WO2008053340A1 - Produit de combinaison comprenant au moins un lipide substitué en position alpha et au moins un agent hypoglycémique - Google Patents

Produit de combinaison comprenant au moins un lipide substitué en position alpha et au moins un agent hypoglycémique Download PDF

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WO2008053340A1
WO2008053340A1 PCT/IB2007/003330 IB2007003330W WO2008053340A1 WO 2008053340 A1 WO2008053340 A1 WO 2008053340A1 IB 2007003330 W IB2007003330 W IB 2007003330W WO 2008053340 A1 WO2008053340 A1 WO 2008053340A1
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group
combination product
lipid
product according
acid
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PCT/IB2007/003330
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Morten Bryhn
Jan Kopecky
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Pronova Biopharma Norge As
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • A61K31/232—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having three or more double bonds, e.g. etretinate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • a combination product comprising at least one lipid substituted in the alpha position and at least one hypoglycemic agent.
  • the present invention relates to a combination product comprising a substituted lipid and a hypoglycemic agent. It also relates to the use of such a combination product in the treatment of diabetic conditions.
  • Type 2 diabetes mellitus is growing in the developed and the developing countries as a function of excess food intake and too little physical exercise.
  • the trend of reduced cardiovascular mortality in the US which has been achieved by national programs to reduce cholesterol, hypertension and smoking has been halted and the mortality curve in women is moving slowly upwards probably as a function of overweight and subsequently type 2 diabetes.
  • the physiologic consequence of a high calory intake and too little physical exercise is increasing adipose tissue volume. When the storing capacity of triglycerides into the adipocytes is stretched, spill-over of triglycerides to other tissues like the liver and muscle is increasing.
  • insulin resistance occurs long before the clinical onset of diabetes. The exact mechanism taking place at the cellular level is still not fully understood. However, the consequence is reduced effect of insulin on peripheral tissues. In order to retain glucose for production of metabolic energy and hence keeping the organism in a state of normoglycemia, increased production and release of insulin is initiated. The complex clinical situation related to insulin resistance is called the metabolic syndrome.
  • Metformin may even be used together with insulin in patients with declining insulin production.
  • Glitazones are ligands to the nuclear receptor class PPAR which are a family of ligand-activated transcription factors that modulate multiple aspects of lipid and carbohydrate metabolism.
  • PPAR ⁇ is primarily implicated in regulation of lipid metabolism, lipoprotein synthesis and metabolism, in liver and other tissue.
  • PPARy plays a pivotal role in adipocyte differentiation and lipid storage in addition to the regulation of glucose metabolism.
  • glitazones like rosiglitazone and pioglitazone, are selective PPARy ligands. Some of the new glitazones also have affinity to the PPAR ⁇ receptor. Since different anti-diabetics used for treatment of type 2 diabetics have different mode-of-action they are frequently used in combination. A product containing metformin and pioglitazone in fixed formulation was recently launched on the market for treatment of diabetes (Deeks and Scott LJ, Drugs 2006;66: 1863-1877). Polyunsaturated fatty acids are natural ligands to the PPAR receptors mainly PPAR ⁇ but also PPARy.
  • DHA docosahexaenoic acid
  • the aim of the present invention is to provide new treatments for diabetic conditions.
  • a combination product comprising: • at least one lipid in the form of a carboxylic acid, or a derivative thereof, a carboxylic ester, a carboxylic anhydride, an alcohol or an amide, which lipid is substituted at carbon 2, counted from the functional group, with at least one substituent, or any pharmaceutically acceptable complex, solvate, salt or pro-drug thereof; and
  • the lipid may have a chain length of 16-24 carbon atoms, and suitably contains at least two double bonds with E and/or Z configuration.
  • the lipid may be an omega-3 lipid compound is selected from the group consisting of: • (all-Z)-4,7,10,13,16,19-docosahexaenoic acid,
  • the lipid may be an omega-6 lipid compound selected from the group consisting of:
  • the substituent at carbon 2 may be selected from the group consisting of a hydrogen atom, a hydroxy group, an alkyl group, a halogen atom, an alkoxy group, an acyloxy group, an acyl group, an alkenyl group, an alkynyl group, an aryl group, an alkylthio group, an alkoxycarbonyl group, a carboxy group, an alkylsulfinyl group, an alkylsulfonyl group, an amino group, and an alkylamino group.
  • the lipid may be (all-Z)-4,7,10,13, 16,19-docosahexaenoic acid (DHA), (all-Z)-5,8,11 ,14,17-eicosapentaenoic acid (EPA) or (all-Z)- 7,10,13,16,19-docosapentaenoic acid, and the substituent may be an alkyl group, e.g. ethyl or propyl, an alkoxy group, e.g. methoxy or ethoxy, and alkylthio group, e.g. thiomethyl or thioethyl, or an aryl group, e.g.
  • the lipid is present in the form of a carboxylic acid, or a derivative thereof, or an ethyl or methyl ester.
  • the derivative of a carboxylic acid may be a salt, a phospholipid, or a tri-, di-, or monoglyceride.
  • Salts of the lipids of the invention may comprise a monovalent cation such as Li + , Na + , K + , NH4 + , meglumine, tris(hydroxymethyl)aminomethane, diethylamine, arginine; a divalent ion such as Mg 2+ , Ca 2+ , ethylenediamine, piperazine; or a polyvalent cation such as chitosan.
  • a monovalent cation such as Li + , Na + , K + , NH4 + , meglumine, tris(hydroxymethyl)aminomethane, diethylamine, arginine
  • a divalent ion such as Mg 2+ , Ca 2+ , ethylenediamine, piperazine
  • a polyvalent cation such as chitosan.
  • lipid when present as a derivative of a carboxylic acid in the form of a phospholipid, such a derivative may be represented by
  • lipid When the lipid is present as a derivative of a carboxylic acid in the form of a triglyceride, such a derivative may be represented by:
  • lipid when present as a derivative of a carboxylic acid in the form of a 1-monoglyceride, such a derivative may be represented by
  • lipid when the lipid is present as a derivative of a carboxylic acid in the form of a 2-monoglyceride, such a derivative may be represented by
  • the hypoglycemic agent is suitably a PPAR Y agonist, a PPAR y partial agonist, and/or a PPAR y modulator, and suitably lowers the blood glucose level.
  • hypoglycemic agents are: a thiazolidinedione (TZD) derivative, e.g. rosiglitazone or pioglitazone, or metformin.
  • the invention also relates to the combination product for use as a medicament and for use in therapy.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a combination product according to the above, and the use of such a pharmaceutical composition as a medicament and in therapy.
  • the lipid and the hypoglycemic agent may be formulated in different pharmaceutical compositions or in a common pharmaceutical composition.
  • the pharmaceutical composition may be formulated to provide a daily dosage of 1 mg to 10 g, 20 mg to 1 g or 20 mg to 400 mg of the lipid, and a daily dosage of 1 to 5000 mg of the hypoglycemic agent.
  • the daily dosage may be 4 to 8 mg; when the hypoglycemic agent is pioglitazone, the daily dosage may be 15 to 30 mg; when the hypoglycemic agent is Metformin, the daily dosage may be 500 to 3000 mg.
  • the present invention relates to the use of:
  • the diabetic condition may be diabetes mellitus type 2, a combination of diabetes mellitus type 2 and an overweight condition, or a combination of diabetes mellitus type 2 and elevated blood lipid levels.
  • the invention also relates to methods for the treatment and/or prevention of the conditions listed above, comprising administering to a mammal in need thereof a pharmaceutically active amount of the combination product.
  • the present invention relates to a kit comprising:
  • a pharmaceutical composition comprising at least one lipid in the form of an acid, or a derivative thereof, an ester, an anhydride, an alcohol or an amide, which lipid is substituted at carbon 2, counted from the functional group, with at least one substituent, or any pharmaceutic! ⁇ acceptable complex, salt, solvate or pro-drug thereof;
  • a pharmaceutical composition comprising at least one hypoglycemic agent, or any pharmaceutically acceptable complex, solvate or pro- drug thereof.
  • Another embodiment of the invention is a method for the manufacture of a combination product according to the invention.
  • DHA docosahexaenoic acid
  • a range of omega-3 lipid derivatives e.g. DHA derivatives
  • IB2006/001155 results of these experiments indicate effects on insulin resistance with potency 10 to 30 times greater than pure DHA.
  • One of the most potent of these DHA derivatives is alpha-ethyl-DHA. This promising compound demonstrated high binding affinity to PPAR ⁇ as well as PPARy in computerbased docking models of these receptors and also in transfected cells containing the DNA binding domain of PPAR ⁇ and PPARy.
  • the DHA derivatives In contrast to many other anti-diabetics the DHA derivatives induce significant weight reduction. This is especially interesting since overweight and obesity is a regular finding in patients with type 2 diabetes. Furthermore, the DHA derivatives reduce serum triglycerides and free fatty acids which are usually increased in patients with type 2 diabetes.
  • the compound was combined with rosiglitazone and also metformin in an animal model of the metabolic syndrome with insulin resistance determined by intraperitoneal glucose tolerance test and plasma insulin.
  • the lipid is an omega-3 fatty acids in the form of an ethyl ester.
  • Lipid (all-Z)-4,7,10,13,16,19-docasahexaenoic acid (DHA):
  • Lipid (aII-Z)-7,10,13,16,19-docosapentaenoic acid (DPA)
  • Lipid (all-Z)-5,8,11 ,14,17-eicosapentaenoic acid (EPA)
  • Lipid (all-Z)-9,12,15-octadecatrienoic acid (Alpha-linolenic acid (ALA))
  • hypoglycemic agents are listed below: Glitazones
  • Metformin is a biguanide hypoglycaemic agent, an agent which lower the blood glucose level, used in the treatment of non-insulin-dependent diabetes mellitus not responding to dietary modification. Metformin improves glycaemic control by improving insulin sensitivity and decreasing intestinal absorption of glucose.
  • hypoglycemic agents are:
  • the term “hypoglycaemic agent” relates to a substance which lowers the blood glucose level.
  • lipid relates to long chain polyunsaturated fatty acids or mono-, di-, or triglycerides thereof, long chain polyunsaturated esters, long chain polyunsaturated anhydrides, long chain polyunsaturated alcohols and long chain polyunsaturated amides.
  • Omega-3 fatty acids constitute a suitable example of a lipid according to the invention.
  • a derivative of a carboxylic acid may be a phospholipid, or a tri-, di-, or monoglyceride, i.e. the compound according to the invention may exist in the form of a phospholipid, a tri-, di- or monoglyceride, or in the form of a free acid.
  • PPAR y modulator relates to partial PPAR y agonists modulating PPAR y activity.
  • the lipid and the hypoglycaemic agent may be administered simultaneously or consecutively. When administered consecutively, either the lipid compound is administered first and thereafter the hypoglycemic agent, or the hypoglycemic agent is administered first and thereafter the lipid compound.
  • the interval between the administrations depends on the drug characteristics, and may e.g. vary from hours to days. However, shorter and longer intervals may be used.
  • Pro-drugs are entities which may or may not possess pharmacological activity as such, but may be administered (such as orally or parenterally) and thereafter subjected to bioactivation (for example metabolization) in the body to form the agent of the present invention which is pharmacologically active.
  • the present invention also includes salts of the carboxylic acid.
  • Suitable pharmaceutically acceptable salts of carboxy groups includes metal salts, such as for example alkali metal salts such as lithium, sodium or potassium, alkaline metal salts such as calcium or magnesium and ammonium or substituted ammonium salts.
  • a “pharmaceutically active amount” relates to an amount that will lead to the desired pharmacological and/or therapeutic effects, i.e. an amount of the combination product which is effective to achieve its intended purpose. While individual patient needs may vary, determination of optimal ranges for effective amounts of the combination product is within the skill of the art. Generally, the dosage regimen for treating a condition with the combination product of this invention is selected in accordance with a variety of factors, including the type, age, weight, sex, diet and medical condition of the patient.
  • a pharmaceutical composition is meant a combination product according to the invention in any form suitable to be used for a medical purpose.
  • Treatment includes any therapeutic application that can benefit a human or non-human mammal. Both human and veterinary treatments are within the scope of the present invention. Treatment may be in respect of an existing condition or it may be prophylactic.
  • the combination product may be used on its own, but will generally be administered in association with a pharmaceutically acceptable carrier, excipient or diluent (including combinations thereof).
  • Acceptable carriers, excipients and diluents for therapeutic use are well known in the pharmaceutical art, and can be selected with regard to the intended route of administration and standard pharmaceutical practice. Examples encompass binders, lubricants, suspending agents, coating agents, solubilising agents, preserving agents, wetting agents, emulsifiers, sweeteners, colourants, flavouring agents, odourants, buffers, suspending agents, stabilising agents, and/or salts.
  • a pharmaceutical composition according to the invention is preferably formulated for oral administration to a human or an animal.
  • the pharmaceutical composition may also be formulated for administration through any other route where the active ingredients may be efficiently absorbed and utilized, e.g. intravenously, subcutaneously, intramuscularly, intranasally, rectally, vaginally or topically.
  • the pharmaceutical composition is shaped in form of a capsule, which could also be a microcapsule generating a powder or a sachet.
  • the capsule may be flavoured.
  • This embodiment also includes a capsule wherein both the capsule and the encapsulated composition according to the invention is flavoured. By flavouring the capsule it becomes more attractive to the user.
  • the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated.
  • the combination product according to the invention is presented in liquid form or as an emulsion.
  • a daily dosage relates to the dosage per 24 hours.
  • the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. Typically, a physician will determine the actual dosage which will be most suitable for an individual subject.
  • the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual undergoing therapy.
  • the combination product of the present invention may be administered in accordance with a regimen of from 1 to 10 times per day, such as once or twice per day.
  • the daily dosage level of the agent may be in single or divided doses.
  • the combination product according to the present invention has primarily shown the following pharmaceutical activities: • anti-diabetic activity
  • PPAR peroxisome proliferator- activated receptor
  • Type 1 diabetes which is known as insulin-dependent diabetes mellitus (IDDM)
  • type 2 diabetes which is also known as non-insulin-dependent diabetes mellitus (NIDDM).
  • IDDM insulin-dependent diabetes mellitus
  • NIDDM non-insulin-dependent diabetes mellitus
  • Type 2 diabetes is related to obesity/overweight and lack of exercise, often of gradual onset, usually in adults, and caused by reduced insulin sensitivity, so called periferral insulin resistance. This leads to a compensatory increase in insulin production.
  • This stage before developing full fetched type 2 diabetes is called the metabolic syndrome and characterized by hyperinsulinemia, insulin resistance, obesity, glucose intolerance, hypertension, abnormal blood lipids, hypercoagulopathia, dyslipidemia and inflammation.
  • the combination product according to the invention may be used for treatment and/or prevention of metabolic syndrome, and the conditions mentioned above. Later when insulin production seizes, type 2 diabetes mellitus develops. In one embodiment, the combination product may be used for the treatment of type 2 diabetes.
  • the combination product according to the invention may also be used for the treatment of other types of diabetes selected from the group consisting of secondary diabetes, such as pancreatic, extrapancreatic/endocrine or drug-induced diabetes, or exceptional forms of diabetes, such as lipoatrophic, myatonic or a disease caused by disturbance of the insulin receptors.
  • secondary diabetes such as pancreatic, extrapancreatic/endocrine or drug-induced diabetes
  • exceptional forms of diabetes such as lipoatrophic, myatonic or a disease caused by disturbance of the insulin receptors.
  • the combination product may activate nuclear receptors, preferably PPAR (peroxisome proliferator-activated receptor) ⁇ and/or ⁇ .
  • PPAR peroxisome proliferator-activated receptor
  • pSG5-GAL4-hPPAR ⁇ Another construct (5XUAS-LUC) was also made which contains the DNA binding sites for GAL4.
  • UAS upstream activation sequences is cloned to a reporter gene, luciferase (LUC).
  • Fatty acids/ligands Rosiglitazone (BRL), WY-14,643, Clofibrate and PRBs (stock solutions) were solubilized to 0.1 M final concentration in DMSO. Then, solubilized to 1OmM in DMSO and stored in 1.5 ml tubes (homoplymer, plastic tubes) flushed with argon and stored at -20 0 C.
  • COS-1 cells (ATCC no. CRL 1650) were cultured in DMEM supplemented with L-glutamine (2MM), penicillin (50 U/ml), streptomycin (50 ⁇ G/mL), fungizone (2.5 ⁇ g/mL), and 10% inactivated FBS. The cells were incubated at 37°C in a humidified atmosphere of 5% CO2 and 95% air and used for transient transfections. Every third day, the cells in each flask were split into new flasks containing fresh media.
  • Transfected cells were maintained for 24h before lysis by reporter lysis buffer. Binding of PRBs or fatty acids to the LBD of PPAR activates GAL4 binding to UAS, which in turn stimulates the tk promoter to drive luciferase expression. Luciferase activity was measured using a luminometer (TD-20/20 luminometer; Turner Designs, Sunnycvale, CA) and normalized against protein content.
  • Synthetic compounds that induce peroxisomal proliferation in rodents and hypolipidemic agents such as clofibrate and WY- 14,643 have been shown to specifically bind to and activate PPAR ⁇ .
  • PRB1 is ethyl (all-Z)-2-methyl-4,7,10,13,16,19-docosahexaenoate
  • PRB2 is ethyl (all-Z)-2-ethyl-4,7,10,13,16,19-docosahexaenoate
  • PRB3 is ethyl (all-Z)-2-ethoxy-4,7,10,13,16,19-docosahexaenoate
  • PRB5 is ethyl (all-Z ⁇ -dimethyMJ.IO.IS.I ⁇ .i ⁇ -docosahexaenoate
  • PRB6 is ethyl (all-Z)-2-thiomethyl-4,7,10,13,16,19-docosahexaenoate
  • PRB7 is ethyl (all-Z)-2-thioethyl-4,7,10,13,16,19-docosahexaenoate
  • PRB8 is ethyl (all-Z)-2,2-diethyl-4,7,10,13,16,19-docosahexaenoate
  • PRB9 is ethyl (all-Z)-2-benzyl-4,7,10,13,16,19-docosahexaenoate
  • PRB14 is ethyl (all-Z)-2-methoxy-4,7,10,13,16,19-docosahexaenoate
  • the most potent PPARs showed a sixth fold activation of hPPAR ⁇ compared to clofibrate.
  • PRB-2 is one of the most potent activators, increasing the activation five fold compared to clofibrate.
  • mice Combination treatment of mice by alpha-substituted lipid derivative, rosiglitazone and metformin admixed to a high-fat diet
  • Adipose prone mice of the C57BL/6 strain develop leptin resistance after 16 days on a high fat diet (van Heek et al. J Clin Invest 1997;99:385- 390). When fed high fat diet over a longer period of time they are getting obese (Fig. 1) and develop insulin resistance which can be documented by elevated plasma insulin levels and a high area-under-the-curve (AUC) value in the intraperitoneal glucose tolerance test.
  • the C57BL/6 mice are ideal for testing of compounds with effects on lipid and glucose metabolism and obesity.
  • mice All experiments were performed on male C57BL/6N mice (supplier: Charles River, Germany), fed ad libitum and maintained at 22 0 C, with 12 h light/dark cycle (light from 7 am to 7 pm).
  • animals were 14-week-old and maintained (since weaning) on a standard chow diet (STD; with protein, fat and carbohydrate forming 33, 9, and 58 energy %, respectively; ssniff R/M-H from SSNIFF Spezialdieten GmbH, Soest, Germany).
  • STD standard chow diet
  • the treatment included the following diets: (i) The STD diet, (ii) high-fat diet prepared in the laboratory (cHF), i.e. high-fat composite diet with protein, fat and carbohydrate forming 15, 59, and 26 energy %, respectively, and well characterized fatty acid composition (with most of the lipids coming from corn oil; see Ruzickova et al, 2004 Lipids 39: 1177-1185), (iii) the cHF diet as above, but with 1.5% of its lipids replaced by alfa- ethyl-DHA ethyl- ester, PRB-2 (PRB2-1.5%), (iv) the cHF diet as above, but with 2 g metformin/kg diet (Met), (v) the cHF diet as above, but with 10 mg rosiglitazone/kg diet (Rosi), (vi) the cHF diet as above, but with 2 g metformin /kg diet, and with
  • mice treated by the combination of PRB-2 with either metformin (M+P) or rosiglitazone (R+P) tended to weight less than the PRB2-1.5% animals. This difference tended to be more pronounced between the PRB2-1.5% and M+P groups than the difference between the PRB2-1.5% and R+P group. Similar conclusions can be drawn from the evaluation of body weight gains during the treatment (Table 1).
  • Glucose tolerance expressed as AUC for glucose (as estimated by GTT; Table 3), was higher in the cHF mice compared with the STD mice, indicating again a deterioration of glucose homeostasis and insulin sensitivity induced by a high-fat diet. While Met or Rosi had no effect on AUC value, this parameter of glucose homeostasis was positively affected to a similar extent by PRB2-1.5%, M+P, and R+P, respectively.
  • Type 2 diabetic patients are usually obese and it is very negative that the two antidiabetics pharmaceuticals used in the present experiment do not reduce weight gain at all.
  • the lack of effect on obesity has been shown previously in clinical studies.
  • Some of the glitazones have even induced weight gain, which must be regarded as highly unwanted.
  • the combination with PRB2 reduced weight gain significantly compared to the control group (cHF), and even somewhat better than PRB2 alone.
  • Rosiglitazone as well as the other glitazones reduce insulin in plasma by positive interference with insulin resistance. This effect is very relevant again addressing the very pathophysiologic basis for the disease.
  • the combination of rosiglitazone and PRB2 had an even better effect on plasma insulin. This combinative effect has not been shown previously favoring a combination product of both compounds for treatment of type 2 diabetes.
  • Metformin on the other hand, does not effect insulin resistance but lowers blood glucose by another mechanisms. Combined with PRB2 a dual effect was obtained indicating that a combination product with metformin and PRB2 could be very interesting by combining two compounds with completely different mode-of-action.
  • metformin nor rosiglitazone reduced AUC glucose in the intraperitoneal glucose tolerance test in the present experiment. This makes sense for metformin not having an effect on glucose tolerance but not for rosiglitazone. The reason for not being able to improve the glucose tolerance test by rosiglitazone is obscure.
  • the glucose tolerance (GT) test is a sensitive marker of glucose handling by mechanisms induced by insulin. Animals and patients with glucose intolerance have delayed glucose elimination in the GT test. Pharmaceuticals reducing insulin resistance normalise glucose utilisation. Compounds acting as PPARy ligands reduce insulin resistance. It is therefore an unexpected finding that rosiglitazone should not give lower AUC in the GT test.
  • PRB2 on the other hand being a combined PPARy/ PPAR ⁇ ligand demonstrated significant reduction of the AUC as expected. From the experiment presented it seems that a combination of PRB2 and metformin or rosiglitazone would improve the hypoglycaemic effects of these pharmaceuticals by reducing peripheral insulin resistance. Metformin acts through yet another mode-of-action different from the thiazolidinediones, which is one of the reasons why a new combinative product has been launched on the market for the treatment of type 2 diabetes. A combination of Metformin and PRB2 seems to another logic combination with the potential of addressing several of the pathophysiologic events common for patients witn type 2 diabetes.

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Abstract

Produit de combinaison comprenant: au moins un lipide sous la forme d'acide carboxylique, ou un dérivé correspondant, un ester carboxylique, un anhydride carboxylique, un alcool ou un amide, ce lipide substitué à l'atome de carbone 2, compté à partir du groupe fonctionnel, avec au moins un substituant, ou un complexe, sel, solvate ou promédicament correspondant pharmaceutiquement acceptable; et au moins un agent hypoglycémique ou un complexe, solvate ou promédicament correspondant pharmaceutiquement acceptable. Également, utilisation de ce produit de combinaison pour le traitement d'affections diabétiques.
PCT/IB2007/003330 2006-11-03 2007-11-02 Produit de combinaison comprenant au moins un lipide substitué en position alpha et au moins un agent hypoglycémique WO2008053340A1 (fr)

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CN103533833A (zh) * 2011-01-12 2014-01-22 西蒂斯制药有限责任公司 降脂抗糖尿病剂
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US10722481B2 (en) 2015-04-28 2020-07-28 Basf As Substituted fatty acids for treating non-alcoholic steatohepatitis
US11351139B2 (en) 2013-02-28 2022-06-07 Basf As Composition comprising a lipid compound, a triglyceride, and a surfactant, and methods of using the same
US11925614B2 (en) 2017-12-06 2024-03-12 Basf As Fatty acid derivatives for treating non-alcoholic steatohepatitis

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WO2009134147A1 (fr) * 2008-05-02 2009-11-05 Pronova Biopharma Norge As Compositions lipidiques renfermant des dérivés d’epa et de dha et leur utilisation
EP2147910A1 (fr) * 2008-07-15 2010-01-27 Pronova BioPharma Norge AS Nouveaux composés lipidiques
US8759558B2 (en) 2008-07-15 2014-06-24 Pronova Biopharma Norge As Sulphur containing lipids for use as food supplement or as medicament
EP2313090A1 (fr) * 2008-07-15 2011-04-27 Pronova BioPharma Norge AS Nouveaux lipides contenant du soufre pour utilisation en tant que supplément alimentaire ou médicament
EP2313090A4 (fr) * 2008-07-15 2012-01-18 Pronova Biopharma Norge As Nouveaux lipides contenant du soufre pour utilisation en tant que supplément alimentaire ou médicament
WO2010039040A1 (fr) * 2008-09-30 2010-04-08 Epax As Composition comprenant au moins un agoniste de ppar et un composant phospholipidique
US11253497B2 (en) 2009-03-16 2022-02-22 Lipopharma Therapeutics, S.L. Use of derivatives of polyunsaturated fatty acids as medicaments
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US8735436B2 (en) 2009-05-08 2014-05-27 Pronova Biopharma Norge As Polyunsaturated fatty acids for the treatment of diseases related to cardiovascular, metabolic and inflammatory disease areas
JP2012526094A (ja) * 2009-05-08 2012-10-25 プロノヴァ・バイオファーマ・ノルゲ・アーエス 心血管性、代謝性および炎症性疾患領域に関する疾患の処置のための多価不飽和脂肪酸
EP2427415A4 (fr) * 2009-05-08 2015-07-22 Pronova Biopharma Norge As Acides gras polyinsaturés pour le traitement de maladies relatives au domaine des maladies cardiovasculaires, métaboliques et inflammatoires.
WO2010128401A1 (fr) 2009-05-08 2010-11-11 Pronova Biopharma Norge As Acides gras polyinsaturés pour le traitement de maladies relatives au domaine des maladies cardiovasculaires, métaboliques et inflammatoires.
EP2248798A1 (fr) * 2009-05-08 2010-11-10 Pronova BioPharma Norge AS Nouveaux composés de lipides
EA021177B1 (ru) * 2009-05-08 2015-04-30 Пронова Биофарма Норге Ас Полиненасыщенные жирные кислоты для лечения заболеваний, связанных с сердечно-сосудистыми, метаболическими и воспалительными заболеваниями
CN102740712A (zh) * 2009-12-07 2012-10-17 雀巢产品技术援助有限公司 低热量脂肪替代品
WO2011069958A3 (fr) * 2009-12-07 2011-08-04 Nestec S.A. Produits hypocaloriques de remplacement des graisses
EP2332427A1 (fr) * 2009-12-07 2011-06-15 Nestec S.A. Succédanés à faible teneur calorique en gras
US9394228B2 (en) 2010-11-05 2016-07-19 Pronova Biopharma Norge As Methods of treatment using lipid compounds
CN103533833A (zh) * 2011-01-12 2014-01-22 西蒂斯制药有限责任公司 降脂抗糖尿病剂
WO2014008374A3 (fr) * 2012-07-06 2014-02-27 Thetis Pharmaceuticals Llc Thérapies combinées comprenant des sels de metformine et des agents antihyperglycémie ou des agents antihyperlipidémie
WO2014008374A2 (fr) * 2012-07-06 2014-01-09 Thetis Pharmaceuticals Llc Thérapies combinées comprenant des sels de metformine et des agents antihyperglycémie ou des agents antihyperlipidémie
WO2014134053A1 (fr) * 2013-02-26 2014-09-04 Jiva Pharma, Inc. Esters d'ascorbate d'acides gras oméga 3
US11351139B2 (en) 2013-02-28 2022-06-07 Basf As Composition comprising a lipid compound, a triglyceride, and a surfactant, and methods of using the same
US10722481B2 (en) 2015-04-28 2020-07-28 Basf As Substituted fatty acids for treating non-alcoholic steatohepatitis
US11234948B2 (en) 2015-04-28 2022-02-01 Basf As Substituted fatty acids for treating non-alcoholic steatohepatitis
US11911354B2 (en) 2015-04-28 2024-02-27 Basf Substituted fatty acids for treating non-alcoholic steatohepatitis
US11925614B2 (en) 2017-12-06 2024-03-12 Basf As Fatty acid derivatives for treating non-alcoholic steatohepatitis

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