1 (SEQ ID NO.l *) surprisingly reduces the size of the myocardial infarction expressed as the necrotic area as a fraction of the risk area measured 3 hours after the reperfusion of LAD. The maximum inhibitory effect of the a-MSH # 1 analogue (SEQ ID NO.l *) is achieved at a dose of 200 μg / kg body weight where the reduction in infarct size is ~ 30% compared to rats treated with Vehicle (Vehicle: 50.6 + 2.6% risk area vs analogous to a-MSH # 1 (SEQ ID NO.l *): 35.7 ± 5.6% risk area, p = 0.01). At a dose of 1000 μg / kg of body weight, the reduction in infarct size is also ~ 30% compared to rats treated with Vehicle (analogous to a-MSH # 1 (SEQ ID NO.l *): 35.0 ± 4.4% risk area, p <0.01 vs Vehicle) (See Figure 5). The measurement of the diastolic pressure of the left ventricular end (LVEDP) in an additional animal configuration 14 days after the obstruction during 60 minutes of LAD, shows that the beneficial effect of the analog of a-MSH # 1 (SEQ ID NO.l *) on the size of the infarcts was associated with a marked reduction in LVEDP and thus the development of congestive heart failure after infarction (LVEDP: analog of a-MSH # 1 (SEQ ID NO.l *): 10.4 + 2.9 mmHg; vs Vehicle: 20.0 + 2.2 mmHg; P <0.01; vs time control: 7.5 ± 2.3 mmHg; NS) (see Figure 6).

Inhibition of renal insufficiency induced by bilateral obstruction during 40 minutes of the renal arteries in rats Bilateral renal ischemia during 60 minutes (RIR) induces a marked post-ischemic polyuria. Rats with RIR have a sustained polyuria, which on day 5 after the ischemic attack is increased by 101% in comparison with control rats operated in a mock manner (RIR-Vehicle: 34.8 ± 3.3 ml / 24 hours vs time-control: 17.3 ± 2.1 ml / 24 hours, p <0.01). Treatment with a-MSH is unable to reduce polyuria (RIR-a-MSH: 29.0 ± 2.9 ml / 24 hours, NS vs RIR-Vehicle). Surprisingly, the analog of a-MSH # 1 (SEQ ID NO.l *) is capable of inducing a complete normalization of the urine flow rate (RIR-analog of a-MSH # 1 (SEQ ID NO.l *) : 18.8 ± 3.6 ml / 24 hours, NS vs time-control, P <0.01 vs RIR-Vehicle) (see figure 7).

Inhibition of cisplatin-induced renal failure Treatment with cisplatin induces marked hypomagnesemia and nephrotoxicity as evidenced by a decrease in GFR. Accordingly, rats treated with cisplatin and vehicle induced hypomagnesemia (Mg in Plasma: 0.61 ± 0.04 mM vs. control rats: 0.77 ± 0.05 mM, P <0.05) and a marked decrease in GFR. The Mg in the plasma is also reduced in the rats treated with cisplatin and a-MSH (0.37 + 0.04 mM, P <0.05 vs control rats). Surprisingly, treatment with the a-MSH # 1 analogue (SEQ ID NO.l *) prevents cisplatin-induced hypomagnesemia (0.84 + 0.04 mM, NS vs. control rats) and prevents the decrease in GFR induced by cisplatin.

Example 2 The test compound is the analog of α-MSH # 2: Ac-Lys-Lys-Lys-Lys-Lys-Lys-Ser-Tyr-Ser-Nle-Glu-His- (D-Phe) -Arg- Trp-Gly-Lys-Pro-Val-NH2 (SEQ.NO.sub.5 * acetylated at the N-terminus and amidated at the C-terminus) The analogue of a-MSH # 2 (SEQ.NO.sub.5) differs from the analogue of -MSH # 1 (SEQ ID NO.l *) by the substitution of Met by Nle at position 10 and by the stereochemical substitution of Phe by (D-Phe) at position 13. The compound is tested in the configurations experimental 1-3 and 5-7.

Inhibition of LPS-induced TNF-α production by human leukocytes in vi tro Both a-MSH and the a-MSH # 2 analogue (SEQ.NO. 5 *) reduce TNF- accumulation in a dose-dependent manner to LPS-induced suspension in human leukocytes. Surprisingly, the inhibitory effect of the a-MSH # 2 analogue (SEQ.NO.5 *) is markedly more pronounced than the anti-inflammatory effect of the native a-MSH peptide. Α-MSH inhibits the accumulation of TNF-α at 73 + 9% of the maximum response (LPS-Vehicle). In contrast to this, the analog of a-MSH # 2 (SEQ.NO.5 *) is able to reduce the accumulation of TNF-a at 42 ± 11% of the vehicle (P <0.01 vs a-MSH) (see Figure 8).

Inhibition of LPS-induced TNF-a production in rats in vivo Both a-MSH and the a-MSH # 2 analogue (SEQ.

NO.5 *) reduce the accumulation of TNF-a in rats during the i.v. of LPS. The maximum inhibitory effect of a-MSH as well as the a-MSH # 2 analogue (SEQ.NO.5 *) is achieved at a dose of 200 μg / kg body weight. Surprisingly, the inhibitory effect of the a-MSH # 2 analogue (SEQ.NO.5 *) is markedly more pronounced than the anti-inflammatory effect of the native a-MSH peptide. While α-MSH inhibits the concentration of TNF-α in the plasma of rats at 17 ± 3% of the maximal response (LPS-Vehicle), the analog of α-MSH # 2 (SEQ.NO.5 *) is able to reduce the accumulation of TNF-a to 9 ± 1% of the vehicle (P <0.05 vs a-MSH) (see Figure 9).

Inhibition of neutrophil and eosinophil infiltration after inhalation of LPS in rats Both a-MSH and the analogue of a-MSH # 2 (SEQ.

NO.5 *) reduce the inflammatory response to inhalation of LPS within the alveolar space as shown by a marked reduction of eosinophils in the BALF collected 24 hours after inhalation of LPS. The treatment with a-MSH reduces the number of eosinophils within the BALF to 26. 714.3 x 105 cells (P vs. Vehicle <0.05) and the a-MSH # 1 analogue (SEQ.NO.5 *) reduce the number of eosinophils to 34. 0 ± 8.6 x 105 cells (P vs Vehicle <0.05) compared to vehicle-treated rats where the number of eosinophils within the BALF is 164.6 + 42.2 x 10 5 cells (see figure 10). Surprisingly, the a-MSH # 2 analogue (SEQ.NO.5 *) has much more pronounced inhibitory effects on neutrophils within BALF than a-MSH (analogue of a-MSH # 2 (SEQ.NO. 5 *) : 9.1 ± 2.4 x 105 cells vs a-MSH: 20.1 ± 2.5 x 10 5 cells, P <0.05) (see Figure 11).

Inhibition of the size of myocardial infarction, induced by a 60 minute obstruction of the left anterior descending coronary artery in rats In contrast to a-MSH, the a-MSH analogue # 2 (SEQ. NO.5 *) surprisingly reduces the size of the myocardial infarction expressed as the necrotic area as a fraction of the risk area measured 3 hours after the reperfusion of LAD. The maximum inhibitory effect of α-MSH analog # 2 (SEQ.NO.5 *) is achieved at a dose of 200 μg / kg body weight where the reduction in infarct size is ~ 27% compared to rats treated with Vehicle (Vehicle: 51.4 ± 2.1% risk area vs analogous to a-MSH # 2 (SEQ.NO.5 *): 37.4 ± 5.1% risk area, p = 0.01) (see Figure 12). Measurement of diastolic pressure of the left ventricular end (LVEDP) in an additional animal configuration 14 days after the obstruction during 60 minutes of LAD, shows that the beneficial effect of the analogue of a-MSH # 2 (SEQ.NO.5 *) on the size of infarcts is associated with a marked reduction in LVEDP and therefore the development of congestive heart failure after infarction.

Inhibition of renal insufficiency induced by bilateral obstruction during 40 minutes of the renal arteries in rats Bilateral renal ischemia during 60 minutes (RIR) induces a marked post-ischemic polyuria. Rats with RIR have a sustained polyuria, which on day 5 after the ischemic attack is increased by 101% compared to control rats operated in a sham (RIR-Vehicle: 34.8 ± 3.3 ml / 24 hours vs. time- control: 17.3 + 2.1 ml / 24 hours, p <0.01). Treatment with a-MSH is incapable of reducing polyuria (RIR-a-MSH: 29.0 + 2.9 ml / 24 hours; NS vs. RIR-Vehicle) in contrast to this treatment with the analogue of a-MSH # 2 (SEQ. NO.5 *) markedly reduces the degree of polyuria found after of the RIR. Inhibition of cisplatin-induced renal failure Treatment with cisplatin induces marked hypomagnesemia and nephrotoxicity as evidenced by a decrease in GFR. Accordingly, rats treated with cisplatin and vehicle develop hypomagnesemia (Mg in Plasma: 0.61 ± 0.04 mM vs. control rats: 0.77 ± 0.05 mM, P <0.05) associated with a decrease in GFR. The Mg in the plasma is also reduced in the rats treated with cisplatin and a-MSH (0.37 + 0.04 mM, P <0.05 vs control rats). In contrast to this, the a-MSH # 2 analogue (SEQ.NO.5 *) prevents cisplatin-induced hypomagnesemia as well as the decrease in GFR induced by cisplatin.

Example 3 The test compound is the analog of α-MSH # 3: Ac-Lys-Lys-Lys-Lys-Lys-Lys-Ser-Tyr-Ser-Nle-Glu-His-D-Nal-Arg-Trp- Gly-Lys-Pro-Val-NH2 (SEQ NO.9 * acetylated at the N-terminus and amidated at the C-terminus) The analogue of a-MSH # 3 (SEQ.NO.9) differs from the analogue of a-MSH # 1 (SEQ ID NO.l *) by the replacement of Met by Nle at position 10 and by the substitution of Phe by D-Nal at position 13. The compound is tested in the experimental configurations 1, 2 and 5.

Inhibition of LPS-induced TNF-α production by human leukocytes in vi tro Both a-MSH and the analogue of a-MSH # 2 (SEQ ID NO.9 *) reduce the accumulation of TNF-α induced by LPS in the suspension of human leukocytes in a dose-dependent manner. Surprisingly, the inhibitory effect of the a-MSH # 3 analog (SEQ ID NO.9 *) is markedly more pronounced than the anti-inflammatory effect of the native a-MSH peptide. Α-MSH inhibits the accumulation of TNF-α at 73 ± 9% of the maximum response (LPS-Vehicle). In contrast to this, the a-MSH # 3 analogue (SEQ ID NO.9 *) is capable of reducing the accumulation of TNF-α at 53 ± 13% of the vehicle (P <0.05 vs a-MSH) (see Figure 13).

Inhibition of LPS-induced TNF-α production in rats in vivo Both a-MSH and the a-MSH # 3 analogue (SEQ ID NO.9 *) reduce the accumulation of TNF-α in rats during the i.v. of LPS. The maximum inhibitory effect of a-MSH as well as the a-MSH # 3 analogue (SEQ ID NO.9 *) is achieved at a dose of 200 μg / kg body weight. Surprisingly, the inhibitory effect of the a-MSH # 3 analogue (SEQ ID NO.9 *) is markedly more pronounced than the anti-inflammatory effect of the native peptide a-MSH. While α-MSH inhibits the concentration of TNF-α in the plasma of rats at 17 + 3% of the maximum response (LPS-Vehicle), the analog of α-MSH # 3 (SEQ ID NO.9 *) is able to reduce the accumulation of TNF-α at 11 ± 3% of the vehicle (P <0.p5 vs a-MSH) (see Figure 14).

Inhibition of myocardial infarct size, induced by a 60 minute obstruction of the left anterior descending coronary artery in rats In contrast to a-MSH, the a-MSH # 3 analog (SEQ ID NO.9 *) surprisingly reduces the size of the myocardial infarction expressed as the necrotic area as a fraction of the risk area measured 3 hours after the reperfusion of LAD. The maximum inhibitory effect of the a-MSH # 3 analogue (SEQ ID NO.9 *) is achieved at a dose of 200 μg / kg body weight where the reduction in infarct size is ~ 24% compared to rats treated with Vehicle (Vehicle: 51.3 ± 2.1% risk area vs analogue of a-MSH # 3 (SEQ ID NO.9 *): 39.0 ± 3.4% risk area, p = 0.05) (see Figure 15) . Measurement of diastolic pressure of the left ventricular end (LVEDP) in an additional animal configuration 14 days after the obstruction during 60 minutes of LAD, shows that the beneficial effect of the analog of a-MSH # 3 (SEQ ID NO.9 *) on the size of heart attacks is associated with a marked reduction in LVEDP and thus the development of congestive heart failure after infarction.

Example 4 The test compound is the analog of 0.-MSH # 4: Ac-Lys-Lys-Lys-Lys-Lys-Lys-Ser-Ser-lie-lie-Ser-His-Phe-Arg-Trp-Gly -Lys-Pro-Val-NH2 (SEQ NO.13 * acetylated at the N-terminus and amidated at the C-terminus) The analogue of a-MSH # 4 (SEQ NO.13) differs from the analogue of a-MSH # 1 (SEQ ID NO.l *) for the replacement of Tyr by Ser in position 8, by the substitution of Being by lie in position 9, by the substitution of Met by lie in position 10 and by the replacement of Glu by Being in position 11. The compound is tested in experimental configurations 1 and 2.

Inhibition of LPS-induced TNF-α production by human leukocytes in vi tro Both a-MSH and the a-MSH # 4 analogue (SEQ.

NO.13 *) reduce the accumulation of TNF-a induced by LPS in the suspension of human leukocytes in a dose-dependent manner. Surprisingly, the effect A-MSH # 4 analogue inhibitor (SEQ.NO.13 *) is markedly more pronounced than the anti-inflammatory effect of the native a-MSH peptide. Inhibition of LPS-induced TNF-α production in rats in vivo Both a-MSH and the a-MSH # 4 analogue (SEQ.No.13 *) reduce the accumulation of TNF-a in rats during the i.v. of LPS. The maximum inhibitory effect of a-MSH as well as the analog of a-MSH # 4 is achieved at a dose of 200 μg / kg body weight. Surprisingly, the inhibitory effect of the a-MSH # 4 analog is markedly more pronounced than the anti-inflammatory effect of the native a-MSH peptide. While a-MSH inhibits the concentration of TNF-α in the plasma of rats at 17 ± 3% of the maximum response (LPS-Vehicle), the analog of a-MSH # 4 (SEQ ID NO.13 *) is capable of reducing the accumulation of TNF-a at 12 + 2% of the vehicle (P <0.05 vs a-MSH) (see Figure 16).

Example 5 The test compound is the analogue of a-MSH # 5: Ac-Lys-Lys-Lys-Lys-Lys-Lys-Ser-Ser-Ile-Ile-Ser-His- (D-Phe) -Arg-Trp-Gly-Lys-Pro-Val-NH2 (SEQ. 17 * acetylated at terminal N and amidated at terminal C) The analogue of a-MSH # 5 (SEQ.NO.17) differs from the analogue of a-MSH # 1 (SEQ ID NO.l *) by substitution of Tyr by Being in position 8, by the substitution of Being by lie in position 9, by the substitution of Met by lie in position 10, by the replacement of Glu by Being in position 11 and by the stereochemical substitution of Phe by (D-Phe) at position 13. The compound is tested in experimental configurations 1 and 2.

Inhibition of LPS-induced TNF-α production by human leukocytes in vi tro Both a-MSH and the a-MSH # 5 analogue (SEQ.NO.17 *) reduce dose-dependently accumulation of TNF- to LPS-induced suspension in human leukocytes. Surprisingly, the inhibitory effect of the a-MSH # 5 analogue (SEQ.NO.17 *) is markedly more pronounced than the anti-inflammatory effect of the native a-MSH peptide.

Inhibition of LPS-induced TNF-a production in rats in vivo Both a-MSH and the a-MSH # 5 analog (SEQ.

NO.17 *) reduce the accumulation of TNF-a in rats during the i.v. of LPS. The maximum inhibitory effect of a-MSH as well as the analog of α-MSH # 5 (SEQ.NO.17 *) is achieved at a dose of 200 μg / kg body weight.

Surprisingly, the inhibitory effect of the a-MSH # 5 analogue (SEQ.NO: 17 *) is markedly more pronounced than the anti-inflammatory effect of the native a-MSH peptide.

Example 6 The test compound is the analog of α-MSH # 6: Ac-Glu-Glu-Glu-Glu-Glu-Glu-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly- Lys-Pro-Val-NH2 (SEQ NO.2 * acetylated at the N-terminus and amidated at the C-terminus) The analogue of a-MSH # 6 (SEQ NO.2) differs from the analogue of a-MSH # 1 (SEQ ID NO.l *) by the replacement of (Lys) e by (Glu) 6 in position 1-6. The compound is tested in experimental configurations 1 and 2.

Inhibition of LPS-induced TNF-α production by human leukocytes in vi tro Both a-MSH and the a-MSH # 6 analogue (SEQ.NO.2 *) reduce TNF- accumulation in a dose-dependent manner to LPS-induced suspension in human leukocytes. Surprisingly, the inhibitory effect of the a-MSH # 6 analogue (SEQ.NO.2 *) is markedly more pronounced than the anti-inflammatory effect of the native a-MSH peptide. 1 7 Inhibition of LPS-induced TNF-α production in rats in vivo Both a-MSH and the a-MSH # 6 analogue (SEQ.NO.2 *) reduce the accumulation of TNF-a in rats during the i.v. of LPS. The maximum inhibitory effect of a-MSH as well as the analogue of a-MSH # 6 (SEQ.NO.2 *) is achieved at a dose of 200 μg / kg body weight. Surprisingly, the inhibitory effect of the a-MSH # 6 analogue (SEQ.NO: 2 *) is markedly more pronounced than the anti-inflammatory effect of the native a-MSH peptide.

Example 7 The test compound is the analog of a-MSH # 7: Ac-Lys-Lys-Lys-Lys-Lys-Lys-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly- Lys -Pro- (D-Val) -NH2 (SEQ.NO.3 * acetylated at the N-terminus and amidated at the C-terminus) The analogue of a-MSH # 7 (SEQ.NO.3) differs from the analogue of -MSH # 1 (SEQ ID NO.l *) by the stereochemical substitution of Phe by (D-Val) at position 19. The compound is tested in experimental configurations 1 and 2.

Inhibition of LPS-induced TNF-α production by human leukocytes in vi tro Both a-MSH and the analogue of a-MSH # 7 (SEQ.NO.3 *) reduce in a dose-dependent manner the accumulation of TNF-a induced by LPS in the suspension of human leukocytes. Surprisingly, the inhibitory effect of the a-MSH # 7 analogue (SEQ.NO.3 *) is markedly more pronounced than the anti-inflammatory effect of the native a-MSH peptide.

Inhibition of LPS-induced TNF-α production in rats in vivo Both a-MSH and the a-MSH # 7 analogue (SEQ.NO.3 *) reduce the accumulation of TNF-a in rats during the i.v. of LPS. The maximum inhibitory effect of α-MSH as well as the analog of α-MSH # 7 (SEQ.NO.3 *) is achieved at a dose of 200 μg / kg body weight. Surprisingly, the inhibitory effect of the a-MSH # 7 analogue (SEQ.NO: 3 *) is markedly more pronounced than the anti-inflammatory effect of the native a-MSH peptide.

Legends for the Figures Figure 1 Accumulation of TNF-a induced by LPS in a suspension of human lymphocytes The figure shows the maximum anti-inflammatory effect of the analogue of a-MSH # 1 (SEQ ID NO.l *) (MCA # 1) in the experimental configuration 1. The maximum inhibitory effect on the production of TNF-a induced by LPS was achieved by 10"7 M for both a-MSH and MCA # 1. Mean ± SE (N = 6-9 in each group). *: p <0.05 vs Vehicle # : p <0.05 vs a-MSH.

Figure 2 Accumulation of TNF-a induced by plasma LPS The figure shows the maximum anti-inflammatory effect of the analogue of a-MSH # 1 (SEQ ID NO.l *) (MCA # 1) in experimental setup 2. The effect inhibitory effect on TNF-a production induced by LPS in rats was achieved by 200 μg / kg pc administered i.v. for both a-MSH and MCA # 1. Mean ± SE (N = 4-6 in each group). *: p < 0.05 vs Vehicle #: p < 0.05 vs a-MSH. Figure 3 Eosinophils The figure shows the effect of a-MSH and the analog of a-MSH # 1 (SEQ ID NO.l *) (MCA # 1) on the accumulation of eosinophils within the lungs in the experimental configuration 3. Both compounds were administered in a dose of 200 μg / kg pc administered i.v. bid. Mean ± SE (N = 6-9 in each group). *: different from the vehicle.

Figure 4 Pulmonary artery pressure The figure shows the effect of the a-MSH analogue # 1 (SEQ ID NO.l *) (MCA # 1) on changes in pulmonary artery pressure induced by LPS in pigs. Media + SE (N = 3 and 6 in the two groups). * different from the vehicle.

Figure 5 Infarct size 3 hours after reperfusion The figure shows the protective effect of the analog of a-MSH # 1 (SEQ ID NO.l *) (MCA # 1) on the size of the myocardial infarction in the experimental configuration. The maximum effect of MCA # 1 was achieved by 200 μg / kg pc administered i.v. Mean + SE (N = 5-10 in each group). *: different from the vehicle.

Figure 6 LVEDP two weeks after the LAD obstruction for 60 minutes The figure shows the protective effect of the a-MSH # 1 analogue (SEQ ID NO.l *) (MCA # 1) on the development of congestive heart failure after of infarction in the experimental setting 4. The effect of MCA # 1 was achieved by 200 μg / kg of PC Mean + SE (N = 6-9 in each group). *: p < 0.05 vs False; #: p < 0.05 vs vehicle.

Figure 7 Diuresis The figure shows "the protective effect of the analogue of a-MSH # 1 (SEQ ID NO.l *) (MCA # 1) on the development of post-ischemic polyuria in the experimental setting. 5. The effect of MCA # 1 was achieved by 200 μg / kg pc administered i.v. Mean + SE (N = 5-7 in each group). *: different from the vehicle.

Figure 8 Accumulation of TNF-a induced by LPS in a suspension of human lymphocytes The figure shows the maximum anti-inflammatory effect of the analogue of a-MSH # 2 (SEQ.NO. 5) (MCA # 2) in the experimental configuration 1 The maximum inhibitory effect of TNF-a production induced by LPS was achieved by 10"7 M for both a-MSH and MCA # 2 Mean ± SE (N = 6-9 in each group). *: P < 0.05 vs Vehicle; #: p <0.05 vs a-MSH.

Figure 9 Accumulation of TNF-a induced by plasma LPS The figure shows the maximum anti-inflammatory effect of the a-MSH analog, a-MSH # 2 analogue (SEQ.NO. 5) (MCA # 2) in the configuration Experimental 2. The maximum inhibitory effect on the production of TNF-a induced by LPS in rats was achieved by 200 μg / kg pc administered i.v. for both the a-MSH and the MCA # 2. Mean + SE (N = 4-6 in each group). *: p < 0.05 vs Vehicle; #: p < 0.05 vs a-MSH.

Figure 10 Eosinophils The figure shows the effect of a-MSH and the analogue of a-MSH # 2 (SEQ ID NO.5 *) (MCA # 2) on the accumulation of eosinophils within the lungs in the experimental configuration 3. Both compounds were administered in a dose of 200 μg / kg p.c. administered i.v. bid. Mean ± SE (N = 6-9 in each group). *: different from the vehicle.

Figure 11 Neutrophils The figure shows the effect of a-MSH and the analogue of a-MSH # 2 (SEQ ID NO.5 *) (MCA # 2) on the accumulation of neutrophils within the lungs in the experimental configuration 3. Both compounds were administered in a dose of 200 μg / kg pc administered i.v. bid. Mean ± SE (N = 6-9 in each group). *: different from the vehicle.

Figure 12 Infarct size 3 hours after reperfusion The figure shows the protective effect of the analog of a-MSH # 2 (SEQ ID NO.5 *) (MCA # 2) on the size of the myocardial infarction in the experimental configuration. The effect of MCA # 3 was achieved by 200 μg / kg pc administered i.v. Mean ± SE (N = 5-10 in each group). *: different from the vehicle.

Figure 13 Accumulation of TNF-a induced by LPS in a suspension of human lymphocytes The figure shows the maximum anti-inflammatory effect of the a-MSH # 3 analogue (SEQ ID NO.9 *) (MCA # 3) in the experimental setting 1. The maximum inhibitory effect on the production of TNF- a LPS-induced was achieved by 10"7 M for both the a-MSH and the MCA # 3. Mean ± SE (N = 6-9 in each group). *: p <0.05 vs. Vehicle; #: p < 0.05 vs a-MSH.

Figure 14 Accumulation of TNF-α induced by plasma LPS The figure shows the maximum anti-inflammatory effect of the a-MSH # 3 analogue (SEQ.NO. 9) (MCA # 3) in experimental setup 2. The inhibitory effect maximum on the production of TNF-a induced by LPS in rats was achieved by 200 μg / kg pc administered i.v. for both the a-MSH and the MCA # 3. Mean + SE (N = 4-6 in each group). *: p < 0.05 vs Vehicle; #: p < 0.05 VS a-MSH.

Figure 15 Infarct size 3 hours after reperfusion The figure shows the protective effect of the a-MSH # 3 analogue (SEQ ID NO. 9 *) (MCA # 3) on the size of the myocardial infarction in the experimental configuration. The effect of MCA # 3 was achieved by 200 μg / kg pc administered i.v. Mean ± SE (N = 5-10 in each group). *: different from the vehicle. 4 Figure 16 Accumulation of TNF-a induced by plasma LPS The figure shows the maximum anti-inflammatory effect of the analogue of a-MSH # 4 (SEQ.NO. 13) (MCA # 4) in the experimental configuration 2. The inhibitory effect maximum on the production of TNF-a induced by LPS in rats was achieved by 200 μg / kg pc administered i.v. For both a-MSH and MCA # 4. Mean ± SE (N = 4-6 in each group). *: p < 0.05 vs Vehicle; #: p < 0.05 vs a-MSH.

References U.S. Patent No. 4,288,627 WO 91/17243 WO 99/46283 Beaucage, S.L. and Caruthers, M.H. Tetrahedron Letters 22, 1981, pages 1859-1869 Bodanszky, M. and Bodanszky, A., "The Practice of Peptide Synthesis ", 2. Ed, Springer-Verlag, 1994. Catania, A., Rajora, F., Capsoni, F., Minonzio, RA, Star, and Upton, JM Peptides 17: 675-679, 1996. Ehrlich, 1978 , Proc. Nati, Acad. Sci. USA 75: 1433), Guo and Sherman, 1995, Molecular Cellular Biology 15: 5983- 5990. Hartmeyer, M., Scholzen T., Becher E., Bhardwaj RS, Schwarz T. and Luger T.A., J. Immunol. , 159: 1930-1937, 1997. Hiltz M.E. et al. (1991), Peptides, 12, 767-771.

Hruby V.J. et al. (1995), J. Med. Chem., 38, 3454-3461. Jones, J. "The Chemical Synthesis of Peptides", Clarendon Press, 1991. Kullmann, W. 1987, Enzymatic Peptide Synthesis, CRC Press, Boca Raton, Florida, pages 41-59. Lipton, J.M. and Catania, A. Immunol. Today 18: 140-145, 1997. Liu et al., 1996, J. Am. Chem. Soc. 118: 307-312 and Dawson et al., 1996, 226: 776. Luger, T.A., Scholzen T. and Grabbe S., J. Investig.

Dermatol. Symp. Proc. 2: 87-93, 1997. Matthes et al., EMBO Journal 3, 1984, pages 801-805. MANIATIS, T., E.F. FRITSCH and J. SAMBROOK, 1982 Molecular Cloning: A Laboratory Manual. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY. Remington: The science and practice of pharmacy "20th ed.

Mack Publishing, Easton PA, 2000 ISBN 0-912734-04-3 and "Encyclopedia of Pharmaceutical Technology", edited by Swarbrick, J. & J. C. Boylan, Marcel Dekker, Inc., New York, 1988 ISBN 0-8247-2800-9. Rajora, N., Boccoli, G., Catania and Lipton J.M. , Peptides, 18: 381-385, 1997. Remington: The science and practice of pharmacy "20th ed.

Mack Publishing, Easton PA, 2000 ISBN 0-912734-04-3. Rizzi A. et al. (2002), British Journal of Pharmacology, 137, 369-374. Romans et al., 1992, Yeast 8: 423-488. Sawyer T.K. (1980), Proc. Nat. Acad. Sci., 10, 5754-5758.

Schióth H. B. et al. (1998), Eur. J. Pharm., 349, 359-366. Star, R.A., Rajora N., Huang J., Stock R.C., Catania A. and Lipton J.M .; Proc. Nati Acad. Sci. E.U.A, 92: 8016-8020, 1995. Wong, K.Y., Rojora, G., Boccoli, A., Catania, A. and Lipton J. M., Neuroimmunomodulation, 4: 37-41, 1997. Useful proteins from recombinant bacteria "in Scientific American, 1980, 242: 74-94.

Claims (37)

1. CLAIMS 1. A peptide, characterized in that it consists of the sequence: Lys-Lys-Lys-Lys-Lys-Lys-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val (SEQ ID NO: 1), wherein the amino terminus of the peptide is CH3-C (= 0) -.
2. 2. A peptide, characterized in that it consists of the sequence: Glu-Glu-Glu-Glu-Glu-Glu-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val ( SEQ ID NO: 2), wherein the amino terminus of the peptide is CH3-C (= 0) -.
3. 3. A peptide according to claim 1 or 2, characterized in that the carboxy terminus of the peptide is -C (-0) -0H.
4. 4. A peptide according to claim 1 or 2, characterized in that the carboxy terminus of the peptide is -C (= 0) -NH2.
5. 5. A peptide, characterized in that it is selected from the group consisting of: Lys-Lys-Lys-Lys-Lys-Lys-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro - (D-Val) (SEQ ID NO: 3), Glu-Glu-Glu-Glu-Glu-Glu-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro- (D-Val) (SEQ ID NO: 4), Lys-Lys-Lys-Lys-Lys-Lys-Ser-Tyr-Ser-Nle-Glu-His- (D-Phe) -Arg-Trp-Gly-Lys -Pro-Val (SEQ ID NO: 5), Glu-Glu-Glu-Glu-Glu-Glu-Ser-Tyr-Ser-Nle-Glu-His- (D-Phe) -Arg-Trp-Gly-Lys- Pro-Val (SEQ ID NO: 6), Lys-Lys-Lys-Lys-Lys-Lys-Ser-Tyr-Ser-Nle-Glu-His- (D-Phe) -Arg-Trp-Gly-Lys- Pro- (D-Val) (SEQ ID NO: 7), Glu-Glu-Glu-Glu-Glu-Glu-Ser-Tyr-Ser-Nle-Glu-His- (D-Phe) -Arg-Trp-Gly -Lys-Pro- (D-Val) (SEQ ID NO: 8), Lys-Lys-Lys-Lys-Lys-Lys-Ser-Tyr-Ser-Nle-Glu-His-D-Nal-Arg-Trp- Gly-Lys-Pro-Val (SEQ ID NO: 9), Glu-Glu-Glu-Glu-Glu-Glu-Ser-Tyr-Ser-Nle-Glu-His-D-Nal-Arg-Trp-Gly-Lys -Pro-Val (SEQ ID NO: 10), Lys-Lys-Lys-Lys-Lys-Lys-Ser-Tyr-Ser-Nle-Glu-His-D-Nal-Arg-Trp-Gly-Lys-Pro- (D-Val) (SEQ ID NO: 11), Glu-Glu-Glu-Glu-Glu-Glu-Ser-Tyr-Ser-Nle-Glu-His-D-Nal-Arg-Trp-Gly-Lys-Pro - (D-Val) (SEQ ID NO: 12), Lys-Lys-Lys-Lys-Lys-Lys-Ser-Ser-lie-Ile-Ser-His-Phe-Arg-Trp-Gly-Lys-Pro- Val (SEQ ID NO: 13), Glu-Glu-Glu-Glu-Glu-Glu-Ser-Ser-lie-lie-Ser-His-Phe-Arg-Trp-Gly-Lys-Pro-Val (SEQ ID NO. : 14), Lys-Lys-Lys-Lys-Lys-Lys-Ser-Ser-Ile-Ile-Ser-His-Phe-Arg-Trp-Gly-Lys-Pro- (D-Val) (SEQ ID NO: 15), Glu-Glu-Glu-Glu-Glu-Glu-Ser-Ser-lie-lie-Ser-His-Phe-Arg-Trp-Gly-Lys-Pro- (D-Val) (SEQ ID NO: 16 ), Lys-Lys-Lys-Lys-Lys-Lys-Ser-Ser-Ile-Ile-Ser-His- (D-Phe) -Arg-Trp-Gly-Lys-Pro-Val (SEQ ID NO: 17), Glu-Glu-Glu-Glu-Glu-Glu-Ser-Ser-Ile-Ile-Ser-His- (D-Phe) -Arg-Trp-Gly-Lys-Pro-Val (SEQ ID NO: 18 ), Lys-Lys-Lys-Lys-Lys-Lys-Ser-Ser-Ile-Ile-Ser-His- (D-Phe) -Arg-Trp-Gly-Lys-Pro- (D-Val) (SEQ ID NO: 19), Glu-Glu-Glu-Glu-Glu-Glu-Ser-Ser-Ile-Ile-Ser-His- (D-Phe) -Arg-Trp-Gly-Lys-Pro- (D-Val) (SEQ ID NO: 20), Lys-Lys-Lys-Lys-Lys-Lys-Ser-Ser-Ile-Ile-Ser-His-D-Nal-Arg-Trp-Gly-Lys-Pro-Val (SEQ ID NO: 21), Glu-Glu-Glu-Glu-Glu-Glu-Ser-Ser-Ile-Ile Ser-His-D-Nal-Arg-Trp-Gly-Lys-Pro-Val (SEQ ID NO: 22), Lys-Lys-Lys-Lys-Lys-Lys-Ser-Serie-lie-Ser-His -D-Nal-Arg-Trp-Gly-Lys-Pro- (D-Val) (SEQ ID NO: 23), Glu-Glu-Glu-Glu-Glu-Glu-Ser-Serie-lie-Ser- His-D-Nal-Arg-Trp-Gly-Lys-Pro- (D-Val) (SEQ ID NO: 24), Lys-Lys-Lys-Lys-Lys-Lys-Met-Glu-His-Phe-Arg -Trp-Gly-Lys-Pro-Val (SEQ ID NO: 25), Glu-Glu-Glu-Glu-Glu-Glu-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val ( SEQ ID NO: 26), Lys-Lys-Lys-Lys-Lys-Lys-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro- (D-Val) (SEQ ID NO: 27), Glu-Glu-Glu-Glu-Glu-Glu-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro- (D-Val) (SEQ ID NO: 28), Lys-Lys-Lys-Lys -Lys-Lys-Nle-Glu-His- (D-Phe) -Arg-Trp-Gly-Lys-Pro-Val (SEQ ID NO: 29), Glu-Glu-Glu-Glu-Glu-Glu-Nle- Glu-His- (D-Phe) -Arg-Trp-Gly-Lys-Pro-Val (SEQ ID NO: 30), Lys-Lys-Lys-Lys-Lys-Lys-Nle-Glu-His- (D-) Phe) -Arg-Trp-Gly-Lys-Pro- (D-Val) (SEQ ID NO: 31), Glu-Glu-Glu-Glu-Glu-Glu-Nle-Glu-His- (D-Phe) - Arg-Trp-Gly-Lys-Pro- (D-Val) (SEQ ID NO: 32), Lys-Lys-Lys-Lys-Lys-Lys-Nle-Glu-His-D-Nal-Arg -Trp-Gly-Lys-Pro-Val (SEQ ID NO: 33), Glu-Glu-Gl? -Glu-Glu-Gl? -Nle-Glu-His-D-Nal-Arg-Trp-Gly-Lys- Pro-Val (SEQ ID NO: 34), Lys-Lys-Lys-Lys-Lys-Lys-Nle-Glu-His-D-Nal-Arg-Trp-Gly-Lys-Pro-. (D-Val) ( SEQ ID NO: 35) and Glu-Glu-Glu-Glu-Glu-Glu-Nle-Glu-His-D-Nal-Arg-Trp-Gly-Lys-Pro- (D-Val) (SEQ ID NO: 36 ), wherein the amino terminus of the peptide is (B4) HN-, (B4) (B5) N- or (B6) HN-, wherein B4 and B5 are independently selected from H, alkyl of 1 to 6 carbon atoms. carbon, alkenyl of 2 to 6 carbon atoms, aryl of 6 to 10 carbon atoms, aralkyl of 7 to 16 carbon atoms and alkylaryl of 7 to 16 carbon atoms; B6 is B4-C (= 0) -; and wherein the carboxy terminus of the peptide is -C (= 0) B1, wherein Bl is selected from OH, NH2, NHB2, N (B2) (B3), OB2 and B2, wherein B2 and B3 are independently selected from alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, aryl of 6 to 10 carbon atoms, aralkyl of 7 to 16 carbon atoms and alkylaryl of 7 to 16 carbon atoms.
6. 6. A peptide according to claim 5, characterized in that the peptide consists of the sequence: Lys-Lys-Lys-Lys-Lys-Lys-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp- Gly-Lys-Pro- (D-Val) (SEQ ID NO: 3).
7. 7. A peptide according to claim 5, characterized in that the peptide consists of the sequence: Lys-Lys-Lys-Lys-Lys-Lys-Ser-Tyr-Ser-Nle-Glu-His- (D-Phe) - Arg-Trp-Gly-Lys-Pro-Val (SEQ ID NO: 5).
8. 8. A peptide according to claim 5, characterized in that the peptide consists of the sequence: Lys-Lys-Lys-Lys-Lys-Lys-Ser-Tyr-Ser-Nle-Glu-His-D-Nal-Arg- Trp-Gly-Lys-Pro-Val (SEQ ID NO: 9).
9. 9. A peptide according to claim 5, characterized in that the peptide consists of the sequence: Lys-Lys-Lys-Lys-Lys-Lys-Ser-Ser-Ile-Ile Ser-His-Phe-Arg-Trp-Gly-Lys-Pro-Val (SEQ ID NO: 13).
10. 10. A peptide according to claim 5, characterized in that the peptide consists of the sequence: Lys-Lys-Lys-Lys-Lys-Lys-Ser-Ser-Ile-Ile-Ser-His- (D-Phe) - Arg-Trp-Gly-Lys-Pro-Val (SEQ ID NO: 17).
11. 11. A peptide according to any of claims 5-10, characterized in that the amino terminus of the peptide is H2N-.
12. 12. A peptide according to any of claims 5-10, characterized in that the amino terminus of the peptide is CH3-C (= 0) -.
13. 13. A peptide according to any of claims 5-12, characterized in that the carboxy terminus of the peptide is -C (= 0) -OH.
14. 14. A peptide according to any of claims 5-12, characterized in that the carboxy terminus of the peptide is -C (= 0) -NH2.
15. 15. A peptide according to any of the preceding claims, characterized in that the peptide has the ability to stimulate one or more melanocortin receptors selected from the melanocortin receptor type 1, 3, 4 and 5.
16. 16. A peptide according to any of the preceding claims, characterized in that the peptide has at least one of the following properties: a) inhibit the production of TNF-a induced by LPS by human leukocytes, b) inhibit the infiltration of eosinophils induced by inflammation within the lungs, c) inhibit neutrophil infiltration induced by inflammation within the lungs, d) inhibit the accumulation of TNF-a induced by inflammation in circulating blood, e) reduce acute renal failure induced by ischemia, f) reduce the size of myocardial infarction, g) reduce the degree of heart failure after myocardial infarction, h ) reduce pulmonary vascular hypertension, i) reduce renal insufficiency induced by cisplatin.
17. 17. The use of a peptide according to any of the preceding claims for the manufacture of a product for use in medicine.
18. 18. The use of a peptide according to any of claims 1-16 for the manufacture of a pharmaceutical composition for the treatment or prophylaxis- of a condition in the tissue of one or more organs of a mammal.
19. The use of a peptide according to claim 18, wherein the organ is selected from the group consisting of kidney, liver, brain, heart, muscles, bone marrow, skin, skeleton, lungs, respiratory tract, spleen, glands exocrine, bladder, glands endocrine, reproductive organs that include the fallopian tubes, eye, ear, vascular system, the gastrointestinal tract that includes the small intestine, colon and rectum and anal canal and prostate gland.
20. 20. The use of a peptide according to any of claims 18-19, wherein the condition is an ischemic or inflammatory condition.
21. 21. The use of a peptide according to any of claims 18-20, wherein the condition is due to the insufficiency of cells, tissues or organs induced by toxins or drugs.
22. 22. The use of a peptide according to claim 20, wherein the condition is an ischemic condition.
23. 23. The use of a peptide according to claim 22, wherein the condition is acute, subacute or chronic ischaemia.
24. 24. The use of a peptide according to claim 22 or 23, wherein the condition is secondary ischaemia.
25. 25. The use of a peptide according to claim 24, wherein the secondary ischemia is due to septic shock or conditions associated with systemic hypotension.
26. 26. The use of a peptide in accordance with any of claims 18-23, wherein the condition is myocardial ischemia.
27. 27. The use of a peptide according to claim 26, wherein the condition is angina or myocardial infarction.
28. 28. The use of a peptide according to claim 20, wherein the condition is an inflammatory condition.
29. 29. The use of a peptide according to claim 28, wherein the inflammatory condition is selected from lung inflammation, arthritis, dermatitis, pancreatitis, inflammatory bowel diseases, vasculitis, bacterial septicemia, pericarditis, myocarditis and endocarditis.
30. 30. The use of a peptide according to claims 18-21, wherein the condition is associated with cardiac arrhythmia.
31. 31. The use of a peptide according to any of claims 1-4 for the manufacture of a pharmaceutical composition for inhibiting or reducing pulmonary hypertension.
32. 32. The use of a peptide according to any of claims 1-4 for the manufacture of a pharmaceutical composition for reducing acute renal failure induced by ischemia.
33. 33. The use of a peptide according to any of claims 1-4 for the manufacture of a pharmaceutical composition for reducing the damage induced by cardiac ischemia.
34. 34. A pharmaceutical composition, characterized in that it comprises a peptide according to any of claims 1-16.
35. 35. A pharmaceutical composition according to claim 34, characterized in that it also comprises one or more pharmaceutical carriers.
36. 36. A pharmaceutical composition according to claim 34 or 35, characterized in that it also comprises one or more pharmaceutically acceptable excipients.
37. 37. A pharmaceutical composition according to any of claims 34-36, characterized in that the composition is a parenteral, oral, topical, transmucosal or transdermal composition.