JP2001512450A - Use of nitric oxide synthase inhibitors for the treatment of diabetes - Google Patents

Abstract

  (57) [Summary] A method of treating and / or preventing type II diabetes, comprising a non-toxic pharmaceutically acceptable amount of a NO synthase inhibitor, eg, aminoguanidine, or a pharmaceutically acceptable salt thereof, which is effective in a human or non-human mammal. And administering a derivative.

Description

DETAILED DESCRIPTION OF THE INVENTION Use of a Nitric Oxide Synthase Inhibitor for the Treatment of Diabetes The present invention provides a novel method for the treatment and / or prevention of non-insulin dependent (NIDDM or type II) diabetes, in particular It relates to the use of a NO synthase inhibitor such as aminoguanidine for said treatment and / or prevention. Hydrazinecarboximidamide (hereinafter referred to as aminoguanidine) is a known compound (Journal of American Chemical Society, 57, 2730 (1935)). Aminoguanidine is known to be an inhibitor of protein glycation and has been evaluated in animal models for the treatment of diabetic complications (Diabetes 42, 221-232 1993; Diabetologia 35, 946- 950). Aminoguanidine is a NO synthase inhibitor (Eur. J Pharmacol., 233, 119-125) and is useful in the treatment of conditions characterized by overproduction of NO (European J. of Pharmacology, 233, ( 1993), 119-125). Inhibition of nitric oxide formation is believed to be particularly related to the known activity of aminoguanidine in the treatment of diabetic complications. Aminoguanidine has been evaluated in animal models for the treatment of diabetic complications (Diabetes 42: 221-2321993; Diabetologia 35: 946-950). To date, there is no suggestion that aminoguanidine or any other NO synthase inhibitor would have a beneficial effect on Type II diabetes itself. As mentioned above, the emphasis has been on the complications of diabetes. The inventors have now surprisingly found that aminoguanidine has potential use in the treatment and / or prevention of type II diabetes itself. In particular, aminoguanidine has been shown to slow or prevent the progression of non-insulin-dependent diabetes from hyperinsulinemia to overt diabetes. This new and surprising effect is thought to be due to the NO synthase inhibitory activity of aminoguanidine in the pancreas of type II diabetes. Accordingly, the present invention provides a method for treating and / or preventing type II diabetes, comprising a non-toxic pharmaceutically acceptable amount of a NO synthase inhibitor or a pharmaceutically acceptable salt thereof, which is effective in a human or non-human mammal. A method comprising administering a derivative. Preferably, the present invention provides a method for the prophylactic treatment of Type II diabetes, particularly a method for delaying or preventing the progression from hyperinsulinemia to hyperglycemia. Suitable inhibitors of NO synthase include protein and non-protein compounds, eg, aminoguanidine, n-monomethylarginine, or other analogs of 1-arginine. A particular NO synthase inhibitor is aminoguanidine. As used herein, the term "NO synthase inhibitor" refers to a substance that inhibits the formation of nitric oxide from 1-arginine. The NO synthase inhibitory activity of the compounds is determined by inhibition of [ ³ H] 1-arginine to [ ³ H] citrulline or nitric oxide by cell or tissue extracts or by in vitro recombinant nitric oxide synthase isoenzyme. It is measured in routine tests such as inhibition of production (FASEB. J 1993; 7: 349-360). A suitable pharmaceutically acceptable derivative is a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof. Suitable pharmaceutically acceptable salts include acid addition salts. Suitable acid addition salts are pharmaceutically acceptable inorganic salts, such as sulfates, nitrates, phosphates, borates, hydrochlorides and hydrobromides, and pharmaceutically acceptable organic acid addition salts, For example acetate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, methane-sulfonate, a-ketoglutarate and a-glycerophosphate, especially maleate Is included. Suitable pharmaceutically acceptable solvates include hydrates. The NO synthase inhibitor used in the method of the present invention may be prepared according to a conventional method such as the method disclosed in the aforementioned publication. A mer. Chem. Soc. 57, 2730 (1935). Salts and / or solvates may be prepared and isolated according to conventional methods. In a further aspect of the present invention, the present invention also provides a NO synthase inhibitor such as aminoguanidine or a pharmaceutically acceptable derivative thereof for use in the treatment and / or prevention of type II diabetes. Also provided is a NO synthase inhibitor such as aminoguanidine or a pharmaceutically acceptable derivative thereof for use in the manufacture of a medicament for the treatment and / or prevention of type II diabetes. In the above treatments and / or prophylaxis, a NO synthase inhibitor such as aminoguanidine or a pharmaceutically acceptable derivative thereof may be administered per se, or preferably a medicament comprising a pharmaceutically acceptable carrier. It may be administered as a composition. Therefore, the present invention also provides a pharmaceutical composition for the treatment and / or prevention of type II diabetes, comprising a NO synthase such as aminoguanidine or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier thereof. A composition comprising: As used herein, the term "pharmaceutically acceptable" includes compounds, compositions and components for human and veterinary use: for example, "pharmaceutically acceptable salts" The term includes veterinarily acceptable salts. The composition may, if desired, be in a pack with written or printed instructions accompanying it. Usually, the pharmaceutical compositions of the invention will be adapted for oral administration, although compositions for administration by other routes, eg, injection and transdermal absorption, are also contemplated. Particularly suitable compositions for oral administration are unit dosage forms such as tablets and capsules. Other fixed unit dosage forms, such as powders in sachets, may also be used. According to conventional pharmaceutical practice, the carrier may include diluents, fillers, disintegrants, wetting agents, lubricants, coloring agents, flavoring agents or other conventional additives. Typical carriers include, for example, microcrystalline cellulose, starch, sodium starch glycolate, polyvinylpyrrolidone, polyvinylpolypyrrolidone, magnesium stearate, sodium lauryl sulfate or sucrose. Most suitably, the compositions will be formulated in a unit dosage form. Such a unit dose will usually contain from 0.1 to 1000 mg, more usually 0.1 to 500 mg, more particularly 0.1 to 250 mg, of the active ingredient. Conveniently, the active ingredient may be administered as a pharmaceutical composition as hereinbefore defined, which forms a separate aspect of the present invention. In the above treatment, a NO synthase inhibitor such as aminoguanidine or a pharmaceutically acceptable derivative thereof is administered one to six times a day at the above dose, generally a total dose of 70 kg adult daily. It may be given in such a manner as to range from 0.1 to 6000 mg, more usually about 1 to 1500 mg, generally about 0.5 to 10 mg. That is, 1.429 × 10 ^{−3 to} 58.714 mg / kg / day, more usually about 1.429 × 10 ^{−2 to} 21.429 mg / kg / day, and generally about 7.143 × 10 ^{−3 to} 0.1429 mg / kg. / Day range. No unacceptable toxicological effects are observed when the active compound is administered according to the above of the invention. The following examples illustrate the invention but do not limit the invention in any way. EXAMPLES Methodology of the dbdb Mouse Model Obese db / db mice are a genetic model of insulin-resistant and hyperglycemic type 2 non-insulin-dependent diabetes mellitus. Six week old male animals were obtained. A blood sample for measuring blood glucose before treatment was obtained by cutting off the tip of the tail. Animals were assigned to treatment and control groups such that the mean and standard deviation of fasting blood glucose levels in each group were similar. On study day 0, a group of obese animals and their lean littermates were sacrificed for biochemical and histological baseline measurements. In addition, one group of animals (control; n = 14) received a standard diet, and another group received aminoguanidine (500 mg / kg; n = 14) in the same diet. Animals had free access to food and water, and their intake was measured daily. Urine production for 24 hours was also measured weekly. Mice (n = 7) were killed on days 30 and 85 from the start of treatment. Blood was collected for measurement of glucose and insulin levels, and the pancreas was removed for histological analysis and measurement of pancreatic insulin. Data from the dbdb mouse model Food intake and weight gain of the control and treated groups were similar throughout the experimental period. Obese animals immediately before administration had normal blood glucose levels (blood glucose 10.4 ± 0.97 mM), but had hyperinsulinemia compared to their lean littermates (serum insulin 127 in obese animals). ± 37 ng / ml, 3.05 ± 1.03 ng / ml in lean animals). By day 30 of the administration period, the obese control group was hyperglycemic (blood glucose 24.9 ± 1.0 mM) and had significantly lower serum insulin levels (30.75 ± 4 compared to pre-treatment values). .3 mM). By day 85 of the treatment period, fasting blood glucose had risen to 28.1 ± 2 mM and serum insulin levels had further dropped to 11.7 ± 1.8 ng / ml. Aminoguanidine suppressed the decrease in fasting insulin concentration (58.3 ± 13 ng / ml on day 30, 23.3 ± 4.1 ng / ml on day 85) Hyperglycemia was significantly reduced (21 ± 1.7 mM). The pancreatic insulin content of the aminoguanidine-treated group of obese animals was twice that of the untreated animals (64.3 ± 17.8 ng / mg compared to 30.0 ± 2.6 ng / mg pancreas, respectively). From day 63 of the experimental period, the obese control animals were significantly more drunk and polyuric than compared to day 7. This increase in water intake and urine production was characteristic of diabetes (hyperglycemia) and was prevented by treatment with aminoguanidine (FIG. 1). Similarly, urinary glucose excretion continually increased over the duration of the experiment in both untreated and treated animals, but was lower in the aminoguanidine treated group from day 35 (FIG. 1). The onset of diabetes (hyperglycemia) was associated with a change in islet morphology, with the islets of untreated control animals becoming significantly enlarged, destructed, and had abnormal borders. Islet insulin content was significantly depleted. At day 30 of the treatment period, normal islet morphology was maintained in the aminoguanidine-treated animals, and the islet insulin content was higher.

────────────────────────────────────────────────── ─── Continuation of front page    (81) Designated countries EP (AT, BE, CH, DE, DK, ES, FI, FR, GB, GR, IE, IT, L U, MC, NL, PT, SE), OA (BF, BJ, CF) , CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (KE, LS, MW, SD, S Z, UG), EA (AM, AZ, BY, KG, KZ, MD , RU, TJ, TM), AL, AM, AT, AU, AZ , BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, G E, HU, IL, IS, JP, KE, KG, KP, KR , KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, P L, PT, RO, RU, SD, SE, SG, SI, SK , TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU (72) Inventor Piercy, Valerie             UK, EIL 6.9 EIR, Ha             Tetfordshire, Welwyn, The             Frith, Smithkline Beecham Hu             Armaturicals

Claims (1)

[Claims] 1. A method for treating and / or preventing type II diabetes, which is human or non-human A non-toxic pharmaceutically acceptable amount of a NO synthase inhibitor effective in mammals, or Administering a pharmaceutically acceptable derivative thereof. 2. 2. The method according to claim 1, for prophylactic treatment of type II diabetes. 3. Claim 1 for delaying or preventing progression from hyperinsulinemia to hyperglycemia. Or the method of 2. 4. NO synthase inhibitors are aminoguanidine, n-monomethylarginine or Is selected from other analogues of 1-arginine. the method of. 5. 5. The method according to claim 1, wherein the NO synthase inhibitor is aminoguanidine. The method described in the section. 6. NO sinter for use in the treatment and / or prevention of type II diabetes An inhibitor or a pharmaceutically acceptable derivative thereof. 7. For use in the manufacture of a medicament for the treatment and / or prevention of type II diabetes NO synthase inhibitor or a pharmaceutically acceptable derivative thereof. 8. A pharmaceutical composition for the treatment and / or prevention of type II diabetes, comprising: Synthase inhibitor or pharmaceutically acceptable derivative thereof and pharmaceutically acceptable carrier thereof A composition comprising a body.