WO1996016645A1 - Utilisation de donneurs d'oxyde nitrique dans le domaine medical - Google Patents

Utilisation de donneurs d'oxyde nitrique dans le domaine medical Download PDF

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Publication number
WO1996016645A1
WO1996016645A1 PCT/GB1995/002745 GB9502745W WO9616645A1 WO 1996016645 A1 WO1996016645 A1 WO 1996016645A1 GB 9502745 W GB9502745 W GB 9502745W WO 9616645 A1 WO9616645 A1 WO 9616645A1
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WO
WIPO (PCT)
Prior art keywords
donor
restenosis
group
optionally substituted
cooh
Prior art date
Application number
PCT/GB1995/002745
Other languages
English (en)
Inventor
Adam Julian De Belder
Edward John Langford
Christoph Christopher Lees
John Martin
Daryl David Rees
Marek Radomski
Original Assignee
The Wellcome Foundation Limited
King's College London
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 The Wellcome Foundation Limited, King's College London filed Critical The Wellcome Foundation Limited
Priority to AU38788/95A priority Critical patent/AU3878895A/en
Publication of WO1996016645A1 publication Critical patent/WO1996016645A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • A61K38/063—Glutathione
    • 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
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]

Definitions

  • the present invention relates to the use of nitric oxide (NO) donors, in combating restenosis and/or thrombotic conditions involving platelets.
  • NO nitric oxide
  • Restenosis can occur following a number of invasive surgical techniques, for example, transplant surgery, vein grafting, coronary by-pass grafting, arteriovenous anastamosis and most commonly, following angioplasty.
  • Restenosis tends to develop over a period ranging from 1 to 6 months after angioplasty has been performed. It usually presents itself as the recurrence of angina-like symptoms, a decrease in the threshold for effort angina, or acute events (sudden death, myocardial infarction, and unstable angina along with the need for bypass surgery) . It is thought to occur in greater than 30% of cases and in many patients may be asymptomatic.
  • nitric oxide (NO) donors have a particular utility as anti-thrombotic agents and in the treatment and/or prophylaxis of restenosis in mammals. Accordingly the present invention provides the use of an NO donor in the manufacture of a medicament for combating restenosis and/or thrombotic conditions involving platelets. There is further provided a method of treatment and/or prophylaxis of restenosis and/or thrombotic conditions involving platelets comprising administering to a mammal in need thereof an effective amount of a NO donor.
  • NO donors may be used whenever it is desired to inhibit platelet aggregation, to reduce the adhesive character of platelets, and to treat or prevent the formation of thrombi in mammals, including man.
  • they may be used in the treatment and prevention of myocardial infarcts, in the treatment of peripheral vascular disease, to treat and prevent post-operative thrombosis, to promote patency of vascular grafts following surgery, as additives to blood, blood products, blood substitutes, and other fluids which are used in extra-corporeal circulation and the fusion of isolated body portions, to treat complications of arteriosclerosis and conditions such as atherosclerosis, blood clotting defects due to lipemia, as well as other clinical conditions in which the underlying etiology is associated with lipid imbalance of hyperlipidemia, and in the treatment of disseminated intravascular coagulation.
  • the NO donors are of use in the prevention of restenosis following transplant surgery, vein grafting, coronary by-pass grafting and in particular, following angioplasty.
  • NO donor any compound which is capable of liberating NO in vivo .
  • a preferred group of compounds are S-nitroso compounds of the formula R-SNO wherein R is one or more amino acid derived fragments.
  • the NO donors of the present invention are a group of compounds of formula (I)
  • n 0 or 1
  • X is a Ci-g straight or branched alkylene chain
  • Y and Z may be the same or different and are each a C ⁇ hydrocarbyl chain optionally substituted by one or more groups R 4 and R ? wherein R 4 and R 5 may be the same or different and are selected from hydrogen, C 1. - 4 alkyl or C 6 - 10 aryl; R 1 is hydrogen or a group COR 3 , wherein R 3 C0 2 H is a natural L-amino acid (other than cysteine) and/or the D- isomer thereof •
  • R 2 is OH or a group NR 6 R 7 , wherein HNR 6 R 7 is a natural L- amino acid (other than cysteine) and/or the D-isomer thereof-
  • the NO donors of the present invention are a group of compounds of formula (IA)
  • n, p, q, X, Y and Z are as hereinbefore defined;
  • R la is hydrogen or a group COR 3a wherein R 3a is a Cj.j hydrocarbyl group which is optionally substituted by one or two substituents which may be the same or different and are selected from OH, COOH, NH 2 ;
  • R 2a is OH or a group NR 6a R 7a wherein R 6a is a C-
  • R 7a is hydrogen or a C 1-8 hydrocarbyl group which is optionally substituted by one or two substituents which may be the same or different and are selected from OH, COOH, NH 2 or a C ⁇ alkyl group optionally substituted by COOH; or R 6a and R 7a may be joined to form a 5- or 6- membered heterocyclic ring; and salts, esters and amides thereof.
  • a particularly preferred NO donor for use according to the present invention is S-nitroso-glutathione (GSNO) and all salts, esters and amides thereof.
  • GSNO S-nitroso-glutathione
  • the NO donors of the present invention may be administered before, coincidentally with or at any time after invasive surgery, such as angioplasty. It is preferred that the administration of the NO donor is commenced before or coincidentally with surgery, and most preferably before surgery.
  • the NO donors Whilst it may be possible for the NO donors to be administered as the raw chemical, it is preferable to present them as a pharmaceutical formulation.
  • pharmaceutical formulations for use in the methods of the invention comprising at least one NO donor, or a pharmaceutically acceptable salt, ester or amide thereof, together with one or more pharmaceutically acceptable carriers or excipients and optionally one or more other therapeutic ingredients.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the effective amount of active ingredient required is from 10 mg/day to 500mg/day, suitably 20mg/day to 360mg/day, depending on the particular NO donor administered. Suitably, sufficient compound is given which will liberate 50 ⁇ mol to lmmol of NO/day.
  • Pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Pharmaceutical formulations may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual) , rectal, nasal, topical (including buccal, sublingual or transdermal) , vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intracoronary, intraarticular or intradermal) route.
  • Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s) .
  • the NO donors are administered orally (e.g. sub-lingually) , topically (e.g. by means of a patch) or parenterally (e.g. by infusion) .
  • compositions adapted for oral administration may be presented as discrete units such as capsules or tablets,* powders or granules; solutions or suspensions in aqueous or non-aqueous liquids,- edible foams or whips,* or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
  • compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
  • the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986) .
  • compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
  • compositions adapted for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oil solutions of the active ingredient.
  • compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostatis and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
  • Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
  • formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
  • flavouring agents for example those suitable for oral administration may include flavouring agents.
  • the procedure was standardised, such that baseline samples were collected before positioning of the angioplasty guide wire and balloon.
  • a further pre-PTCA sample was taken 10 minutes after starting the GSNO infusion.
  • GSNO infusion was then continued throughout the PTCA procedure and for 10 minutes afterwards. Timing following PTCA started at the end of the final inflation, at which point the balloon was withdrawn. No contrast medium was injected after the first inflation until the final collection at 10 minutes. Blood pressure was monitored via the guide catheter.
  • FITC fluorescein isothiocyanate
  • Immunotech immunotech
  • GPIIIa GPIIIa monoclonal antibodies
  • Samples were analysed in duplicate using a FACScan (Becton Dickinson) flow cytometer calibrated daily with fluorescent microbead standards (Becton Dickinson) .
  • the platelet population was identified on the basis of size and granularity of cells, and specific binding of P-selectin and GPIIIa (part of the GPIIb/IIIa complex) were measured (figure 1) .
  • P-selectin is only expressed following platelet activation with alpha granule secretion. Antibody binding was therefore measure, after subtracting non-specific fluorescence, as the percentage of platelets positive for the P-selectin antibody.
  • all platelets express GPIIb/IIIa.
  • GPIIb/IIIa is present on the surface-connected canalicular system and the number of receptors expressed increases with platelet activation. Therefore GPIIb/IIIa antibody binding was measured as the relative change in fluorescence intensity per platelet (figure 2) .
  • Results are expressed as mean ⁇ SEM. Statistical differences were determined using the Wilcoxon test for paired data and the Mann-Whitney U test for unpaired data and p ⁇ 0.05 was taken as statistically significant.
  • the two groups of patients were closely matched. All angioplasties were performed on lesions with at least 70% stenosis. Angiography at the end of the study confirmed successful PTCA in all cases, defined as less than 50% residual stenosis with at least a 20% reduction in the original stenosis.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne l'utilisation d'un donneur de NO pour le traitement et/ou la prévention de resténoses et/ou de thromboses anormales impliquant les plaquettes. Les donneurs préférés de NO sont des composés S-nitroso de la formule R-SNO, où R représente un ou plusieurs fagments dérivés d'acides aminés.
PCT/GB1995/002745 1994-11-25 1995-11-24 Utilisation de donneurs d'oxyde nitrique dans le domaine medical WO1996016645A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU38788/95A AU3878895A (en) 1994-11-25 1995-11-24 Use of nitric oxide donors in medicine

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9423868A GB9423868D0 (en) 1994-11-25 1994-11-25 Compounds for use in medicine
GB9423868.0 1994-11-25

Publications (1)

Publication Number Publication Date
WO1996016645A1 true WO1996016645A1 (fr) 1996-06-06

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PCT/GB1995/002745 WO1996016645A1 (fr) 1994-11-25 1995-11-24 Utilisation de donneurs d'oxyde nitrique dans le domaine medical

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AU (1) AU3878895A (fr)
GB (1) GB9423868D0 (fr)
WO (1) WO1996016645A1 (fr)

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998009948A2 (fr) * 1996-09-04 1998-03-12 Nicox S.A. Derives d'esters nitriques et leur application pour le traitement de l'incontinence urinaire et autres maladies
US5770645A (en) * 1996-08-02 1998-06-23 Duke University Medical Center Polymers for delivering nitric oxide in vivo
US6057367A (en) * 1996-08-30 2000-05-02 Duke University Manipulating nitrosative stress to kill pathologic microbes, pathologic helminths and pathologically proliferating cells or to upregulate nitrosative stress defenses
WO2000057891A1 (fr) * 1999-03-30 2000-10-05 Trustees Of Boston University Composition et procedes correspondants permettant de produire des plaquettes et/ou des proplaquettes a partir de megacaryocytes
US6153186A (en) * 1995-09-15 2000-11-28 Duke University Medical Center Red blood cells loaded with S-nitrosothiol and uses therefor
US6197745B1 (en) 1995-09-15 2001-03-06 Duke University Methods for producing nitrosated hemoglobins and therapeutic uses therefor
US6232434B1 (en) 1996-08-02 2001-05-15 Duke University Medical Center Polymers for delivering nitric oxide in vivo
WO2002034705A2 (fr) * 2000-10-26 2002-05-02 Duke University Composes c-nitroso et utilisation associee
US6627738B2 (en) 1995-09-15 2003-09-30 Duke University No-modified hemoglobins and uses therefor
US6656966B2 (en) 2000-06-22 2003-12-02 Nitromed, Inc. Nitrosated and nitrosylated taxanes, compositions and methods of use
WO2004024186A2 (fr) * 2002-09-11 2004-03-25 Nitromed, Inc. Inhibition de maladies et de troubles induits par la cyclooxygenase-3
US6800612B2 (en) 1999-01-27 2004-10-05 Lacer, S.A. S-nitrosothiols as agents for the treatment of circulatory dysfunctions
US6855691B1 (en) 1995-09-15 2005-02-15 Duke University Methods for producing and using S-nitrosohemoglobins
US6911427B1 (en) 1995-09-15 2005-06-28 Duke University No-modified hemoglobins and uses therefore
US6916471B2 (en) 1995-09-15 2005-07-12 Duke University Red blood cells loaded with S-nitrosothiol and uses therefor
US7049308B2 (en) 2000-10-26 2006-05-23 Duke University C-nitroso compounds and use thereof
WO2022107160A1 (fr) 2020-11-20 2022-05-27 Institute Of Life Sciences Composition pour augmentation de la génération d'oxyde nitrique intracellulaire

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WO1995024908A1 (fr) * 1994-03-17 1995-09-21 The United States Of America, Represented By The Secretary, Department Of Health And Human Services Utilisation de polymeres liberant de l'acide nitrique dans le but de traiter la restenose et des maladies apparentees
WO1995024898A1 (fr) * 1994-03-17 1995-09-21 Comedicus, Incorporated Complexes formes par l'oxyde nitrique et des amines cardio-vasculaires et utilises comme agents cardio-vasculaires a double activite
WO1995026725A1 (fr) * 1994-03-30 1995-10-12 Isis Pharma Gmbh Preparations pharmaceutiques et medicaments pour la prevention et le traitement d'un dysfonctionnement endothelial
DE4420523A1 (de) * 1994-06-13 1995-12-14 Cassella Ag Verwendung von NO-freisetzenden Verbindungen zur Behandlung und Vorbeugung von systemischen Entzündungssyndromen

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Cited By (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6203789B1 (en) 1995-09-15 2001-03-20 Duke University Red blood cells loaded with S-nitrosothiol and uses therefor
US6916471B2 (en) 1995-09-15 2005-07-12 Duke University Red blood cells loaded with S-nitrosothiol and uses therefor
US6911427B1 (en) 1995-09-15 2005-06-28 Duke University No-modified hemoglobins and uses therefore
US6884773B1 (en) 1995-09-15 2005-04-26 Duke University Modified hemoglobins, including nitrosylhemoglobins, and uses thereof
US6855691B1 (en) 1995-09-15 2005-02-15 Duke University Methods for producing and using S-nitrosohemoglobins
US6153186A (en) * 1995-09-15 2000-11-28 Duke University Medical Center Red blood cells loaded with S-nitrosothiol and uses therefor
US6627738B2 (en) 1995-09-15 2003-09-30 Duke University No-modified hemoglobins and uses therefor
US6197745B1 (en) 1995-09-15 2001-03-06 Duke University Methods for producing nitrosated hemoglobins and therapeutic uses therefor
US6232434B1 (en) 1996-08-02 2001-05-15 Duke University Medical Center Polymers for delivering nitric oxide in vivo
US6673891B2 (en) 1996-08-02 2004-01-06 Duke University Polymers for delivering nitric oxide in vivo
US6875840B2 (en) 1996-08-02 2005-04-05 Duke University Polymers for delivering nitric oxide in vivo
US7417109B2 (en) 1996-08-02 2008-08-26 Duke University Polymers for delivering nitric oxide in vivo
US6403759B2 (en) 1996-08-02 2002-06-11 Duke University Polymers for delivering nitric oxide in vivo
US7087709B2 (en) 1996-08-02 2006-08-08 Duke University Polymers for delivering nitric oxide in vivo
US5770645A (en) * 1996-08-02 1998-06-23 Duke University Medical Center Polymers for delivering nitric oxide in vivo
US7022737B2 (en) 1996-08-30 2006-04-04 Duke University Manipulating nitrosative stress to kill pathologic microbes, pathologic helminths and pathologically proliferating cells or to upregulate nitrosative stress defenses
US6180824B1 (en) 1996-08-30 2001-01-30 Duke University Manipulating nitrosative stress to kill pathologic microbes, pathologic helminths and pathologically, proliferating cells or to upregulate nitrosative stress defenses
US6057367A (en) * 1996-08-30 2000-05-02 Duke University Manipulating nitrosative stress to kill pathologic microbes, pathologic helminths and pathologically proliferating cells or to upregulate nitrosative stress defenses
US6608110B2 (en) 1996-08-30 2003-08-19 Duke University Manipulating nitrosative stress to kill pathologic microbes, pathologic helminths and pathologically proliferating cells or to upregulate nitrosative stress defenses
US6359004B1 (en) 1996-08-30 2002-03-19 Duke University Manipulating nitrosative stress to upregulate nitrosative stress defenses
WO1998009948A3 (fr) * 1996-09-04 1998-06-04 Nicox Sa Derives d'esters nitriques et leur application pour le traitement de l'incontinence urinaire et autres maladies
WO1998009948A2 (fr) * 1996-09-04 1998-03-12 Nicox S.A. Derives d'esters nitriques et leur application pour le traitement de l'incontinence urinaire et autres maladies
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WO2002034705A2 (fr) * 2000-10-26 2002-05-02 Duke University Composes c-nitroso et utilisation associee
US7785616B2 (en) 2000-10-26 2010-08-31 Duke University C-nitroso compounds and use thereof
WO2004024186A3 (fr) * 2002-09-11 2004-08-12 Nitromed Inc Inhibition de maladies et de troubles induits par la cyclooxygenase-3
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