AU4865800A - Nitric oxide (NO) synthase inhibitor to treat or prevent Type II diabetes - Google Patents

Nitric oxide (NO) synthase inhibitor to treat or prevent Type II diabetes Download PDF

Info

Publication number
AU4865800A
AU4865800A AU48658/00A AU4865800A AU4865800A AU 4865800 A AU4865800 A AU 4865800A AU 48658/00 A AU48658/00 A AU 48658/00A AU 4865800 A AU4865800 A AU 4865800A AU 4865800 A AU4865800 A AU 4865800A
Authority
AU
Australia
Prior art keywords
diabetes
pharmaceutically acceptable
synthase inhibitor
treatment
type
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
AU48658/00A
Inventor
Valerie Piercy
Nicholas Charles Turner
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Ltd
Original Assignee
SmithKline Beecham Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by SmithKline Beecham Ltd filed Critical SmithKline Beecham Ltd
Priority to AU48658/00A priority Critical patent/AU4865800A/en
Publication of AU4865800A publication Critical patent/AU4865800A/en
Abandoned legal-status Critical Current

Links

Landscapes

  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Description

AUSTRALIA
PATENTS ACT 1990 DIVISIONAL APPLICATION NAME OF APPLICANT: SmithKline Beecham p.l.c.
ADDRESS FOR SERVICE: DAVIES COLLISON CAVE Patent Attorneys 1 Little Collins Street Melbourne, 3000.
INVENTION TITLE: "Nitric Oxide (NO) Synthase Inhibitor to Treat or Prevent Type II Diabetes" o*.
The following statement is a full description of this invention, including the best method of performing it known to us: -1A- NITRIC OXIDE (NO) SYNTHASE INHIBITOR TO TREAT OR PREVENT TYPE II DIABETES This application is a divisional of Australian Patent Application No. 13794/97, the entire contents of which are incorporated herein by reference.
This invention relates to a novel method for the treatment of and/or prophylaxis of noninsulin dependant (NIDDM or Type II) diabetes, and in particular to the use of an NO synthase inhibitor, such as aminoguanidine, for the said treatment and/or prophylaxis.
Hydrazinecarboximidamide (hereinafter aminoguanidine) is a known compound (Journal of American Chemical Society, 57, 2730, (1935).
Aminoguanidine is known to be an inhibitor of protein glycation and is under evaluation in animal models for the treatment of diabetic complications (Diabetes 42, 221-232 1993; Diabetologia 35, 946-950) Aminoguanidine is known to be an NO synthase inhibitor (Eur. J Pharmacol., 233, 119- 125) and to be useful for the treatment of disease states characterised by over production of NO (European J. of Pharmacology, 233, (1993), 119-125). The inhibition of nitric oxide formation is particularly considered to be linked to the known activity of aminoguanidine in the treatment of diabetic complications European Patent Application, publication number. Aminoguanidine is under evaluation in animal models for the treatment of diabetic complications (Diabetes 42:221- 232 1993; Diabetologia 35:946-950).
To date there has been no indication that aminoguanidine or any other NO synthase inhibitor would have a beneficial effect on Type II diabetes itself. As indicated above the emphasis has been focused upon the complications of diabetes. We have now surprisingly discovered that aminoguanidine shows potential for use in the treatment and/or prophylaxis of Type II diabetes per se. In particular, aminoguanidine is indicated to delay or prevent the 25 progression of non-insulin dependent diabetes from hyperinsulinaemia to overt diabetes. This novel and surprising effect is considered to be due to the NO synthase inhibitor activity of aminoguanidine on the Type II diabetic pancreas.
Accordingly, the present invention provides a method for the treatment and/or prophylaxis of Type II diabetes, which method comprises the administration, to a human or nonhuman mammal, of an effective non-toxic pharmaceutically acceptable amount of an NO synthase inhibitor or a pharmaceutically acceptable derivative thereof.
Preferably, the invention provides a method for the prophylactic treatment of Type II diabetes, in particular delaying or preventing the progression from hyperinsulinaemia to hyperglycaemia.
Suitable, inhibitors of NO synthase include proteins and non-protein compounds, such as aminoguanidine, n-monomethylarginine, or other analogues of 1-arginine.
A particular NO synthase inhibitor is aminoguanidine.
When used herein the term 'NO synthase inhibitor' refers to an agent that inhibits the formation of nitric oxide from 1-arginine.
The NO synthase inhibitor activity of a compound is assessed in conventional tests such as inhibition of 3 H] 1 -arginine to 3 H] to citrulline or inhibition of nitric oxide generation by cells or tissue extracts or by recombinant nitric oxide synthase isoenzymes in vitro.(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 include pharmaceutically acceptable inorganic salts such as the sulphate, nitrate, phosphate, borate, hydrochloride and hydrobromide and pharmaceutically acceptable organic acid addition salts such as acetate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, methane-sulphonate, a-keto glutarate and a-glycerophosphate, especially the maleate salt.
.Suitable pharmaceutically acceptable solvates include hydrates.
i: The NO synthase inhibitors used in the method of the invention may be prepared according to conventional methods such as the methods disclosed in the above mentioned publications for example aminoguanidine may be prepared according to the methods disclosed in 20 J. Amer. Chem. Soc. 57,2730, (1935).
Salts and/or solvates may be prepared and isolated according to conventional procedures.
In a further aspect the present invention also provides an NO synthase inhibitor, such as aminoguanidine, or a pharmaceutically acceptable derivative thereof, for use in the treatment of and/or prophylaxis of Type II diabetes.
25 There is also provided an 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 prophylaxis of Type II diabetes.
In the above mentioned treatments and/or prophylaxis, the NO synthase inhibitor, such as aminoguanidine, or a pharmaceutically acceptable derivative thereof may be administered per s or preferably as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier.
Accordingly, the present invention also provides a pharmaceutical composition for the treatment and/or prophylaxis of Type II diabetes, which composition comprises an NO synthase inhibitor such as aminoguanidine, or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier therefor.
-3-
EXAMPLE
Methodology of dbdb mouse model The obese db/db mouse is a genetic model of type 2 non-insulin dependent diabetes which is both insulin resistant and hyperglycaemic. Male animals were obtained at 6 weeks of age.
Blood samples were taken by tail tip snip for measurement of pre-treatment blood glucose.
Animals were allocated into treated and control groups such that the mean and standard deviation of the fasting blood glucose concentrations of each group was similar.
On day 0 of the study a group of obese animals and their lean litter mates were killed for measurement of baseline biochemistry and histology. In addition one group of animals (control; n 14) were fed a standard diet and a further group received aminoguanidine (500mg/kg; n 14) in the same diet. Animals were allowed free access to food and water and their intake measured daily. At weekly intervals 24hr urine output was also measured. Mice (n 7) were killed at days and 85 days from commencement of treatment. Blood was taken for measurement of glucose and insulin concentrations and the pancreas removed for histological analysis and for measurement of pancreatic insulin.
Data from dbdb mouse model Food intake and body weight gain of the control and treated groups was similar throughout the experimental period.
Immediately prior to dosing obese animals were normoglycaemic (blood glucose 10.4 25 0.97mM) but were hyperinsulinaemic compared to their lean litter mates (serum isulin 127 37 ng/ml in obese animals 3.05 1.03 ng/ml in leans). By day 30 of the dosing period the obese control group were hyperglycaemic (blood glucose 24.9 1.0 mM) and had markedly lower serum insulin levels (30.75 4.3 mM) compared to the pre-treatment values. By day 85 of the treatment period, fasting blood glucose had risen to 28.1 2 mM and serum insulin concentrations had fallen further, to 11.7 1.8 ng/ml. Aminoguanidine attenuated the fall in fasting insulin concentrations (58.3 13 ng/ml on day 30, 23.3 4.1 ng/ml on day 85) and on day 85 had significantly reduced the prevailing fasting hyperglycaemia (21 1.7 mM).
Pancreatic insulin content of the aminoguanidine treated group of obese animals was twice that of the untreated animals (64.3 17.8 ng/mg pancreas compared to 30.0 2.6 ng/mg, respectively). From day 63 of the experimental period obese control animals were markedly -4polydypsic and polyuric compared to day 7. This increase in water intake and urine output is a characteristic of diabetes (hyperglycaemia) and was prevented by treatment with aminoguanidine (Figure Similarly urinary glucose excretion increased steadily over the experimental period, in both untreated and treated animals, but from day 35 was lower in the aminoguanidine treated group (Figure The development of diabetes (hyperglycaemia) was associated with changes in islet morphology, and the islets of untreated control animals were markedly hypertrophic, disorganised and had irregular boundaries. Islet insulin content was markedly depleted. On day 30 of the treatment period normal islet morphology was preserved in the aminoguanidine treated animals, and islet insulin content was greater.
Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
o ooo *ooo *ooo o oo g* *ooo

Claims (8)

1. A method for the treatment and/or prophylaxis of Type II diabetes. which method comprises the administration, to a human or non-human mammal, of an effective non-toxic pharmaceutically acceptable amount of an NO synthase inhibitor or a pharmaceutically acceptable derivative thereof.
2. A method according to claiml, for the prophylactic treatment of Type II diabetes.
3. A method according to claiml or claim 2, for delaying or preventing the progression from hyperinsulinaemia to hyperglycaemia.
4. A method according to any one of claims 1 to 3, wherein the NO synthase inhibitor is selected from aminoguanidine, n-monomethylarginine, or other analogues of 1-arginine.
5. A method according to any one of claims 1 to 4, wherein the NO synthase inhibitor is aminoguanidine.
6. An NO synthase inhibitor, or a pharmaceutically acceptable derivative thereof, for use in the treatment of and/or prophylaxis of Type II diabetes.
7. An NO synthase inhibitor, or a pharmaceutically acceptable derivative thereof, for use in the manufacture of a medicament for the treatment and/or prophylaxis of Type II diabetes. 25
8. A pharmaceutical composition for the treatment and/or prophylaxis of Type II diabetes, which composition comprises an NO synthase inhibito, or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier therefor. DATED this 1 7 th day of July, 2000 SmithKline Beecham p.l.c. By DAVIES COLLISON CAVE Patent Attorneys for the Applicant
AU48658/00A 1995-12-22 2000-07-17 Nitric oxide (NO) synthase inhibitor to treat or prevent Type II diabetes Abandoned AU4865800A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU48658/00A AU4865800A (en) 1995-12-22 2000-07-17 Nitric oxide (NO) synthase inhibitor to treat or prevent Type II diabetes

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9526331 1995-12-22
AU48658/00A AU4865800A (en) 1995-12-22 2000-07-17 Nitric oxide (NO) synthase inhibitor to treat or prevent Type II diabetes

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
AU13794/97A Division AU1379497A (en) 1995-12-22 1996-12-18 Nitric oxide (no) synthase inhibitor to treat or prevent type ii diabetes

Publications (1)

Publication Number Publication Date
AU4865800A true AU4865800A (en) 2000-09-14

Family

ID=3735368

Family Applications (1)

Application Number Title Priority Date Filing Date
AU48658/00A Abandoned AU4865800A (en) 1995-12-22 2000-07-17 Nitric oxide (NO) synthase inhibitor to treat or prevent Type II diabetes

Country Status (1)

Country Link
AU (1) AU4865800A (en)

Similar Documents

Publication Publication Date Title
Tomas et al. Effect of glucocorticoid administration on the rate of muscle protein breakdown in vivo in rats, as measured by urinary excretion of N τ-methylhistidine
Phromphetcharat et al. Ammonia partitioning between glutamine and urea: interorgan participation in metabolic acidosis
Simard-Duquesne et al. The effects of a new aldose reductase inhibitor (tolrestat) in galactosemic and diabetic rats
Wiberg et al. Factors affecting the cardiotoxic potential of cobalt
EP4197537A1 (en) Composition for preventing or treating liver fibrosis, containing triazole derivative as active ingredient
Sennitt et al. Anti-hyperglycaemic action of BRL 26830, a novel β-adrenoceptor agonist, in mice and rats
EP0868175B1 (en) Nitric oxide (no) synthase inhibitor to prevent type ii diabetes
Okamoto Influence of L-thyroxine on kynurenine 3-hydroxylase, monoamine oxidase, and rotenone-insensitive NADH-cytochrome C reductase in mitochondrial outer membrane
AU4865800A (en) Nitric oxide (NO) synthase inhibitor to treat or prevent Type II diabetes
Kaufman et al. Differential catecholamine responses to dietary intake: effects of macronutrients on dopamine and epinephrine excretion in the rat
CA2280871A1 (en) Use of nitric oxide synthase inhibitors for the treatment of diabetes
EP0868176B1 (en) Aminoguanidine for treating niddm
US20040072905A1 (en) Use of nitric oxide synthase inhibitors for the treatment of diabetes
Flåøyen et al. An attempt to reproduce crystal-associated cholangitis in lambs by the experimental dosing of sarsasapogenin or diosgenin alone and in combination with sporidesmin
Oellerich et al. Hydrazonopropionic Acid, a New Class of Hypoglycemic Substances
AU3785500A (en) Aminoguanidine for treating NIDDM
Thiemermann The use of selective inhibitors of inducible nitric oxide synthase in septic shock
Lyles Effects of L-DOPA administration upon monoamine oxidase activity in rat tissues
Baker et al. Idiopathic calcium oxalate urolithiasis and endogenous oxalate production
Gruppuso et al. Chronic hyperglucagonemia in rats: effects on insulin, substrates, and hepatic enzymes of intermediary metabolism
Darnerud et al. Age‐and sex‐dependent dichlorovinyl cysteine (DCVC) accumulation and toxicity in the mouse kidney: relation to development of organic anion transport and β‐lyase activity
NZ502434A (en) Aminoguanidine for treating niddm
de Gasparo et al. Effect of maternal carbohydrate intolerance on the development of the autonomic innervation of the fetal rat pancreas
Cantoni et al. Effects of iron overload on bile secretion and hepatic porphyrin metabolism in ethinyl extradiol-treated rats
Morimoto et al. Absence of mitochondrial enhancement in the remnant liver after partial hepatectomy in cirrhotic rats

Legal Events

Date Code Title Description
MK4 Application lapsed section 142(2)(d) - no continuation fee paid for the application