WO2007121545A1 - Compositions contenant des s-nitrosothiols et utilisation de ces compositions - Google Patents

Compositions contenant des s-nitrosothiols et utilisation de ces compositions Download PDF

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WO2007121545A1
WO2007121545A1 PCT/BR2007/000099 BR2007000099W WO2007121545A1 WO 2007121545 A1 WO2007121545 A1 WO 2007121545A1 BR 2007000099 W BR2007000099 W BR 2007000099W WO 2007121545 A1 WO2007121545 A1 WO 2007121545A1
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fact
composites according
pharmaceutical
nitrosothiols
pharmaceutical composites
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PCT/BR2007/000099
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English (en)
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WO2007121545A8 (fr
Inventor
Marcelo Ganzarolli De Oliveira
Gabriela Freitas Pereira De Souza
Fernando Ganzarolli De Oliveira
Claudio Pinto Marques Souza De Oliveira
Licio Augosto Velloso
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Universidade Estadual De Campinas-Unicamp
Universidade De São Paulo - Usp
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Priority claimed from BRC10602397-5A external-priority patent/BRPI0602397C1/pt
Application filed by Universidade Estadual De Campinas-Unicamp, Universidade De São Paulo - Usp filed Critical Universidade Estadual De Campinas-Unicamp
Priority to EP07719267A priority Critical patent/EP2010164A4/fr
Priority to US12/226,406 priority patent/US20100062059A1/en
Publication of WO2007121545A1 publication Critical patent/WO2007121545A1/fr
Publication of WO2007121545A8 publication Critical patent/WO2007121545A8/fr

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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
    • A61K31/04—Nitro compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C381/00—Compounds containing carbon and sulfur and having functional groups not covered by groups C07C301/00 - C07C337/00

Definitions

  • the present invention refers to the development of pharmaceutical composites containing S-nitrosothiols as the active principle.
  • the referred compositions are intended for the treatment of the fatty liver diseases by the oral or rectal route of administration to the patients. Additionally, the present invention refers to a method of treatment of the fatty liver diseases using the referred pharmaceutical composites.
  • nonalcoholic fatty liver disease also described as nonalcoholic steatohepatitis (NASH) encompasses a wide array of diseases, ranging from benign non-inflammatory steatosis up to fibrotic steatohepatitis and cirrhosis.
  • NAFLD nonalcoholic steatohepatitis
  • NAFLD is recognized as an important chronic liver disease with clinical and histopathological characteristics very similar to those of the alcoholic form of the disease, however, without ethanol ingestion ⁇ Falck-Ytter, Y; Younossi, ZM.; Marchesini, G.; Mccullough, A.J.
  • NAFLD has been referred to as one of the most common types of hepatic disease and has been associated especially with the increasing prevalence of obesity. In the United States, NAFLD currently presents a high incidence of cases with epidemic characteristics (Zafrani, E. S., Non-alcoholic fatty liver disease: an emerging pathological spectrum. Virchows Arch, 2004; 444:3-12).
  • NAFLD neurodegenerative disease
  • plurimetabolic syndrome which includes obesity, type 2 diabetes mellitus, dyslipidemia, visceral adiposity and hypertension
  • jejunoileal bypass protein-calorie malnutrition
  • protein-calorie malnutrition prolonged parenteral nutrition or drug use
  • pathogenesis and the therapeutics of this condition as well as the possibility of progression to chronic liver disease remain unclear.
  • insulin resistance as an initial condition (first hit) for the increased afflux of fatty acids to hepatocytes (Marchesini, G.; Brizi, M.; Bianchi, G.; Tomassetti, S.; Bugianesi, E.; Lenzi, M.; McCullough, AJ.; Natale, S.; Forlani, G.; Melchionda, N., Nonalcoholic fatty liver: a feature of the metabolic syndrome, Diabetes, 2001; 50:1844-1850 / Marchesini, G.; Bugianesi, E.; Forlani, G.; Cerrelli, F.; et al, Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome, Hepatology, 2003; 37(4):917-923 / Chituri, S.; Abeygunasekera, S.; Farrell,
  • Hyperinsulinemia favors lipogenesis and inhibits lipolysis, even in the liver, which increases the afflux of fatty acids to this organ.
  • the excessive offer of fatty acids to the liver may promote the depletion of mitochondrial oxidation and increase in the production of reactive oxygen species (ROS), as well as activation of other lipid oxidation pathways (peroxisomal and microsomal oxidation), which, in turn, triggers the production of more ROS and accentuates the hepatic oxidative stress.
  • ROS reactive oxygen species
  • Macrovesicular steatosis results from a complex combination of pathogenic alterations that includes increased release, inadequate oxidation and decreased secretion of various forms of lipids in the liver and may cause necroinflammation and fibrosis (Brunt, EM. , Nonalcoholic Steatohepatitis: Definition and Pathology, Seminars in Liver Disease, 2001;21(l):3-16).
  • pathogenic alterations that includes increased release, inadequate oxidation and decreased secretion of various forms of lipids in the liver and may cause necroinflammation and fibrosis
  • Oliveira et al. demonstrated an increase in the hepatic oxidative stress in steatotic livers of Wistar rats induced by a choline-deficient diet (a diet that inhibits the exportation of triglycerides from the hepatocytes) (Oliveira, C.P.M.S.; Gayotto, LCC; Tatai, C; Delia Nina, B.I; Janiszewski, M.; Lima, E.S.; Abdalla, D.S.P.; Lopasso, F.P.; Laurindo, F. R. M.; Laudanna, A.
  • NAFLD may actually be associated with oxidative stress and lipid peroxidation.
  • the oxidative stress involves mitochondrial ⁇ - oxidation of short-, middle- and long-chain fatty acids, with production of free electrons, hydrogen peroxide (H 2 O 2 ) and oxygen-reactive species, glutathione and vitamin E (two other notorious antioxidant agents) may exert a therapeutic role in this disease (McCullough, A.J. , Update on Nonalcoholic Fatty Liver Disease, Journal of Clinical Gastroenterology, 2002;34(3):255-262).
  • NO nitric oxide
  • peroxidation initiators such as peroxidase enzymes, or the blockage of radicalar propagation reactions
  • NO is the endothelium- derived relaxing factor (EDRF) and that this diatomic molecule is endogenously produced in the cells of mammalians by a family of enzymes called NO-sintases (NOSs).
  • EDRF endothelium- derived relaxing factor
  • NOSs NO-sintases
  • endogenously synthesized NO is transported by peptides that contain the sulfliydryl functional group (R-SH) in the form of S-nitrosothiols (RSNOs), which, in turn, can transfer NO to endogenous receptor molecules in transnitrosation reactions.
  • R-SH sulfliydryl functional group
  • RSNOs S-nitrosothiols
  • Two of the endogenous NO carriers that have already been identified in the literature are S-nitrosogluthatione and S- nitrosoalbumin.
  • compositions include lecithin, antioxidants and B-complex vitamin to be administered by either the parenteral or the oral route as tablets or powder;
  • US 6.297.229 - Proposes therapeutic methods for the treatment of nonalcoholic hepatic steatosis with effective amounts of ursodeoxycholic acid or a pharmaceutically acceptable derivate of this compound;
  • US 6.596.762 - Refers to compositions that consist essentially in defined amounts of soluble E vitamin mixed with carotenoids and selenium, with possible addition of an additional unspecified agent for the treatment; US 5.760.010 -
  • This invention is directed at the oral administration of erythromycin or a derivate of this drug for the treatment of human patients with liver diseases or disorders.
  • the routes of administration may include the oral, intramuscular, subcutaneous, transdermical, intravenous or other common routes of drug administration to the patients. Additionally, this invention proposes the oral administration of clarithromycin, troleandomycin and azithromycin, for the treatment of human patients with liver diseases or disorders, including, but not limited to, nonalcoholic hepatic steatosis and Reye's syndrome; BR 0.311.843-6 -
  • This invention refers to the use of several types of gastric inhibitory polypeptide (GIP) receptor antagonists to attenuate the after-meal insulin response to GIP in animals and humans, in order to prevent, reduce, inhibit and/or treat nonalcoholic hepatic steatosis due to its potential for prevention and/or reversion of hyperinsulinemia and insulin resistance.
  • This invention is based on the administration of an effective amount of an antagonistic agent, such as GIP antagonist or an antisense molecule, to antagonize, block, inhibit or withdrawal the glucose-dependent insulinotropic polypeptide
  • the patent WO 9.416.740 mentions the use of S- nitrosothiols only for the treatment or prevention of hepatic diseases caused by alcohol ingestion or exposure to pharmacological agents or industrial toxins.
  • this patent proposes the use of nitric oxide-releasing compounds, such as S-nitrosothiols, thionitrites, sydnonimines, furoxanes, organic nitrates, nitroprussiate, nitroglycerin, iron-nitrosyl compounds, or other related compounds.
  • the present invention refers to the development of pharmaceutical composites for the treatment of the Fatty Liver Diseases, more specifically, the Nonalcoholic Fatty Liver Disease (NAFLD), and other diseases associated with the metabolic syndrome, such as obesity, type 2 diabetes mellitus, dyslipidemia, visceral adiposity and hypertension.
  • the pharmaceutical composites contain as the active principle S-nitrosothiols in their pure form as well as S-nitrosothiols produced from precursor thiols, immediately before their administration.
  • the present invention refers to the therapeutic use of the referred composites as a treatment method for liver diseases, specifically NAFLD, and other diseases associated with the metabolic syndrome, such as obesity, type 2 diabetes mellitus, dyslipidemia, visceral adiposity and hypertension, which encompasses a wide array of diseases, ranging from benign non-inflammatory steatosis up to fibrotic steatohepatitis and cirrhosis.
  • the referred treatment method comprehends the administration of the referred composites by the oral or rectal route.
  • the mechanism of action of the active principle of the pharmaceutical composites of the present invention is based not only on the antioxidant action of S-nitrosothiols but also on its.
  • the main advantage of the present invention is that the method of treatment by the oral or rectal administration of the pharmaceutical composites might potentially prevent the development of the nonalcoholic fatty liver disease or even promote the regression of NAFLD and other diseases associated with the metabolic syndrome after their onset in the patient's organism.
  • Figure 1 shows the graphic presentation of hydroperoxide concentration in the liver homogenate of three animal groups.
  • Figure 2 shows the human LDL emission spectrum in aerated PBS suspension.
  • Figure 3 shows the peroxidation kinetic curves of linoleic acid catalyzed by soy lipo-oxygenase (SLO).
  • Figure 4 shows a bar graph of the extension (Ext) and initial velocity (V 0 ) of the SLO-catalyzed linoleic acid (LA) peroxidation reaction.
  • Figure 5A shows the histological characteristics of hepatic tissue of rats fed a choline-deficient diet, Control group.
  • Figure 5B shows the histological characteristics of the hepatic tissue of SNAC -treated rats fed a choline-deficient diet.
  • Figure 6A shows the histological characteristics of the liver tissue of ob/ob mice fed a methionine/choline-deficient diet (Group MCD).
  • Figure 6B shows the histological characteristics of the liver tissue of ob/ob mice fed a hyperlipidemic diet (Group H)
  • Figure 6C shows the histological characteristics of the liver tissue of ob/ob mice fed a MCD diet concomitantly with 30-day SNAC administration.
  • Figure 6D shows the histological characteristics of the liver tissue of ob/ob mice fed an H diet concomitantly with 30-day SNAC administration.
  • Figure 6E shows the histological characteristics of the liver tissue of ob/ob mice fed a MCD diet for 30 days, with SNAC administration started at the 31 st and maintained up to the 60th day.
  • Figure 6F shows the histological characteristics of the liver tissue of ob/ob mice fed an H diet for 30 days, with SNAC administration started at the 31st and maintained up to the 60th day.
  • Figure 7 shows the mass percent variation in animals fed control diet (C), methionine/choline-deficient diet (MCD) and hyperlipidemic diet (H), which either received or not SNAC by gavage during four weeks. Data are expressed as means ⁇ standard deviation.
  • the present invention refers to the development of pharmaceutical composites that comprise in their active principle a pharmaceutically effective amount of the equimolar mixture of a nitrosable thiol and sodium nitrite, where the pharmaceutically effective equimolar amounts of both components may range from 4 ⁇ mol to 40 mmol, with a preferential value of 0.6 mmol, for addition to a final mixture volume of approximately 300 mL. These substances may or may not be dissolved in water.
  • the active principle of the referred composites is generate, as follows: the S-nitrosothiols, which may be obtained in concentrations ranging from 13 ⁇ molar to 130 mmolar, with a preferential value of 2 mmolar.
  • the use of final volumes other than 300 mL for the mixture of S-nitrosothiols is allowed, provided they present proportional equimolar amounts of both components.
  • the pharmaceutical composites of the present invention are effective in the treatment and/or prevention of the Fatty Liver Diseases, more specifically the Nonalcoholic Fatty Liver Disease (NAFLD).
  • the referred composites comprise flavoring substances; edulcorants, such as sucrose, aspartame and others; colorants; effervescent substances, such as excipients; and/or any other pharmaceutically acceptable vehicle that does not interfere with the action of the active principle of the referred composites.
  • the nitrosable thiol used in the present invention may be selected among glutathione, the N-acetylcystein, the cysteine, the homocysteine, the penicillamine, the captopril, the pantothenic acid derivatives, the proteins, such as albumin and hemoglobin, the thiols covalently bound to lipophilic carbon chains, and the dithiols.
  • the substances nitrosable thiol and sodium nitrite may also be replaced by a pharmaceutically acceptable amount of a corresponding S-nitrosothiol where the pharmaceutically effective amount of the S-nitrosothiol may range from 4 ⁇ mol to 40 mmol, with a preferential value of 0.6 mmol, for addition to a final solution volume of approximately 300 mL, thus producing S-nitrosothiol solutions with concentrations ranging from 13 ⁇ molar to 130 mmolar, with a preferential value of 2 mmolar.
  • the S-nitrosothiols used as the active principle in the present invention may be selected among S-nitrosoglutathione, the S-nitroso-N- acetylcystein, the S-nitrosocysteine, the S-nitrosohomocysteine, the S- nitrosopenicillamine, the S-nitrosocaptopril, the S-nitrosopantothenic acid derivatives, the S-nitrosoproteins like S-nitrosoalbumin and S- nitrosohemoglobin, the S-nitrosothiols covalently bound to lipophilic carbon chains, and the S-nitrosodithiols.
  • the formulations in addition to the S-nitrosothiols, the formulations
  • the active principle of the referred pharmaceutical composites is preferably packaged in envelopes.
  • the basic substances of the active principle i.e., the nitrosable thiol and sodium nitrite, may be enclosed together in a single envelope or one envelope may contain one of the basic substances of the active principle, for example, the nitrosable thiol, and the second envelope contains the other substance of the active principle, sodium nitrite.
  • the contents of the ' envelopes should be conjunctly dissolved in water in such a way that the active principle of the pharmaceutical composites of the present invention may be generated.
  • the substances that comprise the active principle of the pharmaceutical composites of the present invention may be presented as powders, powders diluted or dispersed in inert vehicles, water-soluble powders, granules, pastilles, pills, capsules and dragees.
  • the pharmaceutical composites of the present invention may be packaged in any other type of receptacle, such as flasks, in a way that the pharmaceutical composites are protected from water sorption or loss and biological contamination during the storage time.
  • the envelope or receptacle that contains the nitrosable thiol may additionally contain flavoring substances; edulcorants, such as sucrose, aspartame and others; colorants; effervescent substances, such as excipients; and/or any other pharmaceutically acceptable vehicle that does not interfere with the action of active principle of the referred composites.
  • the basic substances of the active principle of the referred composites may be associated with other drugs that present a beneficial effect on the treatment of NADFL, hepatic steatosis and other diseases associated with the metabolic syndrome, such as obesity, type 2 diabetes mellitus, dyslipidemia, visceral adiposity and hypertension, including tocopherol or tocopherol acetate, or vitamin E, metformin, troglitazone, rosiglitazone, pioglitazone, clofibrate, gemfibrozil, atorvastatin and other statins, betaine and nicotinamide.
  • other drugs that present a beneficial effect on the treatment of NADFL, hepatic steatosis and other diseases associated with the metabolic syndrome, such as obesity, type 2 diabetes mellitus, dyslipidemia, visceral adiposity and hypertension, including tocopherol or tocopherol acetate, or vitamin E, metformin, troglitazone, rosi
  • the basic substances of the active principle of the referred composites may be associated with other drugs that potentialize the effect of the S-nitrosothiols, such as the phosphodiesterase-5 inhibitors, among which sildenafil, tandalafil, vardenafil and others.
  • the pharmaceutical composites subject of the present invention are administrated to the patient by the oral or rectal route and are presented preferably as multiple-unit pharmaceutical forms in solid dosages, such as capsules, pills and dragees or pastilles. More specifically, each multiple unit comprehends:
  • the inert nucleus of the referred capsules additionally presents one or more sugars, such as glucose, manitol, lactose, xylitol, dextrose, sucrose among others; microcrystalline cellulose, silicon dioxide, silica, polystyrene, hydroxypropyl methylcellulose or other biocompatible polymers.
  • the referred nucleus includes at least one of the following components: an insoluble material, such as cellulose acetate or paraffin; a soluble material, such as polyvinyl alcohol or polyethylene glycol; or a swellable material, such as hydroxypropyl cellulose.
  • Both the first and the second nucleus' coating layer comprise one or more S-nitrosothiol release-controlling polymers, which are selected from the following: ethylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxypropyl methyl phthalate, cellulose acetate, cellulose acetate phthalate, or any polymer resulting from the mixture of these components, in addition to one or more enteric polymers, which are selected from the following: cellulose acetate phthalate, cellulose acetate, hydroxypropyl methylcellulose acetate phthalate, polyvinyl acetate phthalate), hydroxypropyl phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, methacrylic acid copolymers, or any mixtures of these compounds, or any polymer resulting from the mixture of these components.
  • S-nitrosothiol release-controlling polymers which are selected from the following: ethyl
  • the multiple units are provided with one or more pharmaceutically acceptable excipients, which include surfactants, binders, diluents, disintegrators, lubricants, gliding agents, plastifying agents, stabilizers and colorants.
  • excipients include surfactants, binders, diluents, disintegrators, lubricants, gliding agents, plastifying agents, stabilizers and colorants.
  • the additional coating layers comprehend at least 3 (three) layers, as follows: - a first layer located between the nucleus and the first coating layer, which covers the first portion of the outer surface of the nucleus; - a second layer, which covers at least part of the first layer; - a third layer, which is located over the second layer and covers at least part of the second layer, where one or more additional layers include one or more sealing layers.
  • the components of the sealing layer are preferably selected from the following: hydroxypropyl methylcellulose, polyvinylpyrrolidone and methacrylic acid copolymers.
  • the present invention refers to a method of treatment and/or prevention of the Fatty Liver Diseases, more specifically, the Nonalcoholic Fatty Liver Disease (NAFLD) by the oral or rectal administration of the composites described in the present application.
  • the administrated amount should range from 4 ⁇ mol to 40 mmol, with a preferential value of 0.6 mmol, on a daily basis.
  • the period of treatment may range from approximately 1 month to chronic use. Nevertheless, the administration of the referred composites should be periodically reviewed and should be adjusted according the evolution of the clinical condition.
  • a detailed description will be featured below in the form of examples. Nevertheless, the examples hereby described have a merely illustrative nature, not being restrictive forms of the present invention.
  • Wistar rats with hepatic steatosis induced by a choline-deficient diet were assigned to three groups to perform the tests with the administration of S-nitroso-N-acetylcysteine (SNAC), which is one of the active principles of the present invention, and to evaluate the concentration of hydroperoxides (LOOH) in the liver.
  • SNAC S-nitroso-N-acetylcysteine
  • a first group of animals, group 1, was treated with a solution of S-nitroso-N-acetylcysteine, which was administrated orally to the animals at a dose of 1.4 mg/kg/day.
  • a second group of animals, group 2, was treated with N-acetylcysteine (NAC), which was also administrated orally to the animals at a dose of 7.0 mg/kg/day.
  • the test of the present Example showed that the treatment of group 1, to which the composite of the present invention was administered, resulted in the prevention of hydroperoxide concentration increase in the liver, compared to group 3 (control).
  • group 1 hydroperoxide concentration was 0.3 ⁇ 0.1 nmol/g protein
  • group 3 control group
  • hydroperoxide concentration was 3.2 ⁇ 0.4 nmol/g protein. Comparing the results obtained in group 2 to those obtained in group 3 (control group), it is also observed a prevention of iroperoxide concentration increase in the liver in group 2.
  • LDL low density lipoprotein
  • FIG. 2 features the emission spectrum for the analyzed samples. It is observed on Figure 2 that the curve (a) presents two emission peaks at 410 and 440 nm, which may be attributed to the partial oxidation of the freshly prepared LDL suspension.
  • the 410- and 440-nm emission peaks in the LDL suspension fluorescence spectrum correspond to the formation of a Schiff base adduct between the lipid oxidation products contained in the LDL particles (mainly the malondialdehyde [MDA]) and the free amino groups on LDL apolipoprotein (mainly apo-B-100), and are known as LDL oxidation markers.
  • MDA malondialdehyde
  • Example 3 shows the effect of the SNAC composite on the kinetics of linoleic acid (LA) oxidation at a preferential concentration of 18.76 ⁇ mol/L catalyzed by soy lipoxigenase (SLO). This referred effect may be shown by the analysis of two kinetic parameters: initial velocity and extension of the peroxidation reaction until the chemical equilibrium is reached.
  • LA linoleic acid
  • SLO soy lipoxigenase
  • the first curve (a') refers to a sample of linoleic acid whose peroxidation was catalyzed by incubation with soy lipo-oxygenase at a preferential concentration of 0.056 ⁇ mol/L
  • the second curve (b 5 ) refers to a sample of linoleic acid whose peroxidation was catalyzed by incubation of the linoleic acid with a mixture of soy lipo-oxygenase in the presence of NAC at a preferential concentration of 560 ⁇ mol/L
  • the third curve (c') refers to a sample of linoleic acid whose peroxidation was catalyzed by incubation of soy lipo-oxygenase in the presence of SNAC at a preferential concentration of 56 ⁇ mol/L
  • the fourth curve (d') refers to a sample of linoleic acid whose peroxidation was catalyzed by incubation of
  • Figure 3 illustrates the absorbance curves obtained for the groups of the present Example.
  • the interpretation of the curves is given by the initial velocity, which corresponds to the inclination of the initial section of the curves within approximately 10 seconds, and the extension of the reaction, which corresponds to the absorbance values on the plateaus of the curves.
  • Curve 3(b') shows that, the incubation with NAC reduced the extension and velocity of oxidation, but such reduction is more accentuated in the co-incubation with SNAC, even in a concentration tenfold weaker than that of NAC (Group C), as shows Curve 3(c'). This reduction is considerably much pronounced in Group D, as shows Curve 3(d').
  • Examples may be analyzed in relation to the oxidative stress in NAFLD pathology, as previously described in the literature.
  • SNAC acts as a powerful inhibitor effect of lipid/lipoprotein peroxidation.
  • Rats fed a choline-deficient diet were selected to compose the Control Group when compared to SNAC-treated rats.
  • Hematoxylin and eosin-stained histological sections of hepatic tissue were examined under optical microscopy, as shown on Figures 5A and 5B.
  • Figure 5A illustrates the results obtained for the Control Group, showing moderate macrovacuolar and microvacuolar steatosis in the periportal zone.
  • Figure 5B shows the results obtained in the Group of SNAC-treated animals, indicating a normal liver in the periportal zone. Based on the results obtained by optical microscopy, it is evident the SNAC composite's inhibitor effect on lipid/lipoprotein peroxidation.
  • Example 4
  • mice were selected. A first group of mice was fed a methionine/choline-deficient diet (Group MCD) and a second group of mice was fed a hyperlipidemic diet (Group H). Animals were selected from both groups and hematoxylin and eosin-stained histological sections of the hepatic tissue of these animals were obtained and examined under optical microscopy.
  • MCD methionine/choline-deficient diet
  • H hyperlipidemic diet
  • the histological characteristics of the livers of mice selected from the Group MCD revealed diffused moderate macrovacuolar and microvacuolar steatosis and inflammatory infiltrate, as shown on Figure 6 A, whereas the histological analysis of the livers of mice selected from the Group H revealed diffuse microvacuolar steatosis and discrete inflammatory infiltrate, as shown on Figure 6B.
  • mice selected from both groups of mice, Group MCD and Group H, were submitted to a 30-day treatment consisting of SNAC administration. After the 30th day, hematoxylin and eosin-stained histological sections of the hepatic tissue of these animals were obtained and examined under optical microscopy.
  • Figures 6C and 6D exhibit the histological characteristics of the livers of mice from both groups, Group MCD and Group H, respectively. These histological characteristics were consistent with normal livers for both groups of mice submitted to their respective experimental diets.
  • the remaining animals in Groups H and MCD were maintained on these diets up the 60th day and were put on SNAC administration from the 31st day on. After the 60th day of treatment, hematoxylin and eosin-stained histological sections of the hepatic tissue of these animals were obtained and examined under optical microscopy.
  • Figures 6E and 6F exhibit the histological characteristics of the livers of mice from both groups, Group MCD and Group H, respectively. The histological characteristics observed were consistent with those of normal livers.
  • SNAC administration may either block or revert NAFLD in these animal models, and that, therefore, nitric oxide donors, such as SNAC and others, have potential to be used in the treatment of other diseases associated with the metabolic syndrome, such as obesity, type 2 diabetes mellitus, dyslipidemia, visceral adiposity and hypertension.

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Abstract

L'invention concerne des compositions pharmaceutiques contenant du S-nitrosothiols en tant que principe actif. Ces compositions sont destinées au traitement de la stéatose hépatique et d'autres maladies associées au syndrome métabolique. Cette composition est administrée soit par voie orale, soit par voie rectale.
PCT/BR2007/000099 2006-04-20 2007-04-20 Compositions contenant des s-nitrosothiols et utilisation de ces compositions WO2007121545A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP07719267A EP2010164A4 (fr) 2006-04-20 2007-04-20 Compositions contenant des s-nitrosothiols pour traiter les steatoses hepatiques, l'obesite ainsi que d'autres maladies liees au synchrome matabolique et utilisation de ces compositions
US12/226,406 US20100062059A1 (en) 2006-04-20 2007-04-20 S-Nitrosothiols Containing Composition for the Treatment of Fatty Liver Diseases, Obesity and Other Diseases Associated with the Metabolic Syndrome and the Use of Such Compositions

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BRC10602397-5A BRPI0602397C1 (pt) 2006-04-20 2006-04-20 composições farmacêuticas para o tratamento das doenças gordurosas do fìgado, obesidade e demais doenças associadas à sìndrome metabólica e métodos de tratamento utilizando-se as referidas composições
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Cited By (5)

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Publication number Priority date Publication date Assignee Title
EP2214480A1 (fr) * 2007-11-30 2010-08-11 The Regents of the University of California Procédés de traitement d'une stéatohépatite non alcoolique au moyen de produits à base de cystéamine
WO2015017383A2 (fr) 2013-07-31 2015-02-05 The Children's Hospital Of Philadelphia Compositions et procédés de traitement de troubles du métabolisme des acides gras
US10064850B2 (en) 2007-04-11 2018-09-04 Omeros Corporation Compositions and methods for prophylaxis and treatment of addictions
US10137103B2 (en) 2015-11-06 2018-11-27 The Children's Hospital Of Philadelphia Compositions and methods for the treatment of fatty acid metabolism disorders
US11241420B2 (en) 2007-04-11 2022-02-08 Omeros Corporation Compositions and methods for prophylaxis and treatment of addictions

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EP2636404A3 (fr) * 2007-11-30 2013-10-16 The Regents Of the University of California Procédés de traitement d'une stéatohépatite non alcoolique (NASH) utilisant des produits à base de cystéamine
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