MX2008010141A - Combination of somatostatin-analogs with different selectivity for human somatostatin receptor subtypes - Google Patents

Abstract

Thepresent invention relates to a combination of two or more Somatostatin (SRIF) peptidomimetics (also referred to as Somatostatin- or SRIF-analogs) which have different selectivity for the human somatostatin receptor subtypes SSTR2 and SSTR5, the use of such combination in the treatment of a disease mediated by activation of somatostatin receptors, and to pharmaceutical compositions comprising such a combination.

Description

COMBINATION OF SOM ATOSTATIN ANALOGUES WITH DIFFERENT SELECTIVITY FOR THE SUBTITLES OF THE SOM ATOSTATIN TO HUMAN RECEIVER The present invention relates to a combination of two or more somatostatin peptidomimetics (SRIF) (also referred to as somatostatin or SRIF analogs), which have different selectivity for the five subtypes of the human somatostatin receptor SSTR1, SSTR2, SSTR3, SSTR4 , and SSTR5 (SSTR1-5), to the use of this combination in the treatment of a disease mediated by the activation of somatostatin receptors (SSTR1-5), and to pharmaceutical compositions comprising this combination Somatostatin is a tetradecapeptide having Structure: II H-Ala-Gly-Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys-OH 1 2 3 4 5 6 7 8 9 10 11 12 13 14 The somatostatin class is a known class of small peptides comprising naturally occurring somatostatin-14, and analogs having a somatostatin-related activity, for example as disclosed by AS Dutta in Small Peptides, Volume 19, Elsevier (1993). "Somatostatin analog", as used herein, means any straight or cyclic chain polypeptide having a structure based on that of naturally occurring somatostatin-14, wherein one or more amino acid units have been omitted and / or replaced by one or more different amino radicals, and / or wherein one or more functional groups have been replaced by one or more different functional groups, and / or one or more groups have been replaced by one or more different isothermal groups. In general, the term covers all modified derivatives of native somatostatin-14 that exhibit a somatostatin-related activity, for example that binds to at least one of the five somatostatin receptors (SSTR), preferably in the nanomolar range. Natural somatostatin binds to, and activates, all five somatostatin receptors (SSTR1-5), with nanomolar efficacy, and therefore, causes its multiple physiological effects. The majority of human (neuro-) endocrine tumors express multiple SSTRs. The synthetically available somatostatin analogues differ in their binding affinity to the different somatostatin receptor subtypes, and are often selectively linked to one or a few subtypes with a significantly higher affinity. Somatostatin analogs of a particular interest that predominantly target SSTR2 comprise the following compounds: to. (D) Phe-Cys-Phe- (D) Trp-Lys-Thr-Cys-Thr-ol also known as octreotide. b. (D) Phe-Cys-Tyr- (D) Trp-Lys-Val-Cys-ThrNH2. c. (D) Phe-Cys-Tyr- (D) Trp-Lys-Val-Cys-TrpNH2. also known as vapreotide. d. (D) Trp-Cys-Phe- (D) Trp-Lys-Thr-Cys-ThrNH2. and. (D) Phe-Cys-Phe- (D) Trp-Lys-Thr-Cys-ThrNH2. F. 3- (2- (naphthyl) - (D) Ala-Cys-Tyr- (D) Trp-Lys-Val-Cys-ThrNH2, also known as lanreotide g. (D) Phe-Cys-Tyr- (D) Trp-Lys-Val-Cys-Nal-NH2., H 3- (2-naphthyl) -Ala-Cys-Tyr- (D) Trp-Lys-Val-Cys-Nal-NH2. (D) Phe-Cys-Nal- (D) Trp-Lys-Val-Cys-Thr-NH2.J (D) Phe-Cys-Tyr- (D) Trp-Lys-Leu-Cys-Thr-NH2. (D) Phe-Cys-Tyr- (D) Trp-Lys-Cys-Thr-NH2 A preferred somatostatin analogue which is predominantly directed at SSTR2 is octreotide Somatostatin analogues of a particular interest which predominantly target SSTR5 have been described, for example, in International Publication Number WO 97/01579.These somatostatin analogs comprise the amino acid sequence of Formula I: - (D / L) Trp-Lys-X, -X2- wherein X, is a radical of Formula (a) or (b): co- - NH- co- h-0-CHjR, (a) (b) wherein R is optionally substituted phenyl, wherein the substituent can be halogen, methyl, ethyl, methoxy, or ethoxy, R2 is -Z1-CH2-Ri, -CH2-CO-0-CH2-R wherein Z, is O or S, and X2 is an a-amino acid having an aromatic residue on the side chain Ca, or an amino acid unit selected from Dab, Dpr, Dpm, His, (Bzl) HyPro, thienyl-Ala, cyclohexyl-Ala, and terbutil-Ala, the residue Lys of this sequence corresponding to the residue Lys9 of the native somatostatin-14. Somatostatin analogs of a particular interest that predominantly target SSTR5 have also been described, for example, in International Publication Number WO WO02 / 10192. These somatostatin analogues comprise the compound of the Formula: also called as cycle [. { 4- (NH2-C2H4-NH-CO-0-) Pro} -Phg-DTrp-Lys-Tyr (4-Bzl) -Phe] or pasireotide, as well as the diastereoisomers and mixtures thereof, in free form, in salt or complex form, or in a protected form. Phg means -N-CH (C6H5) -CO-, and Bzl means benzyl. Compounds that have a very high binding affinity in SSTR5, in addition to their high binding affinity in SSTR1, 2, and 3, such as pasireotide, have been shown to have a stronger inhibitory effect on the secretion of various hormones (e.g. , GH, secretion of GH-dependent IGF-1 and GH-independent, ACTH, corticosterone that responds to cortisol), with fewer signs of tachyphylaxis, compared to compounds predominantly targeting SSTR2 (and to a lesser extent, to SSTR5 ), like octreotide. This offers the possibility that compounds like pasireotide have also been active in animals and in patients expressing mainly SSTR5, and less or no SSTR2, in their hormone-secreting tissue or tumor. The greater potency of pasireotide against octreotide has been demonstrated in patients with octreotide-resistant acromegaly and in patients with primary Cushing's disease, a condition in which octreotide was not effective. The superiority of pasireotide against octreotide is also demonstrated in patients suffering from GEP / NET tumors, which become tachyphylactic after prolonged treatment with octreotide, and return to functional response after treatment with pasireotide. However, compounds that target SSTR5 and less strongly to SSTR2, such as pasireotide, sometimes show an iase in glucose levels as an undesired side effect, which has been observed to a lesser degree with the compounds that are targeted predominantly to SSTR2 (and even a minor to SSTR5), such as octreotide. The hyperglycemic effect of pasireotide depends on the dose, while even high doses of octreotide may not iase plasma glucose. This means that the simultaneous activation of SSTR2 by pasireotide is not sufficient to reverse the hyperglycemia induced by the activation of SSTR5. In the same way, the simultaneous activation of SSTR5 by octreotide is not sufficient to induce hyperglycemia. Surprisingly, it has now been found that a combination of compounds predominantly targeting SSTR5, with compounds predominantly targeting SSTR2, still maintains a strong inhibitory effect on hormone secretion (plasma level of GH and IGF-I). ), while showing no hyperglycemic side effect, or only a significantly reduced effect. This synergistic effect allows to use higher doses of the compounds that predominantly target SSTR5 in these combinations, limiting their hyperglycemic side effects. It could also iase the effectiveness of the compounds that are targeted predominantly to SSTR5 and compounds predominantly targeting SSTR2, without iasing the hyperglycemic effects, or lower doses can be used both of the compounds targeting SSTR5 and of the compounds predominantly targeting SSTR2, and are still You can get good efficiency. As shown in Figure 1, 10 micrograms / kilogram of pasireotide iased AUC glucose levels by 56 percent against the control within 1 hour after injection. In contrast, the same dose of octeotride had no effect on this parameter. The combination of both substances at 0.5, 2.5, 5, 7.5, and 15 micrograms / kilogram each, changed the glucose levels in the AUC only by 7, -2, 6, -1, and 14 percent, respectively. This result demonstrates that the combination of pasireotide and octreotide results in a smaller iase or even no iase in glucose, compared to pasireotide alone. Due to the known pharmacokinetic differences of octreotide (t1 2 = 90 minutes) and pasireotide (t1 2 = 11 hours), a comparison of the effects of both compounds is more relevant within the first hour after application (Schmid and Silva, 2005, J. Endocrine, Invest. 28: 28-35, in the additional experiments, it could be shown that even a lower dose of 50 percent and 66 percent of octeotride could prevent hyperglycemia induced by 10 and 30 micrograms / kilogram of pasireotide, respectively, within 1 hour after application. In order to investigate the efficacy of both compounds together, pasireotide and octeotride were infused together (at 3 and 10 micrograms / kilogram / hour), alone, and in different combinations (1.5, 5, and 10 micrograms / kilogram / hour) during 14 days. During the long-term treatment with 3 and 10 micrograms / kilogram / hour of pasireotide alone, the plasma glucose level increased slightly but significantly on days 1 and 7 of the treatment (Figure 2). In contrast, octreotide has no effect, or causes only a small but significant reduction in plasma glucose. Surprisingly, the combined application of 1.5, 5, and 10 micrograms / kilogram / hour of octeotride and pasireotide did not increase plasma glucose, and the levels in all the combination groups were indistinguishable from the groups treated with octeotride for 7 days. and 14 days. For pharmaceutical use, the unexpected finding of a reduction in glucose after the combined application of octeotride and pasireotide is more relevant if this combination does not reduce the potency of the individual agents. Data on the level of IGF-1 and body weight clearly show that the combination of lower doses of 50 percent showed the same potency as the high doses applied individually (Figure 3 and Figure 4). In an unexpected way, the combination of even seven times higher doses of both compounds (1.5 micrograms / kilogram / hour) applied simultaneously, showed the same potency over IGF-1 (Figure 3) and body weight (Figure 4) as the maximum dose of pasireotide tested in this experiment (10 micrograms / kilogram / hour). Even the finding that the combined application of the same dose of 10 micrograms / kilogram / hour, or even a 50 percent lower dose of each compound, resulted in a significantly stronger inhibition of IGF- might be more pharmacologically relevant. 1 on day 1, than 10 micrograms / kilogram / hour of pasireotide alone. In summary, these results indicate that the combination of these two compounds not only increases their potency (based on the level of IGF-1), but, in addition, the combination also reduces the negative hyperglycemic side effects caused by pasireotide. Brief Description of the Figures Figure 1: Acute effect on plasma glucose level Effect of acute subcutaneous injection of octeotride and pasireotide in rats (1 and 10 micrograms / kilogram), and different combinations thereof, on glucose levels accumulated between 0 and 1 hour after the injection. (n = 6 animals per group). * Indicates the statistical significance against pasireotide at 10 micrograms / kilogram, and § indicates the statistical significance against vehicle control.

Figure 2: Long-term effect on plasma glucose concentration Effect of long-term application of octeotride and pasireotide alone and in combination on plasma glucose concentration in rats. The compounds were continuously infused by osmotic minipumps at 3 and 10 micrograms / kilogram / hour for the individual compounds, and at 1.5, 5, and 10 micrograms / kilogram / hour for the combinations. The plasma glucose levels were determined 1 day before, and 1, 7, and 14 days after the implantation of the minipumps. § and * indicate the statistical meaning against day -1 and against vehicle control on the same day, respectively. Figure 3: Long-term effect on plasma levels of IGF-1 Effect of long-term application of octeotride and pasireotide alone and in combination on plasma levels of IGF-1 in rats. The compounds were continuously infused by osmotic minipumps at 3 and 10 micrograms / kilogram / hour for the individual compounds, and at 1.5, 5, and 10 micrograms / kilogram / hour for the combinations. The plasma glucose levels of IGF-1 were determined one day before, and 1, 7, and 14 days after the implantation of the minipumps. * Indicates the statistical meaning against vehicle control on the same day. Figure 4: Long-term effect on body weight Effect of long-term application of octeotride and pasireotide I 1 alone and in combination on body weight in rats. The compounds were continuously infused by osmotic minipumps at 3 and 10 micrograms / kilogram / hour for the individual compounds, and at 1.5, 5, and 10 micrograms / kilogram / hour for the combinations. The body weight of the rats is expressed as the percentage of change in body weight (BW) after 7 and 14 days of treatment, comparing with the body weight on the day before the implantation of the minipumps. In a further aspect, the present invention relates to a combination comprising at least two different somatostatin analogues (SRIF), wherein one SRIF analog is predominantly directed to SSTR2, and another SRIF analog is predominantly directed to SSTR5 (referred to hereinafter as the COMBINATION OF THE INVENTION), to the use of this combination in the treatment of a disease mediated by the activation of somatostatin receptors (SSTR1-5), and to pharmaceutical compositions comprising a COMBINATION OF THE INVENTION. The term "SRIF analog that predominantly targets SSTR2," as used herein, refers to compounds that have a high binding affinity to SSTR2, preferably an IC50 < 1 nanomol / liter, variable affinities with SSTR1, 3, and 4, and a binding affinity with SSTR5 that is at least five times, preferably 10 times lower than the affinity with SSTR2, and includes, but is not limited to, octeotride or lanreotide. The preferred SRIF analog that predominantly targets SSTR2 is octeotride. The term "SRIF analog that predominantly targets SSTR5", as used herein, refers to compounds that have a high binding affinity to SSTR5, preferably an IC50 <1. 1 nanomol / liter, variable affinities with SSTR1, 3, and 4, and a binding affinity with SSTR2 that is at least twice as low as the affinity with SSTR5, and includes, but is not limited to, pasireotide (Schmid et al. , Neuroendocrinol.2004; 80: 47-50). The term "a disease mediated by the activation of somatostatin receptors (SSTR1-5)", as used herein, includes, but is not limited to, disorders with an etiology that comprises or is associated with an excess of secretion of GH and / or an excess of IGF-1, for example, the treatment of acromegaly, as well as the treatment of diabetes mellitus type I or type II, especially the complications thereof, for example angiopathy, diabetic proliferative retinopathy , diabetic macular edema, nephropathy, neuropathy, and dawn phenomenon, and other metabolic disorders related to the release of insulin or glucagon, for example obesity, hyper-and hypo-glycemia, for example pathological obesity or hypothalamic or hyperinsulinemic obesity, enterocutaneous fistula and pancreaticocutaneous, irritable bowel syndrome, inflammatory diseases, for example, Severe, inflammatory bowel disease, psoriasis or rheumatoid arthritis, polycystic kidney disease, rapid emptying syndrome, watery diarrhea syndrome, AIDS-related diarrhea, chemotherapy or radiation-induced diarrhea, acute or chronic pancreatitis, and tumors gastrointestinal hormone secretors (e.g., PEG tumors, e.g., vipomas, glucagonomas, insulinomas, carcinoids, and the like), lymphocyte malignancies, e.g., lymphomas or leukemias, hepatocellular carcinoma, gastrointestinal hemorrhage, e.g. varicose esophageal hemorrhage, sleep, grelinoma, Prader-Willi syndrome. It can be demonstrated, by means of the established test models, that the COMBINATION OF THE INVENTION results in the effective prevention, or preferably the treatment of a disease mediated by the activation of the somatostatin receptors (SSTR1-5). In particular, SRIF analogues that predominantly target SSTR5 can now be used in effective doses without hyperglycemic side effects, or only with reduced hyperglycemic side effects, when administered in a COMBINATION OF THE INVENTION. The person skilled in the relevant art is absolutely qualified to select a relevant test model to test the therapeutic indications and beneficial effects previously and subsequently indicated herein. Pharmacological activity, for example, can be demonstrated in clinical studies in patients with a disease mediated by the activation of somatostatin receptors (SSTR1-5), in a manner similar to that described for octeotride or pasireotide. In accordance with the particular discoveries of the invention, the present invention also provides the treatment of a disease mediated by the activation of somatostatin receptors (SSTR1-5) in a warm-blooded animal in need, which comprises administering to the animal a COMBINATION OF THE INVENTION in an amount that is therapeutically effective jointly against a disease mediated by the activation of somatostatin receptors (SSTR1-5), and wherein the compounds may also be present in the form of their pharmaceutically acceptable salts. The present invention also relates to a pharmaceutical composition comprising an amount that is therapeutically effective against a disease mediated by the activation of somatostatin receptors (SSTR1-5), a COMBINATION OF THE INVENTION, and at least one pharmaceutically vehicle acceptable. The present invention also relates to the use of a COMBINATION OF THE INVENTION for the preparation of a medicament for the treatment of a disease mediated by the activation of somatostatin receptors (SSTR1-5). The present invention also relates to a package commercial comprising a COMBINATION OF THE INVENTION together with instructions for the simultaneous, separate, or sequential use thereof, in the treatment of a disease mediated by the activation of somatostatin receptors (SSTR1-5). The somatostatin analogues can be administered in free form or in pharmaceutically acceptable salt form. These salts can be prepared in a conventional manner, and exhibit the same order of activity as the free compound. Pharmaceutical compositions for the treatment of a disease mediated by the activation of somatostatin receptors (SSTR1-5) comprise an effective amount of the somatostatin analogue in free base form or in pharmaceutically acceptable salt form, together with one or more diluents or pharmaceutically acceptable vehicles. These compositions can be formulated in a conventional manner. The somatostatin analogs can also be administered in a sustained release form, for example in the form of implants, microcapsules, microspheres, or nanospheres, comprising, for example, a biodegradable polymer or copolymer, in the form of a liposomal formulation, or in the form of an autogel, for example a solid or semi-solid composition capable of forming a gel after interaction with the body fluids of the patient. The COMPOUNDS OF THE INVENTION, for example, can be formulated as disclosed in Patent Numbers US5,538,739 (especially octreotide) or WO05 / 046645 (especially pasireotide). The somatostatin analogues, or a pharmaceutically acceptable salt thereof, can be administered by any conventional route, for example parenterally, for example in the form of injectable solutions or suspensions (including, for example, the sustained release form as indicated). above), orally using a conventional absorption enhancer if necessary, in a nasal or suppository form, or topically, for example in the form of an ophthalmic liquid, gel, ointment, or suspension preparation, for example a liposomal formulation, in microspheres, or in nanospheres, for example for instillation, or for intra- or peri-ocular injections of the subconjunctival. The present pharmaceutical compositions are prepared in a manner known per se, and comprise from about 1 percent to 100 percent, preferably from about 1 percent to 40 percent, especially from about 20 percent to 30 percent. percent of the active ingredient. The structure of the active ingredients identified by code numbers, generic or commercial names, can be taken from the current edition of the standard compendium "The Merck Index", or from the databases, for example Patents International (for example, IMS World Publications). The corresponding content thereof is incorporated herein by reference. Any person skilled in the art is absolutely qualified to identify the active ingredients and, based on these references, in the same way is able to manufacture and test the indications and pharmaceutical properties in conventional test models, such as in vitro as in vivo. The term "a combined preparation", as used herein, defines in particular a "kit of parts", in the sense that the first and second active ingredients, as defined above, can be dosed in an independent manner, or by using different fixed combinations with distinguished amounts of the ingredients, that is, in a simultaneous manner or at different points of time. The parts of the kit of parts, for example, can then be administered in a simultaneous or chronologically staggered manner, that is, at different points of time and with equal or different time intervals for any part of the kit of parts. Most preferably, the time intervals are selected such that the effect on the disease treated in the combined use of the parts is greater than the effect that would be obtained by using only any of the active ingredients. The ratio of the total amounts of the active ingredient 1 to the active ingredient 2 to be administered in the combined preparation may be varied, for example, in order to deal with the needs of a sub-population of patients who are going to treat, or with the needs of the individual patient, whose different needs may be due to age, sex, body weight, the expression of SSTR, etc., of the patients. Preferably, there is at least one beneficial effect, for example a mutual improvement of the effect of the first and second active ingredients, in particular a synergism, for example an effect rather than an additive, additional convenient effects, fewer side effects, a combined therapeutic effect in a non-effective dosage of one or both of the first and second active ingredients, and especially a strong synergism of the first and second active ingredients. In particular, a therapeutically effective amount of each of the active ingredients of the COMBINATION OF THE INVENTION may be administered in a simultaneous or sequential manner and in any order, and the components may be administered separately or as a fixed combination, by For example, the method of treatment of the diseases according to the invention may comprise: (i) administration of the first active ingredient in free or pharmaceutically acceptable salt form, and (ii) administration of the second active ingredient in free or pharmaceutically acceptable salt, in a simultaneous or sequential manner in any order, in mutually therapeutically effective amounts, preferably in synergistically effective amounts, for example, in daily dosages corresponding to the amounts described herein. The individual active ingredients of the COMBINATION OF THE INVENTION may be administered separately at different times during the course of therapy, or in a manner concurrent in divided or individual combination forms. Additionally, the term "administration" also encompasses the use of a pro-drug of an active ingredient that is converted in vivo to the active ingredient. It should be understood, therefore, that the present invention encompasses all simultaneous or alternate treatment regimens, and the term "administration" should be interpreted in accordance with the same. It will be understood that in the discussion of the methods, references to the active ingredients are also intended to include the pharmaceutically acceptable salts. If these active ingredients, for example, have at least one basic center, they can form acid addition salts. The corresponding acid addition salts having, if desired, may also be formed, a basic center additionally present. Active ingredients that have an acidic group (for example COOH) can also form salts with bases. The active ingredient or a pharmaceutically acceptable salt thereof, may also be used in the form of a hydrate, or may include other solvents used for crystallization. The results disclosed herein indicate that a combination comprising a COMBINATION OF THE INVENTION achieves a better therapeutic effect by comparing with any compound alone, in the treatment of a disease mediated by the activation of somatostatin receptors (SSTR1-5 ). A particular benefit of the COMBINATION OF THE INVENTION, is that lower doses of the active ingredients of the COMBINATION OF THE INVENTION can be used, for example, that the dosages need not only be smaller, but also that they are applied less frequently, or can be used for the purpose of decrease the incidence of side effects. This is in accordance with the wishes and requirements of the patients to be treated. The pharmacological activity of a COMBINATION OF THE INVENTION, for example, can also be demonstrated in clinical studies. These clinical studies are preferably randomized double-blind clinical trials in patients with a disease mediated by the activation of somatostatin receptors (SSTR1-5). These studies demonstrate, in particular, the synergism of the active ingredients of the COMBINATION OF THE INVENTION. Studies are particularly suitable for comparing the effects of a monotherapy using the active ingredients and a COMBINATION OF THE INVENTION. The effective dosage of each of the active ingredients employed in the COMBINATION OF THE INVENTION may vary depending on the particular compound or pharmaceutical composition employed, the mode of administration, the severity of the condition being treated. Accordingly, the dosage regimen of the COMBINATION OF THE INVENTION is selected according to a variety of factors, including the route of administration, and the renal and hepatic function of the patient. A doctor, A clinician, or veterinarian of ordinary experience, can easily determine and prescribe the effective amount of the individual active ingredients required to prevent, improve, or stop the progress of the condition. The optimal precision to achieve the concentration of the active ingredients within the range that produces efficacy without toxicity requires a regimen based on the kinetics of the availability of the active ingredients for the target sites. This involves a consideration of the distribution, balance, and elimination of the active ingredients. The following Examples serve to illustrate the invention without limiting the invention in its scope. Introduction Based on previous experiments in rats, it was known that acute injection of pasireotide causes an increase in glucose, which is a rapid establishment (within 30 minutes after injection), and reached its peak between 1 and 3 hours, and returned to baseline values after 6 to 8 hours. Repeated or long-term injections of pasireotide in rats resulted in strong tachyphylaxis. Therefore, only moderate increases in glucose have been observed after repeated or long-term treatment with pasireotide, mainly in the first days of treatment. Based on these data, it was expected that short-term experiments would be optimally adequate to examine the effect of octeotride and pasireotide, and their combination, on plasma glucose. With the To investigate the efficacy of both compounds and their combination on a relevant parameter in rats, the levels of GH and IGF-1 in rat plasma were determined, as well as the body weight in rats, within 14 days of continuous infusion with the compounds The levels of GH and IGF-1 were elevated in patients with acromegaly, and can be effectively reduced in approximately 70 percent of all patients by treatment with octeotride. Due to the known pulsatile release pattern of GH, and the low sensitivity of the available GH RIA, the levels of IGF-1 and body weight (BW) are more reliable parameters to determine the effectiveness of the compound on the GH system. IGF-1. GH and IGF-1 are both growth factors that are responsible for the growth of animals and humans, and the lack of those factors results in growth retardation in animals that are still growing (as in rats). Therefore, the measurement of body weight in combination with IGF-1 is an additional relevant parameter to demonstrate the efficacy of somatostatin analogues. Unlike the rapid changes in glucose levels, changes in IGF-1 levels are only observed after 1 to 2 days of treatment with somatostatin analogues. Methods: In order to investigate the effects of a combination of pasireotide and octeotride on efficacy and plasma glucose, the following short-term and long-term experiments were carried out. term in adult male Lewis rats (250 to 300 grams). In the short-term experiment, octeotride and pasireotide, and their combination, were injected subcutaneously into rats in 1 milliliter of serum. Blood samples were taken by sublingual bleeding of the rats at 15 minutes, 30 minutes, 1 hour, 3 hours, 6 hours, and 8 hours after the injection, and blood glucose was determined using the ACCU-Chek Compact ( Roche), which was calibrated before each measurement. In order to determine the overall effect of the treatment on glucose, the area under the curve (AUC) was determined using GraphPad Prism 4.0. In long-term experiments, octeotride and pasireotide, and their combination, were infused subcutaneously into rats, using osmotic minipumps (Alzet, model: 2002). Blood samples were taken by sublingual bleeding on the day before the minipump implant, and after 1, 7, and 14 days. Glucose was determined using the ACCU-Chek Compact (Roche), and IGF-1 levels were determined using a commercial ELISA (rat IGF-1 Octeia from Immunediagnostics, UK).

Claims (15)

1. A combination comprising at least two different somatostatin analogues (SRIF), wherein one SRIF analog is predominantly directed to SSTR2, and another SRIF analog is predominantly directed to SSTR5, wherein the active ingredients are present in each case in the form free or in the form of a pharmaceutically acceptable salt, and optionally at least one pharmaceutically acceptable carrier; for simultaneous, separate, or sequential use.

2. The combination according to claim 1, which is a combined preparation or a pharmaceutical composition.

3. The combination according to claim 1 or 2, which comprises, as the SRIF analog which is predominantly directed to SSTR2, the octeotride.

4. The combination according to any of claims 1 to 3, which comprises, as an SRIF analog that is predominantly directed to SSTR5, pasireotide.

5. A method for the treatment of a disease mediated by the activation of somatostatin receptors (SSTR1-5) in a warm-blooded animal in need thereof, which comprises administering to the animal a combination according to any one of claims 1 to 4, and in an amount that is therapeutically jointly effective against a disease mediated by activation. of somatostatin receptors (SSTR1-5), and wherein the compounds may also be present in the form of their pharmaceutically acceptable salts.

6. A pharmaceutical composition, which comprises an amount that is therapeutically effective against a disease mediated by the activation of somatostatin receptors (SSTR1-5), of a combination according to any of claims 1 to 4, and when less a pharmaceutically acceptable vehicle.

7. The use of a combination according to any of claims 1 to 4, for the preparation of a medicament for the treatment of a disease mediated by the activation of somatostatin receptors (SSTR1-5).

8. The use according to claim 7, for the treatment of acromegaly, type I or type II diabetes mellitus, diabetic proliferative retinopathy, diabetic macular edema, nephropathy, neuropathy, dawn phenomenon, and other metabolic disorders related to the release of insulin or glucagon, for example obesity, hyper- and hypo-glycemia, for example pathological obesity or hypothalamic or hyperinsulinemic obesity, enterocutaneous and pancreaticocutaneous fistula, irritable bowel syndrome, inflammatory diseases, for example Graves disease, inflammatory bowel disease, psoriasis or rheumatoid arthritis, polycystic kidney disease, rapid emptying syndrome, watery diarrhea syndrome, diarrhea related to AIDS, diarrhea induced by chemotherapy or radiation, acute or chronic pancreatitis, and gastrointestinal hormone secreting tumors (eg, PEG tumors, eg, vipomas, glucagonomas, insulinomas, carcinoids, and the like), lymphocyte malignancies, eg, lymphomas or leukemias, hepatocellular carcinoma, gastrointestinal hemorrhage, eg, varicose esophageal hemorrhage, sleep apnea, grelinoma, Prader-Willi syndrome. A commercial package, which comprises a combination according to any of claims 1 to 4, together with instructions for simultaneous, separate, or sequential use, in the treatment of a disease mediated by the activation of the receptors of Somatostatin (SSTR1-5). A combination comprising at least two different somatostatin analogues (SRIF), wherein one SRIF analog that is predominantly targeted to SSTR2 is octeotide, and another SRIF analog that is predominantly directed to SSTR5 is pasireotide, wherein the ingredients active substances are present in each case in free form or in the form of a pharmaceutically acceptable salt, and optionally at least one pharmaceutically acceptable carrier; for simultaneous, separate, or sequential use. 11. A method for the treatment of a disease mediated by the activation of somatostatin receptors (SSTR1-5) in a warm-blooded animal in need thereof, which comprises administering to the animal a combination according to claim 10, and in an amount that is jointly effective therapeutically against a disease mediated by the activation of somatostatin receptors (SSTR1-5), and wherein the compounds may also be present in the form of their pharmaceutically acceptable salts. 12. A pharmaceutical composition, which comprises an amount that is therapeutically effective against a disease mediated by the activation of somatostatin receptors (SSTR1-5), a combination according to claim 10, and at least one pharmaceutically vehicle acceptable. 13. The use of a combination according to claim 10, for the preparation of a medicament for the treatment of a disease mediated by the activation of somatostatin receptors (SSTR1-5). The use according to claim 13, for the treatment of acromegaly, type I or type II diabetes mellitus, diabetic proliferative retinopathy, diabetic macular edema, nephropathy, neuropathy, dawn phenomenon, and other metabolic disorders related to the release of insulin or glucagon, for example obesity, hyper- and hypo-glycemia, for example pathological obesity or hypothalamic or hyperinsulinemic obesity, enterocutaneous and pancreaticocutaneous fistula, irritable bowel syndrome, inflammatory diseases, for example Graves disease, inflammatory bowel disease, psoriasis or rheumatoid arthritis, polycystic kidney disease, rapid emptying syndrome, watery diarrhea syndrome, AIDS-related diarrhea, chemotherapy-induced diarrhea or radiation, acute or chronic pancreatitis, and gastrointestinal hormone-secreting tumors (eg, PEG tumors, eg, vipomas, glucagonomas, insulinomas, carcinoids, and the like), lymphocyte malignancies, for example lymphomas or leukemias, hepatocellular carcinoma, gastrointestinal hemorrhage, for example varicose esophageal hemorrhage, sleep apnea, grelinoma, Prader-Willi syndrome. 15. A commercial package, which comprises a combination according to claim 10, together with instructions for simultaneous, separate, or sequential use, in the treatment of a disease mediated by the activation of somatostatin receptors (SSTR1- 5).