EP1225885A2 - Melange therapeutique d'inhibiteurs de hmg-coa reductase - Google Patents

Melange therapeutique d'inhibiteurs de hmg-coa reductase

Info

Publication number
EP1225885A2
EP1225885A2 EP00984562A EP00984562A EP1225885A2 EP 1225885 A2 EP1225885 A2 EP 1225885A2 EP 00984562 A EP00984562 A EP 00984562A EP 00984562 A EP00984562 A EP 00984562A EP 1225885 A2 EP1225885 A2 EP 1225885A2
Authority
EP
European Patent Office
Prior art keywords
hmg
coa reductase
reductase inhibitor
arginine
pravastatin
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.)
Withdrawn
Application number
EP00984562A
Other languages
German (de)
English (en)
Other versions
EP1225885A4 (fr
Inventor
Wayne H. Kaesemeyer
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.)
Angiogenix Inc
Original Assignee
Nitrosystems Inc
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 Nitrosystems Inc filed Critical Nitrosystems Inc
Publication of EP1225885A2 publication Critical patent/EP1225885A2/fr
Publication of EP1225885A4 publication Critical patent/EP1225885A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • Nitric Oxide Synthase a family of enzymes called Nitric Oxide Synthase (“NOS”) form nitric oxide from L-arginine.
  • NOS Nitric Oxide Synthase
  • the nitric oxide produced is linked to the endothelium dependent relaxation and activation of soluble guanylate cyclase, neurotransmission in the central and peripheral nervous systems, and activated macrophage cytotoxicity.
  • Nitric Oxide Synthase occurs in many distinct isoforms. Formation of nitric oxide by the constitutive form (cNOS) in endothelial cells is thought to play an important role in normal blood pressure regulation, prevention of endothelial dysfunction such as hyperlipodemia, arteriosclerosis, thrombosis, and restenosis.
  • cNOS constitutive form
  • the inducible form of nitric oxide synthase (iNOS) has been found to be present in activated macrophages and is induced in vascular smooth muscle cells, for example, by various cytokines and/or microbial products.
  • L-arginine is enzymatically converted into nitric oxide by NOS.
  • NOS activity has now been described in many cell types. Brain, endothelium, and macrophage isoforms appear to be products of a variety of genes that have approximately 50% amino acid identity. NOS in brain and in endothelium have very similar properties, the major differences being that brain NOS is cytosolic and the endothelial enzyme is mainly a membrane-associated protein.
  • subject means any mammal, including humans, where nitric oxide (“NO") formation from arginine occurs.
  • NO nitric oxide
  • the methods described herein contemplate prophylactic use as well as curative use in therapy of an existing condition.
  • nitric oxide that is produced through the bio-transformation of L-arginine or in the L-arginine dependent pathway "EDRF' or “EDNO” may be used interchangeably with “native NO”
  • endpomts refers to clinical events encountered in the course of treating cardiovascular disease, up to and including death (mortality)
  • L-argimne as used herein includes all biochemical equivalents (/ e , salts, precursors, and its basic form) Bioequivalents of L-arginme include arginase inhibitors, lysme, citrulhne, ormthine, and hydralazine (combinations of biochemical equivalents may also be employed)
  • Antist refers to an agent which stimulates the bio-transformation of a NO precursor, such as L-argmine or L-lysme to EDNO or EDRF either through enzymatic activation, regulation or increasing gene expression (/ e , increased protein levels of c-NOS) Of course, either or both of these mechanisms may be acting simultaneously
  • the term "pharmaceutically acceptable carrier” refers to a carrier medium which does not interfere with the effectiveness of the biological activity of the active ingredients and which is not toxic to the hosts to which it is administered
  • Fig. 1 is a schematic representation of NOS activation
  • Fig 2 is a bar graph illustrating the stimulation of NOS with pravastat
  • Fig 3 is a schematic representation of the dynamics of L- arginine supply to NOS
  • the present invention is preferably a combination of active ingredients, more preferably an agent that stimulates NOS activity and an agent which has another cardiocerebroreno vascular benefit
  • a substrate of NOS is employed in the mixture
  • substrate are the amino acids, L-arginine and L-lysine, individually or in combination, as a mixture or as an oligope tide, or a biologically equivalent compound, such as low molecular weight oligopeptides. having from about 2-10, usually 2-6 amino acids, or acetylated amino acids and oligopeptides, etc.
  • An example of a biologically equivalent compound which appears to function as a substrate for NOS is
  • the amount of the NO precursor agent, statin, or therapeutic mixture will be determined empirically in accordance with known techniques using animal models.
  • the amount of the NO precursor agent (e.g., L-arginine) and/or statin employed preferably provide a physiologically effective amount to reduce proliferation of vascular smooth muscle cells and maintain the dilation of the vessel.
  • a biological equivalent is an agent or composition, or combination thereof, which has a similar biological function or effect as the agent or composition to which it is being deemed equivalent.
  • a biological equivalent of arginine is a chemical compound or combination of chemical compounds which has the same or similar biological function or effect as arginine.
  • Lysine may be considered a biological equivalent of arginine.
  • Other expected biological equivalents include citrulline. arginase inhibitors, hydralazine. and ornitine.
  • Hmg-CoA reductase may have dual applicability in the treatment of hypertension and cardiovascular diseases such that they act as both an inhibitor of the intrinsic biosynthesis of cholesterol and a stimulator or agonist of nitric oxide synthase.
  • the fact that Hmg-CoA reductase may be agonist or stimulant of nitric oxide synthase has remarkable implications.
  • L-arginine provides additional substrate for the Nitric Oxide Synthase and the NOS being catalyzed to enzymatically increase the bio-transformation of L-arginine into nitric oxide.
  • Hmg-CoA reductase inhibitors Virtually any of the family of those substances known as Hmg-CoA reductase inhibitors may be used in the present invention. These are taught for example in U.S. Pat. Nos. 4,857,522, 5,190,970, and 5,461,039, all of which are hereby incorporated by reference for this teaching. Those particular Hmg-CoA reductase inhibitors most preferred for use in conjunction with the present formulation as selected from the group consisting of: atorvastatin, cerivastatin, simvastatin, lovastatin, pravastatin, compactin, fluvastatin, and dalvastatin. U.S. Patent No.
  • Hmg-CoA reductase inhibitors are hereby incorporated by reference in its entirety.
  • the Hmg-CoA reductase inhibitor utilized is pravastatin or atorvastatin.
  • the administration of the present invention includes the Hmg-CoA reductase inhibitor pravastatin. These Hmg-CoA reductase inhibitors are commonly referred to as "statins.”
  • statin treatment not all hypercholesterolemic patients respond to statin treatment as currently known. There are patients who currently receive standard statin treatment but show no significant reductions in major coronary events. These patients and others would benefit from administration of a combination of two statins, one that is hydrophilic (soluble in water) for example, pravastatin, and one which is lipophilic or hydrophobic (insoluble in water) for example, atorvastatin.
  • This dual statin treatment will be referred to as "combistatin” since it refers to administration of statins from two different categories.
  • a hydrophilic and a hydrophobic statin and optimally, with the NOS substrate L-arginine is a method which will provide therapeutic treatment for cardiovascular disease which previously has been unresponsive to known statm therapy Patients which will particularly benefit from such treatment include those with increased cholesterol levels and increased risk for cardiovascular events and whose cholesterol levels do not normalize with pravastatin and L-arginme therapy These patients would then be administered a combination of e.g., pravastatin, a fat soluble statm (such as atorvastatin, lovastatin, simvastatin, cerivastatin, fluvastatin, dalvastatin and compactin); and optimally, L-argmine
  • a lipophilic statm m addition to pravastatin is more effective since the lipophilic, or fat soluble statm is readily taken up by the liver and will be more effective at reducing the cholesterol level than adding 40mg more pravastatin
  • the total statm dose administered in the combistatin treatment should
  • the ratio of pravastatin to atorvastatin is preferably withm the range of 1 2 to 1 50
  • pravastatin/atorvastatin at a ratio of 1:2 would include 40 mg/day pravastatin with 80 mg/day atorvastatin Where the ratio of pravastatin/atorvastatin is at a ratio of 1.20, for example, 20 mg/day pravastatin would be administered with 400 mg/day atorvastatin.
  • Weight ratio of ingredients described herein m regard to the Hmg-CoA reductase inhibitors, lovastatin, pravastatin and atorvastatin are found to be effective, however, each route of administration (e.g. IV, oral, transdermal, etc ) will vary in their requirements
  • the presently disclosed "mixtures” may be described in terms of their relative concentrations (grams) administered as part of a continuous daily and/or monthly regimen
  • the formulation is administered so as to provide the patient with between 20-40 milhgrams per day of the Hmg-CoA reductase inhibitor (e.g. pravastatin) together with a daily dose of atorvastatin of between 100 to 200 mg per day
  • the Hmg-CoA reductase inhibitor such as pravastatin
  • This particular embodiment of the claimed formulation should maintain withm the patient efficient levels of the formulation
  • the ratio of pravastatin to atorvastatin to L-argmine is preferably within the range of 1:1:1 to 1:50.50, wt/wt.
  • administration of pravastatin, atorvastatin and L-arginme at a ratio of 1.1:20 would include 40 mg/day pravastatin with 40 mg/day atorvastatin and 800 mg/day L-arginine.
  • Weight ratio of ingredients described herein in regard to the Hmg-CoA reductase inhibitors, lovastatin, pravastatin and atorvastatin are found to be effective, however, each route of administration (e.g. IV, oral, transdermal, etc ) will vary m their requirements
  • the presently disclosed "mixtures” may be described m terms of their relative concentrations (grams) administered as part of a continuous daily and/or monthly regimen.
  • the formulation is administered so as to provide the patient with between 20-40 milhgrams per day of the Hmg-CoA reductase inhibitor (e g.
  • the Hmg-CoA reductase inhibitor such as lovastatin
  • a daily dose of atorvastatin of between 20-40 mg per day and a dose of L- arginme of 100 to 200 mg per day
  • the Hmg-CoA reductase inhibitor is administered at a daily dose of about 20 mg per day together with a dose of about 20 mg per day atorvastatin together with 200 mg per day dose of L-arginine.
  • This particular embodiment of the claimed formulation should maintain within the patient efficient levels of the formulation.
  • ACE inhibitors squalene synthetase inhibitors
  • fibric acid derivatives bile acid sequestrants
  • MTP inhibitors angiotensin receptor blockers
  • probucol niacin and its biological equivalents
  • isoprenoid phosphonates In some instances it will be beneficial to utilize a mixture of any one or combination of the above agents with an HMG-CoA reductase inhibitor and L-arginine. Additionally, it may be beneficial to utilize a mixture of any one or combination of the above agents with L-arginine.
  • L-arginine There are a number of biological equivalents of L-arginine which can be used in place of L-arginine when this is beneficial to the patient, including L-lysine, arginase inhibitors, citrulline, ornithine, and hydralazine.
  • the presently disclosed "mixtures” may be described in terms of their relative concentrations (grams) administered as part of a continuous daily and/or monthly regimen.
  • the formulation is administered so as to provide the patient with between 20-40 milhgrams per day of the Hmg-CoA reductase inhibitor (e.g., pravastatin) together with a daily dose of L-arginine of between 100 to 200 mg per day.
  • the Hmg-CoA reductase inhibitor such as lovastatin
  • This particular embodiment of the claimed formulation should maintain within the patient efficient levels of the formulation.
  • the Hmg-CoA reductase inhibitors'of the present invention are also characterized by an ability to stimulate receptor-mediated clearance of hepatic low- density lipoproteins (LDL), as an anti-hypercholesterolemic, and as a competitive inhibitor of Hmg-CoA reductase.
  • LDL hepatic low- density lipoproteins
  • lovastatin simvastatin
  • pravastatin The preparation of lovastatin, simvastatin, and pravastatin have been described in the patent literature.
  • the preparation of XU-62-320 (fluvastatin) is described in WIPO Patent W084/02131.
  • BMY 22089(13), CI 981(14), HR 780(15), and SQ 33,600 are also described in the literature cited, and are specifically incorporated herein by reference for the purpose of even more fully describing the chemical structure and synthesis of these Hmg-CoA reductase inhibitors. These methods of preparation are hereby incorporated by reference in their entirety
  • Hmg-CoA reductase inhibitors of the present invention are included the bio-active metabolites of those Hmg-CoA reductase inhibitors described here, such as pravastatin sodium (the bio-active metabolite of mevastatm)
  • Hmg-CoA reductase inhibitor compounds may be mixed with L-arginine or substrate precursor to endogenous nitric oxide to provide a therapeutically effective mixture. This therapeutically effective mixture can then be incorporated into a stent or other delivery device.
  • Fig. 3 is a bar graph of the data generated which illustrates the effects of acetylcholme and pravastatin (10" 6 and 10 5 M) administered for 3 mm periods into the cell/bead perfusion system on NO production with: 1) 10 5 M L-argimne m control (basic) buffer, 2) 10 M of L-NAME in buffer, and 3) 10 3 M of L-arginme in buffer.
  • Pravastatin also caused a concentration-related increase m NO production above basehne levels There was a larger increment in response to the 10 5 M concentrations of pravastatin ( ⁇ 3 X) compared with that of acetylcholme Superfusion of the cell suspension with L-NAME (10 3 M), also blunted NO production m response to pravastatin This suggests that NO production is due at least m part to NOS activity Subsequent perfusion of the cells with a buffer containing L-arginine 10 3 M resulted in a return m NO production to a level above the amount induced by the Pravastatin in control (basis) buffer This restoration of response to Pravastatin after L-arginine addition was greater than that observed for acetylcholme Administration of Pravastatin or acetylcholme into a perfusion system containing only beads without cells did not induce metHb/NO production
  • the presently disclosed "mixtures may be described in terms of their relative concentrations (grams) administered as part of a continuous mtracoronary, mtra-artal, mtra-lummal, intramural, intravenous and intrapericardial infusions
  • the formulation is administered as mixtures of enhancers of NO production (e g , NOS agonist oi Hmg-CoA reductase inhibitors) with other Hmg-CoA reductase inhibitors and/or L-arginine encased in hposomes so as to provide maximum retention time of the mixture in any given vascular bed being perfused by a catheter delivering the therapeutic mixture.
  • enhancers of NO production e g , NOS agonist oi Hmg-CoA reductase inhibitors
  • other Hmg-CoA reductase inhibitors and/or L-arginine encased in hposomes so as to provide maximum retention time of the mixture in any given vascular bed
  • the hposomes containing the mixture may also contain genetic material for transfection of the genetic material into the surrounding tissue of the vascular bed.
  • pellets containing the aforementioned mixtures may be directly implanted into the myocardium at the tune of coronary bypass graft surgery.
  • a therapeutic mixture is repeatedly infused into the pericardial space via an indwelling infusion catheter.
  • compositions of the present invention may be in the form of an agent(s) m combination with at least one other agent, such as stabilizing compound, which may be administered in any sterile, bio-compatible pharmaceutical carrier, including, but not limited to, sahne, buffered saline, dextrose, and water
  • agent such as stabilizing compound
  • the compositions may be administered to a patient alone, or in combination with other agents, drugs or hormones.
  • Pharmaceutically-acceptable carriers may also be comprised of excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
  • the pharmaceutical composition may be provided as a salt and can be formed with many acids, including but not limited to, hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succmic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free base forms.
  • the preferred preparation may be a lyophilized powder which may contain any or all of the following' 1-50 mM histidine, 0.1%-2% sucrose, and 2-7% manmtol, at a pH range of 4.5 to 5.5, that is combined with buffer prior to use.
  • compositions After pharmaceutical compositions have been prepared, they can be placed in an appropriate container and labeled for treatment of an indicated condition. Such labeling would include amount, frequency, and method of administration.
  • Fig. 3 is a schematic representation of the hypothesized dynamics of L-arginine supply to NOS. L-arginine levels are maintained primarily through the activity of the carrier-mediated Na + -independent transporter, y + , while the
  • Concurrent transport of L-arginine to NOS may control NO production.
  • L-arginine supply to NOS can be limiting due to compartmentalization within EC, arginase activity or utilization of L-arginine by NOS. We believe that NO and superoxide anion reduce the activity of the y + transporter and also reduce
  • L-arginine available for NOS Collectively, summation of supply verses demand or availability of L-arginine to NOS will determine whether NO or superoxide anion are formed. Collectively, our findings suggest that although intracellular L-arginine levels far exceed the concentration of L-arginine required by NOS for NO production, the amount of L-arginine available for utilization by NOS can be insufficient especially in conditions of chronic eNOS stimulation. The explanation for this L-arginine paradox may be provided by the work of McDonald and colleagues. Using porcine pulmonary artery endothelial cells with antibodies specific for caveolin, eNOS and the y + transporter, McDonald et al. demonstrated that all of these proteins are co-locahzed within the plasma membrane caveolae.
  • eNOS associated with this complex is sequestered from overall intracellular L-arginine and relies on the de no ⁇ o transport of L-arginine into the cell via the y + transporter within the caveolae for NO production. If the transporter becomes damages as seen with oxidation, L-arginine supply could immediately become limiting and may be the basis for endothelial dysfunction. In addition, this eNOS/y + transporter-caveolae complex may explain why endothelial dysfunction is quickly reversed with increasing extracellular LN. Once the transporter is turned off, L-arginine concentration gradient increases and delivery of L-arginine into cells is shifted towards passive diffusion. Therefore, extracellular supplementation of L-arginine may be helpful in driving passive diffusion of L-arginine when the integrity of carrier-mediated transporters cannot be maintained.
  • Pravastatin functions as both a NOS agonist and as a Hmg-CoA reductase inhibitor. This, along with its hydrophilic/hydrophobic (as well as the other statin's hydrophobicity) nature, leads to the compositions described and claimed herein.

Landscapes

  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Neurosurgery (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Hospice & Palliative Care (AREA)
  • Emergency Medicine (AREA)
  • Psychiatry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne des mélanges thérapeutiques de statines, seules ou combinées à la L-arginine.
EP00984562A 1999-10-19 2000-10-19 Melange therapeutique d'inhibiteurs de hmg-coa reductase Withdrawn EP1225885A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US42081699A 1999-10-19 1999-10-19
US420816 1999-10-19
PCT/US2000/041304 WO2001028499A2 (fr) 1999-10-19 2000-10-19 Melange therapeutique d'inhibiteurs de hmg-coa reductase

Publications (2)

Publication Number Publication Date
EP1225885A2 true EP1225885A2 (fr) 2002-07-31
EP1225885A4 EP1225885A4 (fr) 2004-04-21

Family

ID=23667961

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00984562A Withdrawn EP1225885A4 (fr) 1999-10-19 2000-10-19 Melange therapeutique d'inhibiteurs de hmg-coa reductase

Country Status (5)

Country Link
EP (1) EP1225885A4 (fr)
AU (1) AU2116201A (fr)
CA (1) CA2388530A1 (fr)
MX (1) MXPA02004021A (fr)
WO (1) WO2001028499A2 (fr)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6425881B1 (en) * 1994-10-05 2002-07-30 Nitrosystems, Inc. Therapeutic mixture useful in inhibiting lesion formation after vascular injury
EP1175210A4 (fr) 1999-03-19 2003-07-09 Enos Pharmaceuticals Inc Renforcement de la biodisponibilite des medicaments dans le cerveau
USRE44578E1 (en) 2000-04-10 2013-11-05 Teva Pharmaceutical Industries, Ltd. Stable pharmaceutical compositions containing 7-substituted-3,5-dihydroxyheptanoic acids or 7-substituted-3,5-dihydroxyheptenoic acids
JP2008533044A (ja) * 2005-03-11 2008-08-21 ホン コン ナイトリック オキサイド リミテッド 内皮機能不全、アンギナおよび糖尿病のための組合せ治療
CN105246472B (zh) * 2013-03-15 2018-10-12 武汉朗来科技发展有限公司 含有鸟氨酸和/或门冬氨酸的组合物及其应用
WO2014139469A1 (fr) * 2013-03-15 2014-09-18 Wuhan Qr Science And Technology Development Co. Compositions comprenant de l'ornithine ou de l'aspartate et utilisations associées

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5447922A (en) * 1994-08-24 1995-09-05 Bristol-Myers Squibb Company α-phosphonosulfinic squalene synthetase inhibitors
US5968983A (en) * 1994-10-05 1999-10-19 Nitrosystems, Inc Method and formulation for treating vascular disease

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE MEDLINE [Online] US NATIONAL LIBRARY OF MEDICINE (NLM), BETHESDA, MD, US; 2001, ATHYROS V G ET AL: "Atorvastatin plus pravastatin for the treatment of heterozygous familial hypercholesterolaemia--a pilot study." XP002271257 Database accession no. NLM11922400 & CURRENT MEDICAL RESEARCH AND OPINION. 2001, vol. 17, no. 4, 2001, pages 267-272, ISSN: 0300-7995 *
See also references of WO0128499A2 *

Also Published As

Publication number Publication date
EP1225885A4 (fr) 2004-04-21
CA2388530A1 (fr) 2001-04-26
WO2001028499A3 (fr) 2001-10-04
MXPA02004021A (es) 2004-08-23
AU2116201A (en) 2001-04-30
WO2001028499A2 (fr) 2001-04-26

Similar Documents

Publication Publication Date Title
AU744813B2 (en) Method and formulation for treating vascular disease
Anavi et al. iNOS as a metabolic enzyme under stress conditions
US6425881B1 (en) Therapeutic mixture useful in inhibiting lesion formation after vascular injury
EP1139753B1 (fr) Preparations destinees au traitement de maladies et procedes s'y rapportant
Nyholm Pharmacokinetic optimisation in the treatment of Parkinson’s disease: an update
Walder et al. The involvement of endothelium‐derived relaxing factor in the regulation of renal cortical blood flow in the rat
Cuche et al. Phosphaturic effect of dopamine in dogs. Possible role of intrarenally produced dopamine in phosphate regulation.
Dusting et al. Endogenous nitric oxide in cardiovascular disease and transplantation
US20030114515A1 (en) Therapeutic mixture of HMG-COA reductase inhibitors
Ren et al. Brain natriuretic peptide limits myocardial infarct size dependent of nitric oxide synthase in rats
EP1225885A2 (fr) Melange therapeutique d'inhibiteurs de hmg-coa reductase
Gruhn et al. Tetrahydrobiopterin improves endothelium-dependent vasodilation in nitroglycerin-tolerant rats
JPH08503451A (ja) 癌治療のモダリティーとしての３‐ヒドロキシ‐３‐メチルグルタリルＣｏＡレダクターゼ阻害剤の使用
US8399518B2 (en) Administration of 3,5-diiodothyropropionic acid for stimulating weight loss, and/or lowering triglyceride levels, and/or treatment of metabolic syndrome
CA2361575A1 (fr) Formulations a base de l-arginine utilisees dans le traitement de maladies, et leurs procedes d'utilisation
WO2002009726A1 (fr) Procedes de traitement des affections asociees a la resistance a l'insuline avec l'aicar, (5-amino-4-imidazole carboxamide riboside) et de composes apparentes
US20030212014A1 (en) Methods fo treating conditions associated with insulin resistance with aicar, (5-amino-4-imidazole carboxamide riboside) and related compounds
EP1671630A2 (fr) Formulations basées sur l-arginine pour le traitment des maladies et méthodes utilisants les memes
d'Uscio et al. Role of Nitric Oxide in the Microcirculation
Yang et al. L-Arginine and Ischemia-Reperfusion Injury
US20090093506A1 (en) Copper antagonist compositions
Piatti et al. L-Arginine in the Prevention and Treatment of Cardiovascular Disease: From Basic to Clinical Research Studies
McCafferty et al. The Physiological and Pathophysiological Effects of Nitric Oxide on the Intestinal Circulation
WO2006104399A1 (fr) Compositions antagonistes du cuivre

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20020517

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

AX Request for extension of the european patent

Free format text: AL;LT;LV;MK;RO;SI

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: ANGIOGENIX, INC.

RIC1 Information provided on ipc code assigned before grant

Ipc: 7A 61K 31/40 B

Ipc: 7A 61K 31/19 A

Ipc: 7A 61K 31/35 B

Ipc: 7A 61K 31/22 B

Ipc: 7A 61K 31/198 B

Ipc: 7A 61P 25/28 B

A4 Supplementary search report drawn up and despatched

Effective date: 20040310

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20060411