WO2005046661A2 - Substance - Google Patents

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Publication number
WO2005046661A2
WO2005046661A2 PCT/GB2004/004666 GB2004004666W WO2005046661A2 WO 2005046661 A2 WO2005046661 A2 WO 2005046661A2 GB 2004004666 W GB2004004666 W GB 2004004666W WO 2005046661 A2 WO2005046661 A2 WO 2005046661A2
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WO
WIPO (PCT)
Prior art keywords
donor
compound
nitric oxide
nitroso
drug
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PCT/GB2004/004666
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English (en)
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WO2005046661A3 (fr
Inventor
Eric Arthur Germain Demoncheaux
Wilfred Winston Yeo
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University Of Sheffield
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Publication of WO2005046661A2 publication Critical patent/WO2005046661A2/fr
Publication of WO2005046661A3 publication Critical patent/WO2005046661A3/fr

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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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • 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
    • A61K31/04—Nitro compounds
    • 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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
    • G01N2333/70571—Assays involving receptors, cell surface antigens or cell surface determinants for neuromediators, e.g. serotonin receptor, dopamine receptor

Definitions

  • the present invention relates to the use of a dopamine receptor agonist or antagonist, in particular a nitric oxide donor compound, in the treatment of a drug addiction disorder such as nicotine or cocaine addiction.
  • Drug addiction disorders Drug addiction and/or abuse and/or dependency (collectively referred to herein as "drug addiction disorders") is extremely common. Individuals suffering from such addictions are generally subject to significant symptoms of withdrawal upon attempting to cease use of the addictive substance (whether drugs such as cocaine, heroine, nicotine etc.).
  • VTA midbrain ventral tegmental area
  • NAC mesolimbic nucleus accumbens
  • D-1 type receptors Two D-1 type receptors have been identified, D-1 and D-5. They are excitatory and stimulate the formation of cAMP.
  • the D-2 Type receptor family has three main subtypes, D-2, D-3 and D-4. These receptors are inhibitory and have a number of transduction mechanisms including cAMP formation.
  • D-1 and D-2 type receptors are expressed in areas of the brain innervated by DA-secreting neurones and comprise approximately 80% of all DA receptors. Both subtypes are found in the principal subdivisions of the accumbens. Neurotransmitter interaction at the mesolimbic brain region induces "reward" when DA is released from the neuron at the nucleus accumbens and interacts with the dopamine receptor, particularly the D2 receptor. The reward cascade involves the release of serotonin, which in turn inhibits GABA at the substantia nigra, which in turn fine tunes the amount of DA released at the nucleus accumbens (Blum et al., J. Psychoactive drugs 32: 1-4 (2000)). DA receptors are activated when DA is released into the synapse. This ultimately leads to feelings of well being.
  • the effects of nicotine depend upon its ability to influence impulse flow to the terminal field.
  • Cocaine acts on monoamine transporters blocking reuptake of dopamine, norepinephrine and serotonin from synapses following their release. This acutely increase activity at dopamine, adrenergic and serotonin receptors. Amphetamines also increase dopamine concentration in the nucleus accumbens. Nicotine acts on nicotinic acetylcholine receptors. Little tolerance to nicotine develops however extreme dependence and withdrawal are common.
  • NRT Neurotine replacement therapies
  • the present invention provides the use of a dopamine receptor agonist or antagonist in the manufacture of a medicament for treating a drug addiction disorder.
  • the invention provides a method of treatment of a drug addiction disorder in a human patient which method comprises administering to the patient a therapeutically effective amount of a dopamine receptor agonist or antagonist.
  • Dopamine receptor agonists are substances which, while structurally different from dopamine, bind to different subtypes of dopamine receptors and trigger an effect which is comparable to that of dopamine.
  • Dopamine receptor antagonists are substances which may exert an inhibitory effect on dopamine re-uptake. In this way the amount of bioavailable dopamine is increased.
  • the dopamine receptor is a D-1 type or D-2 type receptor.
  • the D-1 type receptor is a D-1 or D-5 subtype receptor.
  • the D- 2 type receptor is a D-2, D-3 or D-4 subtype receptor.
  • treatment of a drug addiction disorder includes treatment of disorders associated with addiction.
  • the treatment may promote withdrawal from the addictive drug or removal of the dependency on the addictive drug.
  • the drug is selected from the group consisting of opoids, cannabinoids, barbiturates, benzodiazepines, amphetamines, hallucinogens, sedatives, hypnotics, inhalants and anxiolytics including ketamine, PCP (phencychdine), dextromethorphan, LSD, Ecstasy, caffeine, alcohol,_nicotine, tobacco, cocaine, cannabis.
  • Opoids work on family of neurotransmitter receptors, the mu, delta and kappa opoid receptors (MOR, DOR and KOR). Endogenous ligands for these receptors are a family of neuropeptides, the endomorphins, the enkephalins , B-endorphin , and the dynorphins . Receptors are found on peripheral and central nervous system, but also on immune cells (Cami and Farre, New England Journal of Medicine 349(10): 975- 986 (2003)).
  • Cocaine acts on monoamine transporters to block reuptake of dopamine, norepmephrine and serotonin from synapses following their release. This will increase activity of dopamine, adrenergic and serotonin receptors.
  • Cannabinoids act on cannabinoid receptors. CB1 in CNS, CB2 in PNS. Plant derived cannabinoids mimic action of endogenous CB receptor ligands. Barbiturates act on the GABA A receptor, an inhibitory neurotransmitter receptor that is activated by the amino acid GABA to open a chloride channel.
  • Benzodiazepines act as modulators of the GABA A receptor to increase chloride ion conductance. Amphetamines are thought to reverse dopamine and norepinephrine transporters, dumping dopamine and NE into dopaminergic and adrenergic synapses.
  • the use is in the treatment of a drug addiction disorder wherein the drug is nicotine.
  • the use is in the treatment of a drug addiction disorder where the drug is an opoid such heroin, codeine and morphine or a derivative thereof such as pethidine and methadone.
  • the dopamine receptor agonist or antagonist is a nitric oxide donor compound.
  • nitric oxide donor compound which is able to donate, transfer or release nitric oxide, or a related redox species, or more generally provides nitric oxide bioactivity that is activity which is identified with nitric oxide, e.g., vasorelaxation or stimulation or inhibition of a receptor protein.
  • the nitric oxide donor may promote an increase in nitric oxide, for example as a NO synthase substrate, through endogenous stimulation of NO synthesis.
  • the nitric oxide (NO) donor may be selected from the group consisting of O- nitroso, S-nitroso, C-nitroso and N-nitroso compounds and nitro derivatives thereof and metal NO complexes.
  • the O-nitroso compounds may include nitrates (e.g. organic) and organic nitrites.
  • S-nitroso compounds may include thionitrates and thionitrites, for example, S-nitrosothiols.
  • N-nitroso compounds may include N-nitrosamines, N- hydroxy-N-nitrosamines, N-nitrosamides, N-nitrosoguanidines, N-nitrosohydrazines, niframines and N-nifrosoimines.
  • the NO donor may be an inorganic NO donor such as a nitrite, nitrosonium salt or nitrosyl halide, peroxynitrite (HOONO) or sodium azide.
  • the NO donor may be a metal nitrosyl such as nitroprusside, dinitrosyl-iron (H) complex, iron nitrosyl compounds, nitrosyl complex of iron-sulphur cluster or of other transition metals.
  • a metal nitrosyl such as nitroprusside, dinitrosyl-iron (H) complex, iron nitrosyl compounds, nitrosyl complex of iron-sulphur cluster or of other transition metals.
  • the NO donor may be a heterocyclic NO donor such as a sydnorrimine, an oxadiazole (furoxan), oxatriazole or ⁇ azetidine-di-N-oxide.
  • a heterocyclic NO donor such as a sydnorrimine, an oxadiazole (furoxan), oxatriazole or ⁇ azetidine-di-N-oxide.
  • the NO donor may be a nitroxyl-generating compound such as Angeli's salt, Piloty's acid, cyanamide.
  • the NO donor may be an oxime (FK-409 analog), hydroxylamine, N- hydroguanidine, diazeniumdiolate (NONOate) sodium trioxodinitrate (Na 2 N 2 O 3 ), benzenesulfohydroxamic acids (R-SO 2 NHO " ), sodium nitroprusside, nitrosoester compounds.
  • the nitrate may include a nitrate ester, or an organic nitrate.
  • the nitrate is an organic nitrate.
  • the organic nitrate may include ethylene glycol dinitrate; isopropyl nitrate; glyceryl-1-mononitrate; glyceryl-1,2- dinitrate; glyceryl-l,3-dinitrate; nitroglycerin (GTN); butane- 1,2,4-trioltrinitrate- ; erythrityl tetranitrate (ETN); pentaerythrityl tetranitrate (PETN); isosorbide mononitrate (ISMN), which may include isosorbide-2-mononitrate (IS2N) and/or isosorbide-5-mononitrate (IS5N); and/or isosorbide dinitrate (ISDN).
  • Isorsorbide or glyceryl trinitrate may be a NO synthase substrate.
  • the NO donor may include a nitroso polypeptide, nitrosated modified or unmodified oligonucleotides or nitrosated haemoglobin (described in US6538116 and US6207855). Also encompassed are partial pro-drugs that release NO after biotransformation of the nitrite group to NO (described in US6538033), and nucleophile or nitric oxide adducts (nucleophile being a primary, secondary or tertiary amine).
  • the NO donor may be a N 2 O 2 containing compound that may release NO by enzymatic or non-enzymatic oxidation as described in US6511991.
  • dopamine receptor "agonist” or “antagonist” as used herein are not intended to be functionally limiting on the nitric oxide donor compound of the invention such that any nitric oxide donor compound that is useful for treating a drug addiction disorder, but which does not provide said agonistic/antagonistic effect, is encompassed by the invention.
  • the dopamine receptor agonist or antagonist is an antibody, or an active binding fragment of an antibody.
  • said antibody, or binding fragment is a monoclonal antibody.
  • Antibodies or immunoglobulins are a class of structurally related proteins consisting of two pairs of polypeptide chains, one pair of light (L) (low molecular weight) chain (K or ⁇ ), and one pair of heavy (H) chains ( ⁇ , ⁇ , ⁇ , ⁇ and ⁇ ), all four linked together by disulphide bonds. Both H and L chains have regions that contribute to the bmding of antigen and that are highly variable from one Ig molecule to another. In addition, H and L chains contain regions that are non-variable or constant. The L chains consist of two domains. The carboxy-terminal domain is essentially identical among L chains of a given type and is referred to as the "constant" (C) region.
  • C constant
  • variable region contains complementarity determining regions or CDR's which form an antigen binding pocket.
  • the binding pockets comprise H and L variable regions which contribute to antigen recognition. It is possible to create single variable regions, so called single chain antibody variable region fragments (scFv's). If a hybidoma exists for a specific monoclonal antibody it is well within the knowledge of the skilled person to isolate scFv's from mRNA extracted from said hybridoma via RT PCR. Alternatively, phage display screening can be undertaken to identify clones expressing scFv's.
  • the antibody fragment is a single chain antibody fragment.
  • the antibody fragment is a single chain antibody variable region fragment.
  • said antibody, or binding fragment thereof is a chimeric antibody.
  • said antibody, or binding fragment thereof is a humanised antibody.
  • a chimeric antibody is produced by recombinant methods to contain the variable region of an antibody with an invariant or constant region of a human antibody.
  • a humanised antibody is produced by recombinant methods to combine the CDR's of an antibody with both the constant regions and the framework regions from the variable regions of a human antibody.
  • Antibodies from non-human animals provoke an immune response to the foreign antibody and its removal from the circulation.
  • Both chimeric and humanised antibodies have reduced antigenicity when injected to a human subject because there is a reduced amount of rodent (i.e. foreign) antibody witiiin the recombinant hybrid antibody, while the human antibody regions do not elicit an immune response. This results in a weaker immune response and a decrease in the clearance of the antibody. This is clearly desirable when using therapeutic antibodies in the treatment of human diseases.
  • Humanised antibodies are designed to have less "foreign" antibody regions and are therefore thought to be less immunogenic than chrmeric antibodies.
  • the dopamine receptor agonist or antagonist is a peptide.
  • said peptide is a modified peptide.
  • modified amino acids include, by way of example and not by way of limitation, 4-hydroxyproline, 5-hydroxylysine, N - acetyllysine, N 6 -methyllysine, N 6 ,N 6 -dimethyllysine, N 6 ,N ⁇ ,N 6 -trimethyllysine, cyclohexyalanine, D-amino acids, ornithine.
  • Nucleic acids have both linear sequence structure and a three dimensional structure which in part is determined by the linear sequence and also the environment in which these molecules are located.
  • Conventional therapeutic molecules are small molecules, for example, peptides, polypeptides, or antibodies, which bind target molecules to produce an agonistic or antagonistic effect. It has become apparent that nucleic acid molecules also have potential with respect to providing agents with the requisite b ding properties which may have therapeutic utility. These nucleic acid molecules are typically referred to as aptamers. Aptamers are small, usually stabilised, nucleic acid molecules which comprise a binding domain for a target molecule. A screening method to identify aptamers is described in US 5,270,163 which is incorporated by reference.
  • Aptamers are typically oligonucleotides which may be single stranded oligodeoxynucleotides, oligoribonucleotides, or modified oligodeoxynucleotide or oligoribonucleotides.
  • modified nucleotides encompasses nucleotides with a covalently modified base and/or sugar.
  • modified nucleotides include nucleotides having sugars which are covalently attached to low molecular weight organic groups other than a hydroxyl group at the 3' position and other than a phosphate group at the 5' position.
  • modified nucleotides may also include 2' substituted sugars such as 2'-O- methyl-; 2-O-alkyl; 2-O-allyl; 2'-S-alkyl; 2'-S-allyl; 2'- fluoro-; 2'-halo or 2;azido- ribose, carbocyclic sugar analogues a-anomeric sugars; epimeric sugars such as arabinose, xyloses or lyxoses, pyranose sugars, furanose sugars, and sedoheptulose.
  • 2' substituted sugars such as 2'-O- methyl-; 2-O-alkyl; 2-O-allyl; 2'-S-alkyl; 2'-S-allyl; 2'- fluoro-; 2'-halo or 2;azido- ribose, carbocyclic sugar analogues a-anomeric sugars; epimeric sugars such as arabinose, xyloses
  • Modified nucleotides include by example and not by way of limitation; alkylated purines and/or pyrimidines; acylated purines and/or pyrimidines; or other heterocycles. These classes of pyrimidines and purines are known in the art and include, pseudoisocytosine; N4, N4-ethanocytosine; 8-hydroxy- N6-methyladenine; 4-acetylcytosine, 5-(carboxyhydroxylmethyl) uracil; 5- fluorouracil; 5-bromouracil; 5-carboxymethylarmnomethyl-2-thiouracil; 5- carboxymemylaminomethyl uracil; dihydrouracil; inosine; N6-isopentyl-adenine; 1- methyladenine; 1-methylpseudouracil; 1-memylguanine; 2,2-dimethylguanine; 2- methyladenine; 2-methylguanine; 3-methylcytosine; 5-
  • the aptamers of the invention are synthesized using conventional phosphodiester linked nucleotides and synthesized using standard solid or solution phase synthesis techniques which are known in the art.
  • Linkages between nucleotides may use alternative linking molecules.
  • linking groups of the formula P(O)S, (thioate); P(S)S, (dithioate); P(O)NR'2; P(O)R'; P(O)OR6; CO; or CONR'2 wherein R is H (or a salt) or alkyl (1-12C) and R6 is alkyl (1-9C) is joined to adjacent nucleotides through -O- or -S-.
  • the binding of aptamers to a target polypeptide is readily tested by assays hereindisclosed.
  • the antibody, antibody fragment, peptide, aptamer, or other dopamine receptor agonist or antagonist, of the invention to be useful in treating a drug addiction disorder, it must be able to permeate the blood-brain barrier.
  • the dopamine receptor agonist or antagonist is preferably of a molecular weight below 1000, more preferably below 500.
  • Other factors useful in determining whether a substance will pass the blood-brain barrier are described in Clark, DDT: 8, 20 (2003).
  • Drug transporters at the blood-brain barrier may provide means for the uptake of the dopamine receptor agonists/antagonists of the invention into the brain.
  • Receptor- mediated endocytosis provides a means for selective uptake of macromolecules. Cells have receptors for the uptake of many different types of ligands, including hormones, growth factors, enzymes, and plasma proteins.
  • RME is a highly specific type of energy dependent transport (Boer et al, Annu. Rev. Pharmacol. Toxicol. 43: 629-656 (2003).
  • Absorptive-mediated transport is another means for the uptake of molecules into the brain. AME is triggered by an electrostatic interaction between a positively charged substance, usually a charge moiety of a peptide, the negatively charge plasma membrane surface (i.e. glycocalyx).
  • Carrier-mediated efflux is another significant transport mechanism at the blood brain barrier. This mechanism is involved in extruding drugs from the brain, with the ABC (ATP bmding cassette) transporter P-glycoprotein being the principle efflux mechanism of these agents. Efflux transporters may be useful for transporting organic anions, via multidrug resistance associated protein (MRP), and anionic and cationic cyclic peptide. Additionally, peptide transport systems, e.g (PTS)-l, have provided efflux transport of synthetic drugs (Boer et al., Annu. Rev. Pharmacol. Toxicol. 43: 629-656 (2003).
  • MRP multidrug resistance associated protein
  • PTS peptide transport systems
  • the present invention encompasses dopamine receptor agonists/antagonists that have affinity for one of the carrier-mediated transporters within the blood-brain barrier. Also encompassed is a molecule that is capable of permeating the blood brain barrier and which has been grafted with a "NO donor” group thus acting as a NO donor drug.
  • the dopamine receptor agonist/antagonist ie, the active agent
  • the dopamine receptor agonist/antagonist is formulated as a pharmaceutical composition comprising the dopamine receptor agonist in combination with a pharmaceutically acceptable carrier or diluent.
  • Carriers or diluents useful in the pharmaceutical composition may include, but are not limited to, saline, buffered saline, dextrose, water, glycerol, ethanol and combinations thereof.
  • the pharmaceutical composition may be administered in any effective, convenient manner including, for instance, administration by oral, intravenous (injection or infusion), intramuscular, intradermal, intraccavity, intracranal, sublingual, intranasal, topical routes among others.
  • compositions for oral adrrrinistration may be in tablet, capsule, powder (e.g as a compressed pellet) or liquid form.
  • a tablet may comprise a solid carrier such as gelatin or an adjuvant.
  • Liquid pharmaceutical compositions generally comprise a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil. Physiological saline solution, dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol may be included.
  • the active agent may be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has a suitable pH, isotonicity and stability.
  • a parenterally acceptable aqueous solution which is pyrogen-free and has a suitable pH, isotonicity and stability.
  • Those of relevant skill in the art are well able to prepare suitable solutions using, for example, isotonic vehicles such as Sodium Chloride Injection, Ringer's injection, Lactated Ringer's Injection.
  • Preservatives, stabilisers, buffers, antioxidants, solubilising agents and/or other additives may be included, as required.
  • composition may be in the form of a subcutaneous implant or transdermal formulation.
  • the active agent may suitably be formulated together with one or more polymers that are gradually eroded or degraded when in use, e.g. silicone polymers, ethylene vinylacetate, polyethylene or polypropylene.
  • transdermal formulations are concerned, they may be prepared in the form of matrices or membranes or as fluid or viscous formulations in oil or hydrogels.
  • an adhesive which is compatible with the skin may be included, such as polyacrylate, a silicone adhesive or polyisobutylene.
  • Transdermal solutions or gels water or organic solvents or mixtures thereof may be used.
  • Transdermal gels may furthermore contain one or more suitable gelling agents or thickeners such as silicone, starch or starch derivatives, cellulose or cellulose derivatives or polyacrylic acids or derivatives thereof.
  • Transdermal formulations may also suitably contain one or more substances that enhance absorption though the skin, such as bile salts or derivatives thereof and/or phospholipids.
  • the active agent may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative.
  • the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol.
  • the active ingredient may be inhaled using metered-dose inhalers or dry powder inhalers or nebulisers when the active ingredient may be dissolved in suitable solvent. If the active ingredient presents in the gas form, suitable pressurized canisters can be used for precise inhaled delivery (such as system described in WO0001434).
  • a therapeutically effective amount of the active agent is typically one which is sufficient to achieve the desired effect and may vary according to the nature and severity of the addictive disorder and the potency of the active agent.
  • the desired response is withdrawal from the addictive drug and/or removal of the need or desire/craving for the addictive drug. It will be appreciated that different concentrations may be employed for prophylaxis than for treatment of a disorder.
  • the active agent used in the foregoing use or method of treatment preferably is sterile and contain an effective amount of active agent for producing the desired response in a unit of weight or volume suitable for administration to a patient.
  • the doses of active agent administered to a subject can be chosen in accordance with different parameters, in particular in accordance with the mode of administration used and the state of the subject. Other factors include the desired period of treatment. In the event that a response in a subject is insufficient at the initial doses applied, higher doses (or effectively higher doses by a different, more localised delivery route) may be employed to the extent that patient tolerance permits.
  • the daily dosage level of the active agent may be from 0.5 to 50 mg, such as 5, 10, 15 or 30 mg over a 24 hour period. Ultimately, however, the amount of active agent administered will be at the discretion of a physician.
  • the pharmaceutical composition may be administered alone or in combination with other treatments, either simultaneously or sequentially dependent upon the condition to be treated.
  • Other treatments may include drug reduction or replacement therapies such as nicotine reduction therapy (e.g. a nicotine transdermal patch), nicotine replacement therapy or methadone.
  • the invention further provides a kit of parts comprising the active agent, formulated as a pharmaceutical composition, for administration in combination with one or more other active agents described herein or in combination with other treatments, either simultaneously or sequentially dependent upon the condition to be treated.
  • Other treatments may include drug reduction or replacement therapies such as nicotine reduction therapy (e.g. a nicotine transdermal patch), nicotine replacement therapy or methodone.
  • the kit may be useful in the treatment of drug addiction disorders hereindescribed.
  • the kit of parts comprises a nitric oxide donor compound, formulated as a pharmaceutical composition, in combination with an active agent described herein.
  • the invention present invention encompasses a method of treating a drug addiction disorder in a human patient, the method comprising administering to the patient a medicament to increase the systemic concentration of nitric oxide in the patient.
  • the medicament may comprise a substrate for the enzyme, nitric oxide synthase, or other means for increasing the production or activity of nitric oxide synthase in the patient for example, antioxidants (such as tocopherol or vitamin c) may be included to enhance NO bioactivity by scavenging toxic radicals and/or reduced thiols (such as cysteine, glutathione) may be incorporated to protect NO bioactivity.
  • the medicament may comprise means for reducing the effect of substances (e.g superoxide radicals) that inhibit nitric oxide synthase activity, such as by removal of such substances from the systemic system
  • a screening method for the identification of dopamine receptor agonists/antagonists which have a therapeutic effect in treating drug addiction disorders comprising the steps of i) forming a preparation comprising a dopamine receptor and an agonist/antagonist to be tested; and ii) testing the binding of said agonist/antagonist for said receptor.
  • said agonist/antagonist is a nitric oxide donor compound as hereindescribed.
  • said agonist/antagonist is an antibody, or a binding fragment thereof, as hereindescribed.
  • said agonist/antagonist is a peptide, or modified peptide as hereindescribed.
  • said agonist/antagonist is an aptamer as hereindescribed.
  • a randomised, double-blind, double dummy, four-way parallel-design trial investigated the efficacy of treatment with transdermal glyceryl trinitrate (Minitran, Bayer) to aid smoking-cessation.
  • transdermal glyceryl trinitrate Minitran, Bayer
  • fMRI Blood Oxygen-level Dependent functional magnetic resonance imaging
  • the patients are subjects who smoke at least 10 cigarettes per day.
  • the patients attend a 6-week smoking cessation course
  • the patients will be treated for 12 weeks.
  • the primary outcome is difference in quit rates.

Abstract

La présente invention se rapporte à l'utilisation d'un composé donneur d'oxyde d'azote dans la fabrication d'un médicament destiné au traitement d'un trouble de type pharmacodépendance.
PCT/GB2004/004666 2003-11-07 2004-11-05 Substance WO2005046661A2 (fr)

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GBGB0326047.8A GB0326047D0 (en) 2003-11-07 2003-11-07 Substance
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US7745643B2 (en) 2005-08-12 2010-06-29 Alliant Techsystems Inc. Methods of synthesizing cyclic nitro compounds
US20100239692A1 (en) * 2007-09-20 2010-09-23 Kim-Shapiro Daniel B Methods of treatment for hemolysis
CN102008473A (zh) * 2010-11-23 2011-04-13 中国人民解放军第二军医大学 尼古丁的应用和一种药物组合物
WO2012075420A1 (fr) * 2010-12-03 2012-06-07 Geno Llc Traitements à l'oxyde nitrique
US8241650B2 (en) 2005-02-11 2012-08-14 Nolabs Ab Device, method, and use for treatment of neuropathy involving nitric oxide
US8471041B2 (en) 2010-02-09 2013-06-25 Alliant Techsystems Inc. Methods of synthesizing and isolating N-(bromoacetyl)-3,3-dinitroazetidine and a composition including the same
AU2012203798B2 (en) * 2005-08-12 2013-11-07 Northrop Grumman Systems Corporation O-nitro compounds, pharmaceutical compositons thereof and uses thereof
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US9139519B2 (en) 2011-10-07 2015-09-22 Epicentrx, Inc. Organonitro thioether compounds and medical uses thereof
US9427605B2 (en) 2005-03-24 2016-08-30 Novan, Inc. Cosmetic treatment with nitric oxide, device for performing said treatment and manufacturing method therefor
US9855211B2 (en) 2013-02-28 2018-01-02 Novan, Inc. Topical compositions and methods of using the same
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